Locus Coeruleus Noradrenergic - Topics by Science - Gov

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1. Chlorotoxin-mediated disinhibition of noradrenergic locus coeruleus neurons using a conditional

transgenic approach.
PubMed
Salbaum, J Michael; Cirelli, Chiara; Walcott, Elisabeth; Krushel, Les A; Edelman, Gerald M; Tononi,
Giulio
2004-07-30
The noradrenergic locus coeruleus (LC) has been implicated in the promotion of arousal, in focused
attention and learning, and in the regulation of the sleep/waking cycle. The complex biological
functions of the central noradrenergic system have been investigated largely through
electrophysiological recordings and neurotoxic lesions of LC neurons. Activation of LC neurons
through electrical or chemical stimulation has also led to important insights, although these techniques
have limited cellular specificity and short-term effects. Here, we describe a novel method aimed at
stimulating the central noradrenergic system in a highly selective manner for prolonged periods of
time. This was achieved through the conditional expression of a transgene for chlorotoxin (Cltx) in the
LC of adult mice. Chlorotoxin is a component of scorpion venom that partially blocks small
conductance chloride channels. In this manner, the influence of GABAergic and glycinergic inhibitory
inputs on LC cells is greatly reduced, while their ability to respond to excitatory inputs is unaffected.
We demonstrate that the unilateral induction of Cltx expression in the LC is associated with a
concomitant ipsilateral increase in the expression of markers of noradrenergic activity in LC neurons.
Moreover, LC disinhibition is associated with the ipsilateral induction of the immediate early gene
NGFI-A in cortical and subcortical target areas. Unlike previous gain of function approaches,
transgenic disinhibition of LC cells is highly selective and persists for at least several weeks. This
method represents a powerful new tool to assess the long-term effects of LC activation and is
potentially applicable to other neuronal systems.
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1/25/2019 coeruleus lc noradrenergic: Topics by Science.gov
2. CRH Engagement of the Locus Coeruleus Noradrenergic System Mediates Stress-Induced Anxiety.
PubMed
McCall, Jordan G; Al-Hasani, Ream; Siuda, Edward R; Hong, Daniel Y; Norris, Aaron J; Ford,
Christopher P; Bruchas, Michael R
2015-08-05
The locus coeruleus noradrenergic (LC-NE) system is one of the first systems engaged following a
stressful event. While numerous groups have demonstrated that LC-NE neurons are activated by many
different stressors, the underlying neural circuitry and the role of this activity in generating stress-
induced anxiety has not been elucidated. Using a combination of inÂ vivo chemogenetics,
optogenetics, and retrograde tracing, we determine that increased tonic activity ofÂ the LC-NE system
is necessary and sufficient forÂ stress-induced anxiety and aversion. Selective inhibition of LC-NE
neurons during stress prevents subsequent anxiety-like behavior. Exogenously increasing tonic, but not
phasic, activity of LC-NE neurons is alone sufficient for anxiety-like and aversive behavior.
Furthermore, endogenous corticotropin-releasing hormone(+) (CRH(+)) LC inputs from the amygdala
increase tonic LC activity, inducing anxiety-like behaviors. These studies position the LC-NE system
as a critical mediator of acute stress-induced anxiety and offer a potential intervention for preventing
stress-related affective disorders. Copyright Â© 2015 Elsevier Inc. All rights reserved.
3. CRH engagement of the locus coeruleus noradrenergic system mediates stress-induced anxiety
PubMed Central
McCall, Jordan G.; Al-Hasani, Ream; Siuda, Edward R.; Hong, Daniel Y.; Norris, Aaron J.; Ford,
Christopher P.; Bruchas, Michael R.
2015-01-01
Summary The locus coeruleus noradrenergic (LC-NE) system is one of the first systems engaged
following a stressful event. While numerous groups have demonstrated that LC-NE neurons are
activated by many different stressors, the underlying neural circuitry and the role of this activity in
generating stress-induced anxiety has not been elucidated. Using a combination of in vivo
chemogenetics, optogenetics, and retrograde tracing we determine that increased tonic activity of the
LC-NE system is necessary and sufficient for stress-induced anxiety and aversion. Selective inhibition
of LC-NE neurons during stress prevents subsequent anxiety-like behavior. Exogenously increasing
tonic, but not phasic, activity of LC-NE neurons is alone sufficient for anxiety-like and aversive
behavior. Furthermore, endogenous corticotropin releasing hormone+ (CRH+) LC inputs from the
amygdala increase tonic LC activity, inducing anxiety-like behaviors. These studies position the LC-
NE system as a critical mediator of acute stress-induced anxiety and offer a potential intervention for
preventing stress-related affective disorders. PMID:26212712
4. Locus coeruleus to basolateral amygdala noradrenergic projections promote anxiety-like behavior.
PubMed
McCall, Jordan G; Siuda, Edward R; Bhatti, Dionnet L; Lawson, Lamley A; McElligott, Zoe A;
Stuber, Garret D; Bruchas, Michael R
2017-07-14
Increased tonic activity of locus coeruleus noradrenergic (LC-NE) neurons induces anxiety-like and
aversive behavior. While some information is known about the afferent circuitry that endogenously
drives this neural activity and behavior, the downstream receptors and anatomical projections that
mediate these acute risk aversive behavioral states via the LC-NE system remain unresolved. Here we
use a combination of retrograde tracing, fast-scan cyclic voltammetry, electrophysiology, and in vivo
optogenetics with localized pharmacology to identify neural substrates downstream of increased tonic
LC-NE activity in mice. We demonstrate that photostimulation of LC-NE fibers in the BLA evokes
norepinephrine release in the basolateral amygdala (BLA), alters BLA neuronal activity, conditions
aversion, and increases anxiety-like behavior. Additionally, we report that Î²-adrenergic receptors
mediate the anxiety-like phenotype of increased NE release in the BLA. These studies begin to
illustrate how the complex efferent system of the LC-NE system selectively mediates behavior through
distinct receptor and projection-selective mechanisms.
5. Locus coeruleus to basolateral amygdala noradrenergic projections promote anxiety-like behavior
PubMed Central
McCall, Jordan G; Siuda, Edward R; Bhatti, Dionnet L; Lawson, Lamley A; McElligott, Zoe A;
Stuber, Garret D; Bruchas, Michael R
2017-01-01
Increased tonic activity of locus coeruleus noradrenergic (LC-NE) neurons induces anxiety-like and
aversive behavior. While some information is known about the afferent circuitry that endogenously
drives this neural activity and behavior, the downstream receptors and anatomical projections that
mediate these acute risk aversive behavioral states via the LC-NE system remain unresolved. Here we
use a combination of retrograde tracing, fast-scan cyclic voltammetry, electrophysiology, and in vivo
optogenetics with localized pharmacology to identify neural substrates downstream of increased tonic
LC-NE activity in mice. We demonstrate that photostimulation of LC-NE fibers in the BLA evokes
norepinephrine release in the basolateral amygdala (BLA), alters BLA neuronal activity, conditions
aversion, and increases anxiety-like behavior. Additionally, we report that Î²-adrenergic receptors
mediate the anxiety-like phenotype of increased NE release in the BLA. These studies begin to
illustrate how the complex efferent system of the LC-NE system selectively mediates behavior through
distinct receptor and projection-selective mechanisms. DOI: http://dx.doi.org/10.7554/eLife.18247.001
PMID:28708061
6. Functional Neuroanatomy of the Noradrenergic Locus Coeruleus: Its Roles in the Regulation of
Arousal and Autonomic Function Part II: Physiological and Pharmacological Manipulations and
Pathological Alterations of Locus Coeruleus Activity in Humans
PubMed Central
Samuels, E. R; Szabadi, E
2008-01-01
The locus coeruleus (LC), the major noradrenergic nucleus of the brain, gives rise to fibres innervating
most structures of the neuraxis. Recent advances in neuroscience have helped to unravel the neuronal
circuitry controlling a number of physiological functions in which the LC plays a central role. Two
such functions are the regulation of arousal and autonomic activity, which are inseparably linked
largely via the involvement of the LC. Alterations in LC activity due to physiological or
pharmacological manipulations or pathological processes can lead to distinct patterns of change in
arousal and autonomic function. Physiological manipulations considered here include the presentation
of noxious or anxiety-provoking stimuli and extremes in ambient temperature. The modification of
LC-controlled functions by drug administration is discussed in detail, including drugs which directly
modify the activity of LC neurones (e.g., via autoreceptors, storage, reuptake) or have an indirect
effect through modulating excitatory or inhibitory inputs. The early vulnerability of the LC to the
ageing process and to neurodegenerative disease (Parkinsonâ€™s and Alzheimerâ€™s diseases) is of
considerable clinical significance. In general, physiological manipulations and the administration of
stimulant drugs, Î±2-adrenoceptor antagonists and noradrenaline uptake inhibitors increase LC activity
and thus cause heightened arousal and activation of the sympathetic nervous system. In contrast, the
administration of sedative drugs, including Î±2-adrenoceptor agonists, and pathological changes in LC
function in neurodegenerative disorders and ageing reduce LC activity and result in sedation and
activation of the parasympathetic nervous system. PMID:19506724
7. The Longevity of Hippocampus-Dependent Memory Is Orchestrated by the Locus Coeruleus-

Noradrenergic System
PubMed Central
2017-01-01
The locus coeruleus is connected to the dorsal hippocampus via strong fiber projections. It becomes
activated after arousal and novelty, whereupon noradrenaline is released in the hippocampus.
Noradrenaline from the locus coeruleus is involved in modulating the encoding, consolidation,
retrieval, and reversal of hippocampus-based memory. Memory storage can be modified by the
activation of the locus coeruleus and subsequent facilitation of hippocampal long-term plasticity in the
forms of long-term depression and long-term potentiation. Recent evidence indicates that
noradrenaline and dopamine are coreleased in the hippocampus from locus coeruleus terminals, thus
fostering neuromodulation of long-term synaptic plasticity and memory. Noradrenaline is an inductor
of epigenetic modifications regulating transcriptional control of synaptic long-term plasticity to gate
the endurance of memory storage. In conclusion, locus coeruleus activation primes the persistence of
hippocampus-based long-term memory. PMID:28695015
8. Opioid and noradrenergic contributions of tapentadol to the inhibition of locus coeruleus neurons in
the streptozotocin rat model of polyneuropathic pain.
PubMed
Torres-Sanchez, Sonia; Borges, Gisela Da Silva; Mico, Juan A; Berrocoso, Esther
2018-06-01
Tapentadol is an analgesic that acts as an agonist of Âµ opioid receptors (MOR) and that inhibits
noradrenaline reuptake. Data from healthy rats show that tapentadol inhibits neuronal activity in the
locus coeruleus (LC), a nucleus regulated by both the noradrenergic and opioid systems. Thus, we set
out to investigate the effect of tapentadol on LC activity in streptozotocin (STZ)-induced diabetic rats,
a model of diabetic polyneuropathy, by analyzing single-unit extracellular recordings of LC neurons.
Four weeks after inducing diabetes, tapentadol dose-response curves were obtained from animals pre-
treated with RX821002 or naloxone (alpha2-adrenoceptors and opioid receptors antagonists,
respectively). In STZ rats, the spontaneous activity of LC neurons (0.9â€¯Â±â€¯0.1â€¯Hz) was lower
than in naÃ¯ve animals (1.5â€¯Â±â€¯0.1â€¯Hz), and tapentadol's inhibitory effect was also weaker.
Alpha2-adrenoceptors blockade by RX821002 (100â€¯Î¼g/kg i.v.) in STZ animals significantly
increased the spontaneous activity (from 0.8â€¯Â±â€¯0.1 to 1.4â€¯Â±â€¯0.2â€¯Hz) and it dampened
the inhibition of LC neurons produced by tapentadol. However, opioid receptors blockade following
naloxone pre-treatment (5â€¯mg/kg i.v.) did not alter the spontaneous firing rate (0.9â€¯Â±â€¯0.2 vs
0.9â€¯Â±â€¯0.2â€¯Hz) or the inhibitory effect of tapentadol on LC neurons in STZ animals. Thus,
diabetic polyneuropathy appears to exert neuroplastic changes in LC neurotransmission, enhancing the
sensitivity of alpha2-adrenoceptors and dampening opioid receptors expression. Tapentadol's activity
seems to be predominantly mediated through its noradrenergic effects rather than its influence on
opioid receptors in the STZ model of diabetic polyneuropathy. Copyright Â© 2018 Elsevier Ltd. All
rights reserved.
9. Functional neuroanatomy of the central noradrenergic system.
PubMed
Szabadi, Elemer
2013-08-01
The central noradrenergic neurone, like the peripheral sympathetic neurone, is characterized by a
diffusely arborizing terminal axonal network. The central neurones aggregate in distinct brainstem
nuclei, of which the locus coeruleus (LC) is the most prominent. LC neurones project widely to most
areas of the neuraxis, where they mediate dual effects: neuronal excitation by Î±â‚-adrenoceptors and
inhibition by Î±â‚‚-adrenoceptors. The LC plays an important role in physiological regulatory
networks. In the sleep/arousal network the LC promotes wakefulness, via excitatory projections to the
cerebral cortex and other wakefulness-promoting nuclei, and inhibitory projections to sleep-promoting
nuclei. The LC, together with other pontine noradrenergic nuclei, modulates autonomic functions by
excitatory projections to preganglionic sympathetic, and inhibitory projections to preganglionic
parasympathetic neurones. The LC also modulates the acute effects of light on physiological functions
('photomodulation'): stimulation of arousal and sympathetic activity by light via the LC opposes the
inhibitory effects of light mediated by the ventrolateral preoptic nucleus on arousal and by the
paraventricular nucleus on sympathetic activity. Photostimulation of arousal by light via the LC may
enable diurnal animals to function during daytime. LC neurones degenerate early and progressively in
Parkinson's disease and Alzheimer's disease, leading to cognitive impairment, depression and sleep
disturbance.
10. Noradrenergic Dysfunction in Alzheimer's and Parkinson's Diseases-An Overview of Imaging Studies.
PubMed
Peterson, Andrew C; Li, Chiang-Shan R
2018-01-01
Noradrenergic dysfunction contributes to cognitive impairment in Alzheimer's Disease (AD) and

Parkinson's Disease (PD). Conventional therapeutic strategies seek to enhance cholinergic and
dopaminergic neurotransmission in AD and PD, respectively, and few studies have examined
noradrenergic dysfunction as a target for medication development. We review the literature of
noradrenergic dysfunction in AD and PD with a focus on human imaging studies that implicate the
locus coeruleus (LC) circuit. The LC sends noradrenergic projections diffusely throughout the cerebral
cortex and plays a critical role in attention, learning, working memory, and cognitive control. The LC
undergoes considerable degeneration in both AD and PD. Advances in magnetic resonance imaging
have facilitated greater understanding of how structural and functional alteration of the LC may
contribute to cognitive decline in AD and PD. We discuss the potential roles of the noradrenergic
system in the pathogenesis of AD and PD with an emphasis on postmortem anatomical studies,
structural MRI studies, and functional MRI studies, where we highlight changes in LC connectivity
with the default mode network (DMN). LC degeneration may accompany deficient capacity in
suppressing DMN activity and increasing saliency and task control network activities to meet
behavioral challenges. We finish by proposing potential and new directions of research to address
noradrenergic dysfunction in AD and PD.
11. Projection specificity in heterogeneous locus coeruleus cell populations: implications for learning and
memory
PubMed Central
Uematsu, Akira; Tan, Bao Zhen
2015-01-01
Noradrenergic neurons in the locus coeruleus (LC) play a critical role in many functions including
learning and memory. This relatively small population of cells sends widespread projections
throughout the brain including to a number of regions such as the amygdala which is involved in
emotional associative learning and the medial prefrontal cortex which is important for facilitating
flexibility when learning rules change. LC noradrenergic cells participate in both of these functions,
but it is not clear how this small population of neurons modulates these partially distinct processes.
Here we review anatomical, behavioral, and electrophysiological studies to assess how LC
noradrenergic neurons regulate these different aspects of learning and memory. Previous work has
demonstrated that subpopulations of LC noradrenergic cells innervate specific brain regions suggesting
heterogeneity of function in LC neurons. Furthermore, noradrenaline in mPFC and amygdala has
distinct effects on emotional learning and cognitive flexibility. Finally, neural recording data show that
LC neurons respond during associative learning and when previously learned task contingencies
change. Together, these studies suggest a working model in which distinct and potentially opposing
subsets of LC neurons modulate particular learning functions through restricted efferent connectivity
with amygdala or mPFC. This type of model may provide a general framework for understanding
other neuromodulatory systems, which also exhibit cell type heterogeneity and projection specificity.
PMID:26330494
12. Orexin modulates behavioral fear expression through the locus coeruleus.
PubMed
Soya, Shingo; Takahashi, Tohru M; McHugh, Thomas J; Maejima, Takashi; Herlitze, Stefan; Abe,
Manabu; Sakimura, Kenji; Sakurai, Takeshi
2017-11-20
Emotionally salient information activates orexin neurons in the lateral hypothalamus, leading to
increase in sympathetic outflow and vigilance level. How this circuit alters animals' behavior remains
unknown. Here we report that noradrenergic neurons in the locus coeruleus (NA LC neurons)
projecting to the lateral amygdala (LA) receive synaptic input from orexin neurons.
Pharmacogenetic/optogenetic silencing of this circuit as well as acute blockade of the orexin receptor-
1 (OX1R) decreases conditioned fear responses. In contrast, optogenetic stimulation of this circuit
potentiates freezing behavior against a similar but distinct context or cue. Increase of orexinergic tone
by fasting also potentiates freezing behavior and LA activity, which are blocked by pharmacological
blockade of OX1R in the LC. These findings demonstrate the circuit involving orexin, NA LC and LA
neurons mediates fear-related behavior and suggests inappropriate excitation of this pathway may
cause fear generalization sometimes seen in psychiatric disorders, such as PTSD.
13. Effects of bilateral and unilateral locus coeruleus lesions on beam-walking recovery after subsequent
unilateral sensorimotor cortex suction-ablation in the rat.
PubMed
Goldstein, L B
1997-01-01
The recovery of beam-walking ability following a unilateral sensorimotor cortex lesion in the rat is
hypothesized to be noradrenergically-mediated. We carried out two experiments to further test this
hypothesis. In the first experiment, bilateral 6-hydroxydopamine locus coeruleus (LC) lesions or sham
LC lesions were made 2 weeks prior to a right sensorimotor cortex suction-ablation lesion or sham
cortex lesion. In the second experiment, unilateral left or right LC lesions or sham LC lesions were
made 2 weeks prior to a right sensorimotor cortex lesion or sham cortex lesion. Beam-walking
recovery was measured over the 12 days following cortex lesioning in each experiment. Bilateral,
unilateral left, and unilateral right LC lesions resulted in impaired recovery. These data provide
additional support for the hypothesis that beam-walking recovery after sensorimotor cortex injury is, at
least in part, noradrenergically mediated.
14. Locus coeruleus phasic discharge is essential for stimulus-induced gamma oscillations in the prefrontal
cortex.
PubMed
Neves, Ricardo M; van Keulen, Silvia; Yang, Mingyu; Logothetis, Nikos K; Eschenko, Oxana
2018-03-01
The locus coeruleus (LC) noradrenergic (NE) neuromodulatory system is critically involved in
regulation of neural excitability via its diffuse ascending projections. Tonic NE release in the forebrain
is essential for maintenance of vigilant states and increases the signal-to-noise ratio of cortical sensory
responses. The impact of phasic NE release on cortical activity and sensory processing is less
explored. We previously reported that LC microstimulation caused a transient desynchronization of
population activity in the medial prefrontal cortex (mPFC), similar to noxious somatosensory stimuli.
The LC receives nociceptive information from the medulla and therefore may mediate sensory
signaling to its forebrain targets. Here we performed extracellular recordings in LC and mPFC while
presenting noxious stimuli in urethane-anesthetized rats. A brief train of foot shocks produced a robust
phasic response in the LC and a transient change in the mPFC power spectrum, with the strongest
modulation in the gamma (30-90 Hz) range. The LC phasic response preceded prefrontal gamma
power increase, and cortical modulation was proportional to the LC excitation. We also quantitatively
characterized distinct cortical states and showed that sensory responses in both LC and mPFC depend
on the ongoing cortical state. Finally, cessation of the LC firing by bilateral local iontophoretic
injection of clonidine, an Î± 2 -adrenoreceptor agonist, completely eliminated sensory responses in the
mPFC without shifting cortex to a less excitable state. Together, our results suggest that the LC phasic
response induces gamma power increase in the PFC and is essential for mediating sensory information
along an ascending noxious pathway. NEW & NOTEWORTHY Our study shows linear relationships
between locus coeruleus phasic excitation and the amplitude of gamma oscillations in the prefrontal
cortex. Results suggest that the locus coeruleus phasic response is essential for mediating sensory
information
15. Neuromelanin marks the spot: identifying a locus coeruleus biomarker of cognitive reserve in healthy
aging.
PubMed
Clewett, David V; Lee, Tae-Ho; Greening, Steven; Ponzio, Allison; Margalit, Eshed; Mather, Mara
2016-01-01
Leading a mentally stimulating life may build up a reserve of neural and mental resources that
preserve cognitive abilities in late life. Recent autopsy evidence links neuronal density in the locus
coeruleus (LC), the brain's main source of norepinephrine, to slower cognitive decline before death,
inspiring the idea that the noradrenergic system is a key component of reserve (Robertson, I. H. 2013.
A noradrenergic theory of cognitive reserve: implications for Alzheimer's disease. Neurobiol. Aging.
34, 298-308). Here, we tested this hypothesis using neuromelanin-sensitive magnetic resonance
imaging to visualize and measure LC signal intensity in healthy younger and older adults. Established
proxies of reserve, including education, occupational attainment, and verbal intelligence, were linearly
correlated with LC signal intensity in both age groups. Results indicated that LC signal intensity was
significantly higher in older than younger adults and significantly lower in women than in men.
Consistent with the LC-reserve hypothesis, both verbal intelligence and a composite reserve score
were positively associated with LC signal intensity in older adults. LC signal intensity was also more
strongly associated with attentional shifting ability in older adults with lower cognitive reserve.
Together these findings link in vivo estimates of LC neuromelanin signal intensity to cognitive reserve
in normal aging. Copyright Â© 2016 Elsevier Inc. All rights reserved.
16. Locus coeruleus activation accelerates perceptual learning.
PubMed
Glennon, Erin; Carcea, Ioana; Martins, Ana Raquel O; Multani, Jasmin; Shehu, Ina; Svirsky, Mario A;
Froemke, Robert C
2018-05-31
Neural representations of the external world are constructed and updated in a manner that depends on
behavioral context. For neocortical networks, this contextual information is relayed by a diverse range
of neuromodulatory systems, which govern attention and signal the value of internal state variables
such as arousal, motivation, and stress. Neuromodulators enable cortical circuits to differentially
process specific stimuli and modify synaptic strengths in order to maintain short- or long-term memory
traces of significant perceptual events and behavioral episodes. One of the most important subcortical
neuromodulatory systems for attention and arousal is the noradrenergic locus coeruleus. Here we
report that the noradrenergic system can enhance behavior in rats performing a self-initiated auditory
recognition task, and optogenetic stimulation of noradrenergic locus coeruleus neurons accelerated the
rate at which trained rats began correctly responding to a change in reward contingency. Animals
successively progressed through distinct behavioral epochs, including periods of perseverance and
exploration that occurred much more rapidly when animals received locus coeruleus stimulation. In
parallel, we made recordings from primary auditory cortex and found that pairing tones with locus
coeruleus stimulation led to a similar set of changes to cortical tuning profiles. Thus both behavioral
and neural responses go through phases of adjustment for exploring and exploiting environmental
reward contingencies. Furthermore, behavioral engagement does not necessarily recruit optimal locus
coeruleus activity. Copyright Â© 2018. Published by Elsevier B.V.
17. Chronic restraint stress triggers dopaminergic and noradrenergic neurodegeneration: Possible role of
chronic stress in the onset of Parkinson's disease.
PubMed
Sugama, Shuei; Sekiyama, Kazunari; Kodama, Tohru; Takamatsu, Yoshiki; Takenouchi, Takato;
Hashimoto, Makoto; Bruno, Conti; Kakinuma, Yoshihiko
2016-01-01
Parkinson's disease (PD) is a neurodegenerative disease characterized by the loss of dopaminergic

(DA) neurons in the substantia nigra pars compacta (SNpc) and, to a lesser extent, in the noradrenergic
neurons of the locus coeruleus (LC). Most cases of PD are idiopathic and sporadic and are believed to
be the result of both environmental and genetic factors. Here, to the best of our knowledge, we report
the first evidence that chronic restraint stress (8h/day, 5days/week) substantially reduces nigral DA and
LC noradrenergic neuronal cell numbers in rats. Loss of DA neurons in the SNpc was evident after
2weeks of stress and progressed in a time-dependent manner, reaching up to 61% at 16weeks. This
reduction was accompanied by robust microglial activation and oxidative stress and was marked by
nitrotyrosine in the SNpc and LC of the midbrain. These results indicate that chronic stress triggers
DA and noradrenergic neurodegeneration by increasing oxidative stress, and that activated microglia
in the substantia nigra and LC may play an important role in modulating the neurotoxic effects of
oxidative stress. Taken together, these data suggest that exposure to chronic stress triggers DA and
noradrenergic neurodegeneration, which is a cause of PD. Copyright Â© 2015 Elsevier Inc. All rights
reserved.
18. Characterization of noradrenaline release in the locus coeruleus of freely moving awake rats by in vivo
microdialysis.
PubMed
FernÃ¡ndez-Pastor, BegoÃ±a; Mateo, Yolanda; GÃ³mez-Urquijo, Sonia; Javier Meana, J
2005-07-01
The origin and regulation of noradrenaline (NA) in the locus coeruleus (LC) is unknown. The
neurochemical features of NA overflow (nerve impulse dependence, neurotransmitter synthesis,
vesicle storage, reuptake, alpha2-adrenoceptor-mediated regulation) were characterized in the LC.
Brain microdialysis was performed in awake rats. Dialysates were analyzed for NA. NA in the LC
decreased via local infusion of Ca2+-free medium (-42+/-5%) or the sodium channel blocker
tetrodotoxine (TTX) (-47+/-8%) but increased (333+/-40%) via KCl-induced depolarization. The
tyrosine hydroxylase (TH) inhibitor alpha-methyl-p-tyrosine (250 mg kg(-1), i.p.) and the vesicle
depletory drug reserpine (5 mg kg(-1), i.p.) decreased NA. Therefore, extracellular NA in the LC
satisfies the criteria for an impulse flow-dependent vesicular exocytosis of neuronal origin. Local
perfusion of the alpha2-adrenoceptor agonist clonidine (0.1-100 microM) decreased NA
(E(max)=-79+/-5%) in the LC, whereas the opposite effect (E(max)=268+/-53%) was observed with
the alpha2A-adrenoceptor antagonist BRL44408 (0.1-100 microM). This suggests a tonic modulation
of NA release through local alpha2A-adrenoceptors. The selective NA reuptake inhibitor desipramine

(DMI) (0.1-100 microM) administered into the LC increased NA in the LC (E(max)=223+/-40%) and
simultaneously decreased NA in the cingulate cortex, confirming the modulation exerted by NA in the
LC on firing activity of noradrenergic cells and on the subsequent NA release in noradrenergic
terminals. Synaptic processes underlying NA release in the LC are similar to those in noradrenergic
terminal areas. NA in the LC could represent local somatodendritic release, but also the presence of
neurotransmitter release from collateral axon terminals.
19. Mu-opioid receptor redistribution in the locus coeruleus upon precipitation of withdrawal in opiate-
dependent rats.
PubMed
Scavone, Jillian L; Van Bockstaele, Elisabeth J
2009-03-01
Administration of mu-opioid receptor (MOR) agonists is known to produce adaptive changes within
noradrenergic neurons of the rat locus coeruleus (LC). Alterations in the subcellular distribution of
MOR have been shown to occur in the LC in response to full agonists and endogenous peptides;
however, there is considerable debate in the literature whether trafficking of MOR occurs after chronic
exposure to the partial-agonist morphine. In the present study, we examined adaptations in MOR after
chronic opioid exposure using immunofluorescence and electron microscopy (EM), using receptor
internalization as a functional endpoint. MOR trafficking in LC neurons was characterized in
morphine-dependent rats that were given naltrexone at a dose known to precipitate withdrawal. After
chronic morphine exposure, a subtle redistribution of MOR immunoreactivity from the membrane to
the cytosol was detected within dendrites of LC neurons. Interestingly, an acute injection of naltrexone
in rats exposed to chronic morphine produced a robust internalization of MOR, whereas administration
of naltrexone failed to do so in naÃ¯ve animals. These findings provide anatomical evidence for
modified regulation of MOR trafficking after chronic morphine treatment in brain noradrenergic
neurons. Adaptations in the MOR signaling pathways that regulate internalization may occur as a
consequence of chronic treatment and precipitation of withdrawal. Mechanisms underlying this effect
might include differential MOR regulation in the LC, or downstream effects of withdrawal-induced
enkephalin (ENK) release from afferents to the LC. (c) 2009 Wiley-Liss, Inc.
20. Gene expression deficits in pontine locus coeruleus astrocytes in men with major depressive disorder.
PubMed
Chandley, Michelle J; Szebeni, Katalin; Szebeni, Attila; Crawford, Jessica; Stockmeier, Craig A;
Turecki, Gustavo; Miguel-Hidalgo, Jose Javier; Ordway, Gregory A
2013-07-01
Norepinephrine and glutamate are among several neurotransmitters implicated in the neuropathology
of major depressive disorder (MDD). Glia deficits have also been demonstrated in people with MDD,
and glia are critical modulators of central glutamatergic transmission. We studied glia in men with
MDD in the region of the brain (locus coeruleus; LC) where noradrenergic neuronal cell bodies reside
and receive glutamatergic input. The expression of 3 glutamate-related genes (SLC1A3, SLC1A2,
GLUL) concentrated in glia and a glia gene (GFAP) were measured in postmortem tissues from men
with MDD and from paired psychiatrically healthy controls. Initial gene expression analysis of RNA
isolated from homogenized tissue (n = 9-10 pairs) containing the LC were followed by detailed
analysis of gene expressions in astrocytes and oligodendrocytes (n = 6-7 pairs) laser captured from the
LC region. We assessed protein changes in GFAP using immunohistochemistry and immunoblotting (n
= 7-14 pairs). Astrocytes, but not oligodendrocytes, demonstrated robust reductions in the expression
of SLC1A3 and SLC1A2, whereas GLUL expression was unchanged. GFAP expression was lower in
astrocytes, and we confirmed reduced GFAP protein in the LC using immunostaining methods.
Reduced expression of protein products of SLC1A3 and SLC1A2 could not be confirmed because of
insufficient amounts of LC tissue for these assays. Whether gene expression abnormalities were
associated with only MDD and not with suicide could not be confirmed because most of the decedents
who had MDD died by suicide. Major depressive disorder is associated with unhealthy astrocytes in
the noradrenergic LC, characterized here by a reduction in astrocyte glutamate transporter expression.
These findings suggest that increased glutamatergic activity in the LC occurs in men with MDD.
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21. Noradrenergic Regulation of Central Amygdala in Aversive Pavlovian-to-Instrumental Transfer
PubMed Central
Soroeta, Jose M.
2017-01-01
Abstract The neural mechanisms through which a Pavlovian conditioned stimulus (CS) elicits innate
defense responses are well understood. But a Pavlovian CS can also invigorate ongoing instrumental
responding, as shown by studies of aversive Pavlovian-to-instrumental transfer (PIT). While the neural
circuitry of appetitive PIT has been studied extensively, little is known about the brain mechanisms of
aversive PIT. We recently showed the central amygdala (CeA) is essential for aversive PIT. In the
current studies, using pharmacology and designer receptors in rodents, we demonstrate that
noradrenergic (NE) activity negatively regulates PIT via brainstem locus coeruleus (LC) activity and
LC projections to CeA. Our results provide evidence for a novel pathway through which response
modulation occurs between brainstem neuromodulatory systems and CeA to invigorate adaptive
behavior in the face of threat. PMID:29071299
22. Cholecystokinin-8 induces brain-derived neurotrophic factor expression in noradrenergic neuronal

cells.
PubMed
Hwang, Cheol Kyu; Kim, Do Kyung; Chun, Hong Sung
2013-08-01
The sulfated cholecystokinin octapeptide (CCK-8S) is one of the most abundant CCK fragment in the
brain, but the effects of CCK-8S on locus coeruleus (LC) noradrenergic (NA) neuronal cells activity
have not been studied. In this study, we investigated the effects of CCK-8S on the expression of brain-
derived neurotrophic factor (BDNF) in LC NA neuronal cell line, LC3541. Results showed that CCK-
8S (10 nM) elevates BDNF levels time-dependently and by 1.82-fold after 4h of incubation. In
addition, pretreatment with CCK-8S reversed Hâ‚‚Oâ‚‚ (100 Î¼M)-mediated down-regulation of
BDNF expression, and effectively suppressed Hâ‚‚Oâ‚‚-induced caspase-3 activation. Furthermore,
CCK-8S markedly induced expression of neuronal survival markers, such as extracellular signal-
regulated kinase 1/2 (ERK 1/2), Akt/protein kinase B (PKB), Bcl-2, and peroxisome proliferators-
activated receptor gamma coactivator-1Î± (PGC-1Î±). Pharmacological inhibitors of ERK 1/2,
Akt/PKB, and protein kinase A (PKA) reversed CCK-8S-mediated BDNF induction in LC3541 cells.
These results suggest the first evidence that CCK-8S can protect noradrenergic neurons and enhance
the expression of BDNF via ERK 1/2-Akt/PKB-PKA-dependent pathways. Copyright Â© 2013
Elsevier Ltd. All rights reserved.
23. A noradrenergic lesion exacerbates neurodegeneration in a Down syndrome mouse model.
PubMed
Lockrow, Jason; Boger, Heather; Gerhardt, Greg; Aston-Jones, Gary; Bachman, David; Granholm,
Ann-Charlotte
2011-01-01
Individuals with Down syndrome (DS) acquire Alzheimer's-like dementia (AD) and associated
neuropathology earlier and at significantly greater rates than age-matched normosomic individuals.
However, biological mechanisms have not been discovered and there is currently limited therapy for
either DS- or AD-related dementia. Segmental trisomy 16 (Ts65Dn) mice provide a useful model for
many of the degenerative changes which occur with age in DS including cognitive deficits,
neuroinflammation, and degeneration of basal forebrain cholinergic neurons. Loss of noradrenergic
locus coeruleus (LC) neurons is an early event in AD and in DS, and may contribute to the
neuropathology. We report that Ts65Dn mice exhibit progressive loss of norepinephrine (NE)
phenotype in LC neurons. In order to determine whether LC degeneration contributes to memory loss
and neurodegeneration in Ts65Dn mice, we administered the noradrenergic neurotoxin N-(2-
chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4; 2 doses of 50 mg/kg, i.p.) to Ts65Dn mice at four
months of age, prior to working memory loss. At eight months of age, Ts65Dn mice treated with DSP-
4 exhibited an 80% reduction in hippocampal NE, coupled with a marked increase in hippocampal
neuroinflammation. Noradrenergic depletion also resulted in accelerated cholinergic neuron
degeneration and a further impairment of memory function in Ts65Dn mice. In contrast, DSP-4 had
minimal effects on normosomic littermates, suggesting a disease-modulated vulnerability to NE loss in
the DS mouse model. These data suggest that noradrenergic degeneration may play a role in the
progressive memory loss, neuroinflammation, and cholinergic loss occurring in DS individuals,
providing a possible therapeutic avenue for future clinical studies.
24. A Noradrenergic Lesion Exacerbates Neurodegeneration in a Down Syndrome Mouse Model
PubMed Central
Lockrow, Jason; Boger, Heather; Gerhardt, Greg; Aston-Jones, Gary; Bachman, David; Granholm,
Ann-Charlotte
2012-01-01
Individuals with Down syndrome (DS) acquire Alzheimerâ€™s-like dementia (AD) and associated
neuropathology earlier and at significantly greater rates than age-matched normosomic individuals.
However, biological mechanisms have not been discovered and there is currently limited therapy for
either DS- or AD-related dementia. Segmental trisomy 16 (Ts65Dn) mice provide a useful model for
many of the degenerative changes which occur with age in DS including cognitive deficits,
neuroinflammation, and degeneration of basal forebrain cholinergic neurons. Loss of noradrenergic
locus coeruleus (LC) neurons is an early event in AD and in DS, and may contribute to the
neuropathology. We report that Ts65Dn mice exhibit progressive loss of norepinephrine (NE)
phenotype in LC neurons. In order to determine whether LC degeneration contributes to memory loss
and neurodegeneration in Ts65Dn mice, we administered the noradrenergic neurotoxin N-(2-
chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4; 2 doses of 50 mg/kg, i.p.) to Ts65Dn mice at four
months of age, prior to working memory loss. At eight months of age, Ts65Dn mice treated with DSP-
4 exhibited an 80% reduction in hippocampal NE, coupled with a marked increase in hippocampal
neuroinflammation. Noradrenergic depletion also resulted in accelerated cholinergic neuron
degeneration and a further impairment of memory function in Ts65Dn mice. In contrast, DSP-4 had
minimal effects on normosomic littermates, suggesting a disease-modulated vulnerability to NE loss in
the DS mouse model. These data suggest that noradrenergic degeneration may play a role in the
progressive memory loss, neuroinflammation, and cholinergic loss occurring in DS individuals,
providing a possible therapeutic avenue for future clinical studies. PMID:21098982
25. Locus coeruleus degeneration exacerbates olfactory deficits in APP/PS1 transgenic mice.
PubMed
Rey, Nolwen L; Jardanhazi-Kurutz, Daniel; Terwel, Dick; Kummer, Markus P; Jourdan, Francois;
Didier, Anne; Heneka, Michael T
2012-02-01
Neuronal loss in the locus coeruleus (LC) is 1 of the early pathological events in Alzheimer's disease
(AD). Projections of noradrenergic neurons of the LC innervate the olfactory bulb (OB). Because
olfactory deficits have been reported in early AD, we investigated the effect of induced LC
degeneration on olfactory memory and discrimination in an AD mouse model. LC degeneration was
induced by treating APP/PS1 mice with N-(2-chloroethyl)-N-ethyl-bromo-benzylamine (DSP4)
repeatedly between 3 and 12 months of age. Short term odor retention, ability for spontaneous
habituation to an odor, and spontaneous odor discrimination were assessed by behavioral tests. DSP4
treatment in APP/PS1 mice resulted in an exacerbation of short term olfactory memory deficits and
more discrete weakening of olfactory discrimination abilities, suggesting that LC degeneration
contributes to olfactory deficits observed in AD. Importantly, DSP4 treatment also increased amyloid
Î² (AÎ²) deposition in the olfactory bulb of APP/PS1 mice, which correlated with olfactory memory,
not with discrimination deficits. Copyright Â© 2012 Elsevier Inc. All rights reserved.
26. The dorsal tegmental noradrenergic projection: an analysis of its role in maze learning.
PubMed
Roberts, D C; Price, M T; Fibiger, H C
1976-04-01
The hypothesis that the noradrenergic projection from the locus coeruleus (LC) to the cerebral cortex
and hippocampus is an important neural substrate for learning was evaluated. Maze performance was
studied in rats receiving either electrolytic lesions of LC or 6-hydroxydopamine (6-OHDA) lesions of
the dorsal tegmental noradrenergic projection. The LC lesions did not disrupt the acquisition of a
running response for food reinforcement in an L-shaped runway, even though hippocampal-cortical
norepinephrine (NE) was reduced to 29%. Greater telencephalic NE depletions (to 6% of control
levels) produced by 6-OHDA also failed to disrupt the acquisition of this behavior or to impair the
acquisition of a food-reinforced position habit in a T-maze. Neither locomotor activity nor habituation
to a novel environment was affected by the 6-OHDA lesions. Rats with such lesions were, however,
found to be significantly more distractible than were controls during the performance of a previously
trained response. The hypothesis that telencephalic NE is of fundamental importance in learning was
not supported. The data suggest that this system may participate in attentional mechanisms.
27. Lesion of the locus coeruleus aggravates dopaminergic neuron degeneration by modulating microglial
function in mouse models of Parkinson×³s disease.
PubMed
Yao, Ning; Wu, Yanhong; Zhou, Yan; Ju, Lili; Liu, Yujun; Ju, Rongkai; Duan, Deyi; Xu, Qunyuan
2015-11-02
The degeneration of noradrenergic neurons in the locus coeruleus (LC) commonly occurs in patients
with Parkinson's disease (PD), which is characterized by a selective injury of dopaminergic neurons in
the substantia nigra (SN). The pathological impact of the LC on the SN in the disease is unknown. In
the present study, we used a noradrenergic toxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine

(DSP4), to deplete noradrenaline (NA) derived from the LC to explore its influence on degeneration or
injury of dopaminergic neurons in the SN in mouse model produced by intraperitoneal injection of 1-
methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or lipopolysaccharide (LPS). Our results
demonstrated that lesion of the LC could change microglial function in the brain, which led to
enhanced or prolonged expression of pro-inflammatory cytokines, diminished neurotrophic factors,
and weakened ability of anti-oxidation in the SN. The in vitro experiments further confirmed that NA
could reduce the inflammatory reaction of microglia. The selective injury of dopaminergic neurons by
inflammation, however, was due to the inflammation in different brain regions rather than the
depletion of NA. Our results indicate that the lesion in the LC is an important factor in promoting
dopaminergic neuron degeneration by impacting the function of microglia in the midbrain. Copyright
Â© 2015 Elsevier B.V. All rights reserved.
28. Sex differences in the locus coeruleus-norepinephrine system and its regulation by stress.
PubMed
Bangasser, Debra A; Wiersielis, Kimberly R; Khantsis, Sabina
2016-06-15
Women are more likely than men to suffer from post-traumatic stress disorder (PTSD) and major
depression. In addition to their sex bias, these disorders share stress as an etiological factor and
hyperarousal as a symptom. Thus, sex differences in brain arousal systems and their regulation by
stress could help explain increased vulnerability to these disorders in women. Here we review
preclinical studies that have identified sex differences in the locus coeruleus (LC)-norepinephrine (NE)
arousal system. First, we detail how structural sex differences in the LC can bias females towards
increased arousal in response to emotional events. Second, we highlight studies demonstrating that
estrogen can increase NE in LC target regions by enhancing the capacity for NE synthesis, while
reducing NE degradation, potentially increasing arousal in females. Third, we review data revealing
how sex differences in the stress receptor, corticotropin releasing factor 1 (CRF1), can increase LC
neuronal sensitivity to CRF in females compared to males. This effect could translate into
hyperarousal in women under conditions of CRF hypersecretion that occur in PTSD and depression.
The implications of these sex differences for the treatment of stress-related psychiatric disorders are
discussed. Moreover, the value of using information regarding biological sex differences to aid in the
development of novel pharmacotherapies to better treat men and women with PTSD and depression is
also highlighted. This article is part of a Special Issue entitled SI: Noradrenergic System. Copyright
Â© 2015 Elsevier B.V. All rights reserved.
29. Dopamine release from the locus coeruleus to the dorsal hippocampus promotes spatial learning and
memory
PubMed Central
Kempadoo, Kimberly A.; Mosharov, Eugene V.; Choi, Se Joon; Sulzer, David; Kandel, Eric R.
2016-01-01
Dopamine neurotransmission in the dorsal hippocampus is critical for a range of functions from spatial
learning and synaptic plasticity to the deficits underlying psychiatric disorders such as attention-deficit
hyperactivity disorder. The ventral tegmental area (VTA) is the presumed source of dopamine in the
dorsal hippocampus. However, there is a surprising scarcity of VTA dopamine axons in the dorsal
hippocampus despite the dense network of dopamine receptors. We have explored this apparent
paradox using optogenetic, biochemical, and behavioral approaches and found that dopaminergic
axons and subsequent dopamine release in the dorsal hippocampus originate from neurons of the locus
coeruleus (LC). Photostimulation of LC axons produced an increase in dopamine release in the dorsal
hippocampus as revealed by high-performance liquid chromatography. Furthermore, optogenetically
induced release of dopamine from the LC into the dorsal hippocampus enhanced selective attention
and spatial object recognition via the dopamine D1/D5 receptor. These results suggest that spatial
learning and memory are energized by the release of dopamine in the dorsal hippocampus from
noradrenergic neurons of the LC. The present findings are critical for identifying the neural circuits
that enable proper attention selection and successful learning and memory. PMID:27930324
30. Monitoring nitric oxide (NO) in rat locus coeruleus: differential effects of NO synthase inhibitors.
PubMed
Desvignes, C; Robert, F; Vachette, C; Chouvet, G; Cespuglio, R; Renaud, B; LambÃ¡s-SeÃ±as, L
1997-04-14
A porphyrinic microsensor combined with in vivo voltammetry was used to monitor extracellular
nitric oxide (NO) in the locus coeruleus (LC) of anaesthetized rats. Administration of N omega-nitro-
L-arginine p-nitro-anilide (100 mg/kg, i.p) or 7-nitro indazole (30 mg/kg, i.p.), which both inhibit
preferentially neuronal NO synthase (NOS), induced a marked decrease in the NO oxidation peak
height. On the other hand, N omega-nitro-L-arginine methyl ester (L-NAME) (200 mg/kg, i.p.), a less
selective NOS inhibitor, failed to decrease the NO signal. Moreover, intra LC administration of
NMDA, known to activate LC noradrenergic neurones, increased the NO signal. This study
demonstrates the usefulness of in vivo voltammetry to monitor basal levels of NO and their changes in
the LC. Differential effects of NOS inhibitors show that their central activity need to be assessed
through in situ measurement of NO before using these inhibitors as neuropharmacological tools.
31. Dopamine release from the locus coeruleus to the dorsal hippocampus promotes spatial learning and
memory.
PubMed
Kempadoo, Kimberly A; Mosharov, Eugene V; Choi, Se Joon; Sulzer, David; Kandel, Eric R
2016-12-20
Dopamine neurotransmission in the dorsal hippocampus is critical for a range of functions from spatial
learning and synaptic plasticity to the deficits underlying psychiatric disorders such as attention-deficit
hyperactivity disorder. The ventral tegmental area (VTA) is the presumed source of dopamine in the
dorsal hippocampus. However, there is a surprising scarcity of VTA dopamine axons in the dorsal
hippocampus despite the dense network of dopamine receptors. We have explored this apparent
paradox using optogenetic, biochemical, and behavioral approaches and found that dopaminergic
axons and subsequent dopamine release in the dorsal hippocampus originate from neurons of the locus
coeruleus (LC). Photostimulation of LC axons produced an increase in dopamine release in the dorsal
hippocampus as revealed by high-performance liquid chromatography. Furthermore, optogenetically
induced release of dopamine from the LC into the dorsal hippocampus enhanced selective attention
and spatial object recognition via the dopamine D1/D5 receptor. These results suggest that spatial
learning and memory are energized by the release of dopamine in the dorsal hippocampus from
noradrenergic neurons of the LC. The present findings are critical for identifying the neural circuits
that enable proper attention selection and successful learning and memory.
32. Augmentation of the noradrenergic system in alpha-2 adrenergic receptor deficient mice: anatomical
changes associated with enhanced fear memory.
PubMed
Davies, M Frances; Tsui, Janet Y; Flannery, Judy A; Li, Xiangqi; DeLorey, Timothy M; Hoffman,
Brian B
2003-10-03
We have investigated sensitivity to the conditioned fear procedure of mice is influenced by the genetic
deletion of alpha2A adrenoceptors (ARs). We observed a heightened freezing response in the discrete
cue memory test in alpha2A AR knockout (alpha2A AR KO) mice and in D79N mice, a transgenic
mouse strain with functionally impaired alpha2A ARs. No significant differences in contextual
memory were observed between control and alpha2A AR KO or D79N mice suggesting a minimal role
for the noradrenergic system in contextual memory. We speculated that the increased freezing response
of the alpha2A AR KO and D79N mice in the discrete cue setting was due to increased release of
norepinephrine evoked by the unconditioned footshock stimulus. In alpha2A AR KO mice we
measured a doubling in the number of noradrenergic neurons in the locus coeruleus (LC) and a large
increase in the cell volume of tyrosine hydroxylase positive neurons, likely due to selective
preservation of large, multipolar neurons in the subcoeruleus. Hyperplasia of the noradrenergic
neurons in the nucleus tractus solitarius, A5 and A7, was also observed. Alpha2A AR KO mice exhibit
greater c-Fos expression in the LC compared to wild type mice suggesting that the LC neurons in the
alpha2A AR KO mice were spontaneously more active. This study suggests that alpha2A ARs are
involved in the development of the central noradrenergic system and raises the possibility that
alterations in alpha2A AR expression may contribute to variations in fear and stress responses.
33. The Role of Ca2+ and BK Channels of Locus Coeruleus (LC) Neurons as a Brake to the CO2
Chemosensitivity Response of Rats.
PubMed
Imber, Ann N; Patrone, Luis G A; Li, Ke-Yong; Gargaglioni, Luciane H; Putnam, Robert W
2018-06-15
The cellular mechanisms by which LC neurons respond to hypercapnia are usually attributed to an
"accelerator" whereby hypercapnic acidosis causes an inhibition of K + channels or activation of Na +
and Ca +2 channels to depolarize CO 2 -sensitive neurons. Nevertheless, it is still unknown if this
"accelerator" mechanism could be controlled by a brake phenomenon. Whole-cell patch clamping,
fluorescence imaging microscopy and plethysmography were used to study the chemosensitive
response of the LC neurons. Hypercapnic acidosis activates L-type Ca 2+ channels and large
conductance Ca-activated K + (BK) channels, which function as a "brake" on the chemosensitive
response of LC neurons. Our findings indicate that both Ca 2+ and BK currents develop over the first
2â€¯weeks of postnatal life in rat LC slices and that this brake pathway may cause the developmental
decrease in the chemosensitive firing rate response of LC neurons to hypercapnic acidosis. Inhibition
of this brake by paxilline (BK channel inhibitor) returns the magnitude of the chemosensitive firing
rate response from LC neurons in rats older than P10 to high values similar to those in LC neurons
from younger rats. Inhibition of BK channels in LC neurons by bilateral injections of paxilline into the
LC results in a significant increase in the hypercapnic ventilatory response of adult rats. Our findings
indicate that a BK channel-based braking system helps to determine the chemosensitive respiratory
drive of LC neurons and contributes to the hypercapnic ventilatory response. Perhaps, abnormalities of
this braking system could result in hypercapnia-induced respiratory disorders and panic responses.
Copyright Â© 2018 IBRO. Published by Elsevier Ltd. All rights reserved.
34. Social stress exacerbates the aversion to painful experiences in rats exposed to chronic pain: the role of
the locus coeruleus.
PubMed
Bravo, Lidia; Alba-Delgado, Cristina; Torres-Sanchez, Sonia; Mico, Juan Antonio; Neto, Fani L;
Berrocoso, Esther
2013-10-01
Stressful experiences seem to negatively influence pain perception through as yet unknown
mechanisms. As the noradrenergic locus coeruleus (LC) nucleus coordinates many components of the
stress response, as well as nociceptive transmission, we evaluated whether the sensory and affective
dimension of chronic neuropathic pain worsens in situations of stress due to adaptive changes of LC
neurons. Accordingly, male rats were socially isolated for 5 weeks, and in the last 2 weeks,
neuropathic pain was induced by chronic constriction injury. In this situation of stress, chronic pain
selectively heightened the animal's aversion to painful experiences (affective pain), as measured in the
place escape/avoidance test, although no changes were observed in the sensory dimension of pain. In
addition, electrophysiological recordings of LC neurons showed a low tonic but exacerbated
nociceptive-evoked activity when the injured paw was stimulated. These changes were accompanied
by an increase in tyrosine hydroxylase and gephyrin expression in the LC. Furthermore, intra-LC
administration of bicuculline, a Î³-aminobutyric acid-A receptor antagonist, attenuated the negative
affective effects of pain. These data show that changes in the LC are greater than those expected from
the simple summation of each independent factor (pain and stress), revealing mechanisms through
which stressors may exacerbate pain perception without affecting the sensorial dimension. Copyright
Â© 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights
reserved.
35. Optogenetic silencing of locus coeruleus activity in mice impairs cognitive flexibility in an attentional
set-shifting task
PubMed Central
Janitzky, Kathrin; Lippert, Michael T.; Engelhorn, Achim; Tegtmeier, Jennifer; Goldschmidt,
JÃ¼rgen; Heinze, Hans-Jochen; Ohl, Frank W.
2015-01-01
The locus coeruleus (LC) is the sole source of noradrenergic projections to the cortex and essential for
attention-dependent cognitive processes. In this study we used unilateral optogenetic silencing of the
LC in an attentional set-shifting task (ASST) to evaluate the influence of the LC on prefrontal cortex-
dependent functions in mice. We expressed the halorhodopsin eNpHR 3.0 to reversibly silence LC
activity during task performance, and found that silencing selectively impaired learning of those parts
of the ASST that most strongly rely on cognitive flexibility. In particular, extra-dimensional set-
shifting (EDS) and reversal learning was impaired, suggesting an involvement of the medial prefrontal
cortex (mPFC) and the orbitofrontal cortex. In contrast, those parts of the task that are less dependent
on cognitive flexibility, i.e., compound discrimination (CD) and the intra-dimensional shifts (IDS)
were not affected. Furthermore, attentional set formation was unaffected by LC silencing. Our results
therefore suggest a modulatory influence of the LC on cognitive flexibility, mediated by different
frontal networks. PMID:26582980
36. Chemogenetic locus coeruleus activation restores reversal learning in a rat model of Alzheimer's
disease.
PubMed
Rorabaugh, Jacki M; Chalermpalanupap, Termpanit; Botz-Zapp, Christian A; Fu, Vanessa M;

Lembeck, Natalie A; Cohen, Robert M; Weinshenker, David
2017-11-01
See Grinberg and Heinsen (doi:10.1093/brain/awx261) for a scientific commentary on this article.
Clinical evidence suggests that aberrant tau accumulation in the locus coeruleus and noradrenergic
dysfunction may be a critical early step in Alzheimerâ€™s disease progression. Yet, an accurate
preclinical model of these phenotypes that includes early pretangle tau accrual in the locus coeruleus,
loss of locus coeruleus innervation and deficits locus coeruleus/norepinephrine modulated behaviours,
does not exist, hampering the identification of underlying mechanisms and the development of locus
coeruleus-based therapies. Here, a transgenic rat (TgF344-AD) expressing disease-causing mutant
amyloid precursor protein (APPsw) and presenilin-1 (PS1Î”E9) was characterized for histological and
behavioural signs of locus coeruleus dysfunction reminiscent of mild cognitive impairment/early
Alzheimerâ€™s disease. In TgF344-AD rats, hyperphosphorylated tau was detected in the locus
coeruleus prior to accrual in the medial entorhinal cortex or hippocampus, and tau pathology in the
locus coeruleus was negatively correlated with noradrenergic innervation in the medial entorhinal
cortex. Likewise, TgF344-AD rats displayed progressive loss of hippocampal norepinephrine levels
and locus coeruleus fibres in the medial entorhinal cortex and dentate gyrus, with no frank
noradrenergic cell body loss. Cultured mouse locus coeruleus neurons expressing
hyperphosphorylation-prone mutant human tau had shorter neurites than control neurons, but similar
cell viability, suggesting a causal link between pretangle tau accrual and altered locus coeruleus fibre
morphology. TgF344-AD rats had impaired reversal learning in the Morris water maze compared to
their wild-type littermates, which was rescued by chemogenetic locus coeruleus activation via designer
receptors exclusively activated by designer drugs (DREADDs). Our results indicate that TgF344-AD
rats uniquely meet several key criteria for a
37. The PDAPP mouse model of Alzheimer's disease: locus coeruleus neuronal shrinkage.
PubMed
German, Dwight C; Nelson, Omar; Liang, Fen; Liang, Chang-Lin; Games, Dora
2005-11-28
Alzheimer's disease is characterized by neuronal degeneration in the cerebral cortex and hippocampus
and subcortical neuronal degeneration in such nuclei as the locus coeruleus (LC). Transgenic mice
overexpressing mutant human amyloid precursor protein V717F, PDAPP mice, develop several
Alzheimer's disease-like lesions. The present study sought to determine whether there is also loss of
LC noradrenergic neurons or evidence of degenerative changes in these animals. PDAPP hemizygous
and wild-type littermate control mice were examined at 23 months of age, at a time when there are
numerous amyloid-beta (Abeta) plaques in the neocortex and hippocampus. Tissue sections were
stained immunohistochemically with an antibody against tyrosine hydroxylase (TH) to identify LC
neurons. Computer imaging procedures were used to count the TH-immunoreactive somata in sections
through the rostral-caudal extent of the nucleus. There was no loss of LC neurons in the hemizygous
mice. In a second experiment, homozygous PDAPP and wild-type mice were examined, at 2 months
and 24 months of age. Again there was no age-related loss of neurons in the homozygous animals. In
the portion of the LC where neurons reside that project to the cortex and hippocampus, however, the
neurons were decreased in size selectively in the 24-month-old transgenic animals. These data indicate
that overt LC cell loss does not occur following abundant overexpression of Abeta peptide. However,
the selective size reduction of the LC neuronal population projecting to cortical and hippocampal
regions containing Abeta-related neuropathology implies that these cells may be subjected to a
retrograde-mediated stress. Copyright 2005 Wiley-Liss, Inc.
38. Functional and morphological characterization of glutamate transporters in the rat locus coeruleus
PubMed Central
Medrano, M C; Gerrikagoitia, I; MartÃnez-MillÃ¡n, L; Mendiguren, A; Pineda, J
2013-01-01
Background and Purpose Excitatory amino acid transporters (EAATs) in the CNS contribute to the
clearance of glutamate released during neurotransmission. The aim of this study was to explore the
role of EAATs in the regulation of locus coeruleus (LC) neurons by glutamate. Experimental Approach
We measured the effect of different EAAT subtype inhibitors/enhancers on glutamate- and KCl-
induced activation of LC neurons in rat slices. EAAT2â€“3 expression in the LC was also
characterized by immunohistochemistry. Key Results The EAAT2â€“5 inhibitor DL-threo-Î²-
benzyloxaspartic acid (100 Î¼M), but not the EAAT2, 4, 5 inhibitor L-trans-pyrrolidine-2,4-
dicarboxylic acid (100 Î¼M) or the EAAT2 inhibitor dihydrokainic acid (DHK; 100 Î¼M), enhanced
the glutamate- and KCl-induced activation of the firing rate of LC neurons. These effects were blocked
by ionotropic, but not metabotrobic, glutamate receptor antagonists. DHK (100 Î¼M) was the only
EAAT inhibitor that increased the spontaneous firing rate of LC cells, an effect that was due to
inhibition of EAAT2 and subsequent AMPA receptor activation. Chronic treatment with ceftriaxone
(200 mgÂ·kgâˆ’1 i.p., once daily, 7 days), an EAAT2 expression enhancer, increased the actions of
glutamate and DHK, suggesting a functional impact of EAAT2 up-regulation on the glutamatergic
system. Immuhistochemical data revealed the presence of EAAT2 and EAAT3 surrounding
noradrenergic neurons and EAAT2 on glial cells in the LC. Conclusions and Implications These results
remark the importance of EAAT2 and EAAT3 in the regulation of rat LC by glutamate. Neuronal
EAAT3 would be responsible for terminating the action of synaptically released glutamate, whereas
glial EAAT2 would regulate tonic glutamate concentrations in this nucleus. PMID:23638698
39. Locus Coeruleus Stimulation Facilitates Long-Term Depression in the Dentate Gyrus That Requires
Activation of Î²-Adrenergic Receptors
PubMed Central
Hansen, Niels; Manahan-Vaughan, Denise
2015-01-01
Synaptic plasticity comprises a cellular mechanism through which the hippocampus most likely
enables memory formation. Neuromodulation, related to arousal, is a key aspect in information
storage. The activation of locus coeruleus (LC) neurons by novel experience leads to noradrenaline
release in the hippocampus at the level of the dentate gyrus (DG). We explored whether synaptic
plasticity in the DG is influenced by activation of the LC via electrical stimulation. Coupling of test-
pulses that evoked stable basal synaptic transmission in the DG with stimulation of the LC induced Î²-
adrenoreceptor-dependent long-term depression (LTD) at perforant pathâ€“DG synapses in adult rats.
Furthermore, persistent LTD (>24 h) induced by perforant path stimulation also required activation of
Î²-adrenergic receptors: Whereas a Î²-adrenergic receptor antagonist (propranolol) prevented, an
agonist (isoproterenol) strengthened the persistence of LTD for over 24 h. These findings support the
hypothesis that persistent LTD in the DG is modulated by Î²-adrenergic receptors. Furthermore, LC
activation potently facilitates DG LTD. This suggests in turn that synaptic plasticity in the DG is
tightly regulated by activity in the noradrenergic system. This may reflect the role of the LC in
selecting salient information for subsequent synaptic processing in the hippocampus. PMID:24464942
40. Chronic alcohol exposure differentially affects activation of female locus coeruleus neurons and the
subcellular distribution of corticotropin releasing factor receptors.
PubMed
Retson, T A; Reyes, B A; Van Bockstaele, E J
2015-01-02
Understanding the neurobiological bases for sex differences in alcohol dependence is needed to help
guide the development of individualized therapies for alcohol abuse disorders. In the present study,
alcohol-induced adaptations in (1) anxiety-like behavior, (2) patterns of c-Fos activation and (3)
subcellular distribution of corticotropin releasing factor receptor in locus coeruleus (LC) neurons was
investigated in male and female Sprague-Dawley rats that were chronically exposed to ethanol using a
liquid diet. Results confirm and extend reports by others showing that chronic ethanol exposure
produces an anxiogenic-like response in both male and female subjects. Ethanol-induced sex
differences were observed with increased c-Fos expression in LC neurons of female ethanol-treated
subjects compared to controls or male subjects. Results also reveal sex differences in the subcellular
distribution of the CRFr in LC-noradrenergic neurons with female subjects exposed to ethanol
exhibiting a higher frequency of plasmalemmal CRFrs. These adaptations have implications for LC
neuronal activity and its neural targets across the sexes. Considering the important role of the LC in
ethanol-induced activation of the hypothalamo-pituitary-adrenal (HPA) axis, the present results
indicate important sex differences in feed-forward regulation of the HPA axis that may render alcohol
dependent females more vulnerable to subsequent stress exposure. Copyright Â© 2014 Elsevier Inc.
All rights reserved.
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1
2
3
4
5
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2
3
4
5
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41. Exercise offers anxiolytic potential: A role for stress and brain noradrenergic-galaninergic mechanisms
PubMed Central
Sciolino, Natale R.; Holmes, Philip V.
2016-01-01
Although physical activity reduces anxiety in humans, the neural basis for this response is unclear.
Rodent models are essential to understand the mechanisms that underlie the benefits of exercise.
However, it is controversial whether exercise exerts anxiolytic-like potential in rodents. Evidence is
reviewed to evaluate the effects of wheel running, an experimental mode of exercise in rodents, on
behavior in tests of anxiety and on norepinephrine and galanin systems in neural circuits that regulate
stress. Stress is proposed to account for mixed behavioral findings in this literature. Indeed, running
promotes an adaptive response to stress and alters anxiety-like behaviors in a manner dependent on
stress. Running amplifies galanin expression in noradrenergic locus coeruleus (LC) and suppresses
stress-induced activity of the LC and norepinephrine output in LC-target regions. Thus, enhanced
galanin-mediated suppression of brain norepinephrine in runners is supported by current literature as a
mechanism that may contribute to the stress-protective effects of exercise. These data support the use
of rodents to study the emotional and neurobiological consequences of exercise. PMID:22771334
42. Trigeminal, Visceral and Vestibular Inputs May Improve Cognitive Functions by Acting through the
Locus Coeruleus and the Ascending Reticular Activating System: A New Hypothesis
PubMed Central
De Cicco, Vincenzo; Tramonti Fantozzi, Maria P.; Cataldo, Enrico; Barresi, Massimo; Bruschini,
Luca; Faraguna, Ugo; Manzoni, Diego
2018-01-01
It is known that sensory signals sustain the background discharge of the ascending reticular activating
system (ARAS) which includes the noradrenergic locus coeruleus (LC) neurons and controls the level
of attention and alertness. Moreover, LC neurons influence brain metabolic activity, gene expression
and brain inflammatory processes. As a consequence of the sensory control of ARAS/LC, stimulation
of a sensory channel may potential influence neuronal activity and trophic state all over the brain,
supporting cognitive functions and exerting a neuroprotective action. On the other hand, an imbalance
of the same input on the two sides may lead to an asymmetric hemispheric excitability, leading to an
impairment in cognitive functions. Among the inputs that may drive LC neurons and ARAS, those
arising from the trigeminal region, from visceral organs and, possibly, from the vestibular system seem
to be particularly relevant in regulating their activity. The trigeminal, visceral and vestibular control of
ARAS/LC activity may explain why these input signals: (1) affect sensorimotor and cognitive
functions which are not directly related to their specific informational content; and (2) are effective in
relieving the symptoms of some brain pathologies, thus prompting peripheral activation of these input
systems as a complementary approach for the treatment of cognitive impairments and
neurodegenerative disorders. PMID:29358907
43. The Memory Function of Noradrenergic Activity in Non-REM Sleep

ERIC Educational Resources Information Center
Gais, Steffen; Rasch, Bjorn; Dahmen, Johannes C.; Sara, Susan; Born, Jan
2011-01-01
There is a long-standing assumption that low noradrenergic activity during sleep reflects mainly the
low arousal during this brain state. Nevertheless, recent research has demonstrated that the locus
coeruleus, which is the main source of cortical noradrenaline, displays discrete periods of intense
firing during non-REM sleep, without any signs ofâ€¦
44. Noradrenergic Control of Odor Recognition in a Nonassociative Olfactory Learning Task in the Mouse
Veyrac, Alexandra; Nguyen, Veronique; Marien, Marc; Didier, Anne; Jourdan, Francois
2007-01-01
The present study examined the influence of pharmacological modulations of the locus coeruleus
noradrenergic system on odor recognition in the mouse. Mice exposed to a nonrewarded olfactory
stimulation (training) were able to memorize this odor and to discriminate it from a new odor in a
recall test performed 15 min later. At longer delays (30 orâ€¦
45. Intermittent Short Sleep Results in Lasting Sleep Wake Disturbances and Degeneration of Locus
Coeruleus and Orexinergic Neurons
PubMed Central
Zhu, Yan; Fenik, Polina; Zhan, Guanxia; Somach, Rebecca; Xin, Ryan; Veasey, Sigrid
2016-01-01
Study Objectives: Intermittent short sleep (ISS) is pervasive among students and workers in modern
societies, yet the lasting consequences of repeated short sleep on behavior and brain health are largely
unexplored. Wake-activated neurons may be at increased risk of metabolic injury across sustained
wakefulness. Methods: To examine the effects of ISS on wake-activated neurons and wake behavior,
wild-type mice were randomized to ISS (a repeated pattern of short sleep on 3 consecutive days
followed by 4 days of recovery sleep for 4 weeks) or rested control conditions. Subsets of both groups
were allowed a recovery period consisting of 4-week unperturbed activity in home cages with
littermates. Mice were examined for immediate and delayed (following recovery) effects of ISS on
wake neuron cell metabolics, cell counts, and sleep/wake patterns. Results: ISS resulted in sustained
disruption of sleep/wake activity, with increased wakefulness during the lights-on period and reduced
wake bout duration and wake time during the lights-off period. Noradrenergic locus coeruleus (LC)
and orexinergic neurons showed persistent alterations in morphology, and reductions in both neuronal
stereological cell counts and fronto-cortical projections. Surviving wake-activated neurons evidenced
persistent reductions in sirtuins 1 and 3 and increased lipofuscin. In contrast, ISS resulted in no lasting
injury to the sleep-activated melanin concentrating hormone neurons. Conclusions: Collectively these
findings demonstrate for the first time that ISS imparts significant lasting disturbances in sleep/wake
activity, degeneration of wake-activated LC and orexinergic neurons, and lasting metabolic changes in
remaining neurons most consistent with premature senescence. Citation: Zhu Y, Fenik P, Zhan G,
Somach R, Xin R, Veasey S. Intermittent short sleep results in lasting sleep wake disturbances and
degeneration of locus coeruleus and orexinergic neurons. SLEEP 2016;39(8):1601â€“1611.
PMID:27306266
46. Noradrenergic System in Down Syndrome and Alzheimer's Disease A Target for Therapy.
PubMed
Phillips, Cristy; Fahimi, Atoossa; Das, Devsmita; Mojabi, Fatemeh S; Ponnusamy, Ravikumar; Salehi,
Ahmad
2016-01-01
Locus coeruleus (LC) neurons in the brainstem send extensive noradrenergic (NE)-ergic terminals to
the majority of brain regions, particularly those involved in cognitive function. Both Alzheimer's
disease (AD) and Down syndrome (DS) are characterized by similar pathology including significant
LC degeneration and dysfunction of the NE-ergic system. Extensive loss of NE-ergic terminals has
been linked to alterations in brain regions vital for cognition, mood, and executive function. While the
mechanisms by which NE-ergic abnormalities contribute to cognitive dysfunction are not fully
understood, emergent evidence suggests that rescue of NE-ergic system can attenuate neuropathology
and cognitive decline in both AD and DS. Therapeutic strategies to enhance NE neurotransmission
have undergone limited testing. Among those deployed to date are NE reuptake inhibitors, presynaptic
Î±-adrenergic receptor antagonists, NE prodrugs, and Î²-adrenergic agonists. Here we examine
alterations in the NE-ergic system in AD and DS and suggest that NE-ergic system rescue is a
plausible treatment strategy for targeting cognitive decline in both disorders.
47. Interactions of nitric oxide with Î±2 -adrenoceptors within the locus coeruleus underlie the facilitation
of inhibitory avoidance memory by agmatine.
PubMed
Shelkar, Gajanan P; Gakare, Sukanya G; Chakraborty, Suwarna; Dravid, Shashank M; Ugale, Rajesh R
2016-09-01
Agmatine, a putative neurotransmitter, plays a vital role in learning and memory. Although it is
considered an endogenous ligand of imidazoline receptors, agmatine exhibits high affinity for Î±-
adrenoceptors, NOS and NMDA receptors. These substrates within the locus coeruleus (LC) are
critically involved in learning and memory processes. The hippocampus and LC of male Wistar rat
were stereotaxically cannulated for injection. Effects of agmatine, given i.p. or intra-LC, on
acquisition, consolidation and retrieval of inhibitory avoidance (IA) memory were measured. The NO
donor S-nitrosoglutathione, non-specific (L-NAME) and specific NOS inhibitors (L-NIL, 7-NI, L-
NIO), the Î±2 -adrenoceptor antagonist (yohimbine) or the corresponding agonist (clonidine) were
injected intra-LC before agmatine. Intra-hippocampal injections of the NMDA antagonist, MK-801
(dizocilpine), were used to modify the memory enhancing effects of agmatine, SNG and yohimbine.
Expression of tyrosine hydroxylase (TH) and eNOS in the LC was assessed immunohistochemically.
Agmatine (intra-LC or i.p.) facilitated memory retrieval in the IA test. S-nitrosoglutathione
potentiated, while L-NAME and L-NIO decreased, these effects of agmatine. L-NIL and 7-NI did not
alter the effects of agmatine. Yohimbine potentiated, whereas clonidine attenuated, effects of agmatine
within the LC. The effects of agmatine, S-nitrosoglutathione and yohimbine were blocked by intra-
hippocampal MK-801. Agmatine increased the population of TH- and eNOS-immunoreactive
elements in the LC. The facilitation of memory retrieval in the IA test by agmatine is probably
mediated by interactions between eNOS, NO and noradrenergic pathways in the LC. Â© 2016 The
British Pharmacological Society.
48. Interactions of nitric oxide with Î±2â€adrenoceptors within the locus coeruleus underlie the facilitation
of inhibitory avoidance memory by agmatine
PubMed Central
Shelkar, Gajanan P; Gakare, Sukanya G; Chakraborty, Suwarna; Dravid, Shashank M
2016-01-01
Background and Purpose Agmatine, a putative neurotransmitter, plays a vital role in learning and
memory. Although it is considered an endogenous ligand of imidazoline receptors, agmatine exhibits
high affinity for Î±â€adrenoceptors, NOS and NMDA receptors. These substrates within the locus
coeruleus (LC) are critically involved in learning and memory processes. Experimental Approach The
hippocampus and LC of male Wistar rat were stereotaxically cannulated for injection. Effects of
agmatine, given i.p. or intraâ€LC, on acquisition, consolidation and retrieval of inhibitory avoidance
(IA) memory were measured. The NO donor Sâ€nitrosoglutathione, nonâ€specific (Lâ€NAME) and
specific NOS inhibitors (Lâ€NIL, 7â€NI, Lâ€NIO), the Î±2â€adrenoceptor antagonist (yohimbine) or
the corresponding agonist (clonidine) were injected intraâ€LC before agmatine. Intraâ€hippocampal
injections of the NMDA antagonist, MKâ€801 (dizocilpine), were used to modify the memory
enhancing effects of agmatine, SNG and yohimbine. Expression of tyrosine hydroxylase (TH) and
eNOS in the LC was assessed immunohistochemically. Key Results Agmatine (intraâ€LC or i.p.)
facilitated memory retrieval in the IA test. Sâ€nitrosoglutathione potentiated, while Lâ€NAME and
Lâ€NIO decreased, these effects of agmatine. Lâ€NIL and 7â€NI did not alter the effects of agmatine.
Yohimbine potentiated, whereas clonidine attenuated, effects of agmatine within the LC. The effects of
agmatine, Sâ€nitrosoglutathione and yohimbine were blocked by intraâ€hippocampal MKâ€801.
Agmatine increased the population of THâ€ and eNOSâ€immunoreactive elements in the LC.
Conclusions and Implications The facilitation of memory retrieval in the IA test by agmatine is
probably mediated by interactions between eNOS, NO and noradrenergic pathways in the LC.
PMID:27273730
49. Vagus nerve stimulation enhances perforant path-CA3 synaptic transmission via the activation of Î²-
adrenergic receptors and the locus coeruleus.
PubMed
Shen, Huilian; Fuchino, Yuta; Miyamoto, Daisuke; Nomura, Hiroshi; Matsuki, Norio
2012-05-01
Vagus nerve stimulation (VNS) is an approved treatment for epilepsy and depression and has
cognition-enhancing effects in patients with Alzheimer's disease. The hippocampus is widely
recognized to be related to epilepsy, depression, and Alzheimer's disease. One possible mechanism of
VNS involves its effect on the hippocampus; i.e. it increases the release of noradrenaline in the
hippocampus. However, the effect of VNS on synaptic transmission in the hippocampus is unknown.
To determine whether VNS modulates neurotransmission in the hippocampus, we examined the effects
of VNS on perforant path (PP)-CA3 synaptic transmission electrophysiologically in anaesthetized rats.
VNS induces a persistent enhancement of PP-CA3 field excitatory post-synaptic potentials (fEPSPs).
Arc, an immediate early gene, was used to identify active brain regions after VNS. The locus coeruleus
(LC), which contains the perikarya of noradrenergic projections, harboured more Arc-positive cells, as
measured by in-situ hybridization, after 10-min VNS. In addition, electrical lesions of LC neurons or
intraventricular administration of the Î²-adrenergic receptor antagonist timolol prevented the
enhancement of PP-CA3 responses by VNS. In conclusion, the protracted increase in PP-CA3 synaptic
transmission that is induced by VNS entails activation of the LC and Î²-adrenergic receptors. Our
novel findings suggest that information from the periphery modulates synaptic transmission in the
CA3 region of the hippocampus.
50. Reversal of noradrenergic depletion and lipid peroxidation in the pons after brain injury correlates with
motor function recovery in rats.
PubMed
Bueno-Nava, Antonio; Montes, Sergio; DelaGarza-Montano, Paloma; Alfaro-Rodriguez, Alfonso;

Ortiz, Ascencion; Gonzalez-Pina, Rigoberto
2008-09-26
Functional impairment after brain injury (BI) has been attributed to the inhibition of regions that are
related to the injured site. Therefore, noradrenaline (NA) is thought to play a critical role in recovery
from motor injury. However, the mechanism of this recovery process has not been completely
elucidated. Moreover, the locus coeruleus (LC) projects from the pons through the rat sensorimotor
cortex, and injury axotomizes LC fibers, depressing NA function. This was tested by measuring lipid
peroxidation (LP) in the pons after sensorimotor cortex injury. Depression of function in the pons
would be expected to alter areas receiving pontine efferents. Male Wistar rats were divided into three
groups: control (n=16), injured (n=10) and recovering (n=16), and they were evaluated using a beam-
walking assay between 2 and 20 days after cortical injury. We performed measures of NA and LP in
both sides of the pons and cerebellum. We found a decrease of NA in the pons and the cerebellum, and
a concomitant increase in the motor deficit and LP in the pons of injured animals. Recovering rats had
NA and LP levels that were very similar to those observed in control rats. These observations suggest
that the mechanism of remote inhibition after BI involves lipid peroxidation, and that the NA decrease
found in the cerebellum of injured animals is mediated by a noradrenergic depression in the pons, or in
areas receiving NA projections from the pons.
51. A53T-Î±-synuclein overexpression in murine locus coeruleus induces Parkinson's disease-like

pathology in neurons and glia.
PubMed
Henrich, Martin Timo; Geibl, Fanni Fruzsina; Lee, Bolam; Chiu, Wei-Hua; Koprich, James Benjamin;
Brotchie, Jonathan Michael; Timmermann, Lars; Decher, Niels; Matschke, Lina Anita; Oertel,
Wolfgang Hermann
2018-05-10
Degeneration of noradrenergic locus coeruleus neurons occurs during the prodromal phase of
Parkinson's disease and contributes to a variety of non-motor symptoms, e.g. depression, anxiety and
REM sleep behavior disorder. This study was designed to establish the first locus coeruleus Î±-
synucleinopathy mouse model, which should provide sufficient information about the time-course of
noradrenergic neurodegeneration, replicate cardinal histopathological features of the human
Parkinson's disease neuropathology and finally lead to robust histological markers, which are sufficient
to assess the pathological changes in a quantitative and qualitative way. We show that targeted viral
vector-mediated overexpression of human mutant A53T-Î±-synuclein in vivo in locus coeruleus
neurons of wild-type mice resulted in progressive noradrenergic neurodegeneration over a time frame
of 9Â weeks. Observed neuronal cell loss was accompanied by progressive Î±-synuclein
phosphorylation, formation of proteinase K-resistant Î±-synuclein-aggregates, accumulation of Ubi-1-
and p62-positive inclusions in microglia and induction of progressive micro- and astrogliosis. Apart
from this local pathology, abundant Î±-synuclein-positive axons were found in locus coeruleus output
regions, indicating rapid anterograde axonal transport of A53T-Î±-synuclein. Taken together, we
present the first model of Î±-synucleinopathy in the murine locus coeruleus, replicating essential
morphological features of human Parkinson's disease pathology. This new model may contribute to the
research on prodromal Parkinson's disease, in respect to pathophysiology and the development of
disease-modifying therapy.
52. The Role of the Central Noradrenergic System in Behavioral Inhibition
PubMed Central
Stone, Eric A.; Lin, Yan; Sarfraz, Yasmeen; Quartermain, David
2011-01-01
Although the central noradrenergic system has been shown to be involved in a number of behavioral
and neurophysiological processes, the relation of these to its role in depressive illness has been
difficult to define. The present review discusses the hypothesis that one of its chief functions that may
be related to affective illness is the inhibition of behavioral activation, a prominent symptom of the
disorder. This hypothesis is found to be consistent with most previous neuropsychopharmacological
and immunohistochemical experiments on active behavior in rodents in a variety of experimental
conditions using manipulation of neurotransmission at both locus coeruleus and forebrain adrenergic
receptors. The findings support a mechanism in which high rates of noradrenergic neural activity
suppress the neural activity of principal neurons in forebrain regions mediating active behavior. The
suppression may be mediated through postsynaptic galaninergic and adrenergic receptors, and via the
release of corticotrophin-releasing hormone. The hypothesis is consistent with clinical evidence for
central noradrenergic system hyperactivity in depressives and with the view that this hyperactivity is a
contributing etiological factor in the disorder. A similar mechanism may underlie the ability of the
noradrenergic system to suppress seizure activity suggesting that inhibition of the spread of neural
activation may be a unifying function. PMID:21315760
53. Association of Posttraumatic Stress Disorder With Reduced In Vivo Norepinephrine Availability in the
Locus Coeruleus
PubMed Central
Pietrzak, Robert H.; Gallezot, Jean-Dominique; Ding, Yu-Shin; Henry, Shannan; Potenza, Marc N.;
Southwick, Steven M.; Krystal, John H.; Carson, Richard E.; Neumeister, Alexander
2014-01-01
IMPORTANCE Animal data suggest that chronic stress is associated with a reduction in
norepinephrine transporter (NET) availability in the locus coeruleus. However, it is unclear whether
such models are relevant to posttraumatic stress disorder (PTSD), which has been linked to
noradrenergic dysfunction in humans. OBJECTIVES To use positron emission tomography and the
radioligand [11C]methylreboxetine to examine in vivo NET availability in the locus coeruleus in the
following 3 groups of individuals: healthy adults (HC group), adults exposed to trauma who did not
develop PTSD (TC group), and adults exposed to trauma who developed PTSD (PTSD group) and to
evaluate the relationship between NET availability in the locus coeruleus and a contemporary
phenotypic model of PTSD symptoms. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional
positron emission tomography study under resting conditions at academic and Veterans Affairs
medical centers among 56 individuals in the following 3 study groups: HC (n = 18), TC (n = 16), and
PTSD (n = 22). MAIN OUTCOMES AND MEASURES The [11C]methylreboxetine-binding
potential of NET availability in the locus coeruleus and the severity of PTSD symptoms assessed using
the Clinician-Administered PTSD Scale. RESULTS The PTSD group had significantly lower NET
availability than the HC group (41% lower, Cohen d = 1.07). NET availability did not differ
significantly between the TC and HC groups (31% difference, Cohen d = 0.79) or between the TC and
PTSD groups (15% difference, Cohen d = 0.28). In the PTSD group, NET availability in the locus
coeruleus was independently positively associated with the severity of anxious arousal (ie,
hypervigilance) symptoms (r = 0.52) but not with any of the other PTSD symptom clusters.
CONCLUSIONS AND RELEVANCE These results suggest that PTSD is associated with significantly
reduced NET availability in the locus coeruleus and that greater NET availability in this brain region is
associated with increased severity
54. Intermittent Short Sleep Results in Lasting Sleep Wake Disturbances and Degeneration of Locus
Coeruleus and Orexinergic Neurons.
PubMed
Zhu, Yan; Fenik, Polina; Zhan, Guanxia; Somach, Rebecca; Xin, Ryan; Veasey, Sigrid
2016-08-01
Intermittent short sleep (ISS) is pervasive among students and workers in modern societies, yet the
lasting consequences of repeated short sleep on behavior and brain health are largely unexplored.
Wake-activated neurons may be at increased risk of metabolic injury across sustained wakefulness. To
examine the effects of ISS on wake-activated neurons and wake behavior, wild-type mice were
randomized to ISS (a repeated pattern of short sleep on 3 consecutive days followed by 4 days of
recovery sleep for 4 weeks) or rested control conditions. Subsets of both groups were allowed a
recovery period consisting of 4-week unperturbed activity in home cages with littermates. Mice were
examined for immediate and delayed (following recovery) effects of ISS on wake neuron cell
metabolics, cell counts, and sleep/wake patterns. ISS resulted in sustained disruption of sleep/wake
activity, with increased wakefulness during the lights-on period and reduced wake bout duration and
wake time during the lights-off period. Noradrenergic locus coeruleus (LC) and orexinergic neurons
showed persistent alterations in morphology, and reductions in both neuronal stereological cell counts
and fronto-cortical projections. Surviving wake-activated neurons evidenced persistent reductions in
sirtuins 1 and 3 and increased lipofuscin. In contrast, ISS resulted in no lasting injury to the sleep-
activated melanin concentrating hormone neurons. Collectively these findings demonstrate for the first
time that ISS imparts significant lasting disturbances in sleep/wake activity, degeneration of wake-
activated LC and orexinergic neurons, and lasting metabolic changes in remaining neurons most
consistent with premature senescence. Â© 2016 Associated Professional Sleep Societies, LLC.
55. Pupil size signals mental effort deployed during multiple object tracking and predicts brain activity in
the dorsal attention network and the locus coeruleus.
PubMed
AlnÃ¦s, Dag; Sneve, Markus Handal; Espeseth, Thomas; Endestad, Tor; van de Pavert, Steven Harry
Pieter; Laeng, Bruno
2014-04-01
Attentional effort relates to the allocation of limited-capacity attentional resources to meet current task
demands and involves the activation of top-down attentional systems in the brain. Pupillometry is a
sensitive measure of this intensity aspect of top-down attentional control. Studies relate pupillary
changes in response to cognitive processing to activity in the locus coeruleus (LC), which is the main
hub of the brain's noradrenergic system and it is thought to modulate the operations of the brain's
attentional systems. In the present study, participants performed a visual divided attention task known
as multiple object tracking (MOT) while their pupil sizes were recorded by use of an infrared eye
tracker and then were tested again with the same paradigm while brain activity was recorded using
fMRI. We hypothesized that the individual pupil dilations, as an index of individual differences in
mental effort, as originally proposed by Kahneman (1973), would be a better predictor of LC activity
than the number of tracked objects during MOT. The current results support our hypothesis, since we
observed pupil-related activity in the LC. Moreover, the changes in the pupil correlated with activity in
the superior colliculus and the right thalamus, as well as cortical activity in the dorsal attention
network, which previous studies have shown to be strongly activated during visual tracking of multiple
targets. Follow-up pupillometric analyses of the MOT task in the same individuals also revealed that
individual differences to cognitive load can be remarkably stable over a lag of several years. To our
knowledge this is the first study using pupil dilations as an index of attentional effort in the MOT task
and also relating these to functional changes in the brain that directly implicate the LC-NE system in
the allocation of processing resources.
56. Co-release of noradrenaline and dopamine in the cerebral cortex elicited by single train and repeated
train stimulation of the locus coeruleus
PubMed Central
Devoto, Paola; Flore, Giovanna; Saba, Pierluigi; FÃ , Mauro; Gessa, Gian Luigi
2005-01-01
Background Previous studies by our group suggest that extracellular dopamine (DA) and
noradrenaline (NA) may be co-released from noradrenergic nerve terminals in the cerebral cortex. We
recently demonstrated that the concomitant release of DA and NA could be elicited in the cerebral
cortex by electrical stimulation of the locus coeruleus (LC). This study analyses the effect of both
single train and repeated electrical stimulation of LC on NA and DA release in the medial prefrontal
cortex (mPFC), occipital cortex (Occ), and caudate nucleus. To rule out possible stressful effects of
electrical stimulation, experiments were performed on chloral hydrate anaesthetised rats. Results
Twenty min electrical stimulation of the LC, with burst type pattern of pulses, increased NA and DA
both in the mPFC and in the Occ. NA in both cortices and DA in the mPFC returned to baseline within
20 min after the end of the stimulation period, while DA in the Occ reached a maximum increase
during 20 min post-stimulation and remained higher than baseline values at 220 min post-stimulation.
Local perfusion with tetrodotoxin (TTX, 10 Î¼M) markedly reduced baseline NA and DA in the
mPFC and Occ and totally suppressed the effect of electrical stimulation in both areas. A sequence of
five 20 min stimulations at 20 min intervals were delivered to the LC. Each stimulus increased NA to
the same extent and duration as the first stimulus, whereas DA remained elevated at the time next
stimulus was delivered, so that baseline DA progressively increased in the mPFC and Occ to reach
about 130 and 200% the initial level, respectively. In the presence of the NA transport (NAT) blocker
desipramine (DMI, 100 Î¼M), multiple LC stimulation still increased extracellular NA and DA levels.
Electrical stimulation of the LC increased NA levels in the homolateral caudate nucleus, but failed to
modify DA level. Conclusion The results confirm and extend that LC stimulation induces a
concomitant release of DA and NA
57. Roles of the locus coeruleus and adrenergic receptors in brain-mediated hypothalamic-pituitary-
adrenal axis responses to intracerebroventricular alcohol.
PubMed
Selvage, Dan
2012-06-01
Alcohol activates the hypothalamic-pituitary-adrenal (HPA) axis through its actions in both the
periphery and the central nervous system (CNS). The studies presented here were designed to test the
CNS-specific noradrenergic mechanisms by which alcohol stimulates HPA activity in the male rat. We
used an experimental paradigm in which a small, nontoxic amount (5Â Î¼l) of alcohol was slowly
microinfused intracerebroventricularly (icv). Alcohol was administered icv to animals with lesions of
the locus coeruleus (LC) or in animals pretreated with Î±- or Î²-adrenergic receptor antagonists.
Hormonal HPA activation was determined by measuring secretion of the pituitary stress hormone
adrenocorticotropin (ACTH). Neuronal activation was determined by quantification of the expression
of the transcription factor c-fos (Fos). As expected, icv alcohol stimulated ACTH secretion from the
pituitary and Fos expression in the paraventricular nucleus of the hypothalamus (PVN). Bilateral
electrolytic LC lesions blocked the ability of icv alcohol to stimulate ACTH secretion. Pretreatment
with icv propranolol increased basal ACTH secretion levels, but icv alcohol did not increase this
effect. Propranolol also blunted icv alcohol-induced PVN Fos expression. A low dose of
phenoxybenzamine, an Î±-adrenergic receptor antagonist, did not affect the ability of icv alcohol to
stimulate ACTH release. However, a higher dose of the drug was able to block the ACTH response to
icv alcohol. Despite this, phenoxybenzamine did not inhibit alcohol-induced Fos expression. Icv
pretreatment with corynanthine, a selective Î±-1 adrenergic receptor antagonist, modestly raised basal
ACTH levels and blocked the icv alcohol-induced secretion of this hormone. These results indicate
that the LC and norepinephrine play important roles in HPA activation caused by icv alcohol
administration, but that the specific adrenergic receptor subtypes involved in this phenomenon still
need to be identified. Copyright Â© 2012
58. Higher locus coeruleus MRI contrast is associated with lower parasympathetic influence over heart
rate variability.
PubMed
Mather, Mara; Joo Yoo, Hyun; Clewett, David V; Lee, Tae-Ho; Greening, Steven G; Ponzio, Allison;
Min, Jungwon; Thayer, Julian F
2017-04-15
The locus coeruleus (LC) is a key node of the sympathetic nervous system and suppresses
parasympathetic activity that would otherwise increase heart rate variability. In the current study, we
examined whether LC-MRI contrast reflecting neuromelanin accumulation in the LC was associated
with high-frequency heart rate variability (HF-HRV), a measure reflecting parasympathetic influences
on the heart. Recent evidence indicates that neuromelanin, a byproduct of catecholamine metabolism,
accumulates in the LC through young and mid adulthood, suggesting that LC-MRI contrast may be a
useful biomarker of individual differences in habitual LC activation. We found that, across younger
and older adults, greater LC-MRI contrast was negatively associated with HF-HRV during fear
conditioning and spatial detection tasks. This correlation was not accounted for by individual
differences in age or anxiety. These findings indicate that individual differences in LC structure relate
to key cardiovascular parameters. Copyright Â© 2017 Elsevier Inc. All rights reserved.
59. Higher locus coeruleus MRI contrast is associated with lower parasympathetic influence over heart
rate variability
PubMed Central
Mather, Mara; Yoo, Hyun Joo; Clewett, David V.; Lee, Tae-Ho; Greening, Steven G.; Ponzio, Allison;
Min, Jungwon; Thayer, Julian F.
2017-01-01
The locus coeruleus (LC) is a key node of the sympathetic nervous system and suppresses
parasympathetic activity that would otherwise increase heart rate variability. In the current study, we
examined whether LC-MRI contrast reflecting neuromelanin accumulation in the LC was associated
with high-frequency heart rate variability (HF-HRV), a measure reflecting parasympathetic influences
on the heart. Recent evidence indicates that neuromelanin, a byproduct of catecholamine metabolism,
accumulates in the LC through young and mid adulthood, suggesting that LC-MRI contrast may be a
useful biomarker of individual differences in habitual LC activation. We found that, across younger
and older adults, greater LC-MRI contrast was negatively associated with HF-HRV during fear
conditioning and spatial detection tasks. This correlation was not accounted for by individual
differences in age or anxiety. These findings indicate that individual differences in LC structure relate
to key cardiovascular parameters. PMID:28215623
60. Reduced noradrenergic innervation of ventral midbrain dopaminergic cell groups and the subthalamic
nucleus in MPTP-treated parkinsonian monkeys.
PubMed
Masilamoni, Gunasingh Jeyaraj; Groover, Olivia; Smith, Yoland
2017-04-01
There is anatomical and functional evidence that ventral midbrain dopaminergic (DA) cell groups and
the subthalamic nucleus (STN) receive noradrenergic innervation in rodents, but much less is known
about these interactions in primates. Degeneration of NE neurons in the locus coeruleus (LC) and
related brainstem NE cell groups is a well-established pathological feature of Parkinson's disease (PD),
but the development of such pathology in animal models of PD has been inconsistent across species
and laboratories. We recently demonstrated 30-40% neuronal loss in the LC, A5 and A6 NE cell
groups of rhesus monkeys rendered parkinsonian by chronic administration of 1-methyl-4-phenyl-
1,2,3,6-tetrahydropyridine (MPTP). In this study, we used dopamine-beta-hydroxylase (DÎ²H)
immunocytochemistry to assess the impact of this neuronal loss on the number of NE terminal-like
varicosities in the substantia nigra pars compacta (SNC), ventral tegmental area (VTA), retrorubral
field (RRF) and STN of MPTP-treated parkinsonian monkeys. Our findings reveal that the NE
innervation of the ventral midbrain and STN of normal monkeys is heterogeneously distributed being
far more extensive in the VTA, RRF and dorsal tier of the SNC than in the ventral SNC and STN. In
parkinsonian monkeys, all regions underwent a significant (~50-70%) decrease in NE innervation. At
the electron microscopic level, some DÎ²H-positive terminals formed asymmetric axo-dendritic
synapses in VTA and STN. These findings demonstrate that the VTA, RRF and SNCd are the main
ventral midbrain targets of ascending NE inputs, and that these connections undergo a major break-
down in chronically MPTP-treated parkinsonian monkeys. This severe degeneration of the ascending
NE system may contribute to the pathophysiology of ventral midbrain and STN neurons in PD.
Copyright Ã‚Â© 2017 Elsevier Inc. All rights reserved.
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61. The locus coeruleus neurotoxin, DSP4, and/or a high sugar diet induce behavioral and biochemical
alterations in wild-type mice consistent with Alzheimers related pathology.
PubMed
Choudhary, Pooja; Pacholko, Anthony G; Palaschuk, Josh; Bekar, Lane K
2018-06-03
Alzheimer's disease (AD) is the sixth leading cause of death in the United States where it is estimated
that one in three seniors dies with AD or another dementia. Are modern lifestyle habits a contributing
factor? Increased carbohydrate (sugar) consumption, stress and disruption of sleep patterns are quickly
becoming the norm rather than the exception. Interestingly, seven months on a non-invasive high
sucrose diet (20% sucrose in drinking water) has been shown to induce behavioral, metabolic and
pathological changes consistent with AD in wild-type mice. As chronic stress and depression are
associated with loss of locus coeruleus (LC) noradrenergic neurons and projections (source of anti-
inflammatory and trophic factor control), we assessed the ability for a selective LC neurotoxin (DSP4)
to accelerate and aggravate a high-sucrose mediated AD-related phenotype in wild-type mice. Male
C57/Bl6 mice were divided into four groups: 1) saline injected, 2) DSP4 injected, 3) high sucrose
drinking water (20%) or 4) DSP4 injected and high sucrose drinking water. We demonstrate that high
sucrose consumption and DSP4 treatment promote an early-stage AD-related phenotype after only 3-
4Â months, as evidenced by elevated fecal corticosterone, increased despair, spatial memory deficits,
increased AChE activity, elevated NO production, decreased pGSK3Î² and increased pTau. Combined
treatment appears to accelerate and aggravate pathological processes consistent with Alzheimer
disease and dementia. Developing a simple model in wild-type mice will highlight environmental and
lifestyle factors that need to be addressed to slow, prevent or even reverse the rising trend in dementia
patient numbers and cost.
62. Locus coeruleus and dopaminergic consolidation of everyday memory
PubMed Central
Takeuchi, Tomonori; Duszkiewicz, Adrian J.; Sonneborn, Alex; Spooner, Patrick A.; Yamasaki,
Miwako; Watanabe, Masahiko; Smith, Caroline C.; FernÃ¡ndez, GuillÃ©n; Deisseroth, Karl; Greene,
Robert W.; Morris, Richard G. M.
2016-01-01
Summary The retention of episodic-like memory is enhanced, in humans and animals, when something
novel happens shortly before or after encoding. Using an everyday memory task in mice, we sought
the neurons mediating this dopamine-dependent novelty effect, previously thought to originate
exclusively from the tyrosine hydroxylase-expressing (TH+) neurons in the ventral tegmental area
(VTA). We report that neuronal firing in the locus coeruleus (LC) is especially sensitive to
environmental novelty, LC-TH+ neurons project more profusely than VTA-TH+ neurons to the
hippocampus, optogenetic activation of LC-TH+ neurons mimics the novelty effect, and this novelty-
associated memory enhancement is unaffected by VTA inactivation. Surprisingly, two effects of LC-
TH+ photoactivation are sensitive to hippocampal D1/D5 receptor blockade and resistant to
adrenoceptors blockade â€“ memory enhancement and long lasting potentiation of synaptic
transmission in CA1 ex vivo. Thus, LC-TH+ neurons can mediate post-encoding memory
enhancement in a manner consistent with possible co-release of dopamine in hippocampus.
PMID:27602521
63. Stimulatory effect of harmane and other beta-carbolines on locus coeruleus neurons in anaesthetized
rats.
PubMed
Ruiz-DurÃ¡ntez, E; Ruiz-Ortega JA; Pineda, J; Ugedo, L
2001-08-10
Harmane, harmaline and norharmane are beta-carboline related compounds which have been proposed
to be endogenous ligands for imidazoline receptors. The effect of these compounds on the activity of
locus coeruleus (LC) neurons was studied by extracellular recordings techniques.
Intracerebroventricular administration of harmane and harmaline increased the firing rate of LC
neurons. Systemic administration of efaroxan, a mixed alpha(2)-adrenoceptor/I(1)-imidazoline
antagonist or vagotomy failed to modify the harmane effect. Furthermore, local applications of
harmane and harmaline increased the firing rate of LC neurons in a dose-related manner. Finally,
intravenous administration of norharmane also increased the activity of LC neurons. Our results
demonstrate that beta-carbolines stimulate LC neuron activity and indicate that this stimulation occurs
directly in the LC by a mechanism independent of I(1)- and I(2)-imidazoline receptors.
64. Activation of Extracellular Signal-Regulated Kinases (ERK 1/2) in the Locus Coeruleus Contributes to
Pain-Related Anxiety in Arthritic Male Rats
PubMed Central
Borges, Gisela; Miguelez, Cristina; Neto, Fani; Mico, Juan Antonio; Ugedo, Luisa
2017-01-01
Abstract Background: There is increasing evidence suggesting that the Locus Coeruleus plays a role in
pain-related anxiety. Indeed, we previously found that prolonged arthritis produces anxiety-like
behavior in rats, along with enhanced expression of phosphorylated extracellular signal-regulated
kinase 1/2 (a marker of plasticity) in the Locus Coeruleus. However, it is unknown how this effect
correlates with the electrophysiological activity of Locus Coeruleus neurons or pain-related anxiety.
Methods: Using the complete Freundâ€™s adjuvant model of monoarthritis in male Sprague-Dawley
rats, we studied the behavioral attributes of pain and anxiety as well as Locus Coeruleus
electrophysiology in vivo 1 (MA1W) and 4 weeks (MA4W) after disease induction. Results: The
manifestation of anxiety in MA4W was accompanied by dampened tonic Locus Coeruleus activity,
which was coupled to an exacerbated evoked Locus Coeruleus response to noxious stimulation of the
inflamed and healthy paw. When a mitogen-activating extracellular kinase inhibitor was administered
to the contralateral Locus Coeruleus of MA4W, the phosphorylated extracellular signal-regulated
kinase 1/2 levels in the Locus Coeruleus were restored and the exaggerated evoked response was
blocked, reversing the anxiogenic-like behavior while pain hypersensitivity remained unaltered.
Conclusion: As phosphorylated extracellular signal-regulated kinase 1/2 blockade in the Locus
Coeruleus relieved anxiety and counteracted altered LC function, we propose that phosphorylated
extracellular signal-regulated kinase 1/2 activation in the Locus Coeruleus plays a crucial role in pain-
related anxiety. PMID:28158734
65. Activation of Extracellular Signal-Regulated Kinases (ERK 1/2) in the Locus Coeruleus Contributes to
Pain-Related Anxiety in Arthritic Male Rats.
PubMed
Borges, Gisela; Miguelez, Cristina; Neto, Fani; Mico, Juan Antonio; Ugedo, Luisa; Berrocoso, Esther
2017-06-01
There is increasing evidence suggesting that the Locus Coeruleus plays a role in pain-related anxiety.
Indeed, we previously found that prolonged arthritis produces anxiety-like behavior in rats, along with
enhanced expression of phosphorylated extracellular signal-regulated kinase 1/2 (a marker of
plasticity) in the Locus Coeruleus. However, it is unknown how this effect correlates with the
electrophysiological activity of Locus Coeruleus neurons or pain-related anxiety. Using the complete
Freund's adjuvant model of monoarthritis in male Sprague-Dawley rats, we studied the behavioral
attributes of pain and anxiety as well as Locus Coeruleus electrophysiology in vivo 1 (MA1W) and 4
weeks (MA4W) after disease induction. The manifestation of anxiety in MA4W was accompanied by
dampened tonic Locus Coeruleus activity, which was coupled to an exacerbated evoked Locus
Coeruleus response to noxious stimulation of the inflamed and healthy paw. When a mitogen-
activating extracellular kinase inhibitor was administered to the contralateral Locus Coeruleus of
MA4W, the phosphorylated extracellular signal-regulated kinase 1/2 levels in the Locus Coeruleus
were restored and the exaggerated evoked response was blocked, reversing the anxiogenic-like
behavior while pain hypersensitivity remained unaltered. As phosphorylated extracellular signal-
regulated kinase 1/2 blockade in the Locus Coeruleus relieved anxiety and counteracted altered LC
function, we propose that phosphorylated extracellular signal-regulated kinase 1/2 activation in the
Locus Coeruleus plays a crucial role in pain-related anxiety. Â© The Author 2017. Published by
Oxford University Press on behalf of CINP.
66. Locus Coeruleus, Vigilance and Stress: Brain Mechanisms of Adaptive Behavioral Responsiveness
DTIC Science & Technology
1993-05-13
attention is directzd elsewhere, and (b) concurrent activity in the autonomic nervous system (.reflected
in pupillqry diameter), a measure of stress ...LC system, higher-order attentional processing (ERPs),
and vigilance pertormance during normative as well as during stressful conditions. Results of...G.,
Valentino, R.J., Van Bockstaele, E. and Meyerson. A.. Nucleus locus coeruleus and post-traumatic
stress disorder: neurobiological and clinical
67. The Effects of Locus Coeruleus and Norepinephrine in Methamphetamine Toxicity
PubMed Central
Ferrucci, Michela; Giorgi, Filippo S; Bartalucci, Alessia; Busceti, Carla L; Fornai, Francesco
2013-01-01
The activity of locus coeruleus (LC) neurons has been extensively investigated in a variety of
behavioural states. In fact this norepinephrine (NE)-containing nucleus modulates many physiological
and pathological conditions including the sleep-waking cycle, movement disorders, mood alterations,
convulsive seizures, and the effects of drugs such as psychostimulants and opioids. This review
focuses on the modulation exerted by central NE pathways on the behavioural and neurotoxic effects
produced by the psychostimulant methamphetamine, essentially the modulation of the activity of
mesencephalic dopamine (DA) neurons. In fact, although NE in itself mediates some behavioural
effects induced by methamphetamine, NE modulation of DA release is pivotal for methamphetamine-
induced behavioural states and neurotoxicity. These interactions are discussed on the basis of the state
of the art of the functional neuroanatomy of central NE- and DA systems. Emphasis is given to those
brain sites possessing a remarkable overlapping of both neurotransmitters. PMID:23814540
68. Down but Not Out: The Consequences of Pretangle Tau in the Locus Coeruleus
PubMed Central
Chalermpalanupap, Termpanit; Weinshenker, David
2017-01-01
Degeneration of locus coeruleus (LC) is an underappreciated hallmark of Alzheimer's disease (AD).

The LC is the main source of norepinephrine (NE) in the forebrain, and its degeneration is highly
correlated with cognitive impairment and amyloid-beta (AÎ²) and tangle pathology.
Hyperphosphorylated tau in the LC is among the first detectable AD-like neuropathology in the brain,
and while the LC/NE system impacts multiple aspects of AD (e.g., cognition, neuropathology, and
neuroinflammation), the functional consequences of hyperphosphorylated tau accrual on LC neurons
are not known. Recent evidence suggests that LC neurons accumulate aberrant tau species for decades
before frank LC cell body degeneration occurs in AD, suggesting that a therapeutic window exists. In
this review, we combine the literature on how pathogenic tau affects forebrain neurons with the known
properties and degeneration patterns of LC neurons to synthesize hypotheses on hyperphosphorylated
tau-induced dysfunction of LC neurons and the prion-like spread of pretangle tau from the LC to the
forebrain. We also propose novel experiments using both in vitro and in vivo models to address the
many questions surrounding the impact of hyperphosphorylated tau on LC neurons in AD and its role
in disease progression. PMID:29038736
69. Interaction of brain noradrenergic system and the hypothalamic-pituitary-adrenal (HPA) axis in man.
PubMed
Young, Elizabeth A; Abelson, James L; Cameron, Oliver G
2005-09-01
Numerous interactions between the brainstem locus coeruleus system and the HPA axis have been
shown in experimental animals. This relationship is less well characterized in humans and little is
known about the influence of psychiatric disorders, which disturb one of these systems, on this
relationship. Untreated subjects with pure MDD (n = 13), MDD with comorbid anxiety disorders (n =
17), and pure anxiety disorders (n = 15) were recruited by advertising. Age and sex matched control
subjects were recruited for each subject with a psychiatric diagnosis (n = 45). All subjects underwent a
social stressor, the Trier Social Stress Test (TSST), and blood was collected for ACTH assay. These
same subjects also underwent a clonidine challenge study for assessment of growth hormone release as
a marker of tonic noradrenergic activation. Examining log transformed area under the curve response
for each hormone, a significant negative relationship (simple regression) was observed between
systems in normal subjects. This relationship was preserved in anxiety subjects. However, both pure
depressed and comorbid depressed and anxiety subjects demonstrated disruption of this relationship.
Under normal circumstances, noradrenergic systems can influence the magnitude of the HPA axis
response to stress. However, in subjects with major depression, HPA axis activation appears
autonomous of noradrenergic influence.
70. A role for locus coeruleus in Parkinson tremor
PubMed Central
Isaias, Ioannis U.; Marzegan, Alberto; Pezzoli, Gianni; Marotta, Giorgio; Canesi, Margherita; Biella,
Gabriele E. M.; Volkmann, Jens; Cavallari, Paolo
2012-01-01
We analyzed rest tremor, one of the etiologically most elusive hallmarks of Parkinson disease (PD), in
12 consecutive PD patients during a specific task activating the locus coeruleus (LC) to investigate a
putative role of noradrenaline (NA) in tremor generation and suppression. Clinical diagnosis was
confirmed in all subjects by reduced dopamine reuptake transporter (DAT) binding values investigated
by single photon computed tomography imaging (SPECT) with [123I] N-Ï‰-fluoropropyl-2Î²-
carbomethoxy-3Î²-(4-iodophenyl) tropane (FP-CIT). The intensity of tremor (i.e., the power of
Electromyography [EMG] signals), but not its frequency, significantly increased during the task. In six
subjects, tremor appeared selectively during the task. In a second part of the study, we retrospectively
reviewed SPECT with FP-CIT data and confirmed the lack of correlation between dopaminergic loss
and tremor by comparing DAT binding values of 82 PD subjects with bilateral tremor (n = 27),
unilateral tremor (n = 22), and no tremor (n = 33). This study suggests a role of the LC in Parkinson
tremor. PMID:22287946
71. The Neuroanatomy of the Reticular Nucleus Locus Coeruleus in Alzheimerâ€™s Disease
PubMed Central
Giorgi, Filippo S.; Ryskalin, Larisa; Ruffoli, Riccardo; Biagioni, Francesca; Limanaqi, Fiona; Ferrucci,
Michela; Busceti, Carla L.; Bonuccelli, Ubaldo; Fornai, Francesco
2017-01-01
Alzheimerâ€™s Disease (AD) features the accumulation of Î²-amyloid and Tau aggregates, which
deposit as extracellular plaques and intracellular neurofibrillary tangles (NFTs), respectively. Neuronal
Tau aggregates may appear early in life, in the absence of clinical symptoms. This occurs in the
brainstem reticular formation and mostly within Locus Coeruleus (LC), which is consistently affected
during AD. LC is the main source of forebrain norepinephrine (NE) and it modulates a variety of
functions including sleep-waking cycle, alertness, synaptic plasticity, and memory. The iso-dendritic
nature of LC neurons allows their axons to spread NE throughout the whole forebrain. Likewise, a
prion-like hypothesis suggests that Tau aggregates may travel along LC axons to reach out cortical
neurons. Despite this timing is compatible with cross-sectional studies, there is no actual evidence for
a causal relationship between these events. In the present mini-review, we dedicate special emphasis to
those various mechanisms that may link degeneration of LC neurons to the onset of AD pathology.
This includes the hypothesis that a damage to LC neurons contributes to the onset of dementia due to a
loss of neuroprotective effects or, even the chance that, LC degenerates independently from cortical
pathology. At the same time, since LC neurons are lost in a variety of neuropsychiatric disorders we
considered which molecular mechanism may render these brainstem neurons so vulnerable.
PMID:28974926
72. The Neuroanatomy of the Reticular Nucleus Locus Coeruleus in Alzheimer's Disease.
PubMed
Giorgi, Filippo S; Ryskalin, Larisa; Ruffoli, Riccardo; Biagioni, Francesca; Limanaqi, Fiona; Ferrucci,
Michela; Busceti, Carla L; Bonuccelli, Ubaldo; Fornai, Francesco
2017-01-01
Alzheimer's Disease (AD) features the accumulation of Î²-amyloid and Tau aggregates, which deposit
as extracellular plaques and intracellular neurofibrillary tangles (NFTs), respectively. Neuronal Tau
aggregates may appear early in life, in the absence of clinical symptoms. This occurs in the brainstem
reticular formation and mostly within Locus Coeruleus (LC), which is consistently affected during
AD. LC is the main source of forebrain norepinephrine (NE) and it modulates a variety of functions
including sleep-waking cycle, alertness, synaptic plasticity, and memory. The iso-dendritic nature of
LC neurons allows their axons to spread NE throughout the whole forebrain. Likewise, a prion-like
hypothesis suggests that Tau aggregates may travel along LC axons to reach out cortical neurons.
Despite this timing is compatible with cross-sectional studies, there is no actual evidence for a causal
relationship between these events. In the present mini-review, we dedicate special emphasis to those
various mechanisms that may link degeneration of LC neurons to the onset of AD pathology. This
includes the hypothesis that a damage to LC neurons contributes to the onset of dementia due to a loss
of neuroprotective effects or, even the chance that, LC degenerates independently from cortical
pathology. At the same time, since LC neurons are lost in a variety of neuropsychiatric disorders we
considered which molecular mechanism may render these brainstem neurons so vulnerable.
73. The Locus Coeruleus: Essential for Maintaining Cognitive Function and the Aging Brain.
PubMed
Mather, Mara; Harley, Carolyn W
2016-03-01
Research on cognitive aging has focused on how decline in various cortical and hippocampal regions
influence cognition. However, brainstem regions play essential modulatory roles, and new evidence
suggests that, among these, the integrity of the locus coeruleus (LC)-norepinephrine (NE) system plays
a key role in determining late-life cognitive abilities. The LC is especially vulnerable to toxins and
infection and is often the first place Alzheimer's-related pathology appears, with most people showing
at least some tau pathology by their mid-20s. On the other hand, NE released from the LC during
arousing, mentally challenging, or novel situations helps to protect neurons from damage, which may
help to explain how education and engaging careers prevent cognitive decline in later years. Copyright
Â© 2016 Elsevier Ltd. All rights reserved.
74. Reversal of behavioral depression by infusion of an alpha-2 adrenergic agonist into the locus
coeruleus.
PubMed
Simson, P G; Weiss, J M; Hoffman, L J; Ambrose, M J
1986-04-01
This experiment demonstrated that behavioral depression produced by exposure of rats to strong
uncontrollable shocks could be reversed by infusion of the alpha-2 adrenergic agonist clonidine into
the region of the locus coeruleus (LC). A 20-min infusion, through bilateral cannulae, into the locus
coeruleus of clonidine, piperoxane (alpha-2 antagonist) or inactive vehicle (0.85% saline), was given
beginning 70 min after the animals were removed from the stress situation. The dose and volume of
drug given in the infusion (0.16 microgram/microliter, 0.1 microliter/min) had been previously shown
to produce effects specific to the locus coeruleus (Weiss, Simson, Hoffman, Ambrose, Cooper and
Webster, 1986; Neuropharmacology 25: 367-384). At the conclusion of the infusion, active behavior of
animals was measured in a 15-min swim test. Results showed that stressed animals infused with
vehicle exhibited significantly less active behavior in the swim test than did non-stressed animals
infused with vehicle, thereby showing the usual behavioral depression seen after exposure to an
uncontrollable stress. Stressed animals infused with clonidine showed no difference in active behavior
in comparison to non-stressed animals infused with vehicle and showed significantly more activity
than did the stressed animals infused with vehicle. Stressed animals infused with piperoxane showed
no significant difference in activity in comparison to the stressed animals infused with vehicle and
were significantly less active than either the non-stressed animals infused with vehicle or the stressed
animals infused with clonidine. Thus, infusion into the locus coeruleus of the alpha-2 agonist
clonidine, but not the alpha-2 antagonist piperoxane, eliminated behavioral depression.(ABSTRACT
TRUNCATED AT 250 WORDS)
75. Curvilinear locus coeruleus functional connectivity trajectories over the adult lifespan: a 7T MRI
study.
PubMed
Jacobs, Heidi I L; MÃ¼ller-Ehrenberg, Lisa; Priovoulos, Nikos; Roebroeck, Alard
2018-05-24
The locus coeruleus (LC) plays a crucial role in modulating several higher order cognitive functions
via its widespread projections to the entire brain. We set out to investigate the hypothesis that LC
functional connectivity (FC) may fluctuate nonlinearly with age and explored its relation to memory
function. To that end, 49 cognitively healthy individuals (19-74Â years) underwent ultra high-
resolution 7T resting-state functional magnetic resonance imaging and cognitive testing. FC patterns
from the LC to regions of the isodendritic core network and cortical regions were examined using
region of interest-to-region of interest analyses. Curvilinear patterns with age were observed for FC
between the left LC and cortical regions and the nucleus basalis of Meynert. A linear negative
association was observed between age and LC-FC and ventral tegmental area. Higher levels of FC
between the LC and nucleus basalis of Meynert or ventral tegmental area were associated with lower
memory performance from age of 40 years onward. Thus, different LC-FC patterns early in life can
signal subtle memory deficits. Furthermore, these results highlight the importance of intact interactions
between neurotransmitter systems for optimal cognitive aging. Copyright Â© 2018 Elsevier Inc. All
rights reserved.
76. Pharmacological Modulation of Noradrenergic Arousal Circuitry Disrupts Functional Connectivity of

the Locus Ceruleus in Humans
PubMed Central
Song, Andrew H.
2017-01-01
State-dependent activity of locus ceruleus (LC) neurons has long suggested a role for noradrenergic
modulation of arousal. However, in vivo insights into noradrenergic arousal circuitry have been
constrained by the fundamental inaccessibility of the human brain for invasive studies. Functional
magnetic resonance imaging (fMRI) studies performed during site-specific pharmacological
manipulations of arousal levels may be used to study brain arousal circuitry. Dexmedetomidine is an
anesthetic that alters the level of arousal by selectively targeting Î±2 adrenergic receptors on LC
neurons, resulting in reduced firing rate and norepinephrine release. Thus, we hypothesized that
dexmedetomidine-induced altered arousal would manifest with reduced functional connectivity
between the LC and key brain regions involved in the regulation of arousal. To test this hypothesis, we
acquired resting-state fMRI data in right-handed healthy volunteers 18â€“36 years of age (n = 15, 6
males) at baseline, during dexmedetomidine-induced altered arousal, and recovery states. As
previously reported, seed-based resting-state fMRI analyses revealed that the LC was functionally
connected to a broad network of regions including the reticular formation, basal ganglia, thalamus,
posterior cingulate cortex (PCC), precuneus, and cerebellum. Functional connectivity of the LC to
only a subset of these regions (PCC, thalamus, and caudate nucleus) covaried with the level of arousal.
Functional connectivity of the PCC to the ventral tegmental area/pontine reticular formation and
thalamus, in addition to the LC, also covaried with the level of arousal. We propose a framework in
which the LC, PCC, thalamus, and basal ganglia comprise a functional arousal circuitry.
SIGNIFICANCE STATEMENT Electrophysiological studies of locus ceruleus (LC) neurons have long
suggested a role for noradrenergic mechanisms in mediating arousal. However, the fundamental
inaccessibility of the human brain for invasive studies has
77. Activation of Î²-noradrenergic receptors enhances rhythmic bursting in mouse olfactory bulb external
tufted cells.
PubMed
Zhou, Fu-Wen; Dong, Hong-Wei; Ennis, Matthew
2016-12-01
The main olfactory bulb (MOB) receives a rich noradrenergic innervation from the nucleus locus
coeruleus. Despite the well-documented role of norepinephrine and Î²-adrenergic receptors in neonatal
odor preference learning, identified cellular physiological actions of Î²-receptors in the MOB have
remained elusive. Î²-Receptors are expressed at relatively high levels in the MOB glomeruli, the
location of external tufted (ET) cells that exert an excitatory drive on mitral and other cell types. The
present study investigated the effects of Î²-receptor activation on the excitability of ET cells with
patch-clamp electrophysiology in mature mouse MOB slices. Isoproterenol and selective Î² 2 -, but not
Î² 1 -, receptor agonists were found to enhance two key intrinsic currents involved in ET burst
initiation: persistent sodium (I NaP ) and hyperpolarization-activated inward (I h ) currents. Together,
the positive modulation of these currents increased the frequency and strength of ET cell rhythmic
bursting. Rodent sniff frequency and locus coeruleus neuronal firing increase in response to novel
stimuli or environments. The increase in ET excitability by Î²-receptor activation may better enable ET
cell rhythmic bursting, and hence glomerular network activity, to pace faster sniff rates during
heightened norepinephrine release associated with arousal. Copyright Â© 2016 the American
Physiological Society.
78. Effects of locus coeruleus stimulation on the responses of SI neurons of the rat to controlled natural
and electrical stimulation of the skin.
PubMed
Snow, P J; Andre, P; Pompeiano, O
1999-02-01
1. The effects of microstimulation of the locus coeruleus (LC) region on the spontaneous discharge and
the response of SI neurons to natural and electrical stimulation of the skin have been investigated in 26
urethane anesthetized Sprague-Dawley rats. In particular, one or two air puffs, 5-10 msec in duration,
1-2 psi, usually separated by an interval of 40 msec, were applied on the hairy skin of the wrist or the
forepaw at the presentation rate of 1/sec. For units unresponsive to air puffs, similar presentation of
low intensity electrical stimuli (0.2-5.0 V, 0.2-0.4 msec pulses) were applied through two needles
inserted on the most effective area of the skin. Both natural and electrical stimulations of the skin were
applied under control conditions, as well as 50 msec after a 250 msec train of 0.3 msec pulses at 40
Hz. 20-30 microA applied stereotaxically to the LC complex through a tungsten microelectrode. 2. Not
all cortical units exhibited spontaneous discharge. Most of the units, however, which were
spontaneously active, were inhibited by electrical stimulation of the LC complex, while the remaining
ones were excited. The sites of stimulation, which included either the LC proper or the locus
subcoeruleus, were identified following both anatomical and physiological criteria. 3. SI neurons
recorded at sites between 400 and 950 microns below the surface of the cortex, thus being most likely
granule cells of layers III and IV, responded to cutaneous stimuli with spikes which occurred with a
latency of 20-30 msec in response to single air puffs and a latency of 15-20 msec in response to single
electrical pulses to the skin. In both instances the response to the second stimulus applied at the
interstimulus interval of 40 msec was markedly reduced or abolished due to postexcitatory inhibition
following the response to the first stimulus (in-field inhibition). In contrast, units particularly located at
or below 1000 microns from the cortical surface, which were of
79. Individual differences in the locus coeruleus-norepinephrine system: relevance to stress-induced

cardiovascular vulnerability
PubMed Central
Wood, Christopher S.; Valentino, Rita J.; Wood, Susan K.
2016-01-01
Repeated exposure to psychosocial stress is a robust sympathomimetic stressor and as such has
adverse effects on cardiovascular health. While the neurocircuitry involved remains unclear, the
physiological and anatomical characteristics of the locus coeruleus (LC)-norepinephrine (NE) system
suggest that it is poised to contribute to stress-induced cardiovascular vulnerability. A major theme
throughout is to review studies that shed light on the role that the LC may play in individual
differences in vulnerability to social stress-induced cardiovascular dysfunction. Recent findings are
discussed that support a unique plasticity in afferent regulation of the LC, resulting in either excitatory
or inhibitory input to the LC during establishment of different stress coping strategies. This contrasting
regulation of the LC by either afferent regulation, or distinct differences in stress-induced
neuroinflammation would translate to differences in cardiovascular regulation and may serve as the
basis for individual differences in the cardiopathological consequences of social stress. The goal of this
review is to highlight recent developments in the interplay between the LC-NE and cardiovascular
systems during repeated stress in an effort to advance therapeutic treatments for the development of
stress-induced cardiovascular vulnerability. PMID:27423323
80. Respiratory signaling of locus coeruleus neurons during hypercapnic acidosis in the bullfrog,
Lithobates catesbeianus.
PubMed
Santin, J M; Hartzler, L K
2013-02-01
The locus coeruleus (LC) in the brainstem senses alterations in CO(2)/pH and influences ventilatory
adjustments that restore blood gas values to starting levels in bullfrogs (Lithobates catesbeianus). We
hypothesized that neurons of the bullfrog LC are sensitive to changes in CO(2)/pH and that
chemosensitive responses are intrinsic to individual neurons. In addition, we hypothesized putative
respiratory control neurons of the bullfrog LC would be stimulated by hypercapnic acidosis within
physiological ranges of P(CO(2))/pH. 84% of LC neurons depolarized and increased firing rates
during exposure to hypercapnic acidosis (HA). A pH dose response curve shows LC neurons from
bullfrogs increase firing rates during physiologically relevant CO(2)/pH changes. With chemical
synapses blocked, half of chemosensitive neurons lost sensitivity to HA; however, gap junction
blockade did not alter chemosensitive responses. Intrinsically chemosensitive neurons increased input
resistance during HA. These data demonstrate that majority of neurons within the bullfrog LC elicit
robust firing responses during physiological Î”CO(2)/pH, likely enabling adjustment of acid-base
balance through breathing. Copyright Â© 2012 Elsevier B.V. All rights reserved.
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81. Central noradrenergic mechanisms and the acute stress response during painful stimulation.
PubMed
Chapman, C Richard; Bradshaw, David H; Donaldson, Gary W; Jacobson, Robert C; Nakamura,

Yoshio
2014-12-01
Events that threaten tissue integrity including noxious stimulation activate central noradrenergic
circuits, particularly locus coeruleus and its projections. Recent advances in theory hold that an
adaptive, defensive shift in brain activity takes place in response to threat. In principle, this shift may
accentuate the autonomic and central biomarkers of the perception of painful events and the
experience of pain itself. We have examined the effects of an alpha-2 agonist on pupil dilation
responses, skin conductance responses, near field somatosensory evoked potentials and pain reports in
normal volunteers undergoing repeated trials of painful fingertip stimulation delivered at low, medium
and high intensities. In a double-blinded study, 114 healthy male and female volunteers underwent
repeated noxious stimulation under baseline, placebo and active drug conditions where the active drug
was the alpha-2 agonist tizanidine 4 mg. In contrast to baseline and placebo conditions, tizanidine 4
mg significantly reduced the magnitudes of the mean pupil dilation response, the mean skin
conductance response, the mean near field somatosensory evoked potential peak-to-peak amplitude
and the mean pain intensity rating. Stimulus intensity significantly altered all three biomarkers and the
pain report in a graded fashion. There were no sex differences. These findings support the hypotheses
that painful events activate central noradrenergic circuits, and that these circuits play a role in the
autonomic and central arousal associated with pain. Â© The Author(s) 2014.
82. On the Origin of Cortical Dopamine: Is it a Co-Transmitter in Noradrenergic Neurons?
PubMed Central
Devoto, Paola; Flore, Giovanna
2006-01-01
Dopamine (DA) and noradrenaline (NA) in the prefrontal cortex (PFC) modulate superior cognitive
functions, and are involved in the aetiology of depressive and psychotic symptoms. Moreover,
microdialysis studies in rats have shown how pharmacological treatments that induce modifications of
extracellular NA in the medial PFC (mPFC), also produce parallel changes in extracellular DA. To
explain the coupling of NA and DA changes, this article reviews the evidence supporting the
hypothesis that extracellular DA in the cerebral cortex originates not only from dopaminergic
terminals but also from noradrenergic ones, where it acts both as precursor for NA and as a co-
transmitter. Accordingly, extracellular DA concentration in the occipital, parietal and cerebellar cortex
was found to be much higher than expected in view of the scarce dopaminergic innervation in these
areas. Systemic administration or intra-cortical perfusion of Î±2-adrenoceptor agonists and antagonists,
consistent with their action on noradrenergic neuronal activity, produced concomitant changes not only
in extracellular NA but also in DA in the mPFC, occipital and parietal cortex. Chemical modulation of
the locus coeruleus by locally applied carbachol, kainate, NMDA or clonidine modified both NA and
DA in the mPFC. Electrical stimulation of the locus coeruleus led to an increased efflux of both NA
and DA in mPFC, parietal and occipital cortex, while in the striatum, NA efflux alone was enhanced.
Atypical antipsychotics, such as clozapine and olanzapine, or antidepressants, including mirtazapine
and mianserine, have been found to increase both NA and DA throughout the cerebral cortex, likely
through blockade of Î±2-adrenoceptors. On the other hand, drugs selectively acting on dopaminergic
transmission produced modest changes in extracellular DA in mPFC, and had no effect on the occipital
or parietal cortex. Acute administration of morphine did not increase DA levels in the PFC (where NA
is diminished), in
83. On the origin of cortical dopamine: is it a co-transmitter in noradrenergic neurons?
PubMed
Devoto, Paola; Flore, Giovanna
2006-04-01
Dopamine (DA) and noradrenaline (NA) in the prefrontal cortex (PFC) modulate superior cognitive
functions, and are involved in the aetiology of depressive and psychotic symptoms. Moreover,
microdialysis studies in rats have shown how pharmacological treatments that induce modifications of
extracellular NA in the medial PFC (mPFC), also produce parallel changes in extracellular DA.To
explain the coupling of NA and DA changes, this article reviews the evidence supporting the
hypothesis that extracellular DA in the cerebral cortex originates not only from dopaminergic
terminals but also from noradrenergic ones, where it acts both as precursor for NA and as a co-
transmitter.Accordingly, extracellular DA concentration in the occipital, parietal and cerebellar cortex
was found to be much higher than expected in view of the scarce dopaminergic innervation in these
areas.Systemic administration or intra-cortical perfusion of alpha(2)-adrenoceptor agonists and
antagonists, consistent with their action on noradrenergic neuronal activity, produced concomitant
changes not only in extracellular NA but also in DA in the mPFC, occipital and parietal
cortex.Chemical modulation of the locus coeruleus by locally applied carbachol, kainate, NMDA or
clonidine modified both NA and DA in the mPFC.Electrical stimulation of the locus coeruleus led to
an increased efflux of both NA and DA in mPFC, parietal and occipital cortex, while in the striatum,
NA efflux alone was enhanced.Atypical antipsychotics, such as clozapine and olanzapine, or
antidepressants, including mirtazapine and mianserine, have been found to increase both NA and DA
throughout the cerebral cortex, likely through blockade of alpha(2)-adrenoceptors. On the other hand,
drugs selectively acting on dopaminergic transmission produced modest changes in extracellular DA in
mPFC, and had no effect on the occipital or parietal cortex.Acute administration of morphine did not
increase DA levels in the PFC (where NA is diminished
84. The role of iron and copper molecules in the neuronal vulnerability of locus coeruleus and substantia
nigra during aging
PubMed Central
Zecca, Luigi; Stroppolo, Antonella; Gatti, Alberto; Tampellini, Davide; Toscani, Marco; Gallorini,
Mario; Giaveri, Giuseppe; Arosio, Paolo; Santambrogio, Paolo; Fariello, Ruggero G.; Karatekin,
Erdem; Kleinman, Mark H.; Turro, Nicholas; Hornykiewicz, Oleh; Zucca, Fabio A.
2004-01-01
In this study, a comparative analysis of metal-related neuronal vulnerability was performed in two
brainstem nuclei, the locus coeruleus (LC) and substantia nigra (SN), known targets of the etiological
noxae in Parkinson's disease and related disorders. LC and SN pars compacta neurons both degenerate
in Parkinson's disease and other Parkinsonisms; however, LC neurons are comparatively less affected
and with a variable degree of involvement. In this study, iron, copper, and their major molecular forms
like ferritins, ceruloplasmin, neuromelanin (NM), manganese-superoxide dismutase (SOD), and
copper/zinc-SOD were measured in LC and SN of normal subjects at different ages. Iron content in LC
was much lower than that in SN, and the ratio heavy-chain ferritin/iron in LC was higher than in the
SN. The NM concentration was similar in LC and SN, but the iron content in NM of LC was much
lower than SN. In both regions, heavy- and light-chain ferritins were present only in glia and were not
detectable in neurons. These data suggest that in LC neurons, the iron mobilization and toxicity is
lower than that in SN and is efficiently buffered by NM. The bigger damage occurring in SN could be
related to the higher content of iron. Ferritins accomplish the same function of buffering iron in glial
cells. Ceruloplasmin levels were similar in LC and SN, but copper was higher in LC. However, the
copper content in NM of LC was higher than that of SN, indicating a higher copper mobilization in LC
neurons. Manganese-SOD and copper/zinc-SOD had similar age trend in LC and SN. These results
may explain at least one of the reasons underlying lower vulnerability of LC compared to SN in
Parkinsonian syndromes. PMID:15210960
85. Noradrenergic dysregulation in the pathophysiology of PTSD.
PubMed
Hendrickson, Rebecca C; Raskind, Murray A
2016-10-01
A central role for noradrenergic dysregulation in the pathophysiology of post-traumatic stress disorder
(PTSD) is increasingly suggested by both clinical and basic neuroscience research. Here, we integrate
recent findings from clinical and animal research with the earlier literature. We first review the
evidence for net upregulation of the noradrenergic system and its responsivity to stress in individuals
with PTSD. Next, we trace the evidence that the Î± 1 noradrenergic receptor antagonist prazosin
decreases many of the symptoms of PTSD from initial clinical observations, to case series, to
randomized controlled trials. Finally, we review the basic science work that has begun to explain the
mechanism for this efficacy, as well as to explore its possible limitations and areas for further
advancement. We suggest a view of the noradrenergic system as a central, modifiable link in a network
of interconnected stress-response systems, which also includes the amygdala and its modulation by
medial prefrontal cortex. Particular attention is paid to the evidence for bidirectional signaling between
noradrenaline and corticotropin-releasing factor (CRF) in coordinating these interconnected systems.

The multiple different ways in which the sensitivity and reactivity of the noradrenergic system may be
altered in PTSD are highlighted, as is the evidence for possible heterogeneity in the pathophysiology
of PTSD between different individuals who appear clinically similar. We conclude by noting the
importance moving forward of improved measures of noradrenergic functioning in clinical
populations, which will allow better recognition of clinical heterogeneity and further assessment of the
functional implications of different aspects of noradrenergic dysregulation. Published by Elsevier Inc.
86. Cardiorespiratory effects of gap junction blockade in the locus coeruleus in unanesthetized adult rats.
PubMed
Patrone, Luis G A; BÃcego, KÃªnia Cardoso; Hartzler, Lynn K; Putnam, Robert W; Gargaglioni,
Luciane H
2014-01-01
The locus coeruleus (LC) plays an important role in central chemoreception. In young rats (P9 or
younger), 85% of LC neurons increase firing rate in response to hypercapnia vs. only about 45% of
neurons from rats P10 or older. Carbenoxolone (CARB - gap junction blocker) does not affect the % of
LC neurons responding in young rats but it decreases the % responding by half in older animals. We
evaluated the participation of gap junctions in the CO2 ventilatory response in unanesthetized adult
rats by bilaterally microinjecting CARB (300Î¼M, 1mM or 3mM/100nL), glycyrrhizic acid (GZA,
CARB analog, 3mM) or vehicle (aCSF - artificial cerebrospinal fluid) into the LC of Wistar rats.
Bilateral gap junction blockade in LC neurons did not affect resting ventilation; however, the increase
in ventilation produced by hypercapnia (7% CO2) was reduced by âˆ¼25% after CARB 1mM or 3mM
injection (1939.7Â±104.8mLkg(-1)min(-1) for the aCSF group and 1468.3Â±122.2mLkg(-1)min(-1)
for 1mM CARB, P<0.05; 1939.7Â±104.8mLkg(-1)min(-1) for the aCSF group and
1540.9Â±68.4mLkg(-1)min(-1) for the 3mM CARB group, P<0.05) due largely to a decrease in
respiratory frequency. GZA injection or CARB injection outside the LC (peri-LC) had no effect on
ventilation under any conditions. The results suggest that gap junctions in the LC modulate the
hypercapnic ventilatory response of adult rats. Copyright Â© 2013 Elsevier B.V. All rights reserved.
87. The locus coeruleus-norepinephrine network optimizes coupling of cerebral blood volume with
oxygen demand.
PubMed
Bekar, Lane K; Wei, Helen S; Nedergaard, Maiken
2012-12-01
Given the brain's uniquely high cell density and tissue oxygen levels bordering on hypoxia, the ability
to rapidly and precisely match blood flow to constantly changing patterns in neural activity is an
essential feature of cerebrovascular regulation. Locus coeruleus-norepinephrine (LC-NE) projections
innervate the cerebral vasculature and can mediate vasoconstriction. However, function of the LC-
mediated constriction in blood-flow regulation has never been addressed. Here, using intrinsic optical
imaging coupled with an anesthesia regimen that only minimally interferes with LC activity, we show
that NE enhances spatial and temporal aspects of functional hyperemia in the mouse somatosensory
cortex. Increasing NE levels in the cortex using an Î±(2)-adrenergic receptor antagonist paradoxically
reduces the extent of functional hyperemia while enhancing the surround blood-flow reduction.
However, the NE-mediated vasoconstriction optimizes spatial and temporal focusing of the hyperemic
response resulting in a sixfold decrease in the disparity between blood volume and oxygen demand. In
addition, NE-mediated vasoconstriction accelerated redistribution to subsequently active regions,
enhancing temporal synchronization of blood delivery. These observations show an important role for
NE in optimizing neurovascular coupling. As LC neuron loss is prominent in Alzheimer and Parkinson
diseases, the diminished ability to couple blood volume to oxygen demand may contribute to their
pathogenesis.
88. Local and Global Resting State Activity in the Noradrenergic and Dopaminergic Pathway Modulated
by Reboxetine and Amisulpride in Healthy Subjects
PubMed Central
Wiegers, Maike; Walter, Martin; Abler, Birgit; Graf, Heiko
2016-01-01
Background: Various psychiatric populations are currently investigated with resting state fMRI, with
the aim of individualizing diagnostics and treatment options and improving treatment outcomes. Many
of these studies are conducted in large naturalistic samples, providing rich insights regarding disease-
related neural alterations, but with the common psychopharmacological medication limiting
interpretations of the results. We therefore investigated the effects of common noradrenergic and anti-
dopaminergic medications on local and global resting state activity (rs-activity) in healthy volunteers
to further the understanding of the respective effects independent from disease-related alterations.
Methods: Within a randomized, double-blind, placebo-controlled crossover design, we investigated 19
healthy male subjects by resting state fMRI after the intake of reboxetine (4mg/d), amisulpride
(200mg/d), and placebo for 7 days each. Treatment-related differences in local and global rs-activity
were measured by the fractional amplitude of low frequency fluctuations (fALFF) and resting state
functional connectivity (rs-FC). Results: fALFF revealed alterations of local rs-activity within regions
of the core noradrenergic pathway, including the locus coeruleus under reboxetine, correlated with its
plasma levels. Moreover, reboxetine led to increased rs-FC between regions within this pathway, i.e.
the locus coeruleus, tectum, thalamus, and amygdala. Amisulpride modulated local rs-activity of
regions within the dopaminergic pathway, with the altered signal in the putamen correlating with
amisulpride plasma levels. Correspondingly, amisulpride increased rs-FC between regions of the
dopaminergic pathway comprising the substantia nigra and putamen. Conclusion: Our data provide
evidence of how psychopharmacological agents alter local and global rs-activity within the respective
neuroanatomical pathways in healthy subjects, which may help with interpreting data in psychiatric
89. Social stress engages opioid regulation of locus coeruleus norepinephrine neurons and induces a state
of cellular and physical opiate dependence.
PubMed
Chaijale, Nayla N; Curtis, Andre L; Wood, Susan K; Zhang, Xiao-Yan; Bhatnagar, Seema; Reyes,
Beverly As; Van Bockstaele, Elisabeth J; Valentino, Rita J
2013-09-01
Stress is implicated in diverse psychiatric disorders including substance abuse. The locus coeruleus-
norepinephrine (LC-NE) system is a major stress response system that is also a point of intersection
between stress neuromediators and endogenous opioids and so may be a site at which stress can
influence drug-taking behaviors. As social stress is a common stressor for humans, this study
characterized the enduring impact of repeated social stress on LC neuronal activity. Rats were exposed
to five daily consecutive sessions of social stress using the resident-intruder model or control
manipulation. LC discharge rate recorded 2 days after the last manipulation was decreased in stressed
rats compared with controls. By 10 days after the last manipulation, LC rates were comparable
between groups. Systemic administration of the opiate antagonist, naloxone, robustly increased LC
discharge rate in a manner suggestive of opiate withdrawal, selectively in stressed rats when
administered 2 or 10 days after the last manipulation. This was accompanied by behavioral signs of
mild opiate withdrawal. Western blot and electron microscopic studies indicated that repeated social
stress decreased corticotropin-releasing factor type 1 receptor and increased Î¼-opioid receptor levels
in the LC. Together, the results suggest that repeated social stress engages endogenous opioid
modulation of LC activity and induces signs of cellular and physical opiate dependence that endure
after the stress. These cellular effects may predispose individuals with a history of repeated social
stress to substance abuse behaviors.
90. Ionotropic but not metabotropic glutamatergic receptors in the locus coeruleus modulate the
hypercapnic ventilatory response in unanaesthetized rats.
PubMed
Taxini, C L; Puga, C C I; Dias, M B; BÃcego, K C; Gargaglioni, L H
2013-05-01
Central chemoreceptors are important to detect changes of CO2/H(+), and the Locus coeruleus (LC) is
one of the many putative central chemoreceptor sites. Here, we studied the contribution of LC
glutamatergic receptors on ventilatory, cardiovascular and thermal responses to hypercapnia. To this
end, we determined pulmonary ventilation (V(E)), body temperatures (T(b)), mean arterial pressure
(MAP) and heart rate (HR) of male Wistar rats before and after unilateral microinjection of kynurenic
acid (KY, an ionotropic glutamate receptor antagonist, 10 nmol/0.1 Î¼L) or Î±-methyl-4-
carboxyphenylglycine (MCPG, a metabotropic glutamate receptor antagonist, 10 nmol/0.1 Î¼L) into
the LC, followed by 60 min of air breathing or hypercapnia exposure (7% CO2). Ventilatory response
to hypercapnia was higher in animals treated with KY intra-LC (1918.7 Â± 275.4) compared with the
control group (1057.8 Â± 213.9, P < 0.01). However, the MCPG treatment within the LC had no effect
on the hypercapnia-induced hyperpnea. The cardiovascular and thermal controls were not affected by
hypercapnia or by the injection of KY and MCPG in the LC. These data suggest that glutamate acting
on ionotropic, but not metabotropic, receptors in the LC exerts an inhibitory modulation of
hypercapnia-induced hyperpnea. Acta Physiologica Â© 2013 Scandinavian Physiological Society.
91. Locus coeruleus and dopaminergic consolidation of everyday memory.
PubMed
Takeuchi, Tomonori; Duszkiewicz, Adrian J; Sonneborn, Alex; Spooner, Patrick A; Yamasaki,

Miwako; Watanabe, Masahiko; Smith, Caroline C; FernÃ¡ndez, GuillÃ©n; Deisseroth, Karl; Greene,
Robert W; Morris, Richard G M
2016-09-15
The retention of episodic-like memory is enhanced, in humans and animals, when something novel
happens shortly before or after encoding. Using an everyday memory task in mice, we sought the
neurons mediating this dopamine-dependent novelty effect, previously thought to originate exclusively
from the tyrosine-hydroxylase-expressing (TH + ) neurons in the ventral tegmental area. Here we
report that neuronal firing in the locus coeruleus is especially sensitive to environmental novelty, locus
coeruleus TH + neurons project more profusely than ventral tegmental area TH + neurons to the
hippocampus, optogenetic activation of locus coeruleus TH + neurons mimics the novelty effect, and
this novelty-associated memory enhancement is unaffected by ventral tegmental area inactivation.
Surprisingly, two effects of locus coeruleus TH + photoactivation are sensitive to hippocampal D 1 /D
5 receptor blockade and resistant to adrenoceptor blockade: memory enhancement and long-lasting
potentiation of synaptic transmission in CA1 ex vivo. Thus, locus coeruleus TH + neurons can mediate
post-encoding memory enhancement in a manner consistent with possible co-release of dopamine in
the hippocampus.
92. Adolescent Social Stress Produces an Enduring Activation of the Rat Locus Coeruleus and Alters its
Coherence with the Prefrontal Cortex
PubMed Central
Zitnik, Gerard A; Curtis, AndrÃ¨ L; Wood, Susan K; Arner, Jay; Valentino, Rita J
2016-01-01
Early life stress is associated with the development of psychiatric disorders. Because the locus
coeruleus-norepinephrine (LC-NE) system is a major stress-response system that is implicated in
psychopathology, developmental differences in the response of this system to stress may contribute to
increased vulnerability. Here LC single unit and network activity were compared between adult and
adolescent rats during resident-intruder stress. In some rats, LC and medial prefrontal cortex (mPFC)
coherence was quantified. The initial stress tonically activated LC neurons and induced theta
oscillations, while simultaneously decreasing LC auditory-evoked responses in both age groups. Stress
increased LC-mPFC coherence within the theta range. With repeated exposures, adolescent LC
neuronal and network activity remained elevated even in the absence of the stressor and were
unresponsive to stressor presentation. In contrast, LC neurons of adult rats exposed to repeated social
stress were relatively inhibited in the absence of the stressor and mounted robust responses upon
stressor presentation. LC sensory-evoked responses were selectively blunted in adolescent rats
exposed to repeated social stress. Finally, repeated stress decreased LC-mPFC coherence in the high
frequency range (beta and gamma) while maintaining strong coherence in the theta range, selectively
in adolescents. Together, these results suggest that adaptive mechanisms that promote stress recovery
and maintain basal activity of the brain norepinephrine system in the absence of stress are not fully
developed or are vulnerable stress-induced impairments in adolescence. The resulting sustained
activation of the LC-NE system after repeated social stress may adversely impact cognition and future
social behavior of adolescents. PMID:26361057
93. A locus coeruleus-norepinephrine account of individual differences in working memory capacity and
attention control.
PubMed
Unsworth, Nash; Robison, Matthew K
2017-08-01
Studies examining individual differences in working memory capacity (WMC) have suggested that
low WMC individuals have particular deficits in attention control processes compared to high WMC
individuals. In the current article we suggest that part of the WMC-attention control relation is due to
variation in the functioning of the locus coeruleus-norepinephrine system (LC-NE). Specifically, we
suggest that because of dysregulation of LC-NE functioning, the fronto-parietal control network for
low WMC individuals is only weakly activated, resulting in greater default-mode network activity
(and greater mind-wandering) for low WMC individuals compared to high WMC individuals. This
results in disrupted attention control and overall more erratic performance (more lapses of attention)
for low WMC individuals than for high WMC individuals. This framework is used to examine
previous studies of individual differences in WMC and attention control, and new evidence is
examined on the basis of predictions of the framework to pupillary responses as an indirect marker of
LC-NE functioning.
94. Temperature influences neuronal activity and CO2/pH sensitivity of locus coeruleus neurons in the
bullfrog, Lithobates catesbeianus.
PubMed
Santin, Joseph M; Watters, Kayla C; Putnam, Robert W; Hartzler, Lynn K
2013-12-15
The locus coeruleus (LC) is a chemoreceptive brain stem region in anuran amphibians and contains
neurons sensitive to physiological changes in CO2/pH. The ventilatory and central sensitivity to
CO2/pH is proportional to the temperature in amphibians, i.e., sensitivity increases with increasing
temperature. We hypothesized that LC neurons from bullfrogs, Lithobates catesbeianus, would
increase CO2/pH sensitivity with increasing temperature and decrease CO2/pH sensitivity with
decreasing temperature. Further, we hypothesized that cooling would decrease, while warming would
increase, normocapnic firing rates of LC neurons. To test these hypotheses, we used whole cell patch-
clamp electrophysiology to measure firing rate, membrane potential (V(m)), and input resistance
(R(in)) in LC neurons in brain stem slices from adult bullfrogs over a physiological range of
temperatures during normocapnia and hypercapnia. We found that cooling reduced chemosensitive
responses of LC neurons as temperature decreased until elimination of CO2/pH sensitivity at 10Â°C.

Chemosensitive responses increased at elevated temperatures. Surprisingly, chemosensitive LC
neurons increased normocapnic firing rate and underwent membrane depolarization when cooled and
decreased normocapnic firing rate and underwent membrane hyperpolarization when warmed. These
responses to temperature were not observed in nonchemosensitive LC neurons or neurons in a brain
stem slice 500 Î¼m rostral to the LC. Our results indicate that modulation of cellular chemosensitivity
within the LC during temperature changes may influence temperature-dependent respiratory drive
during acid-base disturbances in amphibians. Additionally, cold-activated/warm-inhibited LC neurons
introduce paradoxical temperature sensitivity in respiratory control neurons of amphibians.
95. Perifornical orexinergic neurons modulate REM sleep by influencing locus coeruleus neurons in rats.
PubMed
Choudhary, R C; Khanday, M A; Mitra, A; Mallick, B N
2014-10-24
Activation of the orexin (OX)-ergic neurons in the perifornical (PeF) area has been reported to induce
waking and reduce rapid eye movement sleep (REMS). The activities of OX-ergic neurons are
maximum during active waking and they progressively reduce during non-REMS (NREMS) and
REMS. Apparently, the locus coeruleus (LC) neurons also behave in a comparable manner as that of
the OX-ergic neurons particularly in relation to waking and REMS. Further, as PeF OX-ergic neurons
send dense projections to LC, we argued that the former could drive the LC neurons to modulate
waking and REMS. Studies in freely moving normally behaving animals where simultaneously neuro-
chemo-anatomo-physio-behavioral information could be deciphered would significantly strengthen our
understanding on the regulation of REMS. Therefore, in this study in freely behaving chronically
prepared rats we stimulated the PeF neurons without or with simultaneous blocking of specific
subtypes of OX-ergic receptors in the LC while electrophysiological recording characterizing sleep-
waking was continued. Single dose of glutamate stimulation as well as sustained mild electrical
stimulation of PeF (both bilateral) significantly increased waking and reduced REMS as compared to
baseline. Simultaneous application of OX-receptor1 (OX1R) antagonist bilaterally into the LC
prevented PeF stimulation-induced REMS suppression. Also, the effect of electrical stimulation of the
PeF was long lasting as compared to that of the glutamate stimulation. Further, sustained electrical
stimulation significantly decreased both REMS duration as well as REMS frequency, while glutamate
stimulation decreased REMS duration only. Copyright Â© 2014 IBRO. Published by Elsevier Ltd. All
rights reserved.
96. Essential role of the cAMP-cAMP response-element binding protein pathway in opiate-induced
homeostatic adaptations of locus coeruleus neurons.
PubMed
Cao, Jun-Li; Vialou, Vincent F; Lobo, Mary Kay; Robison, Alfred J; Neve, Rachael L; Cooper, Donald
C; Nestler, Eric J; Han, Ming-Hu
2010-09-28
Excessive inhibition of brain neurons in primary or slice cultures can induce homeostatic intrinsic
plasticity, but the functional role and underlying molecular mechanisms of such plasticity are poorly
understood. Here, we developed an ex vivo locus coeruleus (LC) slice culture system and successfully
recapitulated the opiate-induced homeostatic adaptation in electrical activity of LC neurons seen in
vivo. We investigated the mechanisms underlying this adaptation in LC slice cultures by use of viral-
mediated gene transfer and genetic mutant mice. We found that short-term morphine treatment of slice
cultures almost completely abolished the firing of LC neurons, whereas chronic morphine treatment
increased LC neuronal excitability as revealed during withdrawal. This increased excitability was
mediated by direct activation of opioid receptors and up-regulation of the cAMP pathway and
accompanied by increased cAMP response-element binding protein (CREB) activity. Overexpression
of a dominant negative CREB mutant blocked the increase in LC excitability induced by morphine- or
cAMP-pathway activation. Knockdown of CREB in slice cultures from floxed CREB mice similarly
decreased LC excitability. Furthermore, the ability of morphine or CREB overexpression to up-
regulate LC firing was blocked by knockout of the CREB target adenylyl cyclase 8. Together, these
findings provide direct evidence that prolonged exposure to morphine induces homeostatic plasticity
intrinsic to LC neurons, involving up-regulation of the cAMP-CREB signaling pathway, which then
enhances LC neuronal excitability.
97. Hyperpolarizing and age-dependent depolarizing responses of cultured locus coeruleus neurons to
noradrenaline.
PubMed
Finlayson, P G; Marshall, K C
1984-08-01
The electrical activity and responses to noradrenaline (NA) of locus coeruleus (LC) neurons have been
studied in organotypic cultures using intracellular recording. Most LC neurons were predominantly
quiescent, though occasional bursts of activity were observed; a few cells were tonically active at rates
of 0.5-5/s. In most cells tested, iontophoretic application of NA evoked responses which were initially
hyperpolarizing, sometimes followed by a depolarizing phase and frequently followed by a period of
increased excitatory synaptic activity. The enhanced synaptic activity appeared to be an indirect effect
since it was blocked by bath application of tetrodotoxin (TTX). In the presence of TTX, responses to
NA of all but one cell were simple hyperpolarizations or biphasic (hyperpolarization/depolarization)
responses. The presence of the depolarizing component appeared to be age-dependent, since it was
frequently observed in cultures grown in vitro for less than 26 days, while neurons in older cultures
exhibited only hyperpolarizing responses. If such age-dependent depolarizing responses are present in
vivo, they would represent a unique example of a transmitter response which is present only during a
transient developmental phase.
98. Noradrenergic modulation of neural erotic stimulus perception.
PubMed
Graf, Heiko; Wiegers, Maike; Metzger, Coraline Danielle; Walter, Martin; GrÃ¶n, Georg; Abler, Birgit
2017-09-01
We recently investigated neuromodulatory effects of the noradrenergic agent reboxetine and the
dopamine receptor affine amisulpride in healthy subjects on dynamic erotic stimulus processing.
Whereas amisulpride left sexual functions and neural activations unimpaired, we observed detrimental
activations under reboxetine within the caudate nucleus corresponding to motivational components of
sexual behavior. However, broadly impaired subjective sexual functioning under reboxetine suggested
effects on further neural components. We now investigated the same sample under these two agents
with static erotic picture stimulation as alternative stimulus presentation mode to potentially observe
further neural treatment effects of reboxetine. 19 healthy males were investigated under reboxetine,
amisulpride and placebo for 7 days each within a double-blind cross-over design. During fMRI static
erotic picture were presented with preceding anticipation periods. Subjective sexual functions were
assessed by a self-reported questionnaire. Neural activations were attenuated within the caudate
nucleus, putamen, ventral striatum, the pregenual and anterior midcingulate cortex and in the
orbitofrontal cortex under reboxetine. Subjective diminished sexual arousal under reboxetine was
correlated with attenuated neural reactivity within the posterior insula. Again, amisulpride left neural
activations along with subjective sexual functioning unimpaired. Neither reboxetine nor amisulpride
altered differential neural activations during anticipation of erotic stimuli. Our results verified
detrimental effects of noradrenergic agents on neural motivational but also emotional and autonomic
components of sexual behavior. Considering the overlap of neural network alterations with those
evoked by serotonergic agents, our results suggest similar neuromodulatory effects of serotonergic and
noradrenergic agents on common neural pathways relevant for sexual behavior. Copyright Â© 2017
Elsevier B.V. and
99. The role of orexin type-1 receptors in the development of morphine tolerance in locus coeruleus
neurons: An electrophysiological perspective.
PubMed
Abdollahi, Hakime; Ghaemi-Jandabi, Masoumeh; Azizi, Hossein; Semnanian, Saeed
2016-09-01
Long-term exposure to opioid agonists results in tolerance to their analgesic effects, so the
effectiveness of opioid agonists in the management of pain becomes limited. The locus coeruleus (LC)
nucleus has been involved in the development of tolerance to opiates. Orexin type-1 receptors
(OX1Rs) are highly expressed in LC nucleus. Orexin plays a noteworthy role in the occurrence of
morphine tolerance. The purpose of the present study is to investigate the role of orexin type-1
receptors in the development of morphine tolerance in LC neurons. In this study, adult male Wistar rats
weighing 250-300g were utilized. Induction of morphine tolerance was obtained by single injection of
morphine per day for 6 successive days. An orexin type-1 receptor antagonist (SB-334867) was
injected into the lateral ventricle instantly prior to morphine injection. On day 7, the effect of morphine
on the electrical activity of LC neurons was studied using in vivo extracellular single unit recording.
The results demonstrate that morphine injection for 6 consecutive days led to the development of
morphine-induced tolerance in LC neurons. In other words, there was a significant decrease in LC
neuronal responsiveness to morphine injection. Inhibitory responses of LC neurons to intraperitoneally
applied morphine can be observed with the treatment of the SB-334867 prior to morphine injection.
This study showed that OX1R blockade by SB-334867 prevents the development of morphine
tolerance in LC neurons. We hope that further studies will lead to considerable progress in
understanding the molecular adaptations that contribute to morphine tolerance. Copyright Â© 2016
Elsevier B.V. All rights reserved.
100. Noradrenergic Stimulation Impairs Memory Generalization in Women.
PubMed
Kluen, Lisa Marieke; Agorastos, Agorastos; Wiedemann, Klaus; Schwabe, Lars
2017-07-01
Memory generalization is essential for adaptive decision-making and action. Our ability to generalize
across past experiences relies on medial-temporal lobe structures, known to be highly sensitive to
stress. Recent evidence suggests that stressful events may indeed interfere with memory
generalization. Yet, the mechanisms involved in this generalization impairment are unknown. We
tested here whether a pharmacological elevation of major stress mediators-noradrenaline and
glucocorticoids-is sufficient to disrupt memory generalization. In a double-blind, placebo-controlled
design, healthy men and women received orally a placebo, hydrocortisone, the Î±2-adrenoceptor
antagonist yohimbine that leads to increased noradrenergic stimulation, or both drugs, before they
completed an associative learning task probing memory generalization. Drugs left learning
performance intact. Yohimbine, however, led to a striking generalization impairment in women, but
not in men. Hydrocortisone, in turn, had no effect on memory generalization, neither in men nor in
women. The present findings indicate that increased noradrenergic activity, but not cortisol, is
sufficient to disrupt memory generalization in a sex-specific manner, with relevant implications for
stress-related mental disorders characterized by generalization deficits.
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101. Ethanol Reversal of Cellular Tolerance to Morphine in Rat Locus Coeruleus Neurons
PubMed Central
Llorente, Javier; Withey, Sarah; Rivero, Guadalupe; Cunningham, Margaret; Cooke, Alex; Saxena,
Kunal; McPherson, Jamie; Oldfield, Sue; Dewey, William L.; Bailey, Chris P.; Kelly, Eamonn;
Henderson, Graeme
2013-01-01
Consumption of ethanol is a considerable risk factor for death in heroin overdose. We sought to
determine whether a mildly intoxicating concentration of ethanol could alter morphine tolerance at the
cellular level. In rat locus coeruleus (LC) neurons, tolerance to morphine was reversed by acute
exposure of the brain slice to ethanol (20 mM). Tolerance to the opioid peptide [d-Ala2,N-
MePhe4,Gly-ol]-enkephalin was not reversed by ethanol. Previous studies in LC neurons have
revealed a role for protein kinase C (PKC)Î± in Î¼-opioid receptor (MOPr) desensitization by
morphine and in the induction and maintenance of morphine tolerance, but we have been unable to
demonstrate that 20 mM ethanol produces significant inhibition of PKCÎ±. The ability of ethanol to
reverse cellular tolerance to morphine in LC neurons was absent in the presence of the phosphatase
inhibitor okadaic acid, indicating that dephosphorylation is involved. In human embryonic kidney 293
cells expressing the MOPr, ethanol reduced the level of MOPr phosphorylation induced by morphine.
Ethanol reversal of tolerance did not appear to result from a direct effect on MOPr since acute
exposure to ethanol (20 mM) did not modify the affinity of binding of morphine to the MOPr or the
efficacy of morphine for G-protein activation as measured by guanosine 5â€²-O-(3-
[35S]thio)triphosphate binding. Similarly, ethanol did not affect MOPr trafficking. We conclude that
acute exposure to ethanol enhances the effects of morphine by reversing the processes underlying
morphine cellular tolerance. PMID:23716621
102. Orexin receptor-1 in the locus coeruleus plays an important role in cue-dependent fear memory
consolidation.
PubMed
Soya, Shingo; Shoji, Hirotaka; Hasegawa, Emi; Hondo, Mari; Miyakawa, Tsuyoshi; Yanagisawa,
Masashi; Mieda, Michihiro; Sakurai, Takeshi
2013-09-04
The noradrenergic (NA) projections arising from the locus ceruleus (LC) to the amygdala and bed
nucleus of the stria terminalis have been implicated in the formation of emotional memory. Since NA
neurons in the LC (LC-NA neurons) abundantly express orexin receptor-1 (OX1R) and receive
prominent innervation by orexin-producing neurons, we hypothesized that an OX1R-mediated
pathway is involved in the physiological fear learning process via regulation of LC-NA neurons. To
evaluate this hypothesis, we examined the phenotype of Ox1r(-/-) mice in the classic cued and
contextual fear-conditioning test. We found that Ox1r(-/-) mice showed impaired freezing responses in
both cued and contextual fear-conditioning paradigms. In contrast, Ox2r(-/-) mice showed normal
freezing behavior in the cued fear-conditioning test, while they exhibited shorter freezing time in the
contextual fear-conditioning test. Double immunolabeling of Fos and tyrosine hydroxylase showed
that double-positive LC-NA neurons after test sessions of both cued and contextual stimuli were
significantly fewer in Ox1r(-/-) mice. AAV-mediated expression of OX1R in LC-NA neurons in
Ox1r(-/-) mice restored the freezing behavior to the auditory cue to a comparable level to that in wild-
type mice in the test session. Decreased freezing time during the contextual fear test was not affected
by restoring OX1R expression in LC-NA neurons. These observations support the hypothesis that the
orexin system modulates the formation and expression of fear memory via OX1R in multiple
pathways. Especially, OX1R in LC-NA neurons plays an important role in cue-dependent fear memory
formation and/or retrieval.
103. Xiao Yao San Improves Depressive-Like Behaviors in Rats with Chronic Immobilization Stress
through Modulation of Locus Coeruleus-Norepinephrine System.
PubMed
Ding, Xiu-Fang; Zhao, Xiao-Hua; Tao, Yang; Zhong, Wei-Chao; Fan, Qin; Diao, Jian-Xin; Liu, Yuan-
Liang; Chen, Yu-Yao; Chen, Jia-Xu; Lv, Zhi-Ping
2014-01-01
Most research focuses on the hypothalamic-pituitary-adrenal (HPA) axis, hypothalamus-pituitary-

thyroid (HPT) axis, and hypothalamus-pituitary-gonadal (HPGA) axis systems of abnormalities of
emotions and behaviors induced by stress, while no studies of Chinese herbal medicine such as Xiao
Yao San (XYS) on the mechanisms of locus coeruleus-norepinephrine (LC-NE) system have been
reported. Therefore, experiments were carried out to observe mechanism of LC-NE system in response
to chronic immobilization stress (CIS) and explore the antidepressant effect of XYS. Rat model was
established by CIS. LC morphology in rat was conducted. The serum norepinephrine (NE)
concentrations and NE biosynthesis such as tyrosine hydroxylase (TH), dopamine-Î²-hydroxylase
(DBH), and corticotrophin-releasing-factor (CRF) in LC were determined. Results showed that there
were no discernible alterations in LC in rats. The serum NE concentrations, positive neurons, mean
optical density (MOD), and protein levels of TH, DBH, and CRF in model group were significantly
increased compared to the control group. But XYS-treated group displayed a significantly decreased in
NE levels and expressions of TH, DBH, and CRF compared to the model group. In conclusion, CIS
can activate LC-NE system to release NE and then result in a significant decrease in rats. XYS
treatment can effectively improve depressive-like behaviors in rats through inhibition of LC-NE
neurons activity.
104. Xiao Yao San Improves Depressive-Like Behaviors in Rats with Chronic Immobilization Stress
through Modulation of Locus Coeruleus-Norepinephrine System
PubMed Central
Ding, Xiu-Fang; Zhao, Xiao-Hua; Tao, Yang; Zhong, Wei-Chao; Fan, Qin; Diao, Jian-Xin; Liu, Yuan-
Liang; Chen, Yu-Yao; Chen, Jia-Xu; Lv, Zhi-Ping
2014-01-01
Most research focuses on the hypothalamic-pituitary-adrenal (HPA) axis, hypothalamus-pituitary-

thyroid (HPT) axis, and hypothalamus-pituitary-gonadal (HPGA) axis systems of abnormalities of
emotions and behaviors induced by stress, while no studies of Chinese herbal medicine such as Xiao
Yao San (XYS) on the mechanisms of locus coeruleus-norepinephrine (LC-NE) system have been
reported. Therefore, experiments were carried out to observe mechanism of LC-NE system in response
to chronic immobilization stress (CIS) and explore the antidepressant effect of XYS. Rat model was
established by CIS. LC morphology in rat was conducted. The serum norepinephrine (NE)
concentrations and NE biosynthesis such as tyrosine hydroxylase (TH), dopamine-Î²-hydroxylase
(DBH), and corticotrophin-releasing-factor (CRF) in LC were determined. Results showed that there
were no discernible alterations in LC in rats. The serum NE concentrations, positive neurons, mean
optical density (MOD), and protein levels of TH, DBH, and CRF in model group were significantly
increased compared to the control group. But XYS-treated group displayed a significantly decreased in
NE levels and expressions of TH, DBH, and CRF compared to the model group. In conclusion, CIS
can activate LC-NE system to release NE and then result in a significant decrease in rats. XYS
treatment can effectively improve depressive-like behaviors in rats through inhibition of LC-NE
neurons activity. PMID:25610478
105. Presynaptic Inhibition of Diverse Afferents to the Locus Coeruleus by Kappa Opiate Receptors: a
Novel Mechanism for Regulating the Central Norepinephrine System
PubMed Central
Kreibich, Arati S.; Reyes, Beverly A. S.; Curtis, Andre L.; Ecke, Laurel; Chavkin, Charles; Van
Bockstaele, Elisabeth J.; Valentino, Rita J.
2008-01-01
The norepinephrine nucleus, locus coeruleus (LC), is activated by diverse stimuli and modulates
arousal and behavioral strategies in response to these stimuli through its divergent efferent system.
Afferents communicating information to the LC include excitatory amino acids (EAA), corticotropin-
releasing factor (CRF) and endogenous opioids acting at Î¼-opiate receptors. As the LC is also
innervated by the endogenous Îº-opiate receptor (Îº-OR) ligand, dynorphin, and expresses Îº-ORs, this
study investigated Îº-OR regulation of LC neuronal activity in rat. Immunoelectron microscopy
revealed a prominent localization of Îº-ORs in axon terminals in the LC that also contained either the
vesicular glutamate transporter or CRF. Microinfusion of the Îº-OR agonist, U50488, into the LC did
not alter LC spontaneous discharge but attenuated phasic discharge evoked by stimuli that engage
EAA afferents to the LC, including sciatic nerve stimulation and auditory stimuli and the tonic
activation associated with opiate withdrawal. Inhibitory effects of the Îº-OR agonist were not restricted
to EAA afferents, as U50488 also attenuated tonic LC activation by hypotensive stress, an effect
mediated by CRF afferents. Together, these results indicate that Îº-ORs are poised to presynaptically
inhibit diverse afferent signaling to the LC. This is a novel and potentially powerful means of
regulating the LC-NE system that can impact on forebrain processing of stimuli and the organization
of behavioral strategies in response to environmental stimuli. The results implicate Îº-ORs as a novel
target for alleviating symptoms of opiate withdrawal, stress-related disorders or disorders characterized
by abnormal sensory responses, such as autism. PMID:18562623
106. Ablation of the Locus Coeruleus Increases Oxidative Stress in Tg-2576 Transgenic but Not Wild-Type
Mice
PubMed Central
Hurko, Orest; Boudonck, Kurt; Gonzales, Cathleen; Hughes, Zoe A.; Jacobsen, J. Steve; Reinhart,
Peter H.; Crowther, Daniel
2010-01-01
Mice transgenic for production of excessive or mutant forms of beta-amyloid differ from patients with
Alzheimer's disease in the degree of inflammation, oxidative damage, and alteration of intermediary
metabolism, as well as the paucity or absence of neuronal atrophy and cognitive impairment. Previous
observers have suggested that differences in inflammatory response reflect a discrepancy in the state of
the locus coeruleus (LC), loss of which is an early change in Alzheimer's disease but which is
preserved in the transgenic mice. In this paper, we extend these observations by examining the effects
of the LC on markers of oxidative stress and intermediary metabolism. We compare four groups: wild-
type or Tg2576 AÎ² transgenic mice injected with DSP4 or vehicle. Of greatest interest were
metabolites different between ablated and intact transgenics, but not between ablated and intact wild-
type animals. The Tg2576_DSP4 mice were distinguished from the other three groups by oxidative
stress and altered energy metabolism. These observations provide further support for the hypothesis
that Tg2576 AÎ² transgenic mice with this ablation may be a more congruent model of Alzheimer's
disease than are transgenics with an intact LC. PMID:20981353
107. [The relationships among raphe magnus nucleus, locus coeruleus and dorsal motor nucleus of vagus in
the descending regulation of gastric motility].
PubMed
Qiao, Hui; An, Shu-Cheng; Xu, Chang

2011-02-01
To explore the interrelationship among dorsal motor nucleus of the vagus (DMV), locus coeruleus
(LC) and raphe magnus nucleus (NRM) in the mechanism of the descending regulation on gastric
motility, which may constitute a parasympathetic local circuit, work as a neural center of gastric
modulation in brainstem. Using nucleus location, electric stimulation and lesion, together with
microinjection, and recording the inter-gastric pressure. (1) LC stimulation could inhibit the gastric
motility significantly (P < 0.01), DMV lesion weaken this effect, while blocking the a receptor on
DMV could reverse the effect. (2) NRM stimulation reduced the amplitude of gastric constriction (P <
0.01), DMV lesion could abolish the effect, but blocking the 5-HT2A receptor on DMV depressed the
gastric motility heavily (P < 0.01) like NRM stimulation. While LC lesion could abolish the effect of
NRM stimulation, and microinjection of ritanserin into LC could likewise abolish it. (1) LC inhibit the
gastric motility via a receptor in DMV, and meanwhile may excite it through 5-HT2A receptor in
DMV, these two ways work together to keeping the gastric motility amplitude normally. (2) NRM
inhibit the gastric motility via 5-HT2A receptor in LC.
108. Noradrenergic induction of odor-specific neural habituation and olfactory memories
PubMed Central
Shea, Stephen D.; Katz, Lawrence C.; Mooney, Richard
2008-01-01
For many mammals, individual recognition of conspecifics relies on olfactory cues. Certain individual
recognition memories are thought to be stored when conspecific odor cues coincide with surges of
noradrenaline (NA) triggered by intensely arousing social events. Such familiar stimuli elicit reduced
behavioral responses, a change likely related to NA-dependent plasticity in the olfactory bulb (OB). In
addition to its role in these ethological memories, NA signaling in the OB appears to be relevant for
the discrimination of more arbitrary odorants as well. Nonetheless, no NA-gated mechanism of long-
term plasticity in the OB has ever been directly observed in vivo. Here we report that NA release from
locus coeruleus (LC), when coupled to odor presentation, acts locally in the main olfactory bulb
(MOB) to cause a specific long-lasting suppression of respones to paired odors. These effects were
observed for both food odors and urine, an important social recognition cue. Moreover, in subsequent
behavioral tests, mice exhibited habituation to paired urine stimuli, suggesting that this LC-mediated
olfactory neural plasticity, induced under anesthesia, can store an individual recognition memory that
is observable upon recovery. PMID:18923046
109. Frontotemporal dementia: evidence for impairment of ascending serotoninergic but not noradrenergic
innervation. Immunocytochemical and quantitative study using a graph method.
PubMed
Yang, Y; Schmitt, H P
2001-03-01
A graph method was employed to analyze the spatial neuronal patterns of nuclear grays of the pontine
tegmentum with ascending aminergic projections to the forebrain in 12 cases of frontotemporal
dementia (FTD). The nuclear grays examined were the nucleus centralis superior (NCS), a part of the
nucleus raphae dorsalis (NRD), and the locus coeruleus (LC). The results were compared with 30
cases of Alzheimer's disease (AD) and 35 non-demented controls. In addition to the graph evaluations,
neuronal cytoplasmic inclusion bodies were stained by silver impregnation and ubiquitin (Ub) and tau
immunohistochemistry. The FTD cases showed a significant, 40%, decline in number of neurons in the
NCS and NRD, while the LC was spared. The magnitude of neuronal loss matched that of AD where,
by contrast, the LC was also severely changed. Amyloid deposition and Alzheimer neurofibrillary
tangles occurred in the aminergic nuclei almost exclusively in AD and, to a minor extent, in some aged
controls. No cytoplasmic inclusion bodies were found in the aminergic nuclei of the FTD cases.
However, 6 cases had Ub-positive but tau-negative neuronal inclusions in the hippocampal dentate
fascia and in layer 2 of the prefrontal isocortex, and 3 showed clinical and histological signs of motor
neuron disease. Our results suggest that the serotoninergic raphe nuclei with ascending projections to
the forebrain, but not the LC, become directly or indirectly involved in frontotemporal dementia both
with and without motor neuron disease.
110. Quantifying the accretion of hyperphosphorylated tau in the locus coeruleus and dorsal raphe nucleus:
the pathological building blocks of early Alzheimer's disease.
PubMed
Ehrenberg, A J; Nguy, A K; Theofilas, P; Dunlop, S; Suemoto, C K; Di Lorenzo Alho, A T; Leite, R P;

Diehl Rodriguez, R; Mejia, M B; RÃ¼b, U; Farfel, J M; de Lucena Ferretti-Rebustini, R E;
Nascimento, C F; Nitrini, R; Pasquallucci, C A; Jacob-Filho, W; Miller, B; Seeley, W W; Heinsen, H;
Grinberg, L T
2017-08-01
Hyperphosphorylated tau neuronal cytoplasmic inclusions (ht-NCI) are the best protein correlate of
clinical decline in Alzheimer's disease (AD). Qualitative evidence identifies ht-NCI accumulating in
the isodendritic core before the entorhinal cortex. Here, we used unbiased stereology to quantify ht-
NCI burden in the locus coeruleus (LC) and dorsal raphe nucleus (DRN), aiming to characterize the
impact of AD pathology in these nuclei with a focus on early stages. We utilized unbiased stereology
in a sample of 48 well-characterized subjects enriched for controls and early AD stages. ht-NCI counts
were estimated in 60-Î¼m-thick sections immunostained for p-tau throughout LC and DRN. Data were
integrated with unbiased estimates of LC and DRN neuronal population for a subset of cases. In Braak
stage 0, 7.9% and 2.6% of neurons in LC and DRN, respectively, harbour ht-NCIs. Although the
number of ht-NCI+ neurons significantly increased by about 1.9Ã— between Braak stages 0 to I in LC
(P = 0.02), we failed to detect any significant difference between Braak stage I and II. Also, the
number of ht-NCI+ neurons remained stable in DRN between all stages 0 and II. Finally, the
differential susceptibility to tau inclusions among nuclear subdivisions was more notable in LC than in
DRN. LC and DRN neurons exhibited ht-NCI during AD precortical stages. The ht-NCI increases
along AD progression on both nuclei, but quantitative changes in LC precede DRN changes. Â© 2017
British Neuropathological Society.
111. Role of the locus coeruleus in the emergence of power law wake bouts in a model of the brainstem
sleep-wake system through early infancy.
PubMed
Patel, Mainak; Rangan, Aaditya
2017-08-07
Infant rats randomly cycle between the sleeping and waking states, which are tightly correlated with
the activity of mutually inhibitory brainstem sleep and wake populations. Bouts of sleep and
wakefulness are random; from P2-P10, sleep and wake bout lengths are exponentially distributed with
increasing means, while during P10-P21, the sleep bout distribution remains exponential while the
distribution of wake bouts gradually transforms to power law. The locus coeruleus (LC), via an
undeciphered interaction with sleep and wake populations, has been shown experimentally to be
responsible for the exponential to power law transition. Concurrently during P10-P21, the LC
undergoes striking physiological changes - the LC exhibits strong global 0.3Â Hz oscillations up to
P10, but the oscillation frequency gradually rises and synchrony diminishes from P10-P21, with
oscillations and synchrony vanishing at P21 and beyond. In this work, we construct a biologically
plausible Wilson Cowan-style model consisting of the LC along with sleep and wake populations. We
show that external noise and strong reciprocal inhibition can lead to switching between sleep and wake
populations and exponentially distributed sleep and wake bout durations as during P2-P10, with the
parameters of inhibition between the sleep and wake populations controlling mean bout lengths.
Furthermore, we show that the changing physiology of the LC from P10-P21, coupled with reciprocal
excitation between the LC and wake population, can explain the shift from exponential to power law
of the wake bout distribution. To our knowledge, this is the first study that proposes a plausible
biological mechanism, which incorporates the known changing physiology of the LC, for tying the
developing sleep-wake circuit and its interaction with the LC to the transformation of sleep and wake
bout dynamics from P2-P21. Copyright Â© 2017 Elsevier Ltd. All rights reserved.
112. Noradrenergic modulation of vicarious trial-and-error behavior during a spatial decision-making task
in rats.
PubMed
Amemiya, S; Noji, T; Kubota, N; Nishijima, T; Kita, I
2014-04-18
Deliberation between possible options before making a decision is crucial to responding with an
optimal choice. However, the neural mechanisms regulating this deliberative decision-making process
are still unclear. Recent studies have proposed that the locus coeruleus-noradrenaline (LC-NA) system
plays a role in attention, behavioral flexibility, and exploration, which contribute to the search for an
optimal choice under uncertain situations. In the present study, we examined whether the LC-NA
system relates to the deliberative process in a T-maze spatial decision-making task in rats. To quantify
deliberation in rats, we recorded vicarious trial-and-error behavior (VTE), which is considered to
reflect a deliberative process exploring optimal choices. In experiment 1, we manipulated the difficulty
of choice by varying the amount of reward pellets between the two maze arms (0 vs. 4, 1 vs. 3, 2 vs.
2). A difficulty-dependent increase in VTE was accompanied by a reduction of choice bias toward the
high reward arm and an increase in time required to select one of the two arms in the more difficult
manipulation. In addition, the increase of c-Fos-positive NA neurons in the LC depended on the task
difficulty and the amount of c-Fos expression in LC-NA neurons positively correlated with the
occurrence of VTE. In experiment 2, we inhibited LC-NA activity by injection of clonidine, an agonist
of the alpha2 autoreceptor, during a decision-making task (1 vs. 3). The clonidine injection suppressed
occurrence of VTE in the early phase of the task and subsequently impaired a valuable choice later in
the task. These results suggest that the LC-NA system regulates the deliberative process during
decision-making. Copyright Â© 2014 IBRO. Published by Elsevier Ltd. All rights reserved.
113. Deepened extinction following compound stimulus presentation: Noradrenergic modulation
PubMed Central
Janak, Patricia H.; Corbit, Laura H.
2011-01-01
Behavioral extinction is an active form of new learning involving the prediction of nonreward where
reward has previously been present. The expression of extinction learning can be disrupted by the
presentation of reward itself or reward-predictive stimuli (reinstatement) as well as the passage of time
(spontaneous recovery) or contextual changes (renewal). The following experiments replicated the
demonstration that presenting multiple previously rewarded stimuli in compound during extinction
enhances extinction learning. To explore the pharmacological basis for this we next examined the
effects of pharmacological treatments that either facilitated or blocked noradrenergic activity to test the
hypothesis that increased noradrenergic activity at the time of extinction training would improve,
whereas blockade of noradrenergic activity would impair the extinction of appetitive
stimulusâ€“reward memories. Different groups of rats were trained in a discriminative stimulus
paradigm to lever-press for food reward. Once stable responding was achieved, responding was
extinguished for 2 d. Prior to a third extinction session, rats received systemic administration of either
saline, yohimbine (Î±2 antagonist), atomoxetine (norepinephrine reuptake inhibitor), or propranolol
(Î²-receptor antagonist). Spontaneous recovery of responding to the stimuli was tested 4 wk later. Our
results indicate that increasing noradrenergic activity during extinction augments extinction learning
resulting in less recovery of responding at test. These results have important implications for models of
relapse to drug seeking and the development of extinction-based therapies. PMID:21224211
114. Nicotinic and muscarinic cholinergic receptors are recruited by acetylcholine-mediated

neurotransmission within the locus coeruleus during the organisation of post-ictal antinociception.
PubMed
de Oliveira, Rithiele Cristina; de Oliveira, Ricardo; Biagioni, Audrey Franceschi; Falconi-Sobrinho,

Luiz Luciano; Dos Anjos-Garcia, Tayllon; Coimbra, Norberto Cysne
2016-10-01
Post-ictal antinociception is characterised by an increase in the nociceptive threshold that accompanies

tonic and tonic-clonic seizures (TCS). The locus coeruleus (LC) receives profuse cholinergic inputs
from the pedunculopontine tegmental nucleus. Different concentrations (1Î¼g, 3Î¼g and
5Î¼g/0.2Î¼L) of the muscarinic cholinergic receptor antagonist atropine and the nicotinic cholinergic
receptor antagonist mecamylamine were microinjected into the LC of Wistar rats to investigate the role
of cholinergic mechanisms in the severity of TCS and the post-ictal antinociceptive response. Five
minutes later, TCS were induced by systemic administration of pentylenetetrazole (PTZ) (64mg/kg).
Seizures were recorded inside the open field apparatus for an average of 10min. Immediately after
seizures, the nociceptive threshold was recorded for 130min using the tail-flick test. Pre-treatment of
the LC with 1Î¼g, 3Î¼g and 5Î¼g/0.2Î¼L concentrations of both atropine and mecamylamine did not
cause a significant effect on seizure severity. However, the same treatments decreased the post-ictal
antinociceptive phenomenon. In addition, mecamylamine caused an earlier decrease in the post-ictal
antinociception compared to atropine. These results suggest that muscarinic and mainly nicotinic
cholinergic receptors of the LC are recruited to organise tonic-clonic seizure-induced antinociception.
Copyright Â© 2016 Elsevier Inc. All rights reserved.
115. Vascular Mural Cells Promote Noradrenergic Differentiation of Embryonic Sympathetic Neurons.
PubMed
Fortuna, Vitor; Pardanaud, Luc; Brunet, Isabelle; Ola, Roxana; Ristori, Emma; Santoro, Massimo M;
Nicoli, Stefania; Eichmann, Anne
2015-06-23
The sympathetic nervous system controls smooth muscle tone and heart rate in the cardiovascular
system. Postganglionic sympathetic neurons (SNs) develop in close proximity to the dorsal aorta (DA)
and innervate visceral smooth muscle targets. Here, we use the zebrafish embryo to ask whether the
DA is required for SN development. We show that noradrenergic (NA) differentiation of SN
precursors temporally coincides with vascular mural cell (VMC) recruitment to the DA and vascular
maturation. Blocking vascular maturation inhibits VMC recruitment and blocks NA differentiation of
SN precursors. Inhibition of platelet-derived growth factor receptor (PDGFR) signaling prevents VMC
differentiation and also blocks NA differentiation of SN precursors. NA differentiation is normal in
cloche mutants that are devoid of endothelial cells but have VMCs. Thus, PDGFR-mediated mural cell
recruitment mediates neurovascular interactions between the aorta and sympathetic precursors and
promotes their noradrenergic differentiation. Copyright Â© 2015 The Authors. Published by Elsevier
Inc. All rights reserved.
116. The Locus Coeruleus: Essential for Maintaining Cognitive Function and the Aging Brain
PubMed Central
Mather, Mara; Harley, Carolyn W.
2016-01-01
Research on cognitive aging has focused on how decline in various cortical and hippocampal regions
influence cognition. However, brainstem regions play essential modulatory roles, and new evidence
suggests that among these, the integrity of the locus coeruleus-norepinephrine system plays a key role
in determining late life cognitive abilities. The locus coeruleus is especially vulnerable to toxins and
infection and is often the first place Alzheimerâ€™s related pathology appears, with most people
showing at least some tau pathology by their mid-twenties. On the other hand, norepinephrine released
from the locus coeruleus during arousing, mentally challenging or novel situations helps protect
neurons from damage, which may help explain how education and engaging careers prevent cognitive
decline in later years. PMID:26895736
117. Locus Coeruleus Activity Strengthens Prioritized Memories Under Arousal.
PubMed
Clewett, David V; Huang, Ringo; Velasco, Rico; Lee, Tae-Ho; Mather, Mara
2018-02-07
Recent models posit that bursts of locus ceruleus (LC) activity amplify neural gain such that limited
attention and encoding resources focus even more on prioritized mental representations under arousal.
Here, we tested this hypothesis in human males and females using fMRI, neuromelanin MRI, and
pupil dilation, a biomarker of arousal and LC activity. During scanning, participants performed a
monetary incentive encoding task in which threat of punishment motivated them to prioritize encoding
of scene images over superimposed objects. Threat of punishment elicited arousal and selectively
enhanced memory for goal-relevant scenes. Furthermore, trial-level pupil dilations predicted better
scene memory under threat, but were not related to object memory outcomes. fMRI analyses revealed
that greater threat-evoked pupil dilations were positively associated with greater scene encoding
activity in LC and parahippocampal cortex, a region specialized to process scene information. Across
participants, this pattern of LC engagement for goal-relevant encoding was correlated with
neuromelanin signal intensity, providing the first evidence that LC structure relates to its activation
pattern during cognitive processing. Threat also reduced dynamic functional connectivity between
high-priority (parahippocampal place area) and lower-priority (lateral occipital cortex) category-
selective visual cortex in ways that predicted increased memory selectivity. Together, these findings
support the idea that, under arousal, LC activity selectively strengthens prioritized memory
representations by modulating local and functional network-level patterns of information processing.
SIGNIFICANCE STATEMENT Adaptive behavior relies on the ability to select and store important
information amid distraction. Prioritizing encoding of task-relevant inputs is especially critical in
threatening or arousing situations, when forming these memories is essential for avoiding danger in the
future. However, little
118. Ripple-triggered stimulation of the locus coeruleus during post-learning sleep disrupts ripple/spindle
coupling and impairs memory consolidation.
PubMed
Novitskaya, Yulia; Sara, Susan J; Logothetis, Nikos K; Eschenko, Oxana
2016-05-01
Experience-induced replay of neuronal ensembles occurs during hippocampal high-frequency

oscillations, or ripples. Post-learning increase in ripple rate is predictive of memory recall, while ripple
disruption impairs learning. Ripples may thus present a fundamental component of a
neurophysiological mechanism of memory consolidation. In addition to system-level local and cross-
regional interactions, a consolidation mechanism involves stabilization of memory representations at
the synaptic level. Synaptic plasticity within experience-activated neuronal networks is facilitated by
noradrenaline release from the axon terminals of the locus coeruleus (LC). Here, to better understand
interactions between the system and synaptic mechanisms underlying "off-line" consolidation, we
examined the effects of ripple-associated LC activation on hippocampal and cortical activity and on
spatial memory. Rats were trained on a radial maze; after each daily learning session neural activity
was monitored for 1 h via implanted electrode arrays. Immediately following "on-line" detection of
ripple, a brief train of electrical pulses (0.05 mA) was applied to LC. Low-frequency (20 Hz)
stimulation had no effect on spatial learning, while higher-frequency (100 Hz) trains transiently
blocked generation of ripple-associated cortical spindles and caused a reference memory deficit.
Suppression of synchronous ripple/spindle events appears to interfere with hippocampal-cortical
communication, thereby reducing the efficiency of "off-line" memory consolidation. Â© 2016
Novitskaya et al.; Published by Cold Spring Harbor Laboratory Press.
119. Ripple-triggered stimulation of the locus coeruleus during post-learning sleep disrupts ripple/spindle
coupling and impairs memory consolidation
PubMed Central
Novitskaya, Yulia; Sara, Susan J.; Logothetis, Nikos K.
2016-01-01
Experience-induced replay of neuronal ensembles occurs during hippocampal high-frequency

oscillations, or ripples. Post-learning increase in ripple rate is predictive of memory recall, while ripple
disruption impairs learning. Ripples may thus present a fundamental component of a
neurophysiological mechanism of memory consolidation. In addition to system-level local and cross-
regional interactions, a consolidation mechanism involves stabilization of memory representations at
the synaptic level. Synaptic plasticity within experience-activated neuronal networks is facilitated by
noradrenaline release from the axon terminals of the locus coeruleus (LC). Here, to better understand
interactions between the system and synaptic mechanisms underlying â€œoff-lineâ€ consolidation, we
examined the effects of ripple-associated LC activation on hippocampal and cortical activity and on
spatial memory. Rats were trained on a radial maze; after each daily learning session neural activity
was monitored for 1 h via implanted electrode arrays. Immediately following â€œon-lineâ€ detection
of ripple, a brief train of electrical pulses (0.05 mA) was applied to LC. Low-frequency (20 Hz)
stimulation had no effect on spatial learning, while higher-frequency (100 Hz) trains transiently
blocked generation of ripple-associated cortical spindles and caused a reference memory deficit.
Suppression of synchronous ripple/spindle events appears to interfere with hippocampal-cortical
communication, thereby reducing the efficiency of â€œoff-lineâ€ memory consolidation.
PMID:27084931
120. IRE1Î± pathway of endoplasmic reticulum stress induces neuronal apoptosis in the locus coeruleus of
rats under single prolonged stress.
PubMed
Zhao, Wei; Han, Fang; Shi, Yuxiu
2016-08-01
Our previous studies have shown evidence of endoplasmic reticulum (ER) stress-induced apoptosis in
the hippocampus and mPFC in an animal model of post- traumatic stress disorder (PTSD). Inositol-
requiring enzyme 1Î± (IRE1Î±) and its downstream molecule X-box binding protein 1 (XBP1) play
key roles in the ER-related apoptosis pathway. Dysregulation of the locus coeruleus (LC) has been
reported to contribute to cognitive and/or arousal impairments associated with PTSD. The aim of the
present study was to explore the role of IRE1Î± pathway in neuronal apoptosis in the LC of rat models
of PTSD. We used an acute exposure to prolonged stress (single prolonged stress, SPS) to model
PTSD in rats and examined the effects related to the IRE1Î± pathway. Neuronal apoptosis in LC was
detected by transmission electron microscopy and TUNEL staining. The results showed that the level
of LC neuronal apoptosis was markedly increased after SPS. SPS exposure triggered IRE1Î± pathway,
as evidenced by the increased activity of IRE1Î±, specific splicing of XBP1, and up-regulated
expression of binding immunoglobulin protein/78kDa glucose-regulated protein (BiP/GRP78), and
C/EBP-homologous protein (CHOP). Treatment with STF-083010, an IRE1Î± RNase-specific
inhibitor, successfully attenuated the above changes. These results indicate that excessive activation of
the ER stress-associated IRE1Î± pathway is involved in LC neuronal apoptosis induced by SPS
exposure; this may be a crucial mechanism of the pathogenesis of PTSD. Copyright Â© 2016 Elsevier
Inc. All rights reserved.
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121. Effect of agmatine on locus coeruleus neuron activity: possible involvement of nitric oxide
PubMed Central
Ruiz-DurÃ¡ntez, Eduardo; Ruiz-Ortega, JosÃ© A; Pineda, Joseba; Ugedo, Luisa
2002-01-01
To investigate whether agmatine (the proposed endogenous ligand for imidazoline receptors) controls
locus coeruleus neuron activity and to elucidate its mechanism of action, we used single-unit
extracellular recording techniques in anaesthetized rats. Agmatine (10, 20 and 40â€‰Î¼g, i.c.v.)
increased in a dose-related manner the firing rate of locus coeruleus neurons (maximal increase:
95Â±13% at 40â€‰Î¼g). I1-imidazoline receptor ligands stimulate locus coeruleus neuron activity
through an indirect mechanism originated in the paragigantocellularis nucleus via excitatory amino
acids. However, neither electrolytic lesions of the paragigantocellularis nucleus nor pretreatment with
the excitatory amino acid antagonist kynurenic acid (1â€‰Î¼mol, i.c.v.) modified agmatine effect
(10â€‰Î¼g, i.c.v.). After agmatine administration (20â€‰Î¼g, i.c.v.), dose-response curves for the
effect of clonidine (0.625â€‰â€“â€‰10â€‰Î¼gâ€‰kgâˆ’1 i.v.) or morphine (0.3â€‰â€“â€‰4.8â€
‰mgâ€‰kgâˆ’1 i.v.) on locus coeruleus neurons were not different from those obtained in the control
groups. Pretreatment with the nitric oxide synthase inhibitors NÏ‰-nitro-L-arginine (10â€‰Î¼g,
i.c.v.) or NÏ‰-nitro-L-arginine methyl ester (100â€‰Î¼g, i.c.v.) but not with the less active
stereoisomer NÏ‰-nitro-D-arginine methyl ester (100â€‰Î¼g, i.c.v.) completely blocked agmatine
effect (10 and 40â€‰Î¼g, i.c.v.). Similarly, when agmatine (20â€‰pmoles) was applied into the locus
coeruleus there was an increase that was blocked by NÏ‰-nitro-L-arginine methyl ester (100â€‰Î¼g,
i.c.v.) in the firing rate of the locus coeruleus neurons (maximal increase 53Â±11% and 14Â±10%
before and after nitric oxide synthase inhibition, respectively). This study demonstrates that agmatine
stimulates the firing rate of locus coeruleus neurons via a nitric oxide synthase-dependent mechanism
located in this nucleus. PMID:11877321
122. The role of central noradrenergic dysregulation in anxiety disorders: evidence from clinical studies.
PubMed
Kalk, N J; Nutt, D J; Lingford-Hughes, A R
2011-01-01
The nature of the noradrenergic dysregulation in clinical anxiety disorders remains unclear. In panic
disorder, the predominant view has been that central noradrenergic neuronal networks and/or the
sympathetic nervous system was normal in patients at rest, but hyper-reactive to specific stimuli, for
example carbon dioxide. These ideas have been extended to other anxiety disorders, which share with
panic disorder characteristic subjective anxiety and physiological symptoms of excess sympathetic
activity. For example, Generalized Anxiety Disorder is characterized by chronic free-floating anxiety,
muscle tension, palpitation and insomnia. It has been proposed that there is chronic central
hypersecretion of noradrenaline in Generalized Anxiety Disorder, with consequent hyporesponsiveness
of central post-synaptic receptors. With regards to other disorders, it has been suggested that there is
noradrenergic involvement or derangement, but a more specific hypothesis has not been enunciated.
This paper reviews the evidence for noradrenergic dysfunction in anxiety disorders, derived from
indirect measures of noradrenergic function in clinical populations.
123. Combined Effects of Glucocorticoid and Noradrenergic Activity on Loss Aversion.
PubMed
Margittai, Zsofia; Nave, Gideon; Van Wingerden, Marijn; Schnitzler, Alfons; Schwabe, Lars;
Kalenscher, Tobias
2018-01-01
Loss aversion is a well-known behavioral regularity in financial decision making, describing humans'
tendency to overweigh losses compared to gains of the same amount. Recent research indicates that
stress and associated hormonal changes affect loss aversion, yet the underlying neuroendocrine
mechanisms are still poorly understood. Here, we investigated the causal influence of two major stress
neuromodulators, cortisol and noradrenaline, on loss aversion during financial decision making. In a
double-blind, placebo-controlled between-subject design, we orally administered either the Î±2-
adrenergic antagonist yohimbine (increasing noradrenergic stimulation), hydrocortisone, both
substances, or a placebo to healthy young men. We tested the treatments' influence on a financial
decision-making task measuring loss aversion and risk attitude. We found that both drugs combined,
relative to either drug by itself, reduced loss aversion in the absence of an effect on risk attitude or
choice consistency. Our data suggest that concurrent glucocorticoid and noradrenergic activity prompts
an alignment of reward- with loss-sensitivity, and thus diminishes loss aversion. Our results have
implications for the understanding of the susceptibility to biases in decision making.
124. Noradrenergic modulation of risk/reward decision making.
PubMed
Montes, David R; Stopper, Colin M; Floresco, Stan B
2015-08-01
Catecholamine transmission modulates numerous cognitive and reward-related processes that can
subserve more complex functions such as cost/benefit decision making. Dopamine has been shown to
play an integral role in decisions involving reward uncertainty, yet there is a paucity of research
investigating the contributions of noradrenaline (NA) transmission to these functions. The present
study was designed to elucidate the contribution of NA to risk/reward decision making in rats,
assessed with a probabilistic discounting task. We examined the effects of reducing noradrenergic
transmission with the Î±2 agonist clonidine (10-100 Î¼g/kg), and increasing activity at Î±2A receptor
sites with the agonist guanfacine (0.1-1 mg/kg), the Î±2 antagonist yohimbine (1-3 mg/kg), and the
noradrenaline transporter (NET) inhibitor atomoxetine (0.3-3 mg/kg) on probabilistic discounting.
Rats chose between a small/certain reward and a larger/risky reward, wherein the probability of
obtaining the larger reward either decreased (100-12.5 %) or increased (12.5-100 %) over a session. In
well-trained rats, clonidine reduced risky choice by decreasing reward sensitivity, whereas guanfacine
did not affect choice behavior. Yohimbine impaired adjustments in decision biases as reward
probability changed within a session by altering negative feedback sensitivity. In a subset of rats that
displayed prominent discounting of probabilistic rewards, the lowest dose of atomoxetine increased
preference for the large/risky reward when this option had greater long-term utility. These data
highlight an important and previously uncharacterized role for noradrenergic transmission in mediating
different aspects of risk/reward decision making and mediating reward and negative feedback
sensitivity.
125. Noradrenergic mechanisms of arousal's bidirectional effects on episodic memory.

PubMed
Clewett, David; Sakaki, Michiko; Nielsen, Shawn; Petzinger, Giselle; Mather, Mara
2017-01-01
Arousal's selective effects on cognition go beyond the simple enhancement of emotional stimuli,
sometimes enhancing and other times impairing processing of proximal neutral information. Past work
shows that arousal impairs encoding of subsequent neutral stimuli regardless of their top-down priority
via the engagement of Î²-adrenoreceptors. In contrast, retrograde amnesia induced by emotional
arousal can flip to enhancement when preceding neutral items are prioritized in top-down attention.
Whether Î²-adrenoreceptors also contribute to this retrograde memory enhancement of goal-relevant
neutral stimuli is unclear. In this pharmacological study, we administered 40mg of propranolol or
40mg of placebo to healthy young adults to examine whether emotional arousal's bidirectional effects
on declarative memory relies on Î²-adrenoreceptor activation. Following pill intake, participants
completed an emotional oddball task in which they were asked to prioritize a neutral object appearing
just before an emotional or neutral oddball image within a sequence of 7 neutral objects. Under
placebo, emotional oddballs impaired memory for lower priority oddball+1 objects but had no effect
on memory for high priority oddball-1 objects. Propranolol blocked this anterograde amnesic effect of
arousal. Emotional oddballs also enhanced selective memory trade-offs significantly more in the
placebo than drug condition, such that high priority oddball-1 objects were more likely to be
remembered at the cost of their corresponding lower priority oddball+1 objects under arousal. Lastly,
those who recalled more high priority oddball-1 objects preceding an emotional versus neutral oddball
image showed greater increases in salivary alpha-amylase, a biomarker of noradrenergic system
activation, across the task. Together these findings suggest that different noradrenergic mechanisms
contribute to the anterograde and retrograde mnemonic effects of arousal on proximal neutral
memoranda. Copyright Â© 2016
126. Locus Coeruleus, Vigilance and Stress: Brain Mechanisms of Adaptive Behavioral Responsiveness
1991-12-14
RroFn r nnrCIMENTATION PAGE AD-A265 724 . .. 1 , ,,IIA-%,NUAL 15 Dec 90 TO 14 Dec 91 mqJ

3OUIIILC 5 FLNONG- LOCUS COERULEUS, VIGILANCE AND STRESS ...the autonomic
nervous system (reflected in pupillary diameter), a measure of stress response during the task and a
possibly important concomitant of...vigilance performance during normative as well as during stressful
conditions. Results of these experiments will open the way to examination of afferents
127. Area postrema projects to FoxP2 neurons of the pre-locus coeruleus and parabrachial nuclei: brainstem
sites implicated in sodium appetite regulation.
PubMed
Stein, Matthew K; Loewy, Arthur D
2010-11-04
The area postrema (AP) is a circumventricular organ located in the dorsal midline of the medulla. It
functions as a chemosensor for blood-borne peptides and solutes, and converts this information into
neural signals that are transmitted to the nucleus tractus solitarius (NTS) and parabrachial nucleus
(PB). One of its NTS targets in the rat is the aldosterone-sensitive neurons which contain the enzyme
11 Î²-hydroxysteroid dehydrogenase type 2 (HSD2). The HSD2 neurons are part of a central network
involved in sodium appetite regulation, and they innervate numerous brain sites including the pre-
locus coeruleus (pre-LC) and PB external lateral-inner (PBel-inner) cell groups of the dorsolateral
pons. Both pontine cell groups express the transcription factor FoxP2 and become c-Fos activated
following sodium depletion. Because the AP is a component in this network, we wanted to determine
whether it also projects to the same sites as the HSD2 neurons. By using a combination of anterograde
axonal and retrograde cell body tract-tracing techniques in individual rats, we show that the AP
projects to FoxP2 immunoreactive neurons in the pre-LC and PBel-inner. Thus, the AP sends a direct
projection to both the first-order medullary (HSD2 neurons of the NTS) and the second-order
dorsolateral pontine neurons (pre-LC and PB-el inner neurons). All three sites transmit information
related to systemic sodium depletion to forebrain sites and are part of the central neural circuitry that
regulates the complex behavior of sodium appetite. Copyright Â© 2010 Elsevier B.V. All rights
reserved.
128. Noradrenaline from Locus Coeruleus Neurons Acts on Pedunculo-Pontine Neurons to Prevent REM
Sleep and Induces Its Loss-Associated Effects in Rats
PubMed Central
Khanday, Mudasir Ahmad; Somarajan, Bindu I.; Mehta, Rachna
2016-01-01
Normally, rapid eye movement sleep (REMS) does not appear during waking or non-REMS. Isolated,
independent studies showed that elevated noradrenaline (NA) levels inhibit REMS and induce REMS
loss-associated cytomolecular, cytomorphological, psychosomatic changes and associated symptoms.
However, the source of NA and its target in the brain for REMS regulation and function in health and
diseases remained to be confirmed in vivo. Using tyrosine hydroxylase (TH)-siRNA and virus-coated
TH-shRNA in normal freely moving rats, we downregulated NA synthesis in locus coeruleus (LC)
REM-OFF neurons in vivo. These TH-downregulated rats showed increased REMS, which was
prevented by infusing NA into the pedunculo-pontine tegmentum (PPT), the site of REM-ON neurons,
normal REMS returned after recovery. Moreover, unlike normal or control-siRNA- or shRNA-injected
rats, upon REMS deprivation (REMSD) TH-downregulated rat brains did not show elevated Na-K
ATPase (molecular changes) expression and activity. To the best of our knowledge, these are the first
in vivo findings in an animal model confirming that NA from the LC REM-OFF neurons (1) acts on
the PPT REM-ON neurons to prevent appearance of REMS, and (2) are responsible for inducing
REMSD-associated molecular changes and symptoms. These observations clearly show neuro-physio-
chemical mechanism of why normally REMS does not appear during waking. Also, that LC neurons
are the primary source of NA, which in turn causes some, if not many, REMSD-associated symptoms
and behavioral changes. The findings are proof-of-principle for the first time and hold potential to be
exploited for confirmation toward treating REMS disorder and amelioration of REMS loss-associated
symptoms in patients. PMID:27957531
129. Noradrenaline from Locus Coeruleus Neurons Acts on Pedunculo-Pontine Neurons to Prevent REM
Sleep and Induces Its Loss-Associated Effects in Rats.
PubMed
Khanday, Mudasir Ahmad; Somarajan, Bindu I; Mehta, Rachna; Mallick, Birendra Nath
2016-01-01
Normally, rapid eye movement sleep (REMS) does not appear during waking or non-REMS. Isolated,
independent studies showed that elevated noradrenaline (NA) levels inhibit REMS and induce REMS
loss-associated cytomolecular, cytomorphological, psychosomatic changes and associated symptoms.
However, the source of NA and its target in the brain for REMS regulation and function in health and
diseases remained to be confirmed in vivo . Using tyrosine hydroxylase (TH)-siRNA and virus-coated
TH-shRNA in normal freely moving rats, we downregulated NA synthesis in locus coeruleus (LC)
REM-OFF neurons in vivo . These TH-downregulated rats showed increased REMS, which was
prevented by infusing NA into the pedunculo-pontine tegmentum (PPT), the site of REM-ON neurons,
normal REMS returned after recovery. Moreover, unlike normal or control-siRNA- or shRNA-injected
rats, upon REMS deprivation (REMSD) TH-downregulated rat brains did not show elevated Na-K
ATPase (molecular changes) expression and activity. To the best of our knowledge, these are the first
in vivo findings in an animal model confirming that NA from the LC REM-OFF neurons (1) acts on
the PPT REM-ON neurons to prevent appearance of REMS, and (2) are responsible for inducing
REMSD-associated molecular changes and symptoms. These observations clearly show neuro-physio-
chemical mechanism of why normally REMS does not appear during waking. Also, that LC neurons
are the primary source of NA, which in turn causes some, if not many, REMSD-associated symptoms
and behavioral changes. The findings are proof-of-principle for the first time and hold potential to be
exploited for confirmation toward treating REMS disorder and amelioration of REMS loss-associated
symptoms in patients.
130. Differential Effects of Inescapable Stress on Locus Coeruleus GRK3, Alpha2-Adrenoceptor and CRF1
Receptor Levels in Learned Helpless and Non-Helpless Rats: A potential link to stress resilience
PubMed Central
Taneja, Manish; Salim, Samina; Saha, Kaustuv; Happe, H. Kevin; Qutna, Nidal; Petty, Frederick;
Bylund, David B.; Eikenburg, Douglas C.
2011-01-01
Exposure of rats to unpredictable, inescapable stress results in two distinct behaviors during
subsequent escape testing. One behavior, suggestive of lack of stress resilience, is prolonged escape
latency compared to non-stressed rats and is labeled learned helplessness (LH). The other behavior
suggestive of stress resilience is normal escape latency and is labeled non-helpless (NH). This study
examines the effects of unpredictable, inescapable tail-shock stress (TSS) on alpha2-adrenoceptor
(Î±2-AR) and corticotropin-releasing factor 1 receptor (CRF1) regulation as well as protein levels of G
protein-coupled receptor kinase 3 (GRK3), GRK2, tyrosine hydroxylase (TH) plus carbonylated
protein levels in locus coeruleus (LC), amygdala (AMG), cortex (COR) and striatum (STR). In NH
rats, Î±2-AR and CRF1 receptors were significantly down-regulated in LC after TSS. No changes in
these receptor levels were observed in the LC of LH rats. GRK3, which phosphorylates receptors and
thereby contributes to Î±2-AR and CRF1 receptor down-regulation, was reduced in the LC of LH but
not NH rats. GRK2 levels were unchanged. In AMG, GRK3 but not GRK2 levels were reduced in LH
but not NH rats, and receptor regulation was impaired in LH rats. In STR, no changes in GRK3 or
GRK2 levels were observed. Finally, protein carbonylation, an index of oxidative stress, was increased
in the LC and AMG of LH but not NH rats. We suggest that reduced stress resilience after TSS may be
related to oxidative stress, depletion of GRK3 and impaired regulation of Î±2-AR and CRF1 receptor
in LC. PMID:21333691
131. Dissociable roles of glucocorticoid and noradrenergic activation on social discounting.
PubMed
Margittai, Zsofia; van Wingerden, Marijn; Schnitzler, Alfons; JoÃ«ls, Marian; Kalenscher, Tobias
2018-04-01
People often exhibit prosocial tendencies towards close kin and friends, but generosity decreases as a
function of increasing social distance between donor and recipient, a phenomenon called social
discounting. Evidence suggests that acute stress affects prosocial behaviour in general and social
discounting in particular. We tested the causal role of the important stress neuromodulators cortisol
(CORT) and noradrenaline (NA) in this effect by considering two competing hypotheses. On the one
hand, it is possible that CORT and NA act in concert to increase generosity towards socially close
others by reducing the aversiveness of the cost component in costly altruism and enhancing the
emotional salience of vicarious reward. Alternatively, it is equally plausible that CORT and NA exert
dissociable, opposing effects on prosocial behaviour based on prior findings implicating CORT in
social affiliation, and NA in aggressive and antagonistic tendencies. We pharmacologically
manipulated CORT and NA levels in a sample of men (Nâ€¯=â€¯150) and found that isolated
hydrocortisone administration promoted prosocial tendencies towards close others, reflected in an
altered social discount function, but this effect was offset by concurrent noradrenergic activation
brought about by simultaneous yohimbine administration. These results provide inceptive evidence for
causal, opposing roles of these two important stress neuromodulators on prosocial behaviour, and give
rise to the possibility that, depending on the neuroendocrine response profile, stress neuromodulator
action can foster both tend-and-befriend and fight-or-flight tendencies at the same time. Copyright Â©
2018 Elsevier Ltd. All rights reserved.
132. Corticotropin-Releasing Factor Mediates Pain-Induced Anxiety through the ERK1/2 Signaling
Cascade in Locus Coeruleus Neurons
PubMed Central
Borges, Gisela PatrÃcia; MicÃ³, Juan Antonio; Neto, Fani LourenÃ§a
2015-01-01
Background: The corticotropin-releasing factor is a stress-related neuropeptide that modulates locus

coeruleus activity. As locus coeruleus has been involved in pain and stress-related patologies, we
tested whether the pain-induced anxiety is a result of the corticotropin-releasing factor released in the
locus coeruleus. Methods: Complete Freundâ€™s adjuvant-induced monoarthritis was used as
inflammatory chronic pain model. Î±-Helical corticotropin-releasing factor receptor antagonist was
microinjected into the contralateral locus coeruleus of 4-week-old monoarthritic animals. The
nociceptive and anxiety-like behaviors, as well as phosphorylated extracellular signal-regulated
kinases 1/2 and corticotropin-releasing factor receptors expression, were quantified in the
paraventricular nucleus and locus coeruleus. Results: Monoarthritic rats manifested anxiety and
increased phosphorylated extracellular signal-regulated kinases 1/2 levels in the locus coeruleus and
paraventricular nucleus, although the expression of corticotropin-releasing factor receptors was
unaltered. Î±-Helical corticotropin-releasing factor antagonist administration reversed both the
anxiogenic-like behavior and the phosphorylated extracellular signal-regulated kinases 1/2 levels in the
locus coeruleus. Conclusions: Pain-induced anxiety is mediated by corticotropin-releasing factor
neurotransmission in the locus coeruleus through extracellular signal-regulated kinases 1/2 signaling
cascade. PMID:25716783
133. Role of protein kinase C and Î¼-opioid receptor (MOPr) desensitization in tolerance to morphine in rat
locus coeruleus neurons
PubMed Central
Bailey, C P; Llorente, J; Gabra, B H; Smith, F L; Dewey, W L; Kelly, E; Henderson, G
2009-01-01
In morphine tolerance a key question that remains to be answered is whether Î¼-opioid receptor
(MOPr) desensitization contributes to morphine tolerance, and if so by what cellular mechanisms.
Here we demonstrate that MOPr desensitization can be observed in single rat brainstem locus
coeruleus (LC) neurons following either prolonged (> 4 h) exposure to morphine in vitro or following
treatment of animals with morphine in vivo for 3 days. Analysis of receptor function by an operational
model indicated that with either treatment morphine could induce a profound degree (70â€“80%) of
loss of receptor function. Ongoing PKC activity in the MOPr-expressing neurons themselves,
primarily by PKCÎ±, was required to maintain morphine-induced MOPr desensitization, because
exposure to PKC inhibitors for only the last 30â€“50 min of exposure to morphine reduced the MOPr
desensitization that was induced both in vitro and in vivo. The presence of morphine was also required
for maintenance of desensitization, as washout of morphine for > 2 h reversed MOPr desensitization.
MOPr desensitization was homologous, as there was no change in Î±2-adrenoceptor or ORL1 receptor
function. These results demonstrate that prolonged morphine treatment induces extensive homologous
desensitization of MOPrs in mature neurons, that this desensitization has a significant PKC-dependent
component and that this desensitization underlies the maintenance of morphine tolerance.
PMID:19200236
134. The coeruleus/subcoeruleus complex in idiopathic rapid eye movement sleep behaviour disorder.
PubMed
Ehrminger, Mickael; Latimier, Alice; Pyatigorskaya, Nadya; Garcia-Lorenzo, Daniel; Leu-Semenescu,

Smaranda; Vidailhet, Marie; Lehericy, StÃ©phane; Arnulf, Isabelle
2016-04-01
Idiopathic rapid eye movement sleep behaviour disorder is characterized by nocturnal violence,
increased muscle tone during rapid eye movement sleep and the lack of any other neurological disease.
However, idiopathic rapid eye movement sleep behaviour disorder can precede parkinsonism and
dementia by several years. Using 3 T magnetic resonance imaging and neuromelanin-sensitive
sequences, we previously found that the signal intensity was reduced in the locus
coeruleus/subcoeruleus area of patients with Parkinson's disease and rapid eye movement sleep
behaviour disorder. Here, we studied the integrity of the locus coeruleus/subcoeruleus complex with
neuromelanin-sensitive imaging in 21 patients with idiopathic rapid eye movement sleep behaviour
disorder and compared the results with those from 21 age- and gender-matched healthy volunteers. All
subjects underwent a clinical examination, motor, cognitive, autonomous, psychological, olfactory and
colour vision tests, and rapid eye movement sleep characterization using video-polysomnography and
3 T magnetic resonance imaging. The patients more frequently had preclinical markers of alpha-
synucleinopathies, including constipation, olfactory deficits, orthostatic hypotension, and subtle motor
impairment. Using neuromelanin-sensitive imaging, reduced signal intensity was identified in the
locus coeruleus/subcoeruleus complex of the patients with idiopathic rapid eye movement sleep
behaviour. The mean sensitivity of the visual analyses of the signal performed by neuroradiologists
who were blind to the clinical diagnoses was 82.5%, and the specificity was 81% for the identification
of idiopathic rapid eye movement sleep behaviour. The results confirm that this complex is affected in
idiopathic rapid eye movement sleep behaviour (to the same degree as it is affected in Parkinson's
disease). Neuromelanin-sensitive imaging provides an early marker of non-dopaminergic alpha-
synucleinopathy that can be detected on an individual
135. Locus Coeruleus Neuron Density and Parkinsonism in Older Adults without Parkinsonâ€™s Disease
PubMed Central
Buchman, Aron S.; Nag, Sukriti; Shulman, Joshua M.; Lim, Andrew S.P.; VanderHorst, Veronique
G.J.M.; Leurgans, Sue E.; Schneider, Julie A.; Bennett, David A.
2013-01-01
Objective Prior work has showed that nigral neuron density is related to the severity of parkinsonism
proximate to death in older persons without a clinical diagnosis of Parkinsonâ€™s disease (PD). We
tested the hypothesis that neuron density in other brainstem aminergic nuclei is also related to the
severity of parkinsonism. Design We studied brain autopsies from 125 deceased older adults without
PD enrolled in the Memory and Aging Project, a clinical-pathologic investigation. Parkinsonism was
assessed with a modified version of the Unified Parkinsonâ€™s Disease Rating Scale (UPDRS). We
measured neuron density in the substantia nigra, ventral tegmental area, locus coeruleus and dorsal
raphe; and postmortem indices of Lewy body Alzheimerâ€™s disease and cerebrovascular
pathologies. Results Mean age at death was 88.0 and global parkinsonism was 14.8 (SD=9.50). In a
series of regression models which controlled for demographics and neuron density in the substantia
nigra, neuron density in the locus coeruleus (Estimate, âˆ’0.261, S.E., 0.117, p=0.028) but not in the
ventral tegmental area or dorsal raphe was associated with the severity of global parkinsonism
proximate to death. These findings were unchanged in models which controlled for post-mortem
interval, whole brain weight and other common neuropathologies including Alzheimerâ€™s disease
and Lewy body pathology and cerebrovascular vascular pathologies. Conclusion In older adults
without a clinical diagnosis of PD, neuron density in locus coeruleus nuclei is associated with the
severity of parkinsonism and may contribute to late-life motor impairments. PMID:23038629
136. Evidence for a role of corticopetal, noradrenergic systems in the development of executive function.
PubMed
Mokler, David J; Miller, Christine E; McGaughy, Jill A

2017-09-01
Adolescence is a period during which many aspects of executive function are maturing. Much of the
literature has focused on discrepancies between sub-cortical and cortical development that is
hypothesized to lead to over-processing of reinforcement related stimuli unchecked by fully matured
response inhibition. Specifically, maturation of sub-cortical dopaminergic systems that terminate in the
nucleus accumbens has been suggested to occur prior to the full maturation of corticopetal
dopaminergic systems. However, converging evidence supports the hypothesis that many aspects of
cognitive control are critically linked to cortical noradrenergic systems, that the effectiveness of drugs
used to treat disorders of executive function, e.g. ADHD, may result primarily from increases in
cortical norepinephrine (NE) and that cortical noradrenergic systems mature across adolescence.
However, little attention has been given to the development of this system during adolescence or to its
influence in executive function. In the present paper, we discuss the developmental trajectory of the
noradrenergic system of the forebrain, highlight the interactions between noradrenergic and
dopaminergic systems, and highlight the contribution of the immature corticopetal noradrenergic
systems in the ontogeny of several aspects of executive function. Finally we compare data from
adolescent rats to those gathered after selective depletion of NE in sub-regions of the prefrontal cortex
with an emphasis on the similarities in performance of NE lesioned rats and adolescents. Copyright
Â© 2017 Elsevier Inc. All rights reserved.
137. Transient outwardly rectifying A currents are involved in the firing rate response to altered CO2 in
chemosensitive locus coeruleus neurons from neonatal rats
PubMed Central
Li, Ke-Yong
2013-01-01
The effect of hypercapnia on outwardly rectifying currents was examined in locus coeruleus (LC)
neurons in slices from neonatal rats [postnatal day 3 (P3)â€“P15]. Two outwardly rectifying currents
[4-aminopyridine (4-AP)-sensitive transient current and tetraethyl ammonium (TEA)-sensitive
sustained current] were found in LC neurons. 4-AP induced a membrane depolarization of 3.6 Â± 0.6
mV (n = 4), while TEA induced a smaller membrane depolarization of 1.2 Â± 0.3 mV (n = 4).
Hypercapnic acidosis (HA) inhibited both currents. The maximal amplitude of the TEA-sensitive
current was reduced by 52.1 Â± 4.5% (n = 5) in 15% CO2 [extracellular pH (pHo) 7.00, intracellular
pH (pHi) 6.96]. The maximal amplitude of the 4-AP-sensitive current was reduced by 34.5 Â± 3.0% (n
= 6) in 15% CO2 (pHo 7.00, pHi 6.96), by 29.4 Â± 6.8% (n = 6) in 10% CO2 (pHo 7.15, pHi 7.14),
and increased by 29.0 Â± 6.4% (n = 6) in 2.5% CO2 (pHo 7.75, pHi 7.35). 4-AP completely blocked
hypercapnia-induced increased firing rate, but TEA did not affect it. When LC neurons were exposed
to HA with either pHo or pHi constant, the 4-AP-sensitive current was inhibited. The data show that
the 4-AP-sensitive current (likely an A current) is inhibited by decreases in either pHo or pHi. The
change of the A current by various levels of CO2 is correlated with the change in firing rate induced
by CO2, implicating the 4-AP-sensitive current in chemosensitive signaling in LC neurons.
PMID:23948777
138. Neuropeptide S interacts with the basolateral amygdala noradrenergic system in facilitating object
recognition memory consolidation.
PubMed
Han, Ren-Wen; Xu, Hong-Jiao; Zhang, Rui-San; Wang, Pei; Chang, Min; Peng, Ya-Li; Deng, Ke-Yu;
Wang, Rui
2014-01-01
The noradrenergic activity in the basolateral amygdala (BLA) was reported to be involved in the
regulation of object recognition memory. As the BLA expresses high density of receptors for
Neuropeptide S (NPS), we investigated whether the BLA is involved in mediating NPS's effects on
object recognition memory consolidation and whether such effects require noradrenergic activity.
Intracerebroventricular infusion of NPS (1nmol) post training facilitated 24-h memory in a mouse
novel object recognition task. The memory-enhancing effect of NPS could be blocked by the Î²-
adrenoceptor antagonist propranolol. Furthermore, post-training intra-BLA infusions of NPS
(0.5nmol/side) improved 24-h memory for objects, which was impaired by co-administration of
propranolol (0.5Î¼g/side). Taken together, these results indicate that NPS interacts with the BLA
noradrenergic system in improving object recognition memory during consolidation. Copyright Â©
2013 Elsevier Inc. All rights reserved.
139. Selective deficiencies in descending inhibitory modulation in neuropathic rats: implications for
enhancing noradrenergic tone.
PubMed
Patel, Ryan; Qu, Chaoling; Xie, Jennifer Y; Porreca, Frank; Dickenson, Anthony H
2018-06-22
Pontine noradrenergic neurones form part of a descending inhibitory system that influences spinal
nociceptive processing. Weak or absent descending inhibition is a common feature of chronic pain
patients. We examined the extent to which the descending noradrenergic system is tonically active,
how control of spinal neuronal excitability is integrated into thalamic relays within sensory-
discriminative projection pathways, and how this inhibitory control is altered after nerve injury. In vivo
electrophysiology was performed in anaesthetised spinal nerve-ligated (SNL) and sham-operated rats
to record from wide dynamic range neurones in the ventral posterolateral thalamus (VPL). In sham
rats, spinal block of Î±2-adrenoceptors with atipamezole resulted in enhanced stimulus-evoked and
spontaneous firing in the VPL, and produced conditioned place avoidance. However, in SNL rats,
these conditioned avoidance behaviours were absent. Furthermore, inhibitory control of evoked
neuronal responses was lost, but spinal atipamezole markedly increased spontaneous firing.
Augmenting spinal noradrenergic tone in neuropathic rats with reboxetine, a selective noradrenergic
reuptake inhibitor, modestly reinstated inhibitory control of evoked responses in the VPL but had no
effect on spontaneous firing. By contrast, clonidine, an Î±2 agonist, inhibited both evoked and
spontaneous firing, and exhibited increased potency in SNL rats compared with sham controls. These
data suggest descending noradrenergic inhibitory pathways are tonically active in sham rats. Moreover,
in neuropathic states, descending inhibitory control is diminished, but not completely absent, and
distinguishes between spontaneous and evoked neuronal activity. These observations may have
implications for how analgesics targeting the noradrenergic system provide relief.This is an open
access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits
unrestricted use, distribution, and
140. Restoring Spinal Noradrenergic Inhibitory Tone Attenuates Pain Hypersensitivity in a Rat Model of
Parkinson's Disease
PubMed Central
Wang, Bing; Chen, Li-Hua
2016-01-01
In the present study, we investigated whether restoring descending noradrenergic inhibitory tone can
attenuate pain in a PD rat model, which was established by stereotaxic infusion of 6-hydroxydopamine
(6-OHDA) into the bilateral striatum (CPu). PD rats developed thermal and mechanical
hypersensitivity at the 4th week after surgery. HPLC analysis showed that NE content, but not
dopamine or 5-HT, significantly decreased in lumbar spinal cord in PD rats. Additional noradrenergic
depletion by injection of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) aggravated pain
hypersensitivity in PD rats. At the 5th week after injection of 6-OHDA, systemic treatment with
pharmacological norepinephrine (NE) precursor droxidopa (L-DOPS) or Î±2 adrenoceptor agonist
clonidine significantly attenuated thermal and mechanical pain hypersensitivity in PD rats.
Furthermore, application of norepinephrine (NE) and 5-hydroxytryptamine (5-HT) reuptake inhibitors
duloxetine, but not 5-HT selective reuptake inhibitors sertraline, significantly inhibited thermal and
mechanical pain hypersensitivity in PD rats. Systemic administration of Madopar (L-DOPA) or the
D2/D3 agonist pramipexole slightly inhibited the thermal, but not mechanical, hypersensitivity in PD
rats. Thus, our study revealed that impairment of descending noradrenergic system may play a key role
in PD-associated pain and restoring spinal noradrenergic inhibitory tone may serve as a novel strategy
to manage PD-associated pain. PMID:27747105
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141. Noradrenergic Action in Prefrontal Cortex in the Late Stage of Memory Consolidation
Tronel, Sophie; Feenstra, Matthijs G. P.; Sara, Susan J.
2004-01-01
These experiments investigated the role of the noradrenergic system in the late stage of memory
consolidation and in particular its action at beta receptors in the prelimbic region (PL) of the prefrontal
cortex in the hours after training. Rats were trained in a rapidly acquired, appetitively motivated
foraging task based on olfactoryâ€¦
142. Orphanin FQ/Nociceptin Interacts with the Basolateral Amygdala Noradrenergic System in Memory
Consolidation
Roozendaal, Benno; Lengvilas, Ray; McGaugh, James L.; Civelli, Olivier; Reinscheid, Rainer K.
2007-01-01
Extensive evidence indicates that the basolateral complex of the amygdala (BLA) mediates hormonal
and neurotransmitter effects on the consolidation of emotionally influenced memory and that such
modulatory influences involve noradrenergic activation of the BLA. As the BLA also expresses a high
density of receptors for orphanin FQ/nociceptinâ€¦
143. Facilitation of Learning by Social-Emotional Feedback in Humans Is Beta-Noradrenergic-Dependent
Mihov, Yoan; Mayer, Simon; Musshoff, Frank; Maier, Wolfgang; Kendrick, Keith M.; Hurlemann,
Rene
2010-01-01
Adaptive behavior in dynamic environments critically depends on the ability to learn rapidly and
flexibly from the outcomes of prior choices. In social environments, facial expressions of emotion
often serve as performance feedback and thereby guide declarative learning. Abundant evidence
implicates beta-noradrenergic signaling in the modulatoryâ€¦
144. Fear conditioning selectively disrupts noradrenergic facilitation of GABAergic inhibition in the
basolateral amygdala.
PubMed
Skelly, M J; Ariwodola, O J; Weiner, J L
2017-02-01
Inappropriate fear memory formation is symptomatic of many psychopathologies, and delineating the
neurobiology of non-pathological fear learning may provide critical insight into treating these
disorders. Fear memory formation is associated with decreased inhibitory signaling in the basolateral
amygdala (BLA), and disrupted noradrenergic signaling may contribute to this decrease. BLA
noradrenergic neurotransmission has been implicated in fear memory formation, and distinct
adrenoreceptor (AR) subtypes modulate excitatory and inhibitory neurotransmission in this region. For
example, Î±1-ARs promote GABA release from local inhibitory interneurons, while Î²3-ARs potentiate
neurotransmission at lateral paracapsular (LPC) GABAergic synapses. Conversely, Î²1/2-ARs amplify
excitatory signaling at glutamatergic synapses in the BLA. As increased BLA excitability promotes
fear memory formation, we hypothesized that fear learning shifts the balanced regional effects of
noradrenergic signaling toward excitation. To test this hypothesis, we used the fear-potentiated startle
paradigm in combination with whole cell patch clamp electrophysiology to examine the effects of AR
activation on BLA synaptic transmission following fear conditioning in male Long-Evans rats. We first
demonstrated that inhibitory neurotransmission is decreased at both local and LPC synapses following
fear conditioning. We next measured noradrenergic facilitation of BLA inhibitory signaling at local
and LPC synapses using Î±1-and Î²3-AR agonists (1Â Î¼M A61603 and 10Â Î¼M BRL37344), and
found that the ability of these agents to facilitate inhibitory neurotransmission is disrupted following
fear conditioning. Conversely, we found that fear learning does not disrupt noradrenergic modulation
of glutamatergic signaling via a Î²1/2-AR agonist (1Â Î¼M isoproterenol). Taken together, these
studies suggest that fear learning increases BLA excitability by selectively disrupting the inhibitory
effects of noradrenaline
145. Fear Conditioning Selectively Disrupts Noradrenergic Facilitation of GABAergic Inhibition in the
Basolateral Amygdala
PubMed Central
Skelly, M. J.; Ariwodola, O. J.; Weiner, J. L.
2016-01-01
Inappropriate fear memory formation is symptomatic of many psychopathologies, and delineating the
neurobiology of non-pathological fear learning may provide critical insight into treating these
disorders. Fear memory formation is associated with decreased inhibitory signaling in the basolateral
amygdala (BLA), and disrupted noradrenergic signaling may contribute to this decrease. BLA
noradrenergic neurotransmission has been implicated in fear memory formation, and distinct
adrenoreceptor (AR) subtypes modulate excitatory and inhibitory neurotransmission in this region. For
example, Î±1-ARs promote GABA release from local inhibitory interneurons, while Î²3-ARs potentiate
neurotransmission at lateral paracapsular (LPC) GABAergic synapses. Conversely, Î²1/2-ARs amplify
excitatory signaling at glutamatergic synapses in the BLA. As increased BLA excitability promotes
fear memory formation, we hypothesized that fear learning shifts the balanced regional effects of
noradrenergic signaling toward excitation. To test this hypothesis, we used the fear-potentiated startle
paradigm in combination with whole cell patch clamp electrophysiology to examine the effects of AR
activation on BLA synaptic transmission following fear conditioning in male Long-Evans rats. We first
demonstrated that inhibitory neurotransmission is decreased at both local and LPC synapses following
fear conditioning. We next measured noradrenergic facilitation of BLA inhibitory signaling at local
and LPC synapses using Î±1- and Î²3-AR agonists (1Î¼M A61603 and 10Î¼M BRL37344), and found
that the ability of these agents to facilitate inhibitory neurotransmission is disrupted following fear
conditioning. Conversely, we found that fear learning does not disrupt noradrenergic modulation of
glutamatergic signaling via a Î²1/2-AR agonist (1Î¼M isoproterenol). Taken together, these studies
suggest that fear learning increases BLA excitability by selectively disrupting the inhibitory effects of
noradrenaline. PMID
146. The noradrenergic paradox: implications in the management of depression and anxiety
PubMed Central
Montoya, Alonso; Bruins, Robert; Katzman, Martin A; Blier, Pierre
2016-01-01
Both major depressive disorder and the anxiety disorders are major causes of disability and markedly
contribute to a significant global burden of the disease worldwide. In part because of the significant
socioeconomic burden associated with these disorders, theories have been developed to specifically
build clinical treatment approaches. One such theory, the monoaminergic hypothesis, has led to the
development of several generations of selective and nonselective inhibitors of transporters of serotonin
and norepinephrine, with the goal of augmenting monoaminergic transmission. These efforts have led
to considerable success in the development of antidepressant therapeutics. However, there is a strong
correlation between enhanced noradrenergic activity and fear and anxiety. Consequently, some
physicians have expressed concerns that the same enhanced noradrenergic activity that alleviates
depression could also promote anxiety. The fact that the serotonergic and noradrenergic reuptake
inhibitors are successfully used in the treatment of anxiety and panic disorders seems paradoxical. This
review was undertaken to determine if any clinical evidence exists to show that serotonergic and
noradrenergic reuptake inhibitors can cause anxiety. The PubMed, EMBASE, and Cochrane Library
databases were searched, and the results limited to randomized, double-blind, placebo-controlled
studies performed in nongeriatric adults and with clear outcome measures were reported. Based on
these criteria, a total of 52 studies were examined. Patients in these studies suffered from depression or
anxiety disorders (generalized and social anxiety disorders, panic disorder, and posttraumatic stress
disorder). The large majority of these studies employed venlafaxine or duloxetine, and the remainder
used tri-cyclic antidepressants, atomoxetine, or reboxetine. All the studies reported clinically
significant alleviation of depressive and/or anxious symptoms by these therapeutics. In none of these
147. The noradrenergic system in pathological anxiety: a focus on panic with relevance to generalized
anxiety and phobias.
PubMed
Sullivan, G M; Coplan, J D; Kent, J M; Gorman, J M
1999-11-01
Over the past three decades of psychiatric research, abnormalities in the noradrenergic system have
been identified in particular anxiety disorders such as panic disorder. Simultaneously, neuroscience
research on fear pathways and the stress response have delineated central functions for the
noradrenergic system. This review focuses on the noradrenergic system in anxiety spectrum disorders
such as panic disorder, generalized anxiety disorder, and phobias for the purpose of elucidating current
conceptualizations of the pathophysiologies. Neuroanatomic pathways that are theoretically relevant in
anxiogenesis are discussed and the implications for treatment reviewed.
148. Pupil diameter tracks changes in control state predicted by the adaptive gain theory of locus coeruleus
function
PubMed Central
Gilzenrat, Mark S.; Nieuwenhuis, Sander; Jepma, Marieke; Cohen, Jonathan D.
2010-01-01
An important dimension of cognitive control is the adaptive regulation of the balance between
exploitation (pursuing known sources of reward) and exploration (seeking new ones) in response to
changes in task utility. Recent studies have suggested that the locus coeruleusâ€“norepinephrine
system may play an important role in this function and that pupil diameter can be used to index locus
coeruleus activity. On the basis of this, we reasoned that pupil diameter may correlate closely with
control state and associated changes in behavior. Specifically, we predicted that increases in baseline
pupil diameter would be associated with decreases in task utility and disengagement from the task
(exploration), whereas reduced baseline diameter (but increases in task-evoked dilations) would be
associated with task engagement (exploitation). Findings in three experiments were consistent with
these predictions, suggesting that pupillometry may be useful as an index of both control state and,
indirectly, locus coeruleus function. PMID:20498349
149. Î±(2) noradrenergic receptor suppressed CaMKII signaling in spinal dorsal horn of mice with
inflammatory pain.
PubMed
Wang, Xin-Tai; Lian, Xia; Xu, Ying-Ming; Suo, Zhan-Wei; Yang, Xian; Hu, Xiao-Dong
2014-02-05
Intrathecal application of Î±2 noradrenergic receptor agonists effectively alleviates the pathological
pain induced by peripheral tissue injury. However, the spinal antinociceptive mechanisms of Î±2
noradrenergic receptors remain to be characterized. The present study performed
immunohistochemistry and western blot to elucidate the signaling pathway initiated by Î±2
noradrenergic receptors in spinal dorsal horn of mice, and identified calcium/calmodulin-dependent
protein kinase II (CaMKII) as an important target for noradrenergic suppression of inflammatory pain.
Our data showed that intraplantar injection of Complete Freund's Adjuvant (CFA) substantially
enhanced CaMKII autophosphorylation at Threonine 286, which could be abolished by intrathecal
administration of Î±2 noradrenergic receptor agonist clonidine. Gi protein-coupled Î±2 noradrenergic
receptor might inhibit cAMP-dependent protein kinase (PKA) to disturb CaMKII signaling. We found
that pharmacological activation of PKA in intact mice also enhanced spinal CaMKII
autophosphorylation level, which was completely antagonized by clonidine. Moreover, direct PKA
inhibition in CFA-injected mice mimicked the suppressive effect of Î±2 noradrenergic receptors on
CaMKII. PKA inhibition has been shown to downregulate CaMKII by enhancing protein phosphatase
activity. Consistent with this notion, spinal treatment with protein phosphatase inhibitor okadaic acid
ruled out clonidine-mediated CaMKII dephosphorylation in CFA-injected mice. Through PKA/protein
phosphatase/CaMKII pathway, clonidine noticeably decreased CFA-evoked phosphorylation of N-
methyl-d-aspartate subtype glutamate receptor GluN1 and GluN2B subunit as well as Î±-amino-3-
hydroxy-5-methylisoxazole-4-propionic Acid subtype glutamate receptor GluA1 subunit. These data
suggested that interference with CaMKII signaling might represent an important mechanism
underlying noradrenergic suppression of inflammatory pain. Copyright Â© 2013 Elsevier B.V. All
rights
150. Noradrenergic lesioning with an anti-dopamine beta-hydroxylase immunotoxin
NASA Technical Reports Server (NTRS)
Picklo, M. J.; Wiley, R. G.; Lappi, D. A.; Robertson, D.
1994-01-01
Sympathectomy has been achieved by a variety of methods but each has its limitations. These include
lack of tissue specificity, incomplete lesioning, and the age range of susceptibility to the lesioning. To
circumvent these drawbacks, an immunotoxin was constructed using a monoclonal antibody against
the noradrenergic specific enzyme dopamine beta-hydroxylase (D beta H) coupled via a disulfide bond
to saporin, a ribosomal inactivating protein. Three days after intravenous injection of the anti-D beta H
immunotoxin (50 micrograms) into adult Sprague-Dawley rats, 66% of neurons in the superior
cervical ganglia were chromatolytic. Superior cervical ganglia neurons were poisoned in 1 day old and
1 week old (86% of neurons) neonatal rats following subcutaneous injection of 3.75 and 15
micrograms, respectively. The anti-D beta H immunotoxin will be a useful tool in the study of the
peripheral noradrenergic system in adult and neonatal animals.
151. Noradrenergic blockade stabilizes prefrontal activity and enables fear extinction under stress
PubMed Central
Fitzgerald, Paul J.; Giustino, Thomas F.; Seemann, Jocelyn R.; Maren, Stephen
2015-01-01
Stress-induced impairments in extinction learning are believed to sustain posttraumatic stress disorder
(PTSD). Noradrenergic signaling may contribute to extinction impairments by modulating medial
prefrontal cortex (mPFC) circuits involved in fear regulation. Here we demonstrate that aversive fear
conditioning rapidly and persistently alters spontaneous single-unit activity in the prelimbic and
infralimbic subdivisions of the mPFC in behaving rats. These conditioning-induced changes in mPFC
firing were mitigated by systemic administration of propranolol (10 mg/kg, i.p.), a Î²-noradrenergic
receptor antagonist. Moreover, propranolol administration dampened the stress-induced impairment in
extinction observed when extinction training is delivered shortly after fear conditioning. These
findings suggest that Î²-adrenoceptors mediate stress-induced changes in mPFC spike firing that
contribute to extinction impairments. Propranolol may be a helpful adjunct to behavioral therapy for
PTSD, particularly in patients who have recently experienced trauma. PMID:26124100
152. Differential effects of unilateral olfactory deprivation on noradrenergic and cholinergic systems in the
main olfactory bulb of the rat.
PubMed
GÃ³mez, C; BriÃ±Ã³n, J G; Colado, M I; Orio, L; Vidal, M; Barbado, M V; Alonso, J R
2006-09-15
The lack of environmental olfactory stimulation produced by sensory deprivation causes significant
changes in the deprived olfactory bulb. Olfactory transmission in the main olfactory bulb (MOB) is
strongly modulated by centrifugal systems. The present report examines the effects of unilateral
deprivation on the noradrenergic and cholinergic centrifugal systems innervating the MOB. The
morphology, distribution, and density of positive axons were studied in the MOBs of control and
deprived rats, using dopamine-beta-hydroxylase (DBH)-immunohistochemistry and
acetylcholinesterase (AChE) histochemistry in serial sections. Catecholamine content was compared
among the different groups of MOBs (control, contralateral, and ipsilateral to the deprivation) using
high-performance liquid chromatography analysis. Sensory deprivation revealed that the noradrenergic
system developed adaptive plastic changes after olfactory deprivation, including important
modifications in its fiber density and distribution, while no differences in cholinergic innervation were
observed under the same conditions. The noradrenergic system underwent an important alteration in
the glomerular layer, in which some glomeruli showed a dense noradrenergic innervation that was not
detected in control animals. The DBH-positive glomeruli with the highest noradrenergic fiber density
were compared with AChE-stained sections and it was observed that the strongly noradrenergic-
innervated glomeruli were always atypical glomeruli (characterized by their strong degree of
cholinergic innervation). In addition to the morphological findings, our biochemical data revealed that
olfactory deprivation caused a decrease in the content of dopamine and its metabolite 3,4-
dihydroxyphenylacetic acid in the ipsilateral MOB in comparison to the contralateral and control
MOBs, together with an increase in noradrenaline levels in both the ipsilateral and contralateral
MOBs. Our results show that regulation of the noradrenergic
153. Genetically determined differences in noradrenergic function: The spontaneously hypertensive rat
model.
PubMed
Sterley, Toni-Lee; Howells, Fleur M; Russell, Vivienne A
2016-06-15
While genetic predisposition is a major factor, it is not known how development of attention-
deficit/hyperactivity disorder (ADHD) is modulated by early life stress. The spontaneously
hypertensive rat (SHR) displays the behavioral characteristics of ADHD (poorly sustained attention,
impulsivity, hyperactivity) and is the most widely studied genetic model of ADHD. We have
previously shown that SHR have disturbances in the noradrenergic system and that the early life stress
of maternal separation failed to produce anxiety-like behavior in SHR, contrary to control Sprague-
Dawley and Wistar-Kyoto (WKY) who showed typical anxiety-like behavior in later life. In the
present study we investigated the effect of maternal separation on approach behavior (response to a
novel object in a familiar environment) in preadolescent SHR and WKY. We also investigated whether
maternal separation altered GABAA and NMDA receptor-mediated regulation of norepinephrine
release in preadolescent SHR and WKY hippocampus. We found that female SHR, similar to male
SHR, exhibited greater exploratory activity than WKY. Maternal separation significantly increased
GABAA receptor-mediated inhibition of glutamate-stimulated release of norepinephrine in male and
female SHR hippocampus but had no significant effect in WKY. Maternal separation had opposite
effects on NMDA receptor-mediated inhibition of norepinephrine release in SHR and WKY
hippocampus, as it increased inhibition of both glutamate-stimulated and depolarization-evoked
release in SHR hippocampus but not in WKY. The results of the present study show that noradrenergic
function is similarly altered by the early life stress of maternal separation in male and female SHR,
while GABA- and glutamate-regulation of norepinephrine release remained unaffected by maternal
separation in the control, WKY, rat strain. This article is part of a Special Issue entitled SI:
Noradrenergic System. Copyright Â© 2015 Elsevier B.V. All rights reserved.
154. Prenatal Drug Exposures Sensitize Noradrenergic Circuits to Subsequent Disruption by Chlorpyrifos
PubMed Central
Slotkin, Theodore A.; Skavicus, Samantha; Seidler, Frederic J.
2015-01-01
We examined whether nicotine or dexamethasone, common prenatal drug exposures, sensitize the
developing brain to chlorpyrifos. We gave nicotine to pregnant rats throughout gestation at a dose (3
mg/kg/day) producing plasma levels typical of smokers; offspring were then given chlorpyrifos on
postnatal days 1â€“4, at a dose (1 mg/kg) that produces minimally-detectable inhibition of brain
cholinesterase activity. In a parallel study, we administered dexamethasone to pregnant rats on
gestational days 17â€“19 at a standard therapeutic dose (0.2 mg/kg) used in the management of
preterm labor, followed by postnatal chlorpyrifos. We evaluated cerebellar noradrenergic projections, a
known target for each agent, and contrasted the effects with those in the cerebral cortex. Either drug
augmented the effect of chlorpyrifos, evidenced by deficits in cerebellar Î²-adrenergic receptors; the
receptor effects were not due to increased systemic toxicity or cholinesterase inhibition, nor to altered
chlorpyrifos pharmacokinetics. Further, the deficits were not secondary adaptations to presynaptic
hyperinnervation/hyperactivity, as there were significant deficits in presynaptic norepinephrine levels
that would serve to augment the functional consequence of receptor deficits. The pretreatments also
altered development of cerebrocortical noradrenergic circuits, but with a different overall pattern,
reflecting the dissimilar developmental stages of the regions at the time of exposure. However, in each
case the net effects represented a change in the developmental trajectory of noradrenergic circuits,
rather than simply a continuation of an initial injury. Our results point to the ability of prenatal drug
exposure to create a subpopulation with heightened vulnerability to environmental neurotoxicants.
PMID:26419632
155. Prenatal drug exposures sensitize noradrenergic circuits to subsequent disruption by chlorpyrifos.
PubMed
Slotkin, Theodore A; Skavicus, Samantha; Seidler, Frederic J
2015-12-02
We examined whether nicotine or dexamethasone, common prenatal drug exposures, sensitize the
developing brain to chlorpyrifos. We gave nicotine to pregnant rats throughout gestation at a dose
(3mg/kg/day) producing plasma levels typical of smokers; offspring were then given chlorpyrifos on
postnatal days 1-4, at a dose (1mg/kg) that produces minimally-detectable inhibition of brain
cholinesterase activity. In a parallel study, we administered dexamethasone to pregnant rats on
gestational days 17-19 at a standard therapeutic dose (0.2mg/kg) used in the management of preterm
labor, followed by postnatal chlorpyrifos. We evaluated cerebellar noradrenergic projections, a known
target for each agent, and contrasted the effects with those in the cerebral cortex. Either drug
augmented the effect of chlorpyrifos, evidenced by deficits in cerebellar Î²-adrenergic receptors; the
receptor effects were not due to increased systemic toxicity or cholinesterase inhibition, nor to altered
chlorpyrifos pharmacokinetics. Further, the deficits were not secondary adaptations to presynaptic
hyperinnervation/hyperactivity, as there were significant deficits in presynaptic norepinephrine levels
that would serve to augment the functional consequence of receptor deficits. The pretreatments also
altered development of cerebrocortical noradrenergic circuits, but with a different overall pattern,
reflecting the dissimilar developmental stages of the regions at the time of exposure. However, in each
case the net effects represented a change in the developmental trajectory of noradrenergic circuits,
rather than simply a continuation of an initial injury. Our results point to the ability of prenatal drug
exposure to create a subpopulation with heightened vulnerability to environmental neurotoxicants.
Copyright Â© 2015 Elsevier Ireland Ltd. All rights reserved.
156. Conditional Depletion of Hippocampal Brain-Derived Neurotrophic Factor Exacerbates

Neuropathology in a Mouse Model of Alzheimer's Disease.
PubMed
Braun, David J; Kalinin, Sergey; Feinstein, Douglas L
2017-01-01
Damage occurring to noradrenergic neurons in the locus coeruleus (LC) contributes to the evolution of
neuroinflammation and neurodegeneration in a variety of conditions and diseases. One cause of LC
damage may be loss of neurotrophic support from LC target regions. We tested this hypothesis by
conditional unilateral knockout of brain-derived neurotrophic factor (BDNF) in adult mice. To
evaluate the consequences of BDNF loss in the context of neurodegeneration, the mice harbored
familial mutations for human amyloid precursor protein and presenilin-1. In these mice, BDNF
depletion reduced tyrosine hydroxylase staining, a marker of noradrenergic neurons, in the rostral LC.
BDNF depletion also reduced noradrenergic innervation in the hippocampus, the frontal cortex, and
molecular layer of the cerebellum, assessed by staining for dopamine beta hydroxylase. BDNF
depletion led to an increase in cortical amyloid plaque numbers and size but was without effect on
plaque numbers in the striatum, a site with minimal innervation from the LC. Interestingly, cortical
Iba1 staining for microglia was reduced by BDNF depletion and was correlated with reduced
dopamine beta hydroxylase staining. These data demonstrate that reduction of BDNF levels in an LC
target region can cause retrograde damage to LC neurons, leading to exacerbation of neuropathology
in distinct LC target areas. Methods to reduce BDNF loss or supplement BDNF levels may be of value
to reduce neurodegenerative processes normally limited by LC noradrenergic activities.
157. Conditional Depletion of Hippocampal Brain-Derived Neurotrophic Factor Exacerbates

Neuropathology in a Mouse Model of Alzheimerâ€™s Disease
PubMed Central
Braun, David J.; Kalinin, Sergey
2017-01-01
Damage occurring to noradrenergic neurons in the locus coeruleus (LC) contributes to the evolution of
neuroinflammation and neurodegeneration in a variety of conditions and diseases. One cause of LC
damage may be loss of neurotrophic support from LC target regions. We tested this hypothesis by
conditional unilateral knockout of brain-derived neurotrophic factor (BDNF) in adult mice. To
evaluate the consequences of BDNF loss in the context of neurodegeneration, the mice harbored
familial mutations for human amyloid precursor protein and presenilin-1. In these mice, BDNF
depletion reduced tyrosine hydroxylase staining, a marker of noradrenergic neurons, in the rostral LC.
BDNF depletion also reduced noradrenergic innervation in the hippocampus, the frontal cortex, and
molecular layer of the cerebellum, assessed by staining for dopamine beta hydroxylase. BDNF
depletion led to an increase in cortical amyloid plaque numbers and size but was without effect on
plaque numbers in the striatum, a site with minimal innervation from the LC. Interestingly, cortical
Iba1 staining for microglia was reduced by BDNF depletion and was correlated with reduced
dopamine beta hydroxylase staining. These data demonstrate that reduction of BDNF levels in an LC
target region can cause retrograde damage to LC neurons, leading to exacerbation of neuropathology
in distinct LC target areas. Methods to reduce BDNF loss or supplement BDNF levels may be of value
to reduce neurodegenerative processes normally limited by LC noradrenergic activities.
PMID:28266222
158. Adaptations in Locus Coeruleus Induced by Post-Traumatic Stress Disorder
2013-11-01
optogenetics, channelrhodopsin-2, fear conditioning, pacemaking , calcium, synaptic plasticity,

corticotropin-releasing factor (CRF), endoplasmic...neurons revealed tonic, pacemaking activity was
accompanied by an underlying membrane potential oscillation that was sensitive to the
dihydropyridine...prominent, opening of these channels was not necessary to sustain normal
pacemaking at rest. However, these channels help support LC spiking during
159. Autoradiographic analysis of alpha 1-noradrenergic receptors in the human brain postmortem. Effect
of suicide
SciTech Connect
Gross-Isseroff, R.; Dillon, K.A.; Fieldust, S.J.
In vitro quantitative autoradiography of alpha 1-noradrenergic receptors, using tritiated prazosin as a

ligand, was performed on 24 human brains postmortem. Twelve brains were obtained from suicide
victims and 12 from matched controls. We found significant lower binding to alpha 1 receptors in
several brain regions of the suicide group as compared with matched controls. This decrease in
receptor density was evident in portions of the prefrontal cortex, as well as the temporal cortex and in
the caudate nucleus. Age, sex, presence of alcohol, and time of death to autopsy did not affect prazosin
binding, in our sample, as measuredmoreÂ Â» by autoradiography.Â«Â less
160. One-single physical exercise session after object recognition learning promotes memory persistence
through hippocampal noradrenergic mechanisms.
PubMed
da Silva de Vargas, Liane; Neves, Ben-Hur Souto das; Roehrs, Rafael; Izquierdo, IvÃ¡n; Mello-
Carpes, PÃ¢mela
2017-06-30
Previously we showed the involvement of the hippocampal noradrenergic system in the consolidation
and persistence of object recognition (OR) memory. Here we show that one-single physical exercise
session performed immediately after learning promotes OR memory persistence and increases
norepinephrine levels in the hippocampus. Additionally, effects of exercise on memory are avoided by
an intra-hippocampal beta-adrenergic antagonist infusion. Taken together, these results suggest that
exercise effects on memory can be related to noradrenergic mechanisms and acute physical exercise
can be a non-pharmacological intervention to assist memory consolidation and persistence, with few or
no side effects. Copyright Â© 2017 Elsevier B.V. All rights reserved.
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161. Dopamine modulates male sexual behavior in Japanese quail in part via actions on noradrenergic
receptors.
PubMed
Cornil, Charlotte A; Dejace, Christel; Ball, Gregory F; Balthazart, Jacques
2005-08-30
In rats, dopamine (DA) facilitates male sexual behavior through its combined action on D1- and D2-
like receptors, in the medial preoptic area (MPOA) as well as other brain areas. In Japanese quail,
systemic injections of dopaminergic drugs suggested a similar pharmacology but central injections
have never been performed. Recent electrophysiological experiments demonstrated that DA effects in
the MPOA of quail are mediated mainly through the activation of alpha2-noradrenergic receptors.
Previous studies of DA action on behavior used specific dopaminergic agonists/antagonists and
therefore unintentionally avoided the potential cross-reaction with alpha2-receptors. The present study
was thus designed to investigate directly the effects of DA on male sexual behavior and to test whether
the interaction of DA with heterologous receptors affects this behavior. Intracerebroventricular (i.c.v.)
injection of DA or NE inhibited copulation in a dose-dependent manner. Systemic injections of
yohimbine, an alpha2-noradrenergic antagonist, modulated copulation in a bimodal manner depending
on the dose injected. Interestingly, a behaviorally ineffective dose of yohimbine markedly reduced the
inhibitory effects of DA when injected 15min before. Together, these results show for the first time
that i.c.v. injections of DA itself inhibit male sexual behavior in quail and suggest that the interaction
of DA with alpha2-receptors has behavioral significance.
162. Peripheral markers of serotonergic and noradrenergic function in post-pubertal, caucasian males with
autistic disorder.
PubMed
Croonenberghs, J; Delmeire, L; Verkerk, R; Lin, A H; Meskal, A; Neels, H; Van der Planken, M;

Scharpe, S; Deboutte, D; Pison, G; Maes, M
2000-03-01
Some studies have suggested that disorders in the peripheral and central metabolism of serotonin (5-
HT) and noradrenaline may play a role in the pathophysiology of autistic disorder. This study
examines serotonergic and noradrenergic markers in a study group of 13 male, post-pubertal, caucasian
autistic patients (age 12-18 y; I.Q. > 55) and 13 matched volunteers. [3H]-paroxetine binding Kd
values were significantly higher in patients with autism than in healthy volunteers. Plasma
concentrations of tryptophan, the precursor of 5-HT, were significantly lower in autistic patients than
in healthy volunteers. There were no significant differences between autistic and normal children in
the serum concentrations of 5-HT, or the 24-hr urinary excretion of 5-hydroxy-indoleacetic acid (5-
HIAA), adrenaline, noradrenaline, and dopamine. There were no significant differences in [3H]-
rauwolscine binding Bmax or Kd values, or in the serum concentrations of tyrosine, the precursor of
noradrenaline, between both study groups. There were highly significant positive correlations between
age and 24-hr urinary excretion of 5-HIAA and serum tryptophan. The results suggest that: 1)
serotonergic disturbances, such as defects in the 5-HT transporter system and lowered plasma
tryptophan, may play a role in the pathophysiology of autism; 2) autism is not associated with
alterations in the noradrenergic system; and 3) the metabolism of serotonin in humans undergoes
significant changes between the ages of 12 and 18 years.
163. Infusion of adrenergic receptor agonists and antagonists into the locus coeruleus and ventricular
system of the brain. Effects on swim-motivated and spontaneous motor activity.
PubMed
Weiss, J M; Simson, P G; Hoffman, L J; Ambrose, M J; Cooper, S; Webster, A
1986-04-01
These studies examined how pharmacological stimulation and blockade of alpha receptors would
affect active motor behavior in rats. In experiment I, alpha-2 receptor antagonists (piperoxane,
yohimbine) and agonists [clonidine, norepinephrine (NE)] were infused into various locations in the
ventricular system of the brain, including the locus coeruleus region, and motor activity was measured.
Activity was measured principally in a swim test but spontaneous (ambulatory) activity was also
recorded while drugs were being infused. When infused into the locus coeruleus region, small doses of
the antagonists piperoxane and yohimbine depressed activity in the swim test while infusion of the
agonists clonidine and NE had the opposite effect of stimulating activity. These effects were highly
specific to the region of the locus coeruleus, since infusions of these drugs into other nearby locations
in the ventricular system or use of larger doses had different, often opposite effects. This was
especially true of clonidine and NE which profoundly depressed activity when infused posterior to the
locus coeruleus, particularly over the dorsal vagal complex. Infusion of small doses of these drugs into
the lateral ventricle had effects similar to infusion into the locus coeruleus region, though less
pronounced. Changes in spontaneous motor activity were also observed, but this measure
differentiated the groups less well than did the swim test. In experiment II, the predominantly
postsynaptic receptor agonists isoproterenol (beta agonist) and phenylephrine (alpha-1 agonist) were
infused into the ventricular system. Since infusions of piperoxane and yohimbine into the locus
coeruleus that decreased activity in experiment I increase the release of NE by blocking alpha-2
inhibitory receptors on cell bodies and dendrites of the locus coeruleus, experiment II tested whether
ventricular infusion of predominantly postsynaptic receptor agonists would also decrease activity in
the swim test
164. Both a Nicotinic Single Nucleotide Polymorphism (SNP) and a Noradrenergic SNP Modulate Working
Memory Performance when Attention Is Manipulated
Greenwood, Pamela M.; Sundararajan, Ramya; Lin, Ming-Kuan; Kumar, Reshma; Fryxell, Karl J.;
Parasuraman, Raja
2009-01-01
We investigated the relation between the two systems of visuospatial attention and working memory
by examining the effect of normal variation in cholinergic and noradrenergic genes on working
memory performance under attentional manipulation. We previously reported that working memory
for location was impaired following large location precues,â€¦
165. Ilex paraguariensis Promotes Orofacial Pain Relief After Formalin Injection: Involvement of
Noradrenergic Pathway.
PubMed
de Carvalho, Eudislaine Fonseca; de Oliveira, Simone Kobe; Nardi, Viviane Koepp; Gelinski, Tathiana
Carla; Bortoluzzi, Marcelo Carlos; Maraschin, Marcelo; Nardi, Geisson Marcos
2016-03-01
Drinking mate or chimarrÃ£o, a hot infusion of Ilex paraguariensis (ILEX) leaves, is a common habit
in Southern South America that has a social and almost ritualistic role. It has been used as a stimulant
beverage in South America and analgesic in regions of Argentina for treatment of headache and others
painful inflammatory conditions such as arthritis and rheumatism. The aim of this study was to
evaluate the pharmacological activity of I. paraguariensis infusion (ILEX) on orofacial nociception
model induced by formalin, and study its mechanism of action. The analgesic effect of ILEX was
assessed through writhing test, paw formalin test, paw edema induced by carrageenan, and orofacial
pain induced by formalin. To study the action mechanism of ILEX, opioidergic, dopaminergic,
nitrergic, and adrenergic pathways were investigated. The high-performance liquid chromatography
analysis of ILEX infusion revealed caffeine and theobromine. The treatment with ILEX reduced the
number of writhing. However, it was effective neither in the formalin paw test nor in the paw edema
induced by carrageenan. Different from formalin paw test, ILEX was able to reduce the orofacial
reactivity to formalin in 31.8% (70.4 Â± 2.5 s; first phase), and 20% (127.3 Â± 18.9 s; second phase).
The analgesic effect of ILEX results from the modulation of noradrenergic pathways since prazosin
(Î±1-adrenoceptor antagonist, 0.15 mg/kg; intraperitoneal) reversed the analgesic effect of ILEX. The
present report demonstrates that analgesic effect of ILEX in orofacial formalin test is due mainly to
modulation of noradrenergic pathways. Ilex paraguariensis (ILEX) has been used as a stimulant
beverage in South America and analgesic in regions of Argentina for the treatment of headache and
others painful inflammatory conditions such arthritis and rheumatism.The aim of this study was to
evaluate the pharmacological activity of ILEX on orofacial nociception model induced by formalin,
and study its mechanism of
166. Cholinergic neurons of mouse intrinsic cardiac ganglia contain noradrenergic enzymes, norepinephrine
transporters, and the neurotrophin receptors tropomyosin-related kinase A and p75.
PubMed
Hoard, J L; Hoover, D B; Mabe, A M; Blakely, R D; Feng, N; Paolocci, N
2008-09-22
Half of the cholinergic neurons of human and primate intrinsic cardiac ganglia (ICG) have a dual
cholinergic/noradrenergic phenotype. Likewise, a large subpopulation of cholinergic neurons of the
mouse heart expresses enzymes needed for synthesis of norepinephrine (NE), but they lack the
vesicular monoamine transporter type 2 (VMAT2) required for catecholamine storage. In the present
study, we determined the full scope of noradrenergic properties (i.e. synthetic enzymes and
transporters) expressed by cholinergic neurons of mouse ICG, estimated the relative abundance of
neurons expressing different elements of the noradrenergic phenotype, and evaluated the colocalization
of cholinergic and noradrenergic markers in atrial nerve fibers. Stellate ganglia were used as a positive
control for noradrenergic markers. Using fluorescence immunohistochemistry and confocal
microscopy, we found that about 30% of cholinergic cell bodies contained tyrosine hydroxylase (TH),
including the activated form that is phosphorylated at Ser-40 (pSer40 TH). Dopamine beta-
hydroxylase (DBH) and norepinephrine transporter (NET) were present in all cholinergic somata,
indicating a wider capability for dopamine metabolism and catecholamine uptake. Yet, cholinergic
somata lacked VMAT2, precluding the potential for NE storage and vesicular release. In contrast to
cholinergic somata, cardiac nerve fibers rarely showed colocalization of cholinergic and noradrenergic
markers. Instead, these labels were closely apposed but clearly distinct from each other. Since
cholinergic somata expressed several noradrenergic proteins, we questioned whether these neurons
might also contain trophic factor receptors typical of noradrenergic neurons. Indeed, we found that all
cholinergic cell bodies of mouse ICG, like noradrenergic cell bodies of the stellate ganglia, contained
both tropomyosin-related kinase A (TrkA) and p75 neurotrophin receptors. Collectively, these findings
demonstrate that mouse intrinsic cardiac
167. Cholinergic neurons of mouse intrinsic cardiac ganglia contain noradrenergic enzymes, norepinephrine
transporters, and the neurotrophin receptors TrkA and p75
PubMed Central
Hoard, Jennifer L.; Hoover, Donald B.; Mabe, Abigail M.; Blakely, Randy D.; Feng, Ning; Paolocci,
Nazareno
2008-01-01
Half of the cholinergic neurons of human and primate intrinsic cardiac ganglia (ICG) have a dual
cholinergic/noradrenergic phenotype. Likewise, a large subpopulation of cholinergic neurons of the
mouse heart express enzymes needed for synthesis of norepinephrine (NE), but they lack the vesicular
monoamine transporter type 2 (VMAT2) required for catecholamine storage. In the present study, we
determined the full scope of noradrenergic properties (i.e., synthetic enzymes and transporters)
expressed by cholinergic neurons of mouse ICG, estimated the relative abundance of neurons
expressing different elements of the noradrenergic phenotype, and evaluated the colocalization of
cholinergic and noradrenergic markers in atrial nerve fibers. Stellate ganglia were used as a positive
control for noradrenergic markers. Using fluorescence immunohistochemistry and confocal
microscopy, we found that about 30% of cholinergic cell bodies contained tyrosine hydroxylase (TH),
including the activated form that is phosphorylated at Ser-40 (pSer40 TH). Dopamine Î²-hydroxylase
(DBH) and NE transporter (NET) were present in all cholinergic somata, indicating a wider capability
for dopamine metabolism and catecholamine uptake. Yet, cholinergic somata lacked VMAT2,
precluding the potential for NE storage and vesicular release. In contrast to cholinergic somata, cardiac
nerve fibers rarely showed colocalization of cholinergic and noradrenergic markers. Instead, these
labels were closely apposed but clearly distinct from each other. Since cholinergic somata expressed
several noradrenergic proteins, we questioned whether these neurons might also contain trophic factor
receptors typical of noradrenergic neurons. Indeed, we found that all cholinergic cell bodies of mouse
ICG, like noradrenergic cell bodies of the stellate ganglia, contained both tropomyosin-related kinase
A (TrkA) and p75 neurotrophin receptors. Collectively, these findings demonstrate that mouse intrinsic
cardiac neurons (ICNs
168. Stimulation of the noradrenergic system during memory formation impairs extinction learning but not
the disruption of reconsolidation.
PubMed
Soeter, Marieke; Kindt, Merel
2012-04-01
The noradrenergic system plays a critical role in the 'consolidation' of emotional memory. If we are to
target 'reconsolidation' in patients with anxiety disorders, the noradrenergic strengthening of fear
memory should not impair the disruption of reconsolidation. In Experiment I, we addressed this issue
using a differential fear conditioning procedure allowing selective reactivation of one of two fear
associations. First, we strengthened fear memory by administering an Î±(2)-adrenergic receptor
antagonist (ie, yohimbine HCl; double-blind placebo-controlled study) 30 min before acquisition (time
for peak value yohimbine HCl <1 h). Next, the reconsolidation of one of the fear associations was
manipulated by administering a Î²-adrenergic receptor antagonist (ie, propranolol HCl) 90 min before
its selective reactivation (time for peak value propranolol HCl <2 h). In Experiment II, we
administered propranolol HCl after reactivation of the memory to rule out a possible effect of the
pharmacological manipulation on the memory retrieval itself. The excessive release of noradrenaline
during memory formation not only delayed the process of extinction 48 h later, but also triggered
broader fear generalization. Yet, the Î²-adrenergic receptor blocker during reconsolidation selectively
'neutralized' the fear-arousing aspects of the noradrenergic-strengthened memory and undermined the
generalization of fear. We observed a similar reduction in fear responding when propranolol HCl was
administered after reactivation of the memory. The present findings demonstrate the involvement of
noradrenergic modulation in the formation as well as generalization of human fear memory. Given that
the noradrenergic strengthening of fear memory impaired extinction learning but not the disruption of
reconsolidation, our findings may have implications for the treatment of anxiety disorders.
169. Sex differences in the expression of estrogen receptor alpha within noradrenergic neurons in the sheep
brain stem.
PubMed
Rose, J L; Hamlin, A S; Scott, C J
2014-10-01
In female sheep, high levels of estrogen exert a positive feedback action on gonadotropin releasing
hormone (GnRH) secretion to stimulate a surge in luteinizing hormone (LH) secretion. Part of this
action appears to be via brain stem noradrenergic neurons. By contrast, estrogen action in male sheep
has a negative feedback action to inhibit GnRH and LH secretion. To investigate whether part of this
sex difference is due to differences in estrogen action in the brain stem, we tested the hypothesis that
the distribution of estrogen receptor Î± (ERÎ±) within noradrenergic neurons in the brain stem differs
between rams and ewes. To determine the distribution of ERÎ±, we used double-label fluorescence
immunohistochemistry for dopamine Î²-Hydroxylase, as a marker for noradrenergic and adrenergic
cells, and ERÎ±. In the ventrolateral medulla (A1 region), most ERÎ±-immunoreactive (-ir) cells were
located in the caudal part of the nucleus. Overall, there were more ERÎ±-ir cells in rams than ewes, but
the proportion of double-labeled cells was did not differ between sexes. Much greater numbers of
ERÎ±-ir cells were found in the nucleus of the solitary tract (A2 region), but <10% were double labeled
and there were no sex differences. The majority of ERÎ±-labeled cells in this nucleus was located in
the more rostral areas. ERÎ±-labeled cells were found in several rostral brain stem regions but none of
these were double labeled and so were not quantified. Because there was no sex difference in the
number of ERÎ±-ir cells in the brain stem that were noradrenergic, the sex difference in the action of
estrogen on gonadotropin secretion in sheep is unlikely to involve actions on brain stem noradrenergic
cells. Crown Copyright Â© 2014. Published by Elsevier Inc. All rights reserved.
170. Close Vicinity of PrP Expressing Cells (FDC) with Noradrenergic Fibers in Healthy Sheep Spleen
PubMed Central
Lezmi, S.; Hunsmann, G.; Baron, T.
2001-01-01
In naturally and experimentally occurring scrapie in sheep, prions invade the immune system and
replicate in lymphoid organs. Here we analysed immunohistochemically, in seven spleens of 6-month-
old healthy sheep, the nature of the cells expressing prion protein (PrP) potentially supporting prion
replication, as well as their relationship with autonomic innervation. PrP was identified using either
RB1 rabbit antiserum or 4F2 monoclonal antibody directed against AA 108â€“123 portion of the
bovine and AA 79â€“92 of human prion protein respectively. Using double labelling analysis, we
demonstrated that PrPc is expressed by follicular dendritic cells using a specific monoclonal antibody
(CNA42). We also showed the close vicinity of these PrP expressing cells with noradrenergic fibers,
using a polyclonal tyrosine hydroxylase antibody. Our results may help the study of the cellular
requirements for the possible neuroinvasion from the spleen. PMID:11785673
171. Involvement of brain ketone bodies and the noradrenergic pathway in diabetic hyperphagia in rats.
PubMed
Iwata, Kinuyo; Kinoshita, Mika; Yamada, Shunji; Imamura, Takuya; Uenoyama, Yoshihisa;
Tsukamura, Hiroko; Maeda, Kei-Ichiro
2011-03-01
Uncontrolled type 1 diabetes leads to hyperphagia and severe ketosis. This study was conducted to test
the hypothesis that ketone bodies act on the hindbrain as a starvation signal to induce diabetic
hyperphagia. Injection of an inhibitor of monocarboxylate transporter 1, a ketone body transporter, into
the fourth ventricle normalized the increase in food intake in streptozotocin (STZ)-induced diabetic
rats. Blockade of catecholamine synthesis in the hypothalamic paraventricular nucleus (PVN) also
restored food intake to normal levels in diabetic animals. On the other hand, hindbrain injection of the
ketone body induced feeding, hyperglycemia, and fatty acid mobilization via increased sympathetic
activity and also norepinephrine release in the PVN. This result provides evidence that hyperphagia in
STZ-induced type 1 diabetes is signaled by a ketone body sensed in the hindbrain, and mediated by
noradrenergic inputs to the PVN.
172. Voluntary exercise offers anxiolytic potential and amplifies galanin gene expression in the locus
coeruleus of the rat
PubMed Central
Sciolino, Natale R.; Dishman, Rodney K.; Holmes, Philip V.
2012-01-01
Although exercise improves anxiety in humans, it is controversial whether exercise is anxiolytic in

rodents. We tested the hypothesis that stress influences the effect of exercise on anxiety-like and
defensive behaviors. To explore the neurobiological mechanisms of exercise, we also examined
whether exercise alters gene expression for the stress-related peptide galanin. Rats were housed in the
presence or absence of a running wheel for 21 d. A subset of these rats were (1) not injected or
received a single high, dose of the Î²-carboline FG7142 (inverse agonist at the benzodiazepine receptor
site) immediately prior to testing or (2) were injected repeatedly with vehicle or FG7142 during the
last 10 d of exercise. On day 22, anxiety-like and defensive behaviors were measured in the elevated
plus maze, shock probe defensive burying, and defensive withdrawal tests. Locus coeruleus prepro-
galanin mRNA was measured by in situ hybridization. Exercise and sedentary rats that were not
injected exhibited similar behavior in all tests, whereas FG7142 injected immediately prior to the test
battery produced intense avoidance and immobility consistent with an anxiety-like response. However,
exercise produced anxiolytic-like and active defensive behaviors in the test battery relative to the
sedentary condition in rats injected repeatedly with vehicle or FG7142. Exercise also increased prepro-
galanin mRNA in the locus coeruleus relative to sedentary controls. These data suggest that the
emergence of enhanced adaptive behavior after chronic voluntary exercise is influenced by stress. Our
data support a role for galanin in the beneficial consequences of wheel running. PMID:22580167
173. Activation state of the hyperpolarization-activated current modulates temperature-sensitivity of firing

in locus coeruleus neurons from bullfrogs.
PubMed
Santin, Joseph M; Hartzler, Lynn K
2015-06-15
Locus coeruleus neurons of anuran amphibians contribute to breathing control and have spontaneous
firing frequencies that, paradoxically, increase with cooling. We previously showed that cooling
inhibits a depolarizing membrane current, the hyperpolarization-activated current (I h) in locus
coeruleus neurons from bullfrogs, Lithobates catesbeianus (Santin JM, Watters KC, Putnam RW,
Hartzler LK. Am J Physiol Regul Integr Comp Physiol 305: R1451-R1464, 2013). This suggests an
unlikely role for I h in generating cold activation, but led us to hypothesize that inhibition of I h by
cooling functions as a physiological brake to limit the cold-activated response. Using whole cell
electrophysiology in brain slices, we employed 2 mM Cs(+) (an I h antagonist) to isolate the role of I h
in spontaneous firing and cold activation in neurons recorded with either control or I h agonist (cyclic
AMP)-containing artificial intracellular fluid. I h did not contribute to the membrane potential (V m)
and spontaneous firing at 20Â°C. Although voltage-clamp analysis confirmed that cooling inhibits I h,
its lack of involvement in setting baseline firing and V m precluded its ability to regulate cold
activation as hypothesized. In contrast, neurons dialyzed with cAMP exhibited greater baseline firing
frequencies at 20Â°C due to I h activation. Our hypothesis was supported when the starting level of I h
was enhanced by elevating cAMP because cold activation was converted to more ordinary cold
inhibition. These findings indicate that situations leading to enhancement of I h facilitate firing at
20Â°C, yet the hyperpolarization associated with inhibiting a depolarizing cation current by cooling
blunts the net V m response to cooling to oppose normal cold-depolarizing factors. This suggests that
the influence of I h activation state on neuronal firing varies in the poikilothermic neuronal
environment. Copyright Â© 2015 the American Physiological Society.
174. Initiating or blocking locomotion in spinal cats by applying noradrenergic drugs to restricted lumbar
spinal segments.
PubMed
Marcoux, J; Rossignol, S
2000-11-15
After an acute low thoracic spinal transection (T13), cats can be made to walk with the hindlimbs on a
treadmill with clonidine, an alpha2-noradrenergic agonist. Because previous studies of neonatal rat
spinal cord in vitro suggest that the most important lumbar segments for rhythmogenesis are L1-L2,
we investigated the role of various lumbar segments in the initiation of walking movements on a
treadmill of adult cats spinalized (T13), 5-6 d earlier. The locomotor activities were evaluated from
electromyographic and video recordings. The results show that: (1) localized topical application of
clonidine in restricted baths over either the L3-L4 or the L5-L7 segments was sufficient to induce
walking movements. Yohimbine, an alpha2-noradrenergic antagonist, could block this locomotion
when applied over L3-L4 or L5-L7; (2) microinjections of clonidine in one or two lumbar segments
from L3 to L5 could also induce locomotion; (3) after an intravenous injection of clonidine,
locomotion was blocked by microinjections of yohimbine in segments L3, L4, or L5 but not if the
injection was in L6; (4) locomotion was also blocked in all cases by additional spinal transections at
L3 or L4. These results show that it is possible to initiate walking in the adult spinal cat with a
pharmacological stimulation of a restricted number of lumbar segments and also that the integrity of
the L3-L4 segments is necessary to sustain the locomotor activity.
175. Does Growth Impairment Underlie the Adverse Effects of Dexamethasone on Development of
Noradrenergic Systems?
PubMed
Slotkin, Theodore A; Ko, Ashley; Seidler, Frederic J
2018-06-20
Glucocorticoids are given in preterm labor to prevent respiratory distress but these agents evoke
neurobehavioral deficits in association with reduced brain region volumes. To determine whether the
neurodevelopmental effects are distinct from growth impairment, we gave developing rats
dexamethasone at doses below or within the therapeutic range (0.05, 0.2 or 0.8â€¯mg/kg) at different
stages: gestational days (GD) 17-19, postnatal days (PN) 1-3 or PN7-9. In adolescence and adulthood,
we assessed the impact on noradrenergic systems in multiple brain regions, comparing the effects to
those on somatic growth or on brain region growth. Somatic growth was reduced with exposure in all
three stages, with greater sensitivity for the postnatal regimens; brain region growth was impaired to a
lesser extent. Norepinephrine content and concentration were reduced depending on the treatment
regimen, with a rank order of deficits of PN7-9 > PN1-3 > GD17-19. However, brain growth
impairment did not parallel reduced norepinephrine content in magnitude, dose threshold, sex or
regional selectivity, or temporal pattern, and even when corrected for reduced brain region weights
(norepinephrine per g tissue), the dexamethasone-exposed animals showed subnormal values.
Regression analysis showed that somatic growth impairment accounted for an insubstantial amount of
the reduction in norepinephrine content, and brain growth impairment accounted for only 12%,
whereas specific effects on norepinephrine accounted for most of the effect. The adverse effects of
dexamethasone on noradrenergic system development are not simply related to impaired somatic or
brain region growth, but rather include specific targeting of neurodifferentiation. Copyright Â© 2018.
Published by Elsevier B.V.
176. Noradrenergic Mechanisms of Arousalâ€™s Bidirectional Effects on Episodic Memory
PubMed Central
Clewett, David; Sakaki, Michiko; Nielsen, Shawn; Petzinger, Giselle; Mather, Mara
2016-01-01
Arousalâ€™s selective effects on cognition go beyond the simple enhancement of emotional stimuli,
sometimes enhancing and other times impairing processing of proximal neutral information. Past work
shows that arousal impairs encoding of subsequent neutral stimuli regardless of their top-down priority
via the engagement of Î²-adrenoreceptors. In contrast, retrograde amnesia induced by emotional
arousal can flip to enhancement when preceding neutral items are prioritized in top-down attention.
Whether Î²-adrenoreceptors also contribute to this retrograde memory enhancement of goal-relevant
neutral stimuli is unclear. In this pharmacological study, we administered 40mg of propranolol or
40mg of placebo to healthy young adults to examine whether emotional arousalâ€™s bidirectional
effects on declarative memory relies on Î²-adrenoreceptor activation. Following pill intake, participants
completed an emotional oddball task in which they were asked to prioritize a neutral object appearing
just before an emotional or neutral oddball image within a sequence of 7 neutral objects. Under
placebo, emotional oddballs impaired memory for lower priority oddball+1 objects but had no effect
on memory for high priority oddballâˆ’1 objects. Propranolol blocked this anterograde amnesic effect
of arousal. Emotional oddballs also enhanced selective memory trade-offs significantly more in the
placebo than drug condition, such that high priority oddballâˆ’1 objects were more likely to be
remembered at the cost of their corresponding lower priority oddball+1 objects under arousal. Lastly,
those who recalled more high priority oddballâˆ’1 objects preceding an emotional versus neutral
oddball image showed greater increases in salivary alpha-amylase, a biomarker of noradrenergic
system activation, across the task. Together these findings suggest that different noradrenergic
mechanisms contribute to the anterograde and retrograde mnemonic effects of arousal on proximal
neutral memoranda. PMID
177. Noradrenergic activation of the basolateral amygdala maintains hippocampus-dependent accuracy of

remote memory
PubMed Central
Atucha, Erika; Vukojevic, Vanja; Fornari, Raquel V.; Ronzoni, Giacomo; Demougin, Philippe; Peter,
Fabian; Atsak, Piray; Coolen, Marcel W.; Papassotiropoulos, Andreas; McGaugh, James L.; de
Quervain, Dominique J.-F.; Roozendaal, Benno
2017-01-01
Emotional enhancement of memory by noradrenergic mechanisms is well-described, but the long-term

consequences of such enhancement are poorly understood. Over time, memory traces are thought to
undergo a neural reorganization, that is, a systems consolidation, during which they are, at least partly,
transferred from the hippocampus to neocortical networks. This transfer is accompanied by a decrease
in episodic detailedness. Here we investigated whether norepinephrine (NE) administration into the
basolateral amygdala after training on an inhibitory avoidance discrimination task, comprising two
distinct training contexts, alters systems consolidation dynamics to maintain episodic-like accuracy
and hippocampus dependency of remote memory. At a 2-d retention test, both saline- and NE-treated
rats accurately discriminated the training context in which they had received footshock. Hippocampal
inactivation with muscimol before retention testing disrupted discrimination of the shock context in
both treatment groups. At 28 d, saline-treated rats showed hippocampus-independent retrieval and lack
of discrimination. In contrast, NE-treated rats continued to display accurate memory of the
shockâ€“context association. Hippocampal inactivation at this remote retention test blocked episodic-
like accuracy and induced a general memory impairment. These findings suggest that the NE treatment
altered systems consolidation dynamics by maintaining hippocampal involvement in the memory. This
shift in systems consolidation was paralleled by time-regulated DNA methylation and transcriptional
changes of memory-related genes, namely Reln and PkmÎ¶, in the hippocampus and neocortex. The
findings provide evidence suggesting that consolidation of emotional memories by noradrenergic
mechanisms alters systems consolidation dynamics and, as a consequence, influences the maintenance
of long-term episodic-like accuracy of memory. PMID:28790188
178. Noradrenergic activation of the basolateral amygdala maintains hippocampus-dependent accuracy of

remote memory.
PubMed
Atucha, Erika; Vukojevic, Vanja; Fornari, Raquel V; Ronzoni, Giacomo; Demougin, Philippe; Peter,
Fabian; Atsak, Piray; Coolen, Marcel W; Papassotiropoulos, Andreas; McGaugh, James L; de
Quervain, Dominique J-F; Roozendaal, Benno
2017-08-22
Emotional enhancement of memory by noradrenergic mechanisms is well-described, but the long-term

consequences of such enhancement are poorly understood. Over time, memory traces are thought to
undergo a neural reorganization, that is, a systems consolidation, during which they are, at least partly,
transferred from the hippocampus to neocortical networks. This transfer is accompanied by a decrease
in episodic detailedness. Here we investigated whether norepinephrine (NE) administration into the
basolateral amygdala after training on an inhibitory avoidance discrimination task, comprising two
distinct training contexts, alters systems consolidation dynamics to maintain episodic-like accuracy
and hippocampus dependency of remote memory. At a 2-d retention test, both saline- and NE-treated
rats accurately discriminated the training context in which they had received footshock. Hippocampal
inactivation with muscimol before retention testing disrupted discrimination of the shock context in
both treatment groups. At 28 d, saline-treated rats showed hippocampus-independent retrieval and lack
of discrimination. In contrast, NE-treated rats continued to display accurate memory of the shock-
context association. Hippocampal inactivation at this remote retention test blocked episodic-like
accuracy and induced a general memory impairment. These findings suggest that the NE treatment
altered systems consolidation dynamics by maintaining hippocampal involvement in the memory. This
shift in systems consolidation was paralleled by time-regulated DNA methylation and transcriptional
changes of memory-related genes, namely Reln and Pkm Î¶, in the hippocampus and neocortex. The
findings provide evidence suggesting that consolidation of emotional memories by noradrenergic
mechanisms alters systems consolidation dynamics and, as a consequence, influences the maintenance
of long-term episodic-like accuracy of memory.
179. Is the Noradrenergic Symptom Cluster a Valid Construct in Adjunctive Treatment of Major Depressive
Disorder?
PubMed
Stauffer, Virginia L; Liu, Peng; Goldberger, Celine; Marangell, Lauren B; Nelson, Craig; Gorwood,
Philip; Fava, Maurizio
2017-03-01
To identify symptoms potentially representative of a noradrenergic symptom cluster as possible

predictors of response to the selective norepinephrine reuptake inhibitor (NRI) edivoxetine when used
as monotherapy or adjunctive treatment in patients with DSM-IV-TR major depressive disorder
(MDD). Pooled data from 4 adjunctive treatment trials (selective serotonin reuptake inhibitor [SSRI] +
edivoxetine 6-18 mg/d vs SSRI + placebo; N = 2,066) and data from 1 monotherapy trial (edivoxetine
6-18 mg/d versus placebo; N = 495) were used to identify predictors of response related to
noradrenergic symptoms using a resampling-based ensemble tree method. The trials were conducted
from 2008 to 2013. In the pooled adjunctive trials, no subgroup was identified that demonstrated a
greater edivoxetine-placebo treatment difference than the overall patient cohort. In the edivoxetine
monotherapy trial, no subgroup showing greater mean edivoxetine-placebo differences on the
Montgomery-Asberg Depression Rating Scale versus the overall patient cohort was identified; a
subgroup (67%) with high bâ€‹aseline Massachusetts General Hospital Cognitive and Physical
Functioning Questionnaire (CPFQ) total score (â‰¥ 28) showed statistically significantly (P = .02)
greater mean edivoxetine-placebo differences on the Sheehan Disability Scale versus the overall
patient cohort, and subgroups with baseline CPFQ total score â‰¥ 28 (65%), CPFQ cognition
dimension score â‰¥ 16 (63%), or CPFQ physical dimension score â‰¥ 13 (59%) showed
statistically significantly (P â‰¤ .025) greater mean edivoxetine-placebo differences on the CPFQ
total score versus the overall patient cohort. While we could not identify symptoms predictive of
response to the selective NRI edivoxetine used as adjunctive treatment, impaired cognition and
physical symptoms may predict greater improvement during monotherapy. ClinicalTrials.gov
identifiers: NCT00840034, NCT01173601, NCT01187407, NCT01185340, NCT00795821. Â©
Copyright 2017
180. Examining the effect of the CaMKII inhibitor administration in the locus coeruleus on the naloxone-
precipitated morphine withdrawal signs in rats.
PubMed
Navidhamidi, M; Semnanian, S; Javan, M; Goudarzvand, M; Rohampour, K; Azizi, H
2012-01-15
Drug addiction is an occurrence with physiological, psychological, and social outcomes. Repeated
drug exposure causes neuronal adaptations and dependency. It has been shown that CaMKIIÎ± enzyme
contributes to morphine dependency. The locus coeruleus nucleus has been implied in the morphine
withdrawal syndrome. This research focuses on the behavioral and molecular adaptations that occur in
the locus coeruleus neurons in response to the chronic morphine exposure. Adult male Wistar rats were
injected by morphine sulfate (10 mg/kg/s.c.) at an interval of 12 h for a period of nine subsequent days.
On the tenth day, naloxone (1 mg/kg/i.p.) was injected 2 h after the morphine administration. Somatic
withdrawal signs were investigated for 30 min. We concluded that the inhibition of CaMKIIÎ± by
administration of KN-93, the specific inhibitor of this enzyme, significantly attenuated some of the
withdrawal signs. In molecular method, the expression of CaMKIIÎ± protein has been enhanced in
locus coeruleus of the morphine dependent rats. These findings indicate that CaMKIIÎ± may be
involved in the modulation of the naloxone-induced withdrawal syndrome, and treatment with KN-93
may have some effects on this system. Copyright Â© 2011 Elsevier B.V. All rights reserved.
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181. Photosensory transduction in unicellular eukaryotes: a comparison between related ciliates

Blepharisma japonicum and Stentor coeruleus and photoreceptor cells of higher organisms.
PubMed
Sobierajska, Katarzyna; Fabczak, Hanna; Fabczak, StanisÅ‚aw
2006-06-01
Blepharisma japonicum and Stentor coeruleus are related ciliates, conspicuous by their
photosensitivity. They are capable of avoiding illuminated areas in the surrounding medium, gathering
exclusively in most shaded places (photodispersal). Such behaviour results mainly from motile
photophobic response occurring in ciliates. This light-avoiding response is observed during a relatively
rapid increase in illumination intensity (light stimulus) and consists of cessation of cell movement, a
period of backward movement (ciliary reversal), followed by a forward swimming, usually in a new
direction. The photosensitivity of ciliates is ascribed to their photoreceptor system, composed of
pigment granules, containing the endogenous photoreceptor -- blepharismin in Blepharisma
japonicum, and stentorin in Stentor coeruleus. A light stimulus, applied to both ciliates activates
specific stimulus transduction processes leading to the electrical changes at the plasma membrane,
correlated with a ciliary reversal during photophobic response. These data indicate that both ciliates
Blepharisma japonicum and Stentor coeruleus, the lower eukaryotes, are capable of transducing the
perceived light stimuli in a manner taking place in some photoreceptor cells of higher eukaryotes.
Similarities and differences concerning particular stages of light transduction in eukaryotes at different
evolutional levels are discussed in this article.
182. Glutamatergic transmission in the nucleus of the solitary tract modulates memory through influences
on amygdala noradrenergic systems.
PubMed
Miyashita, Teiko; Williams, Cedric L
2002-02-01
The authors examined whether glutamate release from the vagus nerve onto the nucleus of the solitary
tract (NTS) is one mechanism by which the vagus influences memory and neural activity in limbic
structures. Rats trained to drink from a spout were given a footshock (0.35 mA) on Day 5 after
approaching the spout. Phosphate-buffered saline or 5.0, 50.0, or 100.0 nmol/0.5 microl glutamate was
then infused into the NTS. Glutamate (5.0 or 50.0 nmol) significantly enhanced memory on the
retention test. In Experiment 2, this effect was attenuated by blocking noradrenergic receptors in the
amygdala with propranolol (0.3 microg/0.5 microl). Experiment 3 used in vivo microdialysis to
determine whether footshock plus glutamate (50.0 nmol) alters noradrenergic output in the amygdala.
These treatments caused a significant and long-lasting increase in amygdala noradrenergic
concentrations. The results indicate that glutamate may be one transmitter that conveys the effects of
vagal activation on brain systems that process memory.
183. Enhanced noradrenergic activity in the amygdala contributes to hyperarousal in an animal model of
PTSD.
PubMed
Ronzoni, Giacomo; Del Arco, Alberto; Mora, Francisco; Segovia, Gregorio
2016-08-01
Increased activity of the noradrenergic system in the amygdala has been suggested to contribute to the
hyperarousal symptoms associated with post-traumatic stress disorder (PTSD). However, only two
studies have examined the content of noradrenaline or its metabolites in the amygdala of rats
previously exposed to traumatic stress showing inconsistent results. The aim of this study was to
investigate the effects of an inescapable foot shock (IFS) procedure (1) on reactivity to novelty in an
open-field (as an index of hyperarousal), and (2) on noradrenaline release in the amygdala during an
acute stress. To test the role of noradrenaline in amygdala, we also investigated the effects of
microinjections of propranolol, a Î²-adrenoreceptor antagonist, and clenbuterol, a Î²-adrenoreceptor
agonist, into the amygdala of IFS and control animals. Finally, we evaluated the expression of mRNA
levels of Î²-adrenoreceptors (Î²1 and Î²2) in the amygdala, the hippocampus and the prefrontal cortex.
Male Wistar rats (3 months) were stereotaxically implanted with bilateral guide cannulae. After
recovering from surgery, animals were exposed to IFS (10 shocks, 0.86mA, and 6s per shock) and
seven days later either microdialysis or microinjections were performed in amygdala. Animals exposed
to IFS showed a reduced locomotion compared to non-shocked animals during the first 5min in the
open-field. In the amygdala, IFS animals showed an enhanced increase of noradrenaline induced by
stress compared to control animals. Bilateral microinjections of propranolol (0.5Î¼g) into the
amygdala one hour before testing in the open-field normalized the decreased locomotion observed in
IFS animals. On the other hand, bilateral microinjections of clenbuterol (30ng) into the amygdala of
control animals did not change the exploratory activity induced by novelty in the open field. IFS
modified the mRNA expression of Î²1 and Î²2 adrenoreceptors in the prefrontal cortex and the
hippocampus. These results
184. Slitrk1-deficient mice display elevated anxiety-like behavior and noradrenergic abnormalities.
PubMed
Katayama, K; Yamada, K; Ornthanalai, V G; Inoue, T; Ota, M; Murphy, N P; Aruga, J
2010-02-01
Mutations in SLITRK1 are found in patients with Tourette's syndrome and trichotillomania. SLITRK1
encodes a transmembrane protein containing leucine-rich repeats that is produced predominantly in the
nervous system. However, the role of this protein is largely unknown, except that it can modulate
neurite outgrowth in vitro. To clarify the role of Slitrk1 in vivo, we developed Slitrk1-knockout mice
and analyzed their behavioral and neurochemical phenotypes. Slitrk1-deficient mice exhibited elevated
anxiety-like behavior in the elevated plus-maze test as well as increased immobility time in forced
swimming and tail suspension tests. Neurochemical analysis revealed that Slitrk1-knockout mice had
increased levels of norepinephrine and its metabolite 3-methoxy-4-hydroxyphenylglycol.
Administration of clonidine, an alpha2-adrenergic agonist that is frequently used to treat patients with
Tourette's syndrome, attenuated the anxiety-like behavior of Slitrk1-deficient mice in the elevated
plus-maze test. These results lead us to conclude that noradrenergic mechanisms are involved in the
behavioral abnormalities of Slitrk1-deficient mice. Elevated anxiety due to Slitrk1 dysfunction may
contribute to the pathogenesis of neuropsychiatric diseases such as Tourette's syndrome and
trichotillomania.
185. DIAZINON AND PARATHION DIVERGE IN THEIR EFFECTS ON DEVELOPMENT OF

NORADRENERGIC SYSTEMS
PubMed Central
Slotkin, Theodore A.; Skavicus, Samantha; Seidler, Frederic J.
2017-01-01
Organophosphate pesticides elicit developmental neurotoxicity through mechanisms over and above
their shared property as cholinesterase inhibitors. We compared the consequences of neonatal exposure
(postnatal days PN1-4) to diazinon or parathion on development of norepinephrine systems in rat
brain, using treatments designed to produce equivalent effects on cholinesterase, straddling the
threshold for barely-detectable inhibition. Norepinephrine levels were measured throughout
development from the immediate posttreatment period (PN5), to early adolescence (PN30), young
adulthood (PN60) and full adulthood (PN100); we assessed multiple brain regions containing all the
major noradrenergic synaptic projections. Diazinon elicited a significant overall deficit of
norepinephrine, whereas parathion produced a net increase. The effects were not immediately apparent
(PN5) but rather emerged over the course of development, indicating that the organophosphate effects
represent alteration of the trajectory of development, not just continuance of an initial injury. There
were no comparable effects on Î²-adrenergic receptors, indicating that the presynaptic changes were
not an adaptation to an underlying, primary effect on postsynaptic receptor signaling. Because we used
the cholinesterase inhibition benchmark, the absolute dose of diazinon was much higher than that of
parathion, since the latter is a more potent cholinesterase inhibitor. Our results are consistent with the
growing evidence that the various organophosphates can differ in their impact on brain development
and that consequently, the cholinesterase benchmark is an inadequate predictor of adverse
neurodevelopmental effects. PMID:28235599
186. Dopaminergic and Noradrenergic Contributions to Functionality in ADHD: The Role of

Methylphenidate
PubMed Central
Engert, Veronika; Pruessner, Jens C
2008-01-01
Attention Deficit Hyperactivity Disorder (ADHD) is a childhood psychiatric condition characterized

by severe impulsiveness, inattention and overactivity. Methylphenidate (MPH), a psychostimulant
affecting both the dopaminergic and the noradrenergic systems, is one of the most frequently
prescribed treatments for ADHD. Despite the widespread use of MPH and its proven effectiveness, its
precise neurochemical mechanisms of action are under debate. For the most part, MPHâ€™s influence
on subcortical dopamine neurotransmission is thought to play a crucial role in its behavioral and
cognitive effects. In their hypothesis of biphasic MPH action, Seeman and Madras [42, 43] suggest
that therapeutic doses of MPH elevate tonic dopamine while inhibiting phasic transmitter release in
subcortical structures, leading to reduced postsynaptic receptor stimulation and psychomotor activation
in response to salient stimuli. Volkow and colleagues [56] suggest that by amplifying a weak striatal
dopamine signal, MPH increases the perception of a stimulus or task as salient. The enhanced interest
for the task is thought to increase attention and improve performance. Recent animal studies have
however shown that when administered at doses producing clinically relevant drug plasma levels and
enhancing cognitive function, MPH preferentially activates dopamine and noradrenaline efflux within
the prefrontal cortex relative to the subcortical structures [5]. Overall, we suggest that the delineated
theories of MPH therapeutic action should not be discussed as exclusive. Studies are outlined that
allow integrating the different findings and models. PMID:19587853
187. Social Stress Engages Opioid Regulation of Locus Coeruleus Norepinephrine Neurons and Induces a
State of Cellular and Physical Opiate Dependence
PubMed Central
Chaijale, Nayla N; Curtis, Andre L; Wood, Susan K; Zhang, Xiao-Yan; Bhatnagar, Seema; Reyes,
Beverly AS; Van Bockstaele, Elisabeth J; Valentino, Rita J
2013-01-01
Stress is implicated in diverse psychiatric disorders including substance abuse. The locus
coeruleusâ€“norepinephrine (LCâ€“NE) system is a major stress response system that is also a point of
intersection between stress neuromediators and endogenous opioids and so may be a site at which
stress can influence drug-taking behaviors. As social stress is a common stressor for humans, this
study characterized the enduring impact of repeated social stress on LC neuronal activity. Rats were
exposed to five daily consecutive sessions of social stress using the resident-intruder model or control
manipulation. LC discharge rate recorded 2 days after the last manipulation was decreased in stressed
rats compared with controls. By 10 days after the last manipulation, LC rates were comparable
between groups. Systemic administration of the opiate antagonist, naloxone, robustly increased LC
discharge rate in a manner suggestive of opiate withdrawal, selectively in stressed rats when
administered 2 or 10 days after the last manipulation. This was accompanied by behavioral signs of
mild opiate withdrawal. Western blot and electron microscopic studies indicated that repeated social
stress decreased corticotropin-releasing factor type 1 receptor and increased Î¼-opioid receptor levels
in the LC. Together, the results suggest that repeated social stress engages endogenous opioid
modulation of LC activity and induces signs of cellular and physical opiate dependence that endure
after the stress. These cellular effects may predispose individuals with a history of repeated social
stress to substance abuse behaviors. PMID:23660707
188. Distribution of vasotocin- and vasoactive intestinal peptide-like immunoreactivity in the brain of blue
tit (Cyanistes coeruleus)
PubMed Central
Montagnese, Catherine M.; SzÃ©kely, TamÃ¡s; Csillag, AndrÃ¡s; Zachar, Gergely
2015-01-01
Blue tits (Cyanistes coeruleus) are songbirds, used as model animals in numerous studies covering a
wide field of research. Nevertheless, the distribution of neuropeptides in the brain of this avian species
remains largely unknown. Here we present some of the first results on distribution of Vasotocine
(AVT) and Vasoactive intestinal peptide (VIP) in the brain of males and females of this songbird
species, using immunohistochemistry mapping. The bulk of AVT-like cells are found in the
hypothalamic supraoptic, paraventricular and suprachiasmatic nuclei, bed nucleus of the stria
terminalis, and along the lateral forebrain bundle. Most AVT-like fibers course toward the median
eminence, some reaching the arcopallium, and lateral septum. Further terminal fields occur in the
dorsal thalamus, ventral tegmental area and pretectal area. Most VIP-like cells are in the lateral septal
organ and arcuate nucleus. VIP-like fibers are distributed extensively in the hypothalamus, preoptic
area, lateral septum, diagonal band of Broca. They are also found in the bed nucleus of the stria
terminalis, amygdaloid nucleus of taenia, robust nucleus of the arcopallium, caudo-ventral
hyperpallium, nucleus accumbens and the brainstem. Taken together, these results suggest that both
AVT and VIP immunoreactive structures show similar distribution to other avian species, emphasizing
evolutionary conservatism in the history of vertebrates. The current study may enable future
investigation into the localization of AVT and VIP, in relation to behavioral and ecological traits in the
brain of tit species. PMID:26236200
189. Accurate LC Peak Boundary Detection for 16 O/ 18 O Labeled LC-MS Data
PubMed Central
Cui, Jian; Petritis, Konstantinos; Tegeler, Tony; Petritis, Brianne; Ma, Xuepo; Jin, Yufang; Gao, Shou-
Jiang (SJ); Zhang, Jianqiu (Michelle)
2013-01-01
In liquid chromatography-mass spectrometry (LC-MS), parts of LC peaks are often corrupted by their
co-eluting peptides, which results in increased quantification variance. In this paper, we propose to
apply accurate LC peak boundary detection to remove the corrupted part of LC peaks. Accurate LC
peak boundary detection is achieved by checking the consistency of intensity patterns within peptide
elution time ranges. In addition, we remove peptides with erroneous mass assignment through model
fitness check, which compares observed intensity patterns to theoretically constructed ones. The
proposed algorithm can significantly improve the accuracy and precision of peptide ratio
measurements. PMID:24115998
190. Acute and Chronic Noradrenergic Effects on Cortical Excitability in Healthy Humans
PubMed Central
Kuo, Hsiao-I; Paulus, Walter; Batsikadze, Giorgi; Jamil, Asif; Kuo, Min-Fang
2017-01-01
Abstract Background Noradrenaline is a major neuromodulator in the central nervous system, and it is
involved in the pathophysiology of diverse neuropsychiatric diseases. Previous transcranial magnetic
stimulation studies suggested that acute application of selective noradrenaline reuptake inhibitors
enhances cortical excitability in the human brain. However, other, such like clinical effects, usually
require prolonged noradrenaline reuptake inhibitor treatment, which might go along with different
physiological effects. Methods The purpose of this study was to investigate the acute and chronic
effects of the selective noradrenaline reuptake inhibitor reboxetine on cortical excitability in healthy
humans in a double-blind, placebo-controlled, randomized crossover study. Sixteen subjects were
assessed with different transcranial magnetic stimulation measurements: motor thresholds, input-
output curve, short-latency intracortical inhibition and intracortical facilitation, I-wave facilitation, and
short-interval afferent inhibition before and after placebo or reboxetine (8 mg) single-dose
administration. Afterwards, the same subjects took reboxetine (8 mg/d) consecutively for 21 days.
During this period (subjects underwent 2 experimental sessions with identical transcranial magnetic
stimulation measures under placebo or reboxetine), transcranial magnetic stimulation measurements
were assessed before and after drug intake. Results Both single-dose and chronic administration of
reboxetine increased cortical excitability; increased the slope of the input-output curve, intracortical
facilitation, and I-wave facilitation; but decreased short-latency intracortical inhibition and short-
interval afferent inhibition. Moreover, chronic reboxetine showed a larger enhancement of intracortical
facilitation and I-wave facilitation compared with single-dose application. Conclusions The results
show physiological mechanisms of noradrenergic enhancement possibly underlying the
191. Delayed Noradrenergic Activation in the Dorsal Hippocampus Promotes the Long-Term Persistence of
Extinguished Fear
PubMed Central
Chai, Ning; Liu, Jian-Feng; Xue, Yan-Xue; Yang, Chang; Yan, Wei; Wang, Hui-Min; Luo, Yi-Xiao;
Shi, Hai-Shui; Wang, Ji-Shi; Bao, Yan-Ping; Meng, Shi-Qiu; Ding, Zeng-Bo; Wang, Xue-Yi; Lu, Lin
2014-01-01
Fear extinction has been extensively studied, but little is known about the molecular processes that
underlie the persistence of extinction long-term memory (LTM). We found that microinfusion of
norepinephrine (NE) into the CA1 area of the dorsal hippocampus during the early phase (0â€‰h)
after extinction enhanced extinction LTM at 2 and 14 days after extinction. Intra-CA1 infusion of NE
during the late phase (12â€‰h) after extinction selectively promoted extinction LTM at 14 days after
extinction that was blocked by the Î²-receptor antagonist propranolol, protein kinase A (PKA) inhibitor
Rp-cAMPS, and protein synthesis inhibitors anisomycin and emetine. The phosphorylation levels of
PKA, cyclic adenosine monophosphate response element-binding protein (CREB), GluR1, and the
membrane GluR1 level were increased by NE during the late phase after extinction that was also
blocked by propranolol and Rp-cAMPS. These results suggest that the enhancement of extinction LTM
persistence induced by NE requires the activation of the Î²-receptor/PKA/CREB signaling pathway and
membrane GluR1 trafficking. Moreover, extinction increased the phosphorylation levels of Erk1/2,
CREB, and GluR1, and the membrane GluR1 level during the late phase, and anisomycin/emetine
alone disrupted the persistence of extinction LTM, indicating that the persistence of extinction LTM
requires late-phase protein synthesis in the CA1. Propranolol and Rp-cAMPS did not completely
disrupt the persistence of extinction LTM, suggesting that another Î²-receptor/PKA-independent
mechanism underlies the persistence of extinction LTM. Altogether, our results showed that enhancing
hippocampal noradrenergic activity during the late phase after extinction selectively promotes the
persistence of extinction LTM. PMID:24553734
192. Effects of Propranolol, a Î²-noradrenergic Antagonist, on Memory Consolidation and Reconsolidation

in Mice
PubMed Central
Villain, HÃ©lÃ¨ne; Benkahoul, AÃ¯cha; Drougard, Anne; Lafragette, Marie; Muzotte, Elodie; Pech,
StÃ©phane; Bui, Eric; Brunet, Alain; Birmes, Philippe; Roullet, Pascal
2016-01-01
Memory reconsolidation impairment using the Î²-noradrenergic receptor blocker propranolol is a

promising novel treatment avenue for patients suffering from pathogenic memories, such as post-
traumatic stress disorder (PTSD). However, in order to better inform targeted treatment development,
the effects of this compound on memory need to be better characterized via translational research. We
examined the effects of systemic propranolol administration in mice undergoing a wide range of
behavioral tests to determine more specifically which aspects of the memory consolidation and
reconsolidation are impaired by propranolol. We found that propranolol (10 mg/kg) affected memory
consolidation in non-aversive tasks (object recognition and object location) but not in moderately
(Morris water maze (MWM) to highly (passive avoidance, conditioned taste aversion) aversive tasks.
Further, propranolol impaired memory reconsolidation in the most and in the least aversive tasks, but
not in the moderately aversive task, suggesting its amnesic effect was not related to task aversion.
Moreover, in aquatic object recognition and location tasks in which animals were forced to behave
(contrary to the classic versions of the tasks); propranolol did not impair memory reconsolidation.
Taken together our results suggest that the memory impairment observed after propranolol
administration may result from a modification of the emotional valence of the memory rather than a
disruption of the contextual component of the memory trace. This is relevant to the use of propranolol
to block memory reconsolidation in individuals with PTSD, as such a treatment would not erase the
traumatic memory but only reduce the emotional valence associated with this event. PMID:27014009
193. Transcription factor activating protein 2 beta (TFAP2B) mediates noradrenergic neuronal
differentiation in neuroblastoma.
PubMed
Ikram, Fakhera; Ackermann, Sandra; Kahlert, Yvonne; Volland, Ruth; Roels, Frederik; Engesser,
Anne; Hertwig, Falk; Kocak, Hayriye; Hero, Barbara; Dreidax, Daniel; Henrich, Kai-Oliver; Berthold,
Frank; NÃ¼rnberg, Peter; Westermann, Frank; Fischer, Matthias
2016-02-01
Neuroblastoma is an embryonal pediatric tumor that originates from the developing sympathetic
nervous system and shows a broad range of clinical behavior, ranging from fatal progression to
differentiation into benign ganglioneuroma. In experimental neuroblastoma systems, retinoic acid
(RA) effectively induces neuronal differentiation, and RA treatment has been therefore integrated in
current therapies. However, the molecular mechanisms underlying differentiation are still poorly
understood. We here investigated the role of transcription factor activating protein 2 beta (TFAP2B), a
key factor in sympathetic nervous system development, in neuroblastoma pathogenesis and
differentiation. Microarray analyses of primary neuroblastomas (n = 649) demonstrated that low
TFAP2B expression was significantly associated with unfavorable prognostic markers as well as
adverse patient outcome. We also found that low TFAP2B expression was strongly associated with
CpG methylation of the TFAP2B locus in primary neuroblastomas (n = 105) and demethylation with
5-aza-2'-deoxycytidine resulted in induction of TFAP2B expression in vitro, suggesting that TFAP2B
is silenced by genomic methylation. Tetracycline inducible re-expression of TFAP2B in IMR-32 and
SH-EP neuroblastoma cells significantly impaired proliferation and cell cycle progression. In IMR-32
cells, TFAP2B induced neuronal differentiation, which was accompanied by up-regulation of the
catecholamine biosynthesizing enzyme genes DBH and TH, and down-regulation of MYCN and
REST, a master repressor of neuronal genes. By contrast, knockdown of TFAP2B by lentiviral
transduction of shRNAs abrogated RA-induced neuronal differentiation of SH-SY5Y and SK-N-
BE(2)c neuroblastoma cells almost completely. Taken together, our results suggest that TFAP2B is
playing a vital role in retaining RA responsiveness and mediating noradrenergic neuronal
differentiation in neuroblastoma. Copyright Â© 2015 Federation of European Biochemical Societies
194. Effects of lesions to the dorsal noradrenergic bundle on counterconditioning of punished barpressing.
PubMed
Tsaltas, E; Gray, J A; Preston, G C

1987-01-01
The possible contribution of the dorsal noradrenergic bundle (DB) to the development of a simple
form of counterconditioning (an associative mechanism leading to behavioural tolerance for stress)
was assessed by comparison of the performance of animals with 6-hydroxydopamine-induced lesions
of the DB to that of sham-operated (SH) animals. Animals engaging in barpressing for food reward on
a random-interval (RI) 64 sec schedule were presented with a stimulus signalling the concurrent
operation of an RI-64 sec schedule of response-contingent shock. In the control condition
(punishment), shock and reward never occurred as a result of the same barpress. In the experimental
condition (counterconditioning), the frequency of shock and reward were the same as for the
punishment condition but the two events always occurred in succession, with food following shock, as
a consequence of the same barpress. DB lesions had no effect on the acquisition of rewarded
barpressing or on the initial acquisition of the discrimination between the shock-free and shock-
containing (signalled) components of the schedule. However, once performance on the discrimination
had reached asymptote, DB animals in the punishment control group showed significantly less
suppression to the signal than SH animals. The counterconditioning schedule used was effective,
leading to significantly reduced response suppression in the SH animals in comparison to the SH group
subjected to punishment. The pattern of findings in the DB groups was consistent with a blockade by
the lesion of the development of counterconditioning. These results suggest, therefore, that the DB is
involved in at least one associative mechanism leading to tolerance for stress.
195. In vitro characterization of noradrenergic modulation of chemosensitive neurons in the retrotrapezoid

nucleus
PubMed Central
Kuo, Fu-Shan; Falquetto, BÃ¡rbara; Chen, Dawei; Oliveira, Luiz M.; Takakura, Ana C.
2016-01-01
Chemosensitive neurons in the retrotrapezoid nucleus (RTN) regulate breathing in response to

CO2/H+ changes and serve as an integration center for other autonomic centers, including brain stem
noradrenergic neurons. Norepinephrine (NE) contributes to respiratory control and chemoreception,
and, since disruption of NE signaling may contribute to several breathing disorders, we sought to
characterize effects of NE on RTN chemoreception. All neurons included in this study responded
similarly to CO2/H+ but showed differential sensitivity to NE; we found that NE activated (79%),
inhibited (7%), or had no effect on activity (14%) of RTN chemoreceptors. The excitatory effect of NE
on RTN chemoreceptors was dose dependent, retained in the presence of neurotransmitter receptor
blockers, and could be mimicked and blocked by pharmacological manipulation of Î±1-adrenergic
receptors (ARs). In addition, NE-activation was blunted by XE991 (KCNQ channel blocker), and
partially occluded the firing response to serotonin, suggesting involvement of KCNQ channels.
However, in whole cell voltage clamp, activation of Î±1-ARs decreased outward current and
conductance by what appears to be a mixed effect on multiple channels. The inhibitory effect of NE on
RTN chemoreceptors was blunted by an Î±2-AR antagonist. A third group of RTN chemoreceptors
was insensitive to NE. We also found that chemosensitive RTN astrocytes do not respond to NE with a
change in voltage or by releasing ATP to enhance activity of chemosensitive neurons. These results
indicate NE modulates subsets of RTN chemoreceptors by mechanisms involving Î±1- and Î±2-ARs.
PMID:27306669
196. Noradrenergic stimulation modulates activation of extinction-related brain regions and enhances
contextual extinction learning without affecting renewal
PubMed Central
Lissek, Silke; Glaubitz, Benjamin; GÃ¼ntÃ¼rkÃ¼n, Onur; Tegenthoff, Martin
2015-01-01
Renewal in extinction learning describes the recovery of an extinguished response if the extinction
context differs from the context present during acquisition and recall. Attention may have a role in
contextual modulation of behavior and contribute to the renewal effect, while noradrenaline (NA) is
involved in attentional processing. In this functional magnetic resonance imaging (fMRI) study we
investigated the role of the noradrenergic system for behavioral and brain activation correlates of
contextual extinction and renewal, with a particular focus upon hippocampus and ventromedial
prefrontal cortex (PFC), which have crucial roles in processing of renewal. Healthy human volunteers
received a single dose of the NA reuptake inhibitor atomoxetine prior to extinction learning. During
extinction of previously acquired cue-outcome associations, cues were presented in a novel context
(ABA) or in the acquisition context (AAA). In recall, all cues were again presented in the acquisition
context. Atomoxetine participants (ATO) showed significantly faster extinction compared to placebo
(PLAC). However, atomoxetine did not affect renewal. Hippocampal activation was higher in ATO
during extinction and recall, as was ventromedial PFC activation, except for ABA recall. Moreover,
ATO showed stronger recruitment of insula, anterior cingulate, and dorsolateral/orbitofrontal PFC.
Across groups, cingulate, hippocampus and vmPFC activity during ABA extinction correlated with
recall performance, suggesting high relevance of these regions for processing the renewal effect. In
summary, the noradrenergic system appears to be involved in the modification of established
associations during extinction learning and thus has a role in behavioral flexibility. The assignment of
an association to a context and the subsequent decision on an adequate response, however, presumably
operate largely independently of noradrenergic mechanisms. PMID:25745389
197. Noradrenergic Î±1 Receptor Antagonist Treatment Attenuates Positive Subjective Effects of Cocaine
in Humans: A Randomized Trial
PubMed Central
Newton, Thomas F.; De La Garza, Richard; Brown, Gregory; Kosten, Thomas R.; Mahoney, James J.;
Haile, Colin N.
2012-01-01
Background Preclinical research implicates dopaminergic and noradrenergic mechanisms in mediating

the reinforcing effects of drugs of abuse, including cocaine. The objective of this study was to evaluate
the impact of treatment with the noradrenergic Î±1 receptor antagonist doxazosin on the positive
subjective effects of cocaine. Methods Thirteen non-treatment seeking, cocaine-dependent volunteers
completed this single-site, randomized, placebo-controlled, within-subjects study. In one study phase
volunteers received placebo and in the other they received doxazosin, with the order counterbalanced
across participants. Study medication was masked by over-encapsulating doxazosin tablets and
matched placebo lactose served as the control. Study medication treatment was initiated at 1 mg
doxazosin or equivalent number of placebo capsules PO/day and increased every three days by 1 mg.
After receiving 4 mg doxazosin or equivalent number of placebo capsules participants received
masked doses of 20 and 40 mg cocaine IV in that order with placebo saline randomly interspersed to
maintain the blind. Results Doxazosin treatment was well tolerated and doxazosin alone produced
minimal changes in heart rate and blood pressure. During treatment with placebo, cocaine produced
dose-dependent increases in subjective effect ratings of â€œhighâ€, â€œstimulatedâ€, â€œlike
cocaineâ€, â€œdesire cocaineâ€, â€œany drug effectâ€, and â€œlikely to use cocaine if had accessâ€
(p<.001). Doxazosin treatment significantly attenuated the effects of 20 mg cocaine on ratings of
â€œstimulatedâ€, â€œlike cocaineâ€, and â€œlikely to use cocaine if had accessâ€ (p<.05). There were
trends for doxazosin to reduce ratings of â€œstimulatedâ€, â€œdesire cocaineâ€, and â€œlikely to use
cocaine if had accessâ€ (p<.10). Conclusions Medications that block noradrenergic Î±1 receptors, such
as doxazosin, may be useful as treatments for cocaine dependence, and should be evaluated further.
Trial
198. REM Sleepâ€“like Atonia of Hypoglossal (XII) Motoneurons Is Caused by Loss of Noradrenergic and
Serotonergic Inputs
PubMed Central
Fenik, Victor B.; Davies, Richard O.; Kubin, Leszek
2017-01-01
Rationale Studies of hypoglossal (XII) motoneurons that innervate the genioglossus muscle, an upper
airway dilator, suggested that the suppression of upper airway motor tone during REM sleep is caused
by withdrawal of excitation mediated by norepinephrine and serotonin. Objectives Our objectives were
to determine whether antagonism of aminergic receptors located in the XII nucleus region can abolish
the REM sleepâ€“like atonia of XII motoneurons, and whether both serotonergic and noradrenergic
antagonists are required to achieve this effect. Methods REM sleepâ€“like episodes were elicited in
anesthetized rats by pontine carbachol injections before and at various times after microinjection of
prazosin and methysergide combined, or of only one of the drugs, into the XII nucleus. Measurements
and Main Results Spontaneous XII nerve activity was significantly reduced, by 35 to 81%, by each
antagonist alone and in combination, indicating that XII motoneurons were under both noradrenergic
and serotonergic endogenous excitatory drives. During the 32 to 81 min after microinjections of both
antagonists, pontine carbachol caused no depression of XII nerve activity, whereas other characteristic
effects (activation of the hippocampal and cortical EEG, and slowing of the respiratory rate) remained
intact. A partial recovery of the depressant effect of carbachol then occurred parallel to the recovery of
spontaneous XII nerve activity from the depressant effect of the antagonists. Microinjections of either
antagonist alone did not eliminate the depressant effect of carbachol. Conclusions The REM
sleepâ€“like depression of XII motoneuronal activity induced by pontine carbachol can be fully
accounted for by the combined withdrawal of noradrenergic and serotonergic effects on XII
motoneurons. PMID:16100007
199. Cholinergic, But Not Dopaminergic or Noradrenergic, Enhancement Sharpens Visual Spatial
Perception in Humans
PubMed Central
Wallace, Deanna L.
2017-01-01
unknown. Here we demonstrate that cholinergic enhancement improves detection of a target flanked
by distractors, consistent with sharpened visuospatial perceptual representations. Furthermore, whereas
most pharmacological studies focus on a single neurotransmitter, many neuromodulators can have
related effects on cognition and perception. Thus, we also demonstrate that enhancing noradrenergic
and dopaminergic systems does not systematically improve visuospatial perception or alter its tuning.
Our results link visuospatial tuning effects of acetylcholine at the neuronal and perceptual levels and
provide insights into the connection between cholinergic signaling and visual attention.
PMID:28336568
200. Alleviation of response suppression to conditioned aversive stimuli by lesions of the dorsal
noradrenergic bundle.
PubMed
Tsaltas, E; Gray, J A; Fillenz, M
1984-08-01
Rats with neurotoxic lesions of the dorsal ascending noradrenergic bundle (DB) were compared with
sham-operated (SH) controls on the acquisition, steady state and extinction of response suppression
maintained by a classical (conditioned suppression) or an instrumental (discriminated punishment)
contingency. DB lesions interfered neither with the acquisition of the reference response of sucrose-
rewarded barpressing nor with unconditioned responding to the overhead flashing light subsequently
used as a signal of shock. The acquisition of discriminated response suppression was also unaffected
by the lesion under both types of contingency. However, once discriminated suppression had
stabilized, both the conditioned and the discriminative stimulus used were significantly less effective
in maintaining suppression in DB animals than in SH controls provided that low intensity footshock
(0.2 mA) was used as the unconditioned stimulus (UCS). Upon increase of UCS intensity (to 0.5 mA)
normal suppression was observed in the DB group under both contingencies. Extinction of the
classical contingency reinstated the difference between DB and SH performance: DB lesion resulted in
significantly faster extinction of fear. In contrast, extinction of the discriminated punishment
contingency was unaffected by the lesion, although generalized response suppression dissipated faster
in the DB than in the SH animals trained under this condition. Our results offer no support for the
reinforcement hypothesis of DB function (normal acquisition of barpressing and of discriminated
suppression of barpressing); mixed support (greater initial generalization of suppression in DB
animals) and contradiction (more rapid extinction of conditioned suppression in DB animals) for the
attentional hypothesis; and weak support (reduced suppression and more rapid extinction of
suppression in DB animals, but only within limited experimental parameters) for the anxiety
hypothesis of DB function. Hence none of
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201. Effect of Noradrenergic Neurotoxin DSP-4 and Maprotiline on Heart Rate Spectral Components in
Stressed and Resting Rats.
PubMed
Kur'yanova, E V; Zhukova, Yu D; Teplyi, D L
2017-07-01
The effects of intraperitoneal DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine, a noradrenergic

neurotoxin) and maprotiline (an inhibitor of norepinephrine reuptake in synapses) on spectral
components of heart rhythm variability were examined in outbred male and female rats treated with
these agents in daily doses of 10 mg/kg for 3 days. At rest, DSP-4 elevated LF and VLF spectral
components in male and female rats. Maprotiline elevated LF and VLF components in males at rest,
increased HR and reduced all spectral components in resting females. Stress against the background of
DSP-4 treatment sharply increased heart rate and reduced the powers of all spectral components
(especially LF and VLF components). In maprotiline-treated rats, stress increased the powers of LF
and VLF components. Thus, the central noradrenergic system participates in the formation of LF and
VLF spectral components of heart rate variability at rest and especially during stressful stimulation,
which can determine the phasic character of changes in the heart rate variability observed in stressed
organism.
202. Bilateral thoracoscopic splanchnicectomy for pain in patients with chronic pancreatitis impairs
adrenomedullary but not noradrenergic sympathetic function.
PubMed
Buscher, H C J L; Lenders, J W M; Wilder-Smith, O H G; Sweep, C G J; van Goor, H
2012-08-01
Bilateral thoracoscopic splanchnicectomy (BTS) is a well-known technique to alleviate intractable

pain in patients with chronic pancreatitis. BTS not only disrupts afferent fibers from the pancreas that
mediate pain but also postganglionic sympathetic fibers, which originate in segments T5-T12 and
which innervate the vasculature of the liver, pancreas, and the adrenal gland. The purpose of this study
was to assess whether and how BTS affects sympathetic noradrenergic and adrenomedullary function
in patients with chronic pancreatitis. Sixteen patients with chronic pancreatitis for at least 1 year
underwent autonomic function testing before and 6 weeks after BTS for intractable pain. Testing was
performed during supine rest and during sympathetic stimulation when standing. Supine and standing
systolic and diastolic blood pressure were significantly lower post-BTS compared with pre-BTS (P =
0.001). One patient showed orthostatic hypotension after BTS. Baseline plasma norepinephrine levels
and plasma norepinephrine responses to sympathetic activation during standing were not reduced by
BTS. In contrast, supine plasma epinephrine levels and responses during standing were significantly
reduced (P < 0.001). Parasympathetic activity was unaffected by BTS as shown by unaltered Valsalva
ratio, I-E difference, and Î”HRmax. BTS for pain relief in patients with chronic pancreatitis reduced
adrenomedullary function, due to disruption of the efferent sympathetic fibers to the adrenal gland.
BTS did not affect noradrenergic sympathetic activity, although blood pressure was lower after the
sympathectomy.
203. Post-stress facilitation of serotonergic, but not noradrenergic, neurotransmission in the dorsal
hippocampus prevents learned helplessness development in rats.
PubMed
Joca, SÃ¢mia Regiane LourenÃ§o; Zanelati, Tatiane; GuimarÃ£es, Francisco Silveira
2006-05-04
Recent pieces of evidence suggest that the dorsal hippocampus may mediate adaptation to severe and
inescapable stress, possibly by the facilitation of serotonergic and/or noradrenergic neurotransmission.
Chronic social stress and high corticosteroid levels would impair this coping mechanism, predisposing
animals to learned helplessness. To test the hypothesis that increasing serotonin or noradrenaline levels
in the dorsal hippocampus would attenuate the development of learned helplessness (LH), rats
received inescapable foot shock (IS) and were tested in a shuttle box 24 h latter. Prestressed animals
showed impairment of escape responses. This effect was prevented by bilateral intrahippocampal
injections of zimelidine (100 nmol/0.5 microl), a serotonin reuptake blocker, immediately after IS.
This effect was not observed when zimelidine was administered before or 2 h after IS. Bilateral
intrahippocampal injections of desipramine (3 or 30 nmol/0.5 microl), a noradrenaline reuptake
blocker, before IS or immediately after it did not prevent LH development. Desipramine (30 nmol)
enhanced LH development when injected before IS. These data suggest that poststress facilitation of
hippocampal serotonergic, but not noradrenergic, neurotransmission in the dorsal hippocampus
facilitates adaptation to severe inescapable stress. Antidepressant effects of noradrenaline-selective
drugs seem to depend on other structures than the dorsal hippocampus.
204. Disinhibition by propranolol and chlordiazepoxide of nonrewarded lever-pressing in the rat is

unaffected by dorsal noradrenergic bundle lesion.
PubMed
Salmon, P; Tsaltas, E; Gray, J A
1989-03-01
Ten male Sprague-Dawley rats received 6-hydroxydopamine-induced lesions of the dorsal

noradrenergic bundle and 10 others underwent control operations. The lesion depleted levels of
noradrenaline in the hippocampus to 2% of those in the controls. All rats were then trained for 16
sessions to lever-press in a Skinner box on a variable interval 18 sec schedule of food-reinforcement,
then for 42 days on a successive discrimination between periods of variable interval (VI 18 sec) food-
reinforcement and periods of extinction. This report describes the effects of chlordiazepoxide (CDP; 5
mg/kg) and propranolol (5 and 10 mg/kg) injected intraperitoneally in both groups on modified ABBA
designs after this training. Both drugs increased the response rates in extinction periods. The effect of
propranolol was similar at each dose and smaller than that of CDP. Although CDP and propranolol (5
mg/kg) increased variable interval response rates also, this could not account for the effect on
extinction response rates. Responding did not differ between the lesioned and control animals and the
effects of drugs were similar in each group. It is unlikely that CDP or propranolol release nonrewarded
responding by disrupting transmission in the dorsal noradrenergic bundle.
205. CHOLINERGIC AND NORADRENERGIC MODULATION OF LONG-TERM EXPLICIT

MEMORY ARE ALTERED BY CHRONIC LOW-LEVEL LEAD EXPOSURE. (U915393)
EPA Science Inventory
Recent evidence suggests that septohippocampal cholinergic activity is suppressed in rats exposed to
low levels of lead (Pb). As a result, noradrenergic activity may be elevated due to compensatory
sympathetic sprouting. Therefore, the goals of this study were to (a) determine...
206. Noradrenergic facilitation of shock-probe defensive burying in lateral septum of rats, and modulation
by chronic treatment with desipramine.
PubMed
Bondi, Corina O; Barrera, Gabriel; Lapiz, M Danet S; Bedard, Tania; Mahan, Amy; Morilak, David A
2007-03-30
We have previously shown that acute stress-induced release of norepinephrine (NE) facilitates anxiety-
like behavioral responses to stress, such as reduction in open-arm exploration on the elevated-plus
maze and in social behavior on the social interaction test. Since these responses represent inhibition of
ongoing behavior, it is important to also address whether NE facilitates a response that represents an
activation of behavior. Correspondingly, it is unknown how a chronic elevation in tonic steady-state
noradrenergic (NA) neurotransmission induced by NE reuptake blockade might alter this acute
modulatory function, a regulatory process that may be pertinent to the anxiolytic effects of NE
reuptake blockers such as desipramine (DMI). Therefore, in this study, we investigated noradrenergic
modulation of the shock-probe defensive burying response in the lateral septum (LS). In experiment 1,
shock-probe exposure induced an acute 3-fold increase in NE levels measured in LS of male Sprague-
Dawley rats by microdialysis. Shock-probe exposure also induced a modest rise in plasma ACTH,
taken as an indicator of perceived stress, that returned to baseline more rapidly in rats that were
allowed to bury the probe compared to rats prevented from burying by providing them with minimal
bedding, indicating that the active defensive burying behavior is an effective coping strategy that
reduces the impact of acute shock probe-induced stress. In experiment 2, blockade of either alpha(1)-
or beta-adrenergic receptors in LS by local antagonist microinjection immediately before testing
reduced defensive burying and increased immobility. In the next experiment, chronic DMI treatment
increased basal extracellular NE levels in LS, and attenuated the acute shock probe-induced increase in
NE release in LS relative to baseline. Chronic DMI treatment decreased shock-probe defensive
burying behavior in a time-dependent manner, apparent only after 2 weeks or more of drug treatment.
Moreover
207. Selective inhibition of dopamine-beta-hydroxylase enhances dopamine release from noradrenergic

terminals in the medial prefrontal cortex.
PubMed
Devoto, Paola; Flore, Giovanna; Saba, Pierluigi; Frau, Roberto; Gessa, Gian L
2015-10-01
Disulfiram has been claimed to be useful in cocaine addiction therapy, its efficacy being attributed to
dopamine-beta-hydroxylase (DBH) inhibition. Our previous results indicate that disulfiram and the
selective DBH inhibitor nepicastat increase extracellular dopamine (DA) in the rat medial prefrontal
cortex (mPFC), and markedly potentiated cocaine-induced increase. Concomitantly, in rats with
cocaine self-administration history, cocaine-seeking behavior induced by drug priming was prevented,
probably through overstimulation of D1 receptors due to the DA increase. The present research was
aimed at studying the neurochemical mechanisms originating the enhanced DA release. Noradrenergic
system ablation was attained by intracerebroventricular (i.c.v.) administration of the neurotoxin anti-
DBH-saporin (aDBH-sap). DA, noradrenaline (NA), and DOPAC were assessed by HPLC after
exÂ vivo tissue extraction or inÂ vivo microdialysis. Control and denervated rats were subjected to
microdialysis in the mPFC and caudate nucleus to evaluate the effect of nepicastat-cocaine
combination on extracellular DA levels and their regulation by Î±2-adrenoceptors. Fifteen days after
neurotoxin or its vehicle administration, tissue and extracellular NA were reduced to less than 2% the
control value, while extracellular DA was increased by approximately 100%. In control rats, nepicastat
given alone and in combination with cocaine increased extracellular DA by about 250% and 1100%,
respectively. In denervated rats, nepicastat slightly affected extracellular DA, while in combination
with cocaine increased extracellular DA by 250%. No differences were found in the caudate nucleus.
Clonidine almost totally reversed the extracellular DA elevation produced by nepicastat-cocaine
combination, while it was ineffective in denervated rats. This research shows that the increase of
extracellular DA produced by nepicastat alone or in combination with cocaine was prevented by
noradrenergic denervation. The
208. Adolescent social isolation increases anxiety-like behavior and ethanol intake and impairs fear
extinction in adulthood: Possible role of disrupted noradrenergic signaling.
PubMed
Skelly, M J; Chappell, A E; Carter, E; Weiner, J L
2015-10-01
Alcohol use disorder, anxiety disorders, and post-traumatic stress disorder (PTSD) are highly
comorbid, and exposure to chronic stress during adolescence may increase the incidence of these
conditions in adulthood. Efforts to identify the common stress-related mechanisms driving these
disorders have been hampered, in part, by a lack of reliable preclinical models that replicate their
comorbid symptomatology. Prior work by us, and others, has shown that adolescent social isolation
increases anxiety-like behaviors and voluntary ethanol consumption in adult male Long-Evans rats.
Here we examined whether social isolation also produces deficiencies in extinction of conditioned
fear, a hallmark symptom of PTSD. Additionally, as disrupted noradrenergic signaling may contribute
to alcoholism, we examined the effect of anxiolytic medications that target noradrenergic signaling on
ethanol intake following adolescent social isolation. Our results confirm and extend previous findings
that adolescent social isolation increases anxiety-like behavior and enhances ethanol intake and
preference in adulthood. Additionally, social isolation is associated with a significant deficit in the
extinction of conditioned fear and a marked increase in the ability of noradrenergic therapeutics to
decrease ethanol intake. These results suggest that adolescent social isolation not only leads to
persistent increases in anxiety-like behaviors and ethanol consumption, but also disrupts fear
extinction, and as such may be a useful preclinical model of stress-related psychopathology. Our data
also suggest that disrupted noradrenergic signaling may contribute to escalated ethanol drinking
following social isolation, thus further highlighting the potential utility of noradrenergic therapeutics in
treating the deleterious behavioral sequelae associated with early life stress. Copyright Â© 2015
209. Adolescent social isolation increases anxiety-like behavior and ethanol intake and impairs fear
extinction in adulthood: possible role of disrupted noradrenergic signaling
PubMed Central
Skelly, M. J.; Chappell, A. E.; Carter, E.; Weiner, J. L.
2015-01-01
Alcohol use disorder, anxiety disorders, and post-traumatic stress disorder (PTSD) are highly
comorbid, and exposure to chronic stress during adolescence may increase the incidence of these
conditions in adulthood. Efforts to identify the common stress-related mechanisms driving these
disorders have been hampered, in part, by a lack of reliable preclinical models that replicate their
comorbid symptomatology. Prior work by us, and others, has shown that adolescent social isolation
increases anxiety-like behaviors and voluntary ethanol consumption in adult male Long-Evans rats.
Here we examined whether social isolation also produces deficiencies in extinction of conditioned
fear, a hallmark symptom of PTSD. Additionally, as disrupted noradrenergic signaling may contribute
to alcoholism, we examined the effect of anxiolytic medications that target noradrenergic signaling on
ethanol intake following adolescent social isolation. Our results confirm and extend previous findings
that adolescent social isolation increases anxiety-like behavior and enhances ethanol intake and
preference in adulthood. Additionally, social isolation is associated with a significant deficit in the
extinction of conditioned fear and a marked increase in the ability of noradrenergic therapeutics to
decrease ethanol intake. These results suggest that adolescent social isolation not only leads to
persistent increases in anxiety-like behaviors and ethanol consumption, but also disrupts fear
extinction, and as such may be a useful preclinical model of stress-related psychopathology. Our data
also suggest that disrupted noradrenergic signaling may contribute to escalated ethanol drinking
following social isolation, thus further highlighting the potential utility of noradrenergic therapeutics in
treating the deleterious behavioral sequelae associated with early life stress. PMID:26044636
210. LC-IMS-MS Feature Finder
SciTech Connect
2013-03-07
LC-IMS-MS Feature Finder is a command line software application which searches for possible
molecular ion signatures in multidimensional liquid chromatography, ion mobility spectrometry, and
mass spectrometry data by clustering deisotoped peaks with similar monoisotopic mass values, charge
states, elution times, and drift times. The software application includes an algorithm for detecting
multiple conformations and co-eluting species in the ion mobility dimension. LC-IMS-MS Feature
Finder is designed to create an output file with detected features that includes associated information
about the detected features.
211. Noradrenergic modulation of masseter muscle activity during natural rapid eye movement sleep
requires glutamatergic signalling at the trigeminal motor nucleus
PubMed Central
Schwarz, Peter B; Mir, Saba; Peever, John H
2014-01-01
Noradrenergic neurotransmission in the brainstem is closely coupled to changes in muscle activity

across the sleepâ€“wake cycle, and noradrenaline is considered to be a key excitatory neuromodulator
that reinforces the arousal-related stimulus on motoneurons to drive movement. However, it is
unknown if Î±-1 noradrenoceptor activation increases motoneuron responsiveness to excitatory
glutamate (AMPA) receptor-mediated inputs during natural behaviour. We studied the effects of
noradrenaline on AMPA receptor-mediated motor activity at the motoneuron level in freely behaving
rats, particularly during rapid eye movement (REM) sleep, a period during which both AMPA
receptor-triggered muscle twitches and periods of muscle quiescence in which AMPA drive is silent
are exhibited. Male rats were subjected to electromyography and electroencephalography recording to
monitor sleep and waking behaviour. The implantation of a cannula into the trigeminal motor nucleus
of the brainstem allowed us to perfuse noradrenergic and glutamatergic drugs by reverse microdialysis,
and thus to use masseter muscle activity as an index of motoneuronal output. We found that
endogenous excitation of both Î±-1 noradrenoceptor and AMPA receptors during waking are coupled
to motor activity; however, REM sleep exhibits an absence of endogenous Î±-1 noradrenoceptor
activity. Importantly, exogenous Î±-1 noradrenoceptor stimulation cannot reverse the muscle twitch
suppression induced by AMPA receptor blockade and nor can it elevate muscle activity during quiet
REM, a phase when endogenous AMPA receptor activity is subthreshold. We conclude that the
presence of an endogenous glutamatergic drive is necessary for noradrenaline to trigger muscle
activity at the level of the motoneuron in an animal behaving naturally. PMID:24860176
212. Role of nucleus of the solitary tract noradrenergic neurons in post-stress cardiovascular and hormonal
control in male rats
PubMed Central
Bundzikova-Osacka, Jana; Ghosal, Sriparna; Packard, Benjamin A.; Ulrich-Lai, Yvonne M.; Herman,
James P.
2015-01-01
Chronic stress causes hypothalamo-pituitary-adrenal (HPA) axis hyperactivity and cardiovascular

dyshomeostasis. Noradrenergic neurons in the nucleus of the solitary tract (NTS) are considered to
play a role in these changes. Here, we tested the hypothesis that NTS noradrenergic A2 neurons are
required for cardiovascular and HPA axis responses to both acute and chronic stress. Adult male rats
received bilateral microinjection into the NTS of 6-hydroxydopamine (6-OHDA) to lesion A2 neurons
[cardiovascular study, n= 5; HPA study, n= 5], or vehicle [cardiovascular study, n= 6; HPA study, n=
4]. Rats were exposed to acute restraint stress followed by 14 days of chronic variable stress (CVS).
On the last day of testing, rats were placed in a novel elevated plus maze (EPM) to test post-CVS
stress responses. Lesions of NTS A2 neurons reduced the tachycardic response to acute restraint,
confirming that A2 neurons promote sympathetic activation following acute stress. In addition, CVS
increased the ratio of low frequency to high frequency power for heart rate variability, indicative of
sympathovagal imbalance, and this effect was significantly attenuated by 6-OHDA lesion. Lesions of
NTS A2 neurons reduced acute restraint-induced corticosterone secretion, but did not affect the
corticosterone response to the EPM, indicating that A2 neurons promote acute HPA axis responses, but
are not involved in CVS-mediated HPA axis sensitization. Collectively, these data indicate that A2
neurons promote both cardiovascular and HPA axis responses to acute stress. Moreover, A2
catecholaminergic neurons may contribute to the potentially deleterious enhancement of sympathetic
drive following chronic stress. PMID:25765732
213. Selective Serotonergic (SSRI) Versus Noradrenergic (SNRI) Reuptake Inhibitors with and without
Acetylsalicylic Acid in Major Depressive Disorder.
PubMed
Zdanowicz, Nicolas; Reynaert, Christine; Jacques, Denis; Lepiece, Brice; Dubois, Thomas
2017-09-01
Antidepressant medication efficacy remains a major research challenge. Here, we explored four
questions: whether noradrenergic antidepressants are more effective than serotonergic antidepressants;
whether the addition of 100 mg acetylsalicylic acid (ASA) changes antidepressant efficacy; whether
the long-term efficacy differs depending on the antidepressant and the addition of ASA; and whether
serum levels of brain-derived neurotrophic factor (BDNF) are clinically informative. In a two-year
study, forty people with major depressive disorder were randomly assigned to groups that received an
SSRI (escitalopram) or an SNRI (duloxetine), each group received concomitant ASA (100 mg) or a
placebo. Sociodemographic data were recorded and patients under went regular assessments with the
Hamilton depression scale (HDS) and clinical global impression (CGI) scale. Serum levels of BDNF
were measured four times per year. There was no significant difference in efficacy between the two
antidepressants or between antidepressant treatment with and without ASA. However, subgroup
comparisons revealed that the duloxetine + ASA (DASA) subgroup showed a more rapid improvement
in HDS score as early as 2 months (t=-3.114, p=0.01), in CGI score at 5 months (t=-2.119, p=0.05),
and a better remission rate (Ï‡ 2 =6.296, p 0.012) than the escitalopram + placebo (EP) subgroup.
Serum BDNF before treatment was also higher in the DASA subgroup than in the EP subgroup
(t=3.713; p=0.002). This suggest two hypotheses: either a noradrenergic agent combined with ASA is
more effective in treating depression than a serotonergic agent alone, or the level of serum BDNF
before treatment is a precursor marker of the response to antidepressants. Further research is needed to
test these hypotheses.
214. Enhancement of extinction memory consolidation: the role of the noradrenergic and GABAergic
systems within the basolateral amygdala.
PubMed
Berlau, Daniel J; McGaugh, James L
2006-09-01
Evidence from previous studies indicates that the noradrenergic and GABAergic influences within the
basolateral amygdala (BLA) modulate the consolidation of memory for fear conditioning. The present
experiments investigated whether the same modulatory influences are involved in regulating the
extinction of fear-based learning. To investigate this issue, male Sprague Dawley rats implanted with
unilateral or bilateral cannula aimed at the BLA were trained on a contextual fear conditioning (CFC)
task and 24 and 48 h later were given extinction training. Immediately following each extinction
session they received intra-BLA infusions of the GABAergic antagonist bicuculline (50 ng), the beta-
adrenocepter antagonist propranolol (500 ng), bicuculline with propranolol, norepinephrine (NE) (0.3,
1.0, and 3.0 microg), the GABAergic agonist muscimol (125 ng), NE with muscimol or a control
solution. To investigate the involvement of the dorsal hippocampus (DH) as a possible target of BLA
activation during extinction, other animals were given infusions of muscimol (500 ng) via an
ipsilateral cannula implanted in the DH. Bilateral BLA infusions of bicuculline significantly enhanced
extinction, as did infusions into the right, but not left BLA. Propranolol infused into the right BLA
together with bicuculline blocked the bicuculline-induced memory enhancement. Norepinephrine
infused into the right BLA also enhanced extinction, and this effect was not blocked by co-infusions of
muscimol. Additionally, muscimol infused into the DH did not attenuate the memory enhancing effects
of norepinephrine infused into the BLA. These findings provide evidence that, as with original CFC
learning, noradrenergic activation within the BLA modulates the consolidation of CFC extinction. The
findings also suggest that the BLA influence on extinction is not mediated by an interaction with the
dorsal hippocampus.
215. LC Circuits for Diagnosing Embedded Piezoelectric Devices
Chattin, Richard L.; Fox, Robert Lee; Moses, Robert W.; Shams, Qamar A.
2005-01-01
A recently invented method of nonintrusively detecting faults in piezoelectric devices involves

measurement of the resonance frequencies of inductor capacitor (LC) resonant circuits. The method is
intended especially to enable diagnosis of piezoelectric sensors, actuators, and sensor/actuators that are
embedded in structures and/or are components of multilayer composite material structures.
216. Trans Ova Genetics, L.C.
EPA Pesticide Factsheets
The EPA is providing notice of a proposed Administrative Penalty Assessment against Trans Ova
Genetics, L.C., a business located at 2938 380th Street Sioux Center, IA 51250, for alleged violations
at the Trans Ova Genetics, L.C.â€™s facility located in 12425
217. Development of LC-13C NMR
Dorn, H. C.; Wang, J. S.; Glass, T. E.
1986-01-01
This study involves the development of C-13 nuclear resonance as an on-line detector for liquid
chromatography (LC-C-13 NMR) for the chemical characterization of aviation fuels. The initial focus
of this study was the development of a high sensitivity flow C-13 NMR probe. Since C-13 NMR
sensitivity is of paramount concern, considerable effort during the first year was directed at new NMR
probe designs. In particular, various toroid coil designs were examined. In addition, corresponding
shim coils for correcting the main magnetic field (B sub 0) homogeneity were examined. Based on
these initial probe design studies, an LC-C-13 NMR probe was built and flow C-13 NMR data was
obtained for a limited number of samples.
218. Arousal amplifies biased competition between high and low priority memories more in women than in
men: the role of elevated noradrenergic activity
PubMed Central
Clewett, David; Sakaki, Michiko; Huang, Ringo; Nielsen, Shawn E.; Mather, Mara
2017-01-01
Recent findings indicate that emotional arousal can enhance memory consolidation of goal-relevant
stimuli while impairing it for irrelevant stimuli. According to one recent model, these goal-dependent
memory tradeoffs are driven by arousal-induced release of norepinephrine (NE), which amplifies
neural gain in target sensory and memory processing brain regions. Past work also shows that ovarian
hormones modulate activity in the same regions thought to support NEâ€™s effects on memory, such
as the amygdala, suggesting that men and women may be differentially susceptible to arousalâ€™s
dual effects on episodic memory. Here, we aimed to determine the neurohormonal mechanisms that
mediate arousal-biased competition processes in memory. In a competitive visuo-attention task,
participants viewed images of a transparent object overlaid on a background scene and explicitly
memorized one of these stimuli while ignoring the other. Participants then heard emotional or neutral
audio-clips and provided a subjective arousal rating. Hierarchical generalized linear modeling
(HGLM) analyses revealed that greater pre-to-post task increases in salivary alpha-amylase (sAA), a
biomarker of noradrenergic activity, was associated with significantly greater arousal-enhanced
memory tradeoffs in women than in men. These sex-dependent effects appeared to result from phasic
and background noradrenergic activity interacting to suppress task-irrelevant representations in women
but enhancing them in men. Additionally, in naturally cycling women, low ovarian hormone levels
interacted with increased noradrenergic activity to amplify memory selectivity independently of
emotion-induced arousal. Together these findings suggest that increased noradrenergic transmission
enhances preferential consolidation of goal-relevant memory traces according to phasic arousal and
ovarian hormone levels in women. PMID:28324703
219. Arousal amplifies biased competition between high and low priority memories more in women than in
men: The role of elevated noradrenergic activity.
PubMed
Clewett, David; Sakaki, Michiko; Huang, Ringo; Nielsen, Shawn E; Mather, Mara
2017-06-01
Recent findings indicate that emotional arousal can enhance memory consolidation of goal-relevant
stimuli while impairing it for irrelevant stimuli. According to one recent model, these goal-dependent
memory tradeoffs are driven by arousal-induced release of norepinephrine (NE), which amplifies
neural gain in target sensory and memory processing brain regions. Past work also shows that ovarian
hormones modulate activity in the same regions thought to support NE's effects on memory, such as
the amygdala, suggesting that men and women may be differentially susceptible to arousal's dual
effects on episodic memory. Here, we aimed to determine the neurohormonal mechanisms that mediate
arousal-biased competition processes in memory. In a competitive visuo-attention task, participants

viewed images of a transparent object overlaid on a background scene and explicitly memorized one of
these stimuli while ignoring the other. Participants then heard emotional or neutral audio-clips and
provided a subjective arousal rating. Hierarchical generalized linear modeling (HGLM) analyses
revealed that greater pre-to-post task increases in salivary alpha-amylase (sAA), a biomarker of
noradrenergic activity, was associated with significantly greater arousal-enhanced memory tradeoffs in
women than in men. These sex-dependent effects appeared to result from phasic and background
noradrenergic activity interacting to suppress task-irrelevant representations in women but enhancing
them in men. Additionally, in naturally cycling women, low ovarian hormone levels interacted with
increased noradrenergic activity to amplify memory selectivity independently of emotion-induced
arousal. Together these findings suggest that increased noradrenergic transmission enhances
preferential consolidation of goal-relevant memory traces according to phasic arousal and ovarian
hormone levels in women. Copyright Â© 2017 Elsevier Ltd. All rights reserved.
220. General Unknown Screening by Ion Trap LC/MS/MS
2010-04-01
Subtitle 5 . Report Date April 2010 General Unknown Screening by Ion Trap LC/MS/MS 6 .
Performing Organization Code 7. Author(s) 8... 5 Table 1: Analytical Data for Each of the...359
Compounds in the LC/MS/MS Library . . . . . . . . . . . 6 1 General Unknown ScreeninG by ion Trap
lc/MS/MS INTrOduCTION The Federal Aviation
«
9
10
11
12
13
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221. Functional distribution of Ca2+-coupled P2 purinergic receptors among adrenergic and noradrenergic
bovine adrenal chromaffin cells.
PubMed
TomÃ©, Angelo R; Castro, Enrique; Santos, Rosa M; RosÃ¡rio, LuÃs M
2007-06-14
Adrenal chromaffin cells mediate acute responses to stress through the release of epinephrine.
Chromaffin cell function is regulated by several receptors, present both in adrenergic (AD) and
noradrenergic (NA) cells. Extracellular ATP exerts excitatory and inhibitory actions on chromaffin
cells via ionotropic (P2X) and metabotropic (P2Y) receptors. We have taken advantage of the actions
of the purinergic agonists ATP and UTP on cytosolic free Ca2+ concentration ([Ca2+]i) to determine
whether P2X and P2Y receptors might be asymmetrically distributed among AD and NA chromaffin
cells. The [Ca2+]i and the [Na+]i were recorded from immunolabeled bovine chromaffin cells by
single-cell fluorescence imaging. Among the ATP-sensitive cells ~40% did not yield [Ca2+]i
responses to ATP in the absence of extracellular Ca2+ (Ca2+o), indicating that they expressed P2X
receptors and did not express Ca2+- mobilizing P2Y receptors; the remainder expressed Ca2+-
mobilizing P2Y receptors. Relative to AD-cells approximately twice as many NA-cells expressed P2X
receptors while not expressing Ca2+- mobilizing P2Y receptors, as indicated by the proportion of cells
lacking [Ca2+]i responses and exhibiting [Na+]i responses to ATP in the absence and presence of
Ca2+o, respectively. The density of P2X receptors in NA-cells appeared to be 30-50% larger, as
suggested by comparing the average size of the [Na+]i and [Ca2+]i responses to ATP. Conversely,
approximately twice as many AD-cells expressed Ca2+-mobilizing P2Y receptors, and they appeared
to exhibit a higher (~20%) receptor density. UTP raised the [Ca2+]i in a fraction of the cells and did
not raise the [Na+]i in any of the cells tested, confirming its specificity as a P2Y agonist. The cell
density of UTP-sensitive P2Y receptors did not appear to vary among AD- and NA-cells. Although
neither of the major purinoceptor types can be ascribed to a particular cell phenotype, P2X and Ca2+-
mobilizing P2Y receptors are preferentially located to
222. Acute and chronic effects of noradrenergic enhancement on transcranial direct current stimulation-
induced neuroplasticity in humans.
PubMed
Kuo, Hsiao-I; Paulus, Walter; Batsikadze, Giorgi; Jamil, Asif; Kuo, Min-Fang; Nitsche, Michael A
2017-02-15
Chronic administration of the selective noradrenaline reuptake inhibitor (NRI) reboxetine (RBX)
increased and prolonged the long-term potentiation-like plasticity induced by anodal transcranial direct
current stimulation (tDCS) for over 24Â h. Chronic administration of RBX converted cathodal tDCS-
induced long-term depression-like plasticity into facilitation for 120Â min. Chronic noradrenergic
activity enhancement on plasticity of the human brain might partially explain the delayed therapeutic
impact of selective NRIs in depression and other neuropsychiatric diseases. Noradrenaline affects
cognition and motor learning processes via its impact on long-term potentiation (LTP) and depression
(LTD). We aimed to explore the impact of single dose and chronic administration of the selective
noradrenaline reuptake inhibitor (NRI) reboxetine (RBX) on plasticity induced by transcranial direct
current stimulation (tDCS) in healthy humans via a double-blinded, placebo-controlled, randomized
crossover study. Sixteen healthy volunteers received placebo or single dose RBX (8Â mg) before
anodal or cathodal tDCS of the primary motor cortex. Afterwards, the same subjects took RBX
(8Â mgÂ day -1 ) consecutively for 21Â days. During this period, two additional interventions were
performed (RBX with anodal or cathodal tDCS), to explore the impact of chronic RBX treatment on
plasticity. Plasticity was monitored by motor-evoked potential amplitudes elicited by transcranial
magnetic stimulation. Chronic administration of RBX increased and prolonged the LTP-like plasticity
induced by anodal tDCS for over 24Â h. Chronic RBX significantly converted cathodal tDCS-induced
LTD-like plasticity into facilitation, as compared to the single dose condition, for 120Â min after
stimulation. The results show a prominent impact of chronic noradrenergic enhancement on plasticity
of the human brain that might partially explain the delayed therapeutic impact of selective NRIs in
depression and other
223. Short-term serotonergic but not noradrenergic antidepressant administration reduces attentional
vigilance to threat in healthy volunteers.
PubMed
Murphy, Susannah E; Yiend, Jenny; Lester, Kathryn J; Cowen, Philip J; Harmer, Catherine J
2009-03-01
Anxiety is associated with threat-related biases in information processing such as heightened

attentional vigilance to potential threat. Such biases are an important focus of psychological treatments
for anxiety disorders. Selective serotonin reuptake inhibitors (SSRIs) are effective in the treatment of a
range of anxiety disorders. The aim of this study was to assess the effect of an SSRI on the processing
of threat in healthy volunteers. A selective noradrenergic reuptake inhibitor (SNRI), which is not
generally used in the treatment of anxiety, was used as a contrast to assess the specificity of SSRI
effects on threat processing. Forty-two healthy volunteers were randomly assigned to 7 d double-blind
intervention with the SSRI citalopram (20 mg/d), the SNRI reboxetine (8 mg/d), or placebo. On the
final day, attentional and interpretative bias to threat was assessed using the attentional probe and the
homograph primed lexical decision tasks. Citalopram reduced attentional vigilance towards fearful
faces but did not affect the interpretation of ambiguous homographs as threatening. Reboxetine had no
significant effect on either of these measures. Citalopram reduces attentional orienting to threatening
stimuli, which is potentially relevant to its clinical use in the treatment of anxiety disorders. This
finding supports a growing literature suggesting that an important mechanism through which
pharmacological agents may exert their effects on mood is by reversing the cognitive biases that
characterize the disorders that they treat. Future studies are needed to clarify the neural mechanisms
through which these effects on threat processing are mediated.
224. Noradrenergic synaptic function in the bed nucleus of the stria terminalis varies in animal models of
anxiety and addiction.
PubMed
McElligott, ZoÃ© A; Fox, Megan E; Walsh, Paul L; Urban, Daniel J; Ferrel, Martilias S; Roth, Bryan
L; Wightman, R Mark
2013-08-01
Lewis rats show increased anxiety-like behaviors and drug consumption compared with Sprague-
Dawley rats. Prior work suggests norepinephrine (NE) signaling in the bed nucleus of the stria
terminalis (BNST) could have a role in mediating these phenotypes. Here, we investigated NE content
and dynamics in the ventral BNST (vBNST) using fast-scan cyclic voltammetry in these two rat
strains. We found that NE release evoked by electrical stimulus and its subsequent uptake was
dysregulated in the more anxious Lewis rats. Because addiction is a multifaceted disease influenced by
both genetic and environmental factors, we hypothesized NE dynamics would vary in these strains
after the induction of a physical dependence on morphine. Following naloxone-precipitated morphine
withdrawal, NE release and uptake dynamics were not changed in Lewis rats but were significantly
altered in Sprague-Dawley rats. The alterations in Sprague-Dawley rats were accompanied by an
increase in anxiety-like behavior in those animals as measured with the elevated plus maze. These
studies suggest novel mechanisms involved in the development of affective disorders, and highlight
the noradrenergic system in the vBNST as a common substrate for the manifestation of pathological
anxiety and addiction.
225. Corticosteroid involvement in the changes in noradrenergic responsiveness of tissues from rats made
hypertensive by short-term isolation
PubMed Central
Bennett, T.; Gardiner, Sheila M.
1978-01-01
1 The responses to noradrenaline and to noradrenergic nerve stimulation of spontaneously beating

right atria, electrically driven left atria and vasa deferentia taken from rats made hypertensive by short-
term isolation have been compared with the responses of tissues from normotensive, group-housed
animals. 2 Adrenocortical activity of isolated animals was assessed by plasma corticosterone
determinations and measurement of adrenal weights. 3 The hearts of the isolated animals were
weighed and the myocardial contents of water, sodium, potassium and calcium were measured. 4
Spontaneously beating right atria from isolated animals showed a lower resting rate, no difference in
the response to nerve stimulation but a greater sensitivity to noradrenaline compared to atria from
group-housed animals. 5 Vasa deferentia from isolated animals showed a decreased maximal response
to noradrenaline, but no change in noradrenaline sensitivity or in the response to transmural
stimulation. 6 There were indications of hyperactivity of the adrenals throughout a 5 week period of
isolation, manifest as elevated plasma corticosteroid levels and increased adrenal weights. 7
Myocardial levels of sodium and calcium were elevated at the same time as the tissue level of
potassium was reduced, but heart weights did not significantly change. 8 It is possible that adrenal
steroid action caused the changes in tissue ionic balance. These ionic disturbances may have been
responsible for some of the changes in tissue sensitivity found in the isolated hypertensive animals.
PMID:698476
226. The noradrenergic component in tapentadol action counteracts Î¼-opioid receptor-mediated adverse
effects on adult neurogenesis.
PubMed
Meneghini, Vasco; Cuccurazzu, Bruna; Bortolotto, Valeria; Ramazzotti, Vera; Ubezio, Federica;
Tzschentke, Thomas M; Canonico, Pier Luigi; Grilli, Mariagrazia
2014-05-01
Opiates were the first drugs shown to negatively impact neurogenesis in the adult mammalian
hippocampus. Literature data also suggest that norepinephrine is a positive modulator of hippocampal
neurogenesis in vitro and in vivo. On the basis of these observations, we investigated whether
tapentadol, a novel central analgesic combining Î¼-opioid receptor (MOR) agonism with
norepinephrine reuptake inhibition (NRI), may produce less inhibition of hippocampal neurogenesis
compared with morphine. When tested in vitro, morphine inhibited neuronal differentiation, neurite
outgrowth, and survival of adult mouse hippocampal neural progenitors and their progeny, via MOR
interaction. By contrast, tapentadol was devoid of these adverse effects on cell survival and reduced
neurite outgrowth and the number of newly generated neurons only at nanomolar concentrations where
the MOR component is predominant. On the contrary, at higher (micromolar) concentrations,
tapentadol elicited proneurogenic and antiapoptotic effects via activation of Î²2 and Î±2 adrenergic
receptors, respectively. Altogether, these data suggest that the noradrenergic component in tapentadol
has the potential to counteract the adverse MOR-mediated effects on hippocampal neurogenesis. As a
proof of concept, we showed that reboxetine, an NRI antidepressant, counteracted both antineurogenic
and apoptotic effects of morphine in vitro. In line with these observations, chronic tapentadol treatment
did not negatively affect hippocampal neurogenesis in vivo. In light of the increasing long-term use of
opiates in chronic pain, in principle, the tapentadol combined mechanism of action may result in less
or no reduction in adult neurogenesis compared with classic opiates.
227. Accurate LC peak boundary detection for Â¹â¶O/Â¹â¸O labeled LC-MS data.
PubMed
Cui, Jian; Petritis, Konstantinos; Tegeler, Tony; Petritis, Brianne; Ma, Xuepo; Jin, Yufang; Gao, Shou-
Jiang S J; Zhang, Jianqiu Michelle
2013-01-01
In liquid chromatography-mass spectrometry (LC-MS), parts of LC peaks are often corrupted by their
co-eluting peptides, which results in increased quantification variance. In this paper, we propose to
apply accurate LC peak boundary detection to remove the corrupted part of LC peaks. Accurate LC
peak boundary detection is achieved by checking the consistency of intensity patterns within peptide
elution time ranges. In addition, we remove peptides with erroneous mass assignment through model
fitness check, which compares observed intensity patterns to theoretically constructed ones. The
proposed algorithm can significantly improve the accuracy and precision of peptide ratio
measurements.
228. Region-Specific Dissociation between Cortical Noradrenaline Levels and the Sleep/Wake Cycle
PubMed Central
Bellesi, Michele; Tononi, Giulio; Cirelli, Chiara; Serra, Pier Andrea
2016-01-01
Study Objectives: The activity of the noradrenergic system of the locus coeruleus (LC) is high in wake
and low in sleep. LC promotes arousal and EEG activation, as well as attention, working memory, and
cognitive flexibility. These functions rely on prefrontal cortex and are impaired by sleep deprivation,
but the extent to which LC activity changes during wake remains unclear. Moreover, it is unknown
whether noradrenergic neurons can sustain elevated firing during extended wake. Recent studies show
that relative to LC neurons targeting primary motor cortex (M1), those projecting to medial prefrontal
cortex (mPFC) have higher spontaneous firing rates and are more excitable. These results suggest that
noradrenaline (NA) levels should be higher in mPFC than M1, and that during prolonged wake LC
cells targeting mPFC may fatigue more, but direct evidence is lacking. Methods: We performed in vivo
microdialysis experiments in adult (9â€“10 weeks old) C57BL/6 mice implanted for chronic
electroencephalographic recordings. Cortical NA levels were measured during spontaneous sleep and
wake (n = 8 mice), and in the course of sleep deprivation (n = 6). Results: We found that absolute NA
levels are higher in mPFC than in M1. Moreover, in both areas they decline during sleep and increase
during wake, but these changes are faster in M1 than mPFC. Finally, by the end of sleep deprivation
NA levels decline only in mPFC. Conclusions: Locus coeruleus (LC) neurons targeting prefrontal
cortex may fatigue more markedly, or earlier, than other LC cells, suggesting one of the mechanisms
underlying the cognitive impairment and the increased sleep presure associated with sleep deprivation.
Commentary: A commentary on this article appears in this issue on page 11. Citation: Bellesi M,
Tononi G, Cirelli C, Serra PA. Region-specific dissociation between cortical noradrenaline levels and
the sleep/wake cycle. SLEEP 2016;39(1):143â€“154. PMID:26237776
229. LC3/GABARAP family proteins: autophagy-(un)related functions.
PubMed
Schaaf, Marco B E; Keulers, Tom G; Vooijs, Marc A; Rouschop, Kasper M A
2016-12-01
From yeast to mammals, autophagy is an important mechanism for sustaining cellular homeostasis
through facilitating the degradation and recycling of aged and cytotoxic components. During
autophagy, cargo is captured in double-membraned vesicles, the autophagosomes, and degraded
through lysosomal fusion. In yeast, autophagy initiation, cargo recognition, cargo engulfment, and
vesicle closure is Atg8 dependent. In higher eukaryotes, Atg8 has evolved into the LC3/GABARAP
protein family, consisting of 7 family proteins [LC3A (2 splice variants), LC3B, LC3C, GABARAP,
GABARAPL1, and GABARAPL2]. LC3B, the most studied family protein, is associated with
autophagosome development and maturation and is used to monitor autophagic activity. Given the
high homology, the other LC3/GABARAP family proteins are often presumed to fulfill similar
functions. Nevertheless, substantial evidence shows that the LC3/GABARAP family proteins are
unique in function and important in autophagy-independent mechanisms. In this review, we discuss the
current knowledge and functions of the LC3/GABARAP family proteins. We focus on processing of
the individual family proteins and their role in autophagy initiation, cargo recognition, vesicle closure,
and trafficking, a complex and tightly regulated process that requires selective presentation and
recruitment of these family proteins. In addition, functions unrelated to autophagy of the
LC3/GABARAP protein family members are discussed.-Schaaf, M. B. E., Keulers, T. G, Vooijs, M.
A., Rouschop, K. M. A. LC3/GABARAP family proteins: autophagy-(un)related functions. Â©
FASEB.
230. Effect of first dimension phase selectivity in online comprehensive two dimensional liquid
chromatography (LC Ã— LC)
PubMed Central
Gu, Haiwei; Huang, Yuan; Filgueira, Marcelo; Carr, Peter W.
2012-01-01
In this study, we examined the effect of first dimension column selectivity in reversed phase (RP)
online comprehensive two dimensional liquid chromatography (LC Ã— LC). The second dimension
was always a carbon clad metal oxide reversed phase material. The hydrophobic subtraction model
(HSM) and the related phase selective triangles were used to guide the selection of six different RP
first dimension columns. Various kinds of samples were investigated and thus two different elution
conditions were needed to cause full elution from the first dimension columns. We compared LC Ã—
LC chromatograms, contours plots, and fcoverage plots by measuring peak capacities, peak numbers,
relative spatial coverage, correlation values, etc. The major finding of this study is that the carbon
phase due to its rather different selectivity from other reversed phases is reasonably orthogonal to a
variety of common types of bonded reversed phases. Thus quite surprisingly the six different first
dimension stationary phases all showed generally similar separation patterns when paired to the second
dimension carbon phase. This result greatly simplifies the task of choosing the correct pair of phases
for RP Ã— RP. PMID:21840009
231. Increased Opioid Dependence in a Mouse Model of Panic Disorder
PubMed Central
Gallego, Xavier; Murtra, Patricia; Zamalloa, Teresa; Canals, Josep Maria; Pineda, Joseba; Amador-
Arjona, Alejandro; Maldonado, Rafael; Dierssen, Mara
2009-01-01
Panic disorder is a highly prevalent neuropsychiatric disorder that shows co-occurrence with substance
abuse. Here, we demonstrate that TrkC, the high-affinity receptor for neurotrophin-3, is a key molecule
involved in panic disorder and opiate dependence, using a transgenic mouse model (TgNTRK3).
Constitutive TrkC overexpression in TgNTRK3 mice dramatically alters spontaneous firing rates of
locus coeruleus (LC) neurons and the response of the noradrenergic system to chronic opiate exposure,
possibly related to the altered regulation of neurotrophic peptides observed. Notably, TgNTRK3 LC
neurons showed an increased firing rate in saline-treated conditions and profound abnormalities in
their response to met5-enkephalin. Behaviorally, chronic morphine administration induced a
significantly increased withdrawal syndrome in TgNTRK3 mice. In conclusion, we show here that the
NT-3/TrkC system is an important regulator of neuronal firing in LC and could contribute to the
adaptations of the noradrenergic system in response to chronic opiate exposure. Moreover, our results
indicate that TrkC is involved in the molecular and cellular changes in noradrenergic neurons
underlying both panic attacks and opiate dependence and support a functional endogenous opioid
deficit in panic disorder patients. PMID:20204153
232. Relationships among the behavioral, noradrenergic, and pituitary-adrenal responses to interleukin-1
and the effects of indomethacin.
PubMed
Wieczorek, Marek; Dunn, Adrian J
2006-09-01
Peripheral administration of interleukin-1 (IL-1) is known to activate the hypothalamo-pituitary-

adrenal axis (HPA axis) and brain noradrenergic systems. We studied the relationship between these
responses using in vivo microdialysis to assess the release of hypothalamic norepinephrine (NE), while
simultaneously sampling blood for ACTH and corticosterone, and monitoring body temperature and
behavior in freely moving rats. Rats were implanted with microdialysis probes in the medial
hypothalamus, with intravenous catheters, and with telethermometers in the abdomen. Each rat was
injected with saline and IL-1beta (1 microg ip) in random order, monitoring microdialysate NE, body
temperature and plasma ACTH and corticosterone for 2-4 h after injection. Saline injections were
followed by transient increases in microdialysate NE and in plasma ACTH and corticosterone. IL-
1beta injections resulted in prolonged elevations of microdialysate NE, as well as plasma ACTH and
corticosterone, and body temperature. IL-1beta also induced shivering and a prolonged depression of
locomotor activity. Pretreatment with indomethacin (10 mg/kg sc) prevented the IL-1beta-induced
increases in body temperature and the apparent increase in hypothalamic NE release, but only
attenuated the IL-1beta-induced shivering and the increase in plasma ACTH. The results indicate a
close temporal relationship between the release of NE and HPA axis activation. Such a relationship is
also supported by the similar effects of indomethacin pretreatment on NE and ACTH. The shivering is
likely involved in the increase in body temperature, but indomethacin only attenuated the shivering
while it blocked the fever. However, the effects of indomethacin clearly indicate that neither the
increase in body temperature nor the increase in hypothalamic NE release was essential for HPA axis
activation. These results suggest that hypothalamic NE is involved in the IL-1-induced HPA axis
activation, but that this is not the only
233. Dibutyryl cyclic AMP induces differentiation of human neuroblastoma SH-SY5Y cells into a
noradrenergic phenotype.
PubMed
Kume, Toshiaki; Kawato, Yuka; Osakada, Fumitaka; Izumi, Yasuhiko; Katsuki, Hiroshi; Nakagawa,
Takayuki; Kaneko, Shuji; Niidome, Tetsuhiro; Takada-Takatori, Yuki; Akaike, Akinori
2008-10-10
Dibutyryl cyclic AMP (dbcAMP) and retinoic acid (RA) have been demonstrated to be the inducers of
morphological differentiation in SH-SY5Y cells, a human catecholaminergic neuroblastoma cell line.
However, it remains unclear whether morphologically differentiated SH-SY5Y cells by these
compounds acquire catecholaminergic properties. We focused on the alteration of tyrosine hydroxylase
(TH) expression and intracellular content of noradrenaline (NA) as the indicators of functional
differentiation. Three days treatment with dbcAMP (1mM) and RA (10microM) induced
morphological changes and an increase of TH-positive cells using immunocytochemical analysis in
SH-SY5Y cells. The percentage of TH-expressing cells in dbcAMP (1mM) treatment was larger than
that in RA (10microM) treatment. In addition, dbcAMP increased intracellular NA content, whereas
RA did not. The dbcAMP-induced increase in TH-expressing cells is partially inhibited by KT5720, a
protein kinase A (PKA) inhibitor. We also investigated the effect of butyrate on SH-SY5Y cells,
because dbcAMP is enzymatically degraded by intracellular esterase, thereby resulting in the
formation of butyrate. Butyrate induced the increase of NA content at lower concentrations than
dbcAMP, although the increase in TH-expressing cells by butyrate was smaller than that by dbcAMP.
The dbcAMP (1mM)- and butyrate (0.3mM)-induced increase in NA content was completely
suppressed by alpha-methyl-p-tyrosine (1mM), an inhibitor of TH. These results suggest that dbcAMP
induces differentiation into the noradrenergic phenotype through both PKA activation and butyrate.
234. Noradrenergic innervation of the rat spinal cord caudal to a complete spinal cord transection: effects of
olfactory ensheathing glia.
PubMed
Takeoka, Aya; Kubasak, Marc D; Zhong, Hui; Kaplan, Jennifer; Roy, Roland R; Phelps, Patricia E
2010-03-01
Transplantation of olfactory bulb-derived olfactory ensheathing glia (OEG) combined with step
training improves hindlimb locomotion in adult rats with a complete spinal cord transection. Spinal
cord injury studies use the presence of noradrenergic (NA) axons caudal to the injury site as evidence
of axonal regeneration and we previously found more NA axons just caudal to the transection in OEG-
than media-injected spinal rats. We therefore hypothesized that OEG transplantation promotes
descending coeruleospinal regeneration that contributes to the recovery of hindlimb locomotion. Now
we report that NA axons are present throughout the caudal stump of both media- and OEG-injected
spinal rats and they enter the spinal cord from the periphery via dorsal and ventral roots and along
large penetrating blood vessels. These results indicate that the presence of NA fibers in the caudal
spinal cord is not a reliable indicator of coeruleospinal regeneration. We then asked if NA axons
appose cholinergic neurons associated with motor functions, i.e., central canal cluster and partition
cells (active during fictive locomotion) and somatic motor neurons (SMNs). We found more NA
varicosities adjacent to central canal cluster cells, partition cells, and SMNs in the lumbar enlargement
of OEG- than media-injected rats. As non-synaptic release of NA is common in the spinal cord, more
associations between NA varicosities and motor-associated cholinergic neurons in the lumbar spinal
cord may contribute to the improved treadmill stepping observed in OEG-injected spinal rats. This
effect could be mediated through direct association with SMNs and/or indirectly via cholinergic
interneurons. Copyright 2009 Elsevier Inc. All rights reserved.
235. NORADRENERGIC INNERVATION OF THE RAT SPINAL CORD CAUDAL TO A COMPLETE

SPINAL CORD TRANSECTION: EFFECTS OF OLFACTORY ENSHEATHING GLIA
PubMed Central
Takeoka, Aya; Kubasak, Marc D.; Zhong, Hui; Kaplan, Jennifer; Roy, Roland R.; Phelps, Patricia E.
2010-01-01
Transplantation of olfactory bulb-derived olfactory ensheathing glia (OEG) combined with step
training improves hindlimb locomotion in adult rats with a complete spinal cord transection. Spinal
cord injury studies use the presence of noradrenergic (NA) axons caudal to the injury site as evidence
of axonal regeneration and we previously found more NA axons just caudal to the transection in OEG-
than media-injected spinal rats. We therefore hypothesized that OEG transplantation promotes
descending coeruleospinal regeneration that contributes to the recovery of hindlimb locomotion. Now
we report that NA axons are present throughout the caudal stump of both media- and OEG-injected
spinal rats and they enter the spinal cord from the periphery via dorsal and ventral roots and along
large penetrating blood vessels. These results indicate that the presence of NA fibers in the caudal
spinal cord is not a reliable indicator of coeruleospinal regeneration. We then asked if NA axons
appose cholinergic neurons associated with motor functions, i.e., central canal cluster and partition
cells (active during fictive locomotion) and somatic motor neurons (SMNs). We found more NA
varicosities adjacent to central canal cluster cells, partition cells, and SMNs in the lumbar enlargement
of OEG- than media-injected rats. As non-synaptic release of NA is common in the spinal cord, more
associations between NA varicosities and motor-associated cholinergic neurons in the lumbar spinal
cord may contribute to the improved treadmill stepping observed in OEG-injected spinal rats. This
effect could be mediated through direct association with SMNs and/or indirectly via cholinergic
interneurons. PMID:20025875
236. The involvement of cholinergic and noradrenergic systems in behavioral recovery following
oxotremorine treatment to chronically stressed rats.
PubMed
Srikumar, B N; Raju, T R; Shankaranarayana Rao, B S
2006-12-01
Chronic stress in rats has been shown to impair learning and memory, and precipitate several affective
disorders like depression and anxiety. The mechanisms involved in these stress-induced disorders and
the possible reversal are poorly understood, thus limiting the number of drugs available for their
treatment. Our earlier studies suggest cholinergic dysfunction as the underlying cause in the behavioral
deficits following stress. Muscarinic cholinergic agonist, oxotremorine is demonstrated to have a
beneficial effect in reversing brain injury-induced behavioral dysfunction. In this study, we have
evaluated the effect of oxotremorine treatment on chronic restraint stress-induced cognitive deficits.
Rats were subjected to restraint stress (6 h/day) for 21 days followed by oxotremorine treatment for 10
days. Spatial learning and memory was assessed in a partially baited eight-arm radial maze task.
Stressed rats exhibited impairment in performance, with decreased percentage of correct choices and
an increase in the number of reference memory errors (RMEs). Oxotremorine treatment (0.1 or 0.2
mg/kg, i.p.) to stressed rats resulted in a significant increase in the percent correct choices and a
decrease in the number of RMEs compared with stress as well as the stress+vehicle-treated groups. In
the retention test, oxotremorine treated rats committed less RMEs compared with the stress group.
Chronic restraint stress decreased acetylcholinesterase (AChE) activity in the hippocampus, frontal
cortex and septum, which was reversed by both the doses of oxotremorine. Further, oxotremorine
treatment also restored the norepinephrine levels in the hippocampus and frontal cortex. Thus, this
study demonstrates the potential of cholinergic muscarinic agonists and the involvement of both
cholinergic and noradrenergic systems in the reversal of stress-induced learning and memory deficits.
237. Role of nucleus of the solitary tract noradrenergic neurons in post-stress cardiovascular and hormonal
control in male rats.
PubMed
Bundzikova-Osacka, Jana; Ghosal, Sriparna; Packard, Benjamin A; Ulrich-Lai, Yvonne M; Herman,

James P
2015-01-01
Chronic stress causes hypothalamo-pituitary-adrenal (HPA) axis hyperactivity and cardiovascular

dyshomeostasis. Noradrenergic (NA) neurons in the nucleus of the solitary tract (NTS) are considered
to play a role in these changes. In this study, we tested the hypothesis that NTS NA A2 neurons are
required for cardiovascular and HPA axis responses to both acute and chronic stress. Adult male rats
received bilateral microinjection into the NTS of 6-hydroxydopamine (6-OHDA) to lesion A2 neurons
[cardiovascular study, nâ€‰=â€‰5; HPA study, nâ€‰=â€‰5] or vehicle [cardiovascular study, nâ€
‰=â€‰6; HPA study, nâ€‰=â€‰4]. Rats were exposed to acute restraint stress followed by 14â€‰d
of chronic variable stress (CVS). On the last day of testing, rats were placed in a novel elevated plus
maze (EPM) to test post-CVS stress responses. Lesions of NTS A2 neurons reduced the tachycardic
response to acute restraint, confirming that A2 neurons promote sympathetic activation following
acute stress. In addition, CVS increased the ratio of low-frequency to high-frequency power for heart
rate variability, indicative of sympathovagal imbalance, and this effect was significantly attenuated by
6-OHDA lesion. Lesions of NTS A2 neurons reduced acute restraint-induced corticosterone secretion,
but did not affect the corticosterone response to the EPM, indicating that A2 neurons promote acute
HPA axis responses, but are not involved in CVS-mediated HPA axis sensitization. Collectively, these
data indicate that A2 neurons promote both cardiovascular and HPA axis responses to acute stress.
Moreover, A2 catecholaminergic neurons may contribute to the potentially deleterious enhancement of
sympathetic drive following chronic stress.
238. Metformin normalizes the structural changes in glycogen preceding prediabetes in mice
overexpressing neuropeptide Y in noradrenergic neurons.
PubMed
Ailanen, Liisa; Bezborodkina, Natalia N; Virtanen, Laura; Ruohonen, Suvi T; Malova, Anastasia V;
Okovityi, Sergey V; Chistyakova, Elizaveta Y; Savontaus, Eriika
2018-04-01
Hepatic insulin resistance and increased gluconeogenesis are known therapeutic targets of metformin,
but the role of hepatic glycogen in the pathogenesis of diabetes is less clear. Mouse model of
neuropeptide Y (NPY) overexpression in noradrenergic neurons (OE-NPY D Î²H ) with a phenotype of
late onset obesity, hepatosteatosis, and prediabetes was used to study early changes in glycogen
structure and metabolism preceding prediabetes. Furthermore, the effect of the anti-hyperglycemic
agent, metformin (300Â mg/kg/day/4Â weeks in drinking water), was assessed on changes in glycogen
metabolism, body weight, fat mass, and glucose tolerance. Glycogen structure was characterized by
cytofluorometric analysis in isolated hepatocytes and mRNA expression of key enzymes by qPCR.
OE-NPY D Î²H mice displayed decreased labile glycogen fraction relative to stabile fraction (the
intermediate form of glycogen) suggesting enhanced glycogen cycling. This was supported by
decreased filling of glucose residues in the 10th outer tier of the glycogen molecule, which suggests
accelerated glycogen phosphorylation. Metformin reduced fat mass gain in both genotypes, but
glucose tolerance was improved mostly in wild-type mice. However, metformin inhibited glycogen
accumulation and normalized the ratio between glycogen structures in OE-NPY D Î²H mice indicating
decreased glycogen synthesis. Furthermore, the presence of glucose residues in the 11th tier together
with decreased glycogen phosphorylase expression suggested inhibition of glycogen degradation. In
conclusion, structural changes in glycogen of OE-NPY D Î²H mice point to increased glycogen
metabolism, which may predispose them to prediabetes. Metformin treatment normalizes these
changes and suppresses both glycogen synthesis and phosphorylation, which may contribute to its
preventive effect on the onset of diabetes.
239. Relationships among the behavioral, noradrenergic, and pituitaryâ€“adrenal responses to interleukin-1
and the effects of indomethacin
PubMed Central
Wieczorek, Marek; Dunn, Adrian J.
2007-01-01
Peripheral administration of interleukin-1 (IL-1) is known to activate the

hypothalamoâ€“pituitaryâ€“adrenal axis (HPA axis) and brain noradrenergic systems. We studied the
relationship between these responses using in vivo microdialysis to assess the release of hypothalamic
norepinephrine (NE), while simultaneously sampling blood for ACTH and corticosterone, and
monitoring body temperature and behavior in freely moving rats. Rats were implanted with
microdialysis probes in the medial hypothalamus, with intravenous catheters, and with
telethermometers in the abdomen. Each rat was injected with saline and IL-1Î² (1 Î¼g ip) in random
order, monitoring microdialysate NE, body temperature and plasma ACTH and corticosterone for
2â€“4 h after injection. Saline injections were followed by transient increases in microdialysate NE
and in plasma ACTH and corticosterone. IL-1Î² injections resulted in prolonged elevations of
microdialysate NE, as well as plasma ACTH and corticosterone, and body temperature. IL-1Î² also
induced shivering and a prolonged depression of locomotor activity. Pretreatment with indomethacin
(10 mg/kg sc) prevented the IL-1Î²-induced increases in body temperature and the apparent increase in
hypothalamic NE release, but only attenuated the IL-1Î²-induced shivering and the increase in plasma
ACTH. The results indicate a close temporal relationship between the release of NE and HPA axis
activation. Such a relationship is also supported by the similar effects of indomethacin pretreatment on
NE and ACTH. The shivering is likely involved in the increase in body temperature, but indomethacin
only attenuated the shivering while it blocked the fever. However, the effects of indomethacin clearly
indicate that neither the increase in body temperature nor the increase in hypothalamic NE release was
essential for HPA axis activation. These results suggest that hypothalamic NE is involved in the IL-1-
induced HPA axis activation, but that this is not the only
240. Effects of lesions of the dorsal noradrenergic bundle on conditioned suppression to a CS and to a
contextual background stimulus.
PubMed
Tsaltas, E; Schugens, M M; Gray, J A
1989-01-01
The aim of the experiment was to determine whether the dorsal noradrenergic bundle (DB) plays a role
in conditioning to context. Rats received either bilateral lesions of the DB by local injection of 6-
hydroxydopamine, vehicle injections only, or sham operations. All animals were then trained to
barpress for food on a variable interval (VI) schedule. Two 5-min intrusion periods were superimposed
on the VI baseline during each session. An 'envelope' stimulus (flashing light) was on throughout each
intrusion period. In addition, embedded in the two intrusion periods of each session, there occurred 8
presentations of a 'punctate' conditioned stimulus (CS) (a 15-s clicker), and 8 presentations of a 0.5-s
footshock. Within each surgical condition rats were randomly allocated to one of three conditioning
groups, receiving 100%, 50% or 0% temporal association between CS and shock. Conditioning to the
punctate CS and to the context provided by the envelope stimulus was assessed by the degree of
suppression of the barpress response relative to the VI baseline. Responding was most suppressed in
the punctate CS in the 100 and 50% conditions, and most suppressed in the envelope stimulus in the
0% condition. DB lesions released response suppression to the punctate CS, had no effect on
suppression to the envelope stimulus, and reduced sensitivity to CS-shock probability as measured by
response suppression during the punctate CS. These results confirm previous reports that DB lesions
alleviate response suppression to shock-associated cues, identify some of the parameters that affect this
phenomenon, but fail to support a role for the DB in contextual conditioning.
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241. Preprocessing and Analysis of LC-MS-Based Proteomic Data
PubMed Central
Tsai, Tsung-Heng; Wang, Minkun; Ressom, Habtom W.
2016-01-01
Liquid chromatography coupled with mass spectrometry (LC-MS) has been widely used for profiling
protein expression levels. This chapter is focused on LC-MS data preprocessing, which is a crucial
step in the analysis of LC-MS based proteomics. We provide a high-level overview, highlight
associated challenges, and present a step-by-step example for analysis of data from LC-MS based
untargeted proteomic study. Furthermore, key procedures and relevant issues with the subsequent
analysis by multiple reaction monitoring (MRM) are discussed. PMID:26519169
242. Too much of a good thing: blocking noradrenergic facilitation in medial prefrontal cortex prevents the
detrimental effects of chronic stress on cognition.
PubMed
Jett, Julianne D; Morilak, David A
2013-03-01
Cognitive impairments associated with dysfunction of the medial prefrontal cortex (mPFC) are
prominent in stress-related psychiatric disorders. We have shown that enhancing noradrenergic tone
acutely in the rat mPFC facilitated extra-dimensional (ED) set-shifting on the attentional set-shifting
test (AST), whereas chronic unpredictable stress (CUS) impaired ED. In this study, we tested the
hypothesis that the acute facilitatory effect of norepinephrine (NE) in mPFC becomes detrimental
when activated repeatedly during CUS. Using microdialysis, we showed that the release of NE evoked
in mPFC by acute stress was unchanged at the end of CUS treatment. Thus, to then determine if
repeated elicitation of this NE activity in mPFC during CUS may have contributed to the ED deficit,
we infused a cocktail of Î±(1)-, Î²(1)-, and Î²(2)-adrenergic receptor antagonists into the mPFC prior to
each CUS session, then tested animals drug free on the AST. Antagonist treatment prevented the CUS-
induced ED deficit, suggesting that NE signaling during CUS compromised mPFC function. We
confirmed that this was not attributable to sensitization of adrenergic receptor function following
chronic antagonist treatment, by administering an additional microinjection into the mPFC
immediately prior to ED testing. Acute antagonist treatment did not reverse the beneficial effects of
chronic drug treatment during CUS, nor have any effect on baseline ED performance in chronic
vehicle controls. Thus, we conclude that blockade of noradrenergic receptors in mPFC protected
against the detrimental cognitive effects of CUS, and that repeated elicitation of noradrenergic
facilitatory activity is one mechanism by which chronic stress may promote mPFC cognitive
dysfunction.
243. The antidepressant-like effect of ethynyl estradiol is mediated by both serotonergic and noradrenergic
systems in the forced swimming test.
PubMed
Vega-Rivera, N M; LÃ³pez-Rubalcava, C; Estrada-Camarena, E
2013-10-10
17Î±-Ethynyl-estradiol (EE2, a synthetic steroidal estrogen) induces antidepressant-like effects in the

forced swimming test (FST) similar to those induced by 5-HT and noradrenaline reuptake inhibitors
(dual antidepressants). However, the precise mechanism of action of EE2 has not been studied. In the
present study, the participation of estrogen receptors (ERs) and the serotonergic and the noradrenergic
presynaptic sites in the antidepressant-like action of EE2 was evaluated in the FST. The effects of the
ER antagonist ICI 182,780 (10 Î¼g/rat; i.c.v.), the serotonergic and noradrenergic terminal destruction
with 5,7-dihydroxytryptamine (5,7-DHT; 200 Î¼g/rat, i.c.v.), and N-(2-chloro-ethyl)-N-ethyl-2-
bromobenzylamine (DSP4; 10mg/kg, i.p.) were studied in ovariectomized rats treated with EE2 and
subjected to the FST. In addition, the participation of Î±2-adrenergic receptors in the antidepressant-
like action of EE2 was explored using the selective Î±2-receptor antagonist idazoxan (0.25, 0.5 and
1.0mg/kg, i.p.). EE2 induced an antidepressant-like action characterized by a decrease in immobility
behavior with a concomitant increase in swimming and climbing behaviors. The ER antagonist, 5,7-
DHT, DSP4, and idazoxan blocked the effects of EE2 on the immobility behavior, whereas ICI
182,780 and 5,7-DHT affected swimming behavior. The noradrenergic compound DSP4 altered
climbing behavior, while Idazoxan inhibited the increase of swimming and climbing behaviors induced
by EE2. Our results suggest that the antidepressant-like action of EE2 implies a complex mechanism
of action on monoaminergic systems and estrogen receptors. Copyright Â© 2013 IBRO. Published by
244. Identification of Forced Degradation Products of Itopride by LC-PDA and LC-MS.
PubMed
Joshi, Payal; Bhoir, Suvarna; Bhagwat, A M; Vishwanath, K; Jadhav, R K
2011-05-01
Degradation products of itopride formed under different forced conditions have been identified using
LC-PDA and LC-MS techniques. Itopride was subjected to forced degradation under the conditions of
hydrolysis, photolysis, oxidation, dry and wet heat, in accordance with the International Conference on
Harmonization. The stress solutions were chromatographed on reversed phase C18 (250Ã—4.6 mm, 5
Î¼m) column with a mobile phase methanol:water (55:45, v/v) at a detection wavelength of 215 nm.
Itopride degraded in acid, alkali and oxidative stress conditions. The stability indicating method was
developed and validated. The degradation pathway of the drug to products II-VIII is proposed.
245. Identification of Forced Degradation Products of Itopride by LC-PDA and LC-MS
PubMed Central
Joshi, Payal; Bhoir, Suvarna; Bhagwat, A. M.; Vishwanath, K.; Jadhav, R. K.
2011-01-01
Degradation products of itopride formed under different forced conditions have been identified using
LC-PDA and LC-MS techniques. Itopride was subjected to forced degradation under the conditions of
hydrolysis, photolysis, oxidation, dry and wet heat, in accordance with the International Conference on
Harmonization. The stress solutions were chromatographed on reversed phase C18 (250Ã—4.6 mm, 5
Î¼m) column with a mobile phase methanol:water (55:45, v/v) at a detection wavelength of 215 nm.
Itopride degraded in acid, alkali and oxidative stress conditions. The stability indicating method was
developed and validated. The degradation pathway of the drug to products II-VIII is proposed.
PMID:22457552
246. Structural Features of LC8-Induced Self Association of Swallowâ€
PubMed Central
Kidane, Ariam I.; Song, Yujuan; Nyarko, Afua; Hall, Justin; Hare, Michael; LÃ¶hr, Frank; Barbar,
Elisar
2013-01-01
Cell function depends on the collective activity of protein networks within which a few proteins, called
hubs, participate in a large number of interactions. Dynein light chain LC8, first discovered as a
subunit of the motor protein dynein, is considered to have a role broader than dynein and its
participation in diverse systems fits the description of a hub. Among its partners is Swallow with
which LC8 is essential for proper localization of bicoid mRNA at the anterior cortex of Drosophila
oocytes. Why LC8 is essential in this process is not clear, but emerging evidence suggests that LC8
functions by promoting self-association and/or structural organization of its diverse binding partners.
This work addresses the mechanistic and structural features of LC8-induced Swallow self-association
distant from LC8 binding. Mutational design based on a hypothetical helical wheel, inter-monomer
NOEs assigned to residues expected at interface positions and circular dichroism spectral
characteristics indicate that the LC8-promoted dimer of Swallow is a coiled-coil. Secondary chemical
shifts and 15N backbone relaxation identify the boundaries and distinguishing structural features of the
coiled-coil. Thermodynamic analysis of Swallow polypeptides designed to decouple self-association
from LC8 binding reveals that the higher binding affinity of the engineered bivalent Swallow is of
purely entropic origin and that the linker separating the coiled-coil from the LC8 binding site remains
disordered. We speculate that the LC8-promoted coiled-coil is critical for bicoid mRNA localization
because it could induce structural organization of Swallow, which except for the central LC8-promoted
coiled-coil is primarily disordered. PMID:23914803
247. Coupling of Ultrafast LC with Mass Spectrometry by DESI
NASA Astrophysics Data System (ADS)
Cai, Yi; Liu, Yong; Helmy, Roy; Chen, Hao
2014-10-01
Recently we reported a desorption electrospray ionization (DESI) interface to combine liquid

chromatography (LC) with mass spectrometry (MS) using a new LC eluent splitting strategy through a
tiny orifice on LC capillary tube [ J. Am. Soc. Mass Spectrom. 25, 286 (2014)]. The interface
introduces negligible dead volume and back pressure, thereby allowing "near real-time" MS detection,
fast LC elution, and online MS-directed purification. This study further evaluates the LC/DESI-MS
performance with focus of using ultra-fast LC. Using a monolithic C18 column, metabolites in urine
can be separated within 1.6 min and can be online collected for subsequent structure elucidation (e.g.,
by NMR, UV, IR) in a recovery yield up to 99%. Using a spray solvent with alkaline pH, negative ions
could be directly generated for acidic analytes (e.g., ibuprofen) in acidic LC eluent by DESI, offering a
novel protocol to realize "wrong-way around" ionization for LC/MS analysis. In addition, DESI-MS is
found to be compatible with ultra-performance liquid chromatography (UPLC) for the first time.
248. Activation of Âµ-opioid receptors and block of KIR3 potassium channels and NMDA receptor
conductance by l- and d-methadone in rat locus coeruleus
PubMed Central
Matsui, Aya; Williams, John T
2010-01-01
BACKGROUND AND PURPOSE Methadone activates opioid receptors to increase a potassium

conductance mediated by G-protein-coupled, inwardly rectifying, potassium (KIR3) channels.
Methadone also blocks KIR3 channels and N-methyl-D-aspartic acid (NMDA) receptors. However,
the concentration dependence and stereospecificity of receptor activation and channel blockade by
methadone on single neurons has not been characterized. EXPERIMENTAL APPROACH
Intracellular and whole-cell recording were made from locus coeruleus neurons in brain slices and the
activation of Âµ-opioid receptors and blockade of KIR3 and NMDA channels with l- and d-methadone
was examined. KEY RESULTS The potency of l-methadone, measured by the amplitude of
hyperpolarization was 16.5-fold higher than with d-methadone. A maximum hyperpolarization was
caused by both enantiomers (âˆ¼30 mV); however, the maximum outward current measured with
whole-cell voltage-clamp recording was smaller than the current induced by [Met]5enkephalin. The
KIR3 conductance induced by activation of Î±2-adrenoceptors was decreased with high concentrations
of l- and d-methadone (10â€“30 ÂµM). In addition, methadone blocked the resting inward rectifying
conductance (KIR). Both l- and d-methadone blocked the NMDA receptor-dependent current. The
block of NMDA receptor-dependent current was voltage-dependent suggesting that methadone acted
as a channel blocker. CONCLUSIONS AND IMPLICATIONS Methadone activated Âµ-opioid
receptors at low concentrations in a stereospecific manner. KIR3 and NMDA receptor channel block
was not stereospecific and required substantially higher concentrations. The separation in the
concentration range suggests that the activation of Âµ-opioid receptors rather than the channel
blocking properties mediate both the therapeutic and toxic actions of methadone. PMID:20659105
249. Dysfunctional Sensory Modalities, Locus Coeruleus, and Basal Forebrain: Early Determinants that
Promote Neuropathogenesis of Cognitive and Memory Decline and Alzheimer's Disease.
PubMed
Daulatzai, Mak Adam
2016-10-01
Sporadic Alzheimer's disease (AD) is a devastating neurodegenerative disorder. It is essential to

unravel its etiology and pathogenesis. This should enable us to study the presymptomatic stages of the
disease and to analyze and reverse the antemortem behavioral, memory, and cognitive dysfunction.
Prima facie, an ongoing chronic vulnerability involving neural insult may lead normal elderly to mild
cognitive impairment (MCI) and then to AD. Development of effective preventive and therapeutic
strategies to thwart the disease pathology obviously requires a thorough delineation of underlying
disruptive neuropathological processes. Our sensory capacity for touch, smell, taste, hearing, and
vision declines with advancing age. Declines in different sensory attributes are considered here to be
the primary "first-tier pathologies." Olfactory loss is among the first clinical signs of
neurodegenerative diseases including AD and Parkinson's disease (PD). Sensory dysfunction in the
aged promotes pathological disturbances in the locus coeruleus, basal forebrain, entorhinal cortex,
hippocampus, and several key areas of neocortex and brainstem. Hence, sensory dysfunction is the
pivotal factor that may upregulate cognitive and memory dysfunction. The age-related constellation of
comorbid pathological factors may include apolipoprotein E (APOE) genotype, obesity, diabetes,
hypertension, alcohol abuse, head trauma, and obstructive sleep apnea. The concepts and trajectories
delineated here are the dynamic pillars of the current hypothesis presented-it postulates that the
sensory decline, in conjunction with the above pathologies, is crucial in triggering neurodegeneration
and promoting cognitive/memory dysfunction in aging and AD. The application of this thesis can be
important in formulating new multifactorial preventive and treatment strategies (suggested here) in
order to attenuate cognitive and memory decline and ameliorate pathological dysfunction in aging,
MCI, and AD.
250. The gist and details of sex differences in cognition and the brain: How parallels in sex differences
across domains are shaped by the locus coeruleus and catecholamine systems.
PubMed
Ycaza Herrera, Alexandra; Wang, Jiaxi; Mather, Mara
2018-05-19
Across three different domains, there are similar sex differences in how men and women process
information. There tends to be a male advantage in attending to and remembering the gist (essential
central information of a scene or situation), but a female advantage in attending to and remembering
the details (non-essential peripheral information of a scene or situation). This is seen in emotional
memory, where emotion enhances gist memory more for males than for females, but enhances detail
memory more for females than for males. It also occurs in spatial memory, where men tend to notice
and remember the gist of where they or objects are in space, allowing them to more flexibly
manipulate themselves or objects within that space, whereas women tend to recall the details of the
space around them, allowing them to accurately remember the locations of objects. Finally, such sex
differences have also been noted in perception of stimuli such that men attend to global aspects of
stimuli (such as a large letter E) more than women, whereas women attend more to the local aspects
(such as the many smaller letter Ts making up the E). We review the parallel sex differences seen
across these domains in this paper and how they relate to the different brain systems involved in each
of these task domains. In addition, we discuss how sex differences in evolutionary pressures and in the
locus coeruleus and norepinephrine system may account for why parallel sex differences occur across
these different task domains. Copyright Â© 2018 Elsevier Ltd. All rights reserved.
251. Involvement of noradrenergic and corticoid receptors in the consolidation of the lasting anxiogenic
effects of predator stress.
PubMed
Adamec, R; Muir, C; Grimes, M; Pearcey, K
2007-05-16
The roles of beta-NER (beta-noradrenergic receptor), GR (glucocorticoid) and mineral corticoid

receptors (MR) in the consolidation of anxiogenic effects of predator stress were studied. One minute
after predator stress, different groups of rats were injected (ip) with vehicle, propranolol (beta-NER
blocker, 5 and 10 mg/kg), mifepristone (RU486, GR blocker, 20 mg/kg), spironolactone (MR blocker,
50 mg/kg), propranolol (5 mg/kg) plus RU486 (20 mg/kg) or the anxiolytic, chloradiazepoxide (CPZ,
10 mg/kg). One week later, rodent anxiety was assessed in elevated plus maze, hole board, light/dark
box, social interaction and acoustic startle. Considering all tests except startle, propranolol dose
dependently blocked consolidation of lasting anxiogenic effects of predator stress in all tests. GR
receptor block alone was ineffective. However, GR block in combination with an ineffective dose of
propranolol did blocked consolidation of predator stress effects in all tests, suggesting a synergism
between beta-NER and GR. Surprisingly, MR block prevented consolidation of anxiogenic effects in
all tests except the light/dark box. CPZ post stress was ineffective against the anxiogenic impact of
predator stress. Study of startle was complicated by the fact that anxiogenic effects of stress on startle
amplitude manifested as both an increase and a decrease in startle amplitude. Suppression of startle
occurred in stressed plus vehicle injected groups handled three times prior to predator stress. In
contrast, stressed plus vehicle rats handled five times prior to predator stress showed increases in
startle, as did all predator stressed only groups. Mechanisms of consolidation of the different startle
responses appear to differ. CPZ post stress blocked startle suppression but not enhancement of startle.
Propranolol post stress had no effect on either suppression or enhancement of startle. GR block alone
post stress prevented suppression of startle, but not enhancement. In contrast
252. Involvement of histaminergic and noradrenergic receptors in the oxytocin-induced food intake in
neonatal meat-type chicks.
PubMed
Mirnaghizadeh, Seyed Vahid; Zendehdel, Morteza; Babapour, Vahab

2017-03-01
famotidine, prazosin, yohimbine, metoprolol and SR59230R had no effect on oxytocin- induced food
intake in FD3 broiler chickens. These results suggest that the effect of oxytocin on food intake is
probably mediated by histaminergic (via H1 and H3 receptors) and noradrenergic (via Î²2 receptors)
systems in broiler chickens.
253. Matrix effects break the LC behavior rule for analytes in LC-MS/MS analysis of biological samples
USDA-ARS?s Scientific Manuscript database
High-performance liquid chromatography (HPLC) and liquid chromatography-tandem mass

spectrometry (LC-MS/MS) are generally accepted as the preferred techniques for detecting and
quantitating analytes of interest in biological matrices on the basis of the rule that one chemical
compound yields one LC-...
254. 9. Photocopy of engineering drawing. LC 17 HIGH PRESSURE GAS ...
Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes
Survey
9. Photocopy of engineering drawing. LC 17 HIGH PRESSURE GAS INSTALLATION: SITE &

GRADING PLAN, APRIL 1969. - Cape Canaveral Air Station, Launch Complex 17, Facility 28419,
East end of Lighthouse Road, Cape Canaveral, Brevard County, FL
255. Underivatized oxysterols and nanoLC-ESI-MS: A mismatch.
PubMed
Roberg-Larsen, Hanne; Vesterdal, Caroline; Wilson, Steven Ray; Lundanes, Elsa
2015-07-01
Due to their non-charged character, liquid chromatography-electrospray ionization-mass spectrometry

(LC-ESI-MS) measurements of oxysterols are often performed after derivatization with e.g. charged
Girard reagents. However, derivatization reactions are time-consuming and may require numerous
steps to remove excess reagent. In addition, extensive sample handling can be associated with
cholesterol autoxidation, resulting in analyte artifacts and hence false positives. Nano scale liquid
chromatography in combination with electrospray-mass spectrometry (nanoLC-ESI-MS) is a powerful
tool for analyzing limited samples, due to substantially increased sensitivity compared to conventional
LC-ESI-MS. The signal enhancement may compensate for the poor ionization of the oxysterols; hence
we have explored the possibility to quantify oxysterols without derivatization using nanoLC-ESI-MS.
Non-derivatized oxysterols and nanoLC were however not compatible, due to persistent and large
carry-over. This was attributed to the extended contribution of surface to volume ratio in such
miniaturized systems and interactions with the materials of the nanoLC instrumentation (e.g.
adsorption to the fused silica tubing). Two contemporary MS instruments (Q-Exactiveâ„¢ hybrid
quadrupole-Orbitrap and TSQ Quantivaâ„¢ triple quadrupole) were used. However, both the MS and
MS/MS spectra of non-derivatized oxysterols were ambiguous and/or unrepeatable for both of the
instruments employed. Derivatizing oxysterols is more cumbersome, but provides more selective and
reliable results, and Girard derivatization+nanoLC-ESI-MS continues to be our recommended choice
for measuring oxysterols in very limited samples. These investigations also indicate that extra care
should be taken to remove lipids prior to nanoLC of other analytes, as adsorbed oxysterols, etc. can
compromise analysis. Copyright Â© 2015 Elsevier Inc. All rights reserved.
256. Regulation of the autophagy protein LC3 by phosphorylation
PubMed Central
Cherra, Salvatore J.; Kulich, Scott M.; Uechi, Guy; Balasubramani, Manimalha; Mountzouris, John;
Day, Billy W.
2010-01-01
Macroautophagy is a major catabolic pathway that impacts cell survival, differentiation, tumorigenesis,
and neurodegeneration. Although bulk degradation sustains carbon sources during starvation,
autophagy contributes to shrinkage of differentiated neuronal processes. Identification of autophagy-
related genes has spurred rapid advances in understanding the recruitment of microtubule-associated
protein 1 light chain 3 (LC3) in autophagy induction, although braking mechanisms remain less
understood. Using mass spectrometry, we identified a direct protein kinase A (PKA) phosphorylation
site on LC3 that regulates its participation in autophagy. Both metabolic (rapamycin) and pathological
(MPP+) inducers of autophagy caused dephosphorylation of endogenous LC3. The
pseudophosphorylated LC3 mutant showed reduced recruitment to autophagosomes, whereas the
nonphosphorylatable mutant exhibited enhanced puncta formation. Finally, autophagy-dependent
neurite shortening induced by expression of a Parkinson diseaseâ€“associated G2019S mutation in
leucine-rich repeat kinase 2 was inhibited by dibutyrylâ€“cyclic adenosine monophosphate,
cytoplasmic expression of the PKA catalytic subunit, or the LC3 phosphorylation mimic. These data
demonstrate a role for phosphorylation in regulating LC3 activity. PMID:20713600
257. Chronic treatment with prazosin or duloxetine lessens concurrent anxiety-like behavior and alcohol
intake: evidence of disrupted noradrenergic signaling in anxiety-related alcohol use
PubMed Central
Skelly, Mary J; Weiner, Jeff L
2014-01-01
Background Alcohol use disorders have been linked to increased anxiety, and enhanced central
noradrenergic signaling may partly explain this relationship. Pharmacological interventions believed to
reduce the excitatory effects of norepinephrine have proven effective in attenuating ethanol intake in
alcoholics as well as in rodent models of ethanol dependence. However, most preclinical investigations
into the effectiveness of these drugs in decreasing ethanol intake have been limited to acute
observations, and none have concurrently assessed their anxiolytic effects. The purpose of these
studies was to examine the long-term effectiveness of pharmacological interventions presumed to
decrease norepinephrine signaling on concomitant ethanol self-administration and anxiety-like
behavior in adult rats with relatively high levels of antecedent anxiety-like behavior. Methods Adult
male Long-Evans rats self-administered ethanol on an intermittent access schedule for eight to ten
weeks prior to being implanted with osmotic minipumps containing either an a1-adrenoreceptor
antagonist (prazosin, 1.5 mg/kg/day), a Î²1/2-adrenoreceptor antagonist (propranolol, 2.5 mg/kg/day), a
serotonin/norepinephrine reuptake inhibitor (duloxetine, 1.5 mg/kg/day) or vehicle (10% dimethyl
sulfoxide). These drugs were continuously delivered across four weeks, during which animals
continued to have intermittent access to ethanol. Anxiety-like behavior was assessed on the elevated
plus maze before treatment and again near the end of the drug delivery period. Results Our results
indicate that chronic treatment with a low dose of prazosin or duloxetine significantly decreases
ethanol self-administration (P < 0.05). Furthermore, this decrease in drinking is accompanied by
significant reductions in the expression of anxiety-like behavior (P < 0.05). Conclusions These
findings suggest that chronic treatment with putative inhibitors of central noradrenergic signaling may
attenuate ethanol intake via a
258. Chronic treatment with prazosin or duloxetine lessens concurrent anxiety-like behavior and alcohol
intake: evidence of disrupted noradrenergic signaling in anxiety-related alcohol use.
PubMed
Skelly, Mary J; Weiner, Jeff L
2014-07-01
Alcohol use disorders have been linked to increased anxiety, and enhanced central noradrenergic
signaling may partly explain this relationship. Pharmacological interventions believed to reduce the
excitatory effects of norepinephrine have proven effective in attenuating ethanol intake in alcoholics as
well as in rodent models of ethanol dependence. However, most preclinical investigations into the
effectiveness of these drugs in decreasing ethanol intake have been limited to acute observations, and
none have concurrently assessed their anxiolytic effects. The purpose of these studies was to examine
the long-term effectiveness of pharmacological interventions presumed to decrease norepinephrine
signaling on concomitant ethanol self-administration and anxiety-like behavior in adult rats with
relatively high levels of antecedent anxiety-like behavior. Adult male Long-Evans rats self-
administered ethanol on an intermittent access schedule for eight to ten weeks prior to being implanted
with osmotic minipumps containing either an a1-adrenoreceptor antagonist (prazosin, 1.5 mg/kg/day),
a Î²1/2-adrenoreceptor antagonist (propranolol, 2.5 mg/kg/day), a serotonin/norepinephrine reuptake
inhibitor (duloxetine, 1.5 mg/kg/day) or vehicle (10% dimethyl sulfoxide). These drugs were
continuously delivered across four weeks, during which animals continued to have intermittent access
to ethanol. Anxiety-like behavior was assessed on the elevated plus maze before treatment and again
near the end of the drug delivery period. Our results indicate that chronic treatment with a low dose of
prazosin or duloxetine significantly decreases ethanol self-administration (P < 0.05). Furthermore, this
decrease in drinking is accompanied by significant reductions in the expression of anxiety-like
behavior (P < 0.05). These findings suggest that chronic treatment with putative inhibitors of central
noradrenergic signaling may attenuate ethanol intake via a reduction in anxiety-like behavior.
259. Glucocorticoid receptors participate in the opiate withdrawal-induced stimulation of rats NTS
noradrenergic activity and in the somatic signs of morphine withdrawal.
PubMed
Navarro-Zaragoza, Javier; Hidalgo, Juana M; Laorden, M Luisa; MilanÃ©s, M Victoria
2012-08-01
Recent evidence suggests that glucocorticoid receptor (GR) is a major molecular substrate of addictive
properties of drugs of abuse. Hence, we performed a series of experiments to further characterize the
role of GR signalling in opiate withdrawal-induced physical signs of dependence, enhanced
noradrenaline (NA) turnover in the hypothalamic paraventricular nucleus (PVN) and tyrosine
hydroxylase (TH) phosphorylation (activation) as well as GR expression in the nucleus of the solitary
tract noradrenergic cell group (NTS-Aâ‚‚). The role of GR signalling was assessed by i.p. pretreatment
of the selective GR antagonist, mifepristone. Rats were implanted with two morphine (or placebo)
pellets. Six days later, rats were pretreated with mifepristone or vehicle 30â€ƒmin before naloxone and
physical signs of abstinence, NA turnover, TH activation, GR expression and the hypothalamus-
pituitary-adrenocortical axis activity were measured using HPLC, immunoblotting and RIA.
Mifepristone alleviated the somatic signs of naloxone-induced opiate withdrawal. Mifepristone
attenuated the increase in the NA metabolite, 3-methoxy-4-hydroxyphenylethylen glycol (MHPG), in
the PVN, and the enhanced NA turnover observed in morphine-withdrawn rats. Mifepristone
antagonized the TH phosphorylation at SerÂ³Â¹ and the expression of c-Fos expression induced by
morphine withdrawal. Finally, naloxone-precipitated morphine withdrawal induced up-regulation of
GR in the NTS. These results suggest that the physical signs of opiate withdrawal, TH activation and
stimulation of noradrenergic pathways innervating the PVN are modulated by GR signalling. Overall,
the present data suggest that drugs targeting the GR may ameliorate stress and aversive effects
associated with opiate withdrawal. Â© 2012 The Authors. British Journal of Pharmacology Â© 2012
The British Pharmacological Society.
260. Disinhibition of perifornical hypothalamic neurones activates noradrenergic neurones and blocks
pontine carbachol-induced REM sleep-like episodes in rats
PubMed Central
Lu, Jackie W; Fenik, Victor B; Branconi, Jennifer L; Mann, Graziella L; Rukhadze, Irma; Kubin,
Leszek
2007-01-01
Studies in behaving animals suggest that neurones located in the perifornical (PF) region of the
posterior hypothalamus promote wakefulness and suppress sleep. Among such cells are those that
synthesize the excitatory peptides, orexins (ORX). Lack of ORX, or their receptors, is associated with
narcolepsy/cataplexy, a disorder characterized by an increased pressure for rapid eye movement
(REM) sleep. We used anaesthetized rats in which pontine microinjections of a cholinergic agonist,
carbachol, can repeatedly elicit REM sleep-like episodes to test whether activation of PF cells induced
by antagonism of endogenous, GABAA receptor-mediated, inhibition suppresses the ability of the
brainstem to generate REM sleep-like state. Microinjections of the GABAA receptor antagonist,
bicuculline (20 nl, 1 mm), into the PF region elicited cortical and hippocampal activation, increased
the respiratory rate and hypoglossal nerve activity, induced c-fos expression in ORX and other PF
neurones, and increased c-fos expression in pontine A7 and other noradrenergic neurones. The ability
of pontine carbachol to elicit any cortical, hippocampal or brainstem component of the REM sleep-like
response was abolished during the period of bicuculline-induced activation. The activating and REM
sleep-suppressing effect of PF bicuculline was not attenuated by systemic administration of the ORX
type 1 receptor antagonist, SB334867. Thus, activation of PF neurones that are endogenously inhibited
by GABAA receptors is sufficient to turn off the brainstem REM sleep-generating network; the effect
is, at least in part, due to activation of pontine noradrenergic neurones, but is not mediated by ORX
type 1 receptors. A malfunction of the pathway that originates in GABAA receptor-expressing PF
neurones may cause narcolepsy/cataplexy. PMID:17495048
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261. Vagus nerve stimulation improves locomotion and neuronal populations in a model of Parkinson's
disease.
PubMed
Farrand, Ariana Q; Helke, Kristi L; Gregory, Rebecca A; Gooz, Monika; Hinson, Vanessa K; Boger,
Heather A
Parkinson's disease (PD) is a progressive, neurodegenerative disorder with no disease-modifying

therapies, and symptomatic treatments are often limited by debilitating side effects. In PD, locus
coeruleus noradrenergic (LC-NE) neurons degenerate prior to substantia nigra dopaminergic (SN-DA)
neurons. Vagus nerve stimulation (VNS) activates LC neurons, and decreases pro-inflammatory
markers, allowing improvement of LC targets, making it a potential PD therapeutic. To assess
therapeutic potential of VNS in a PD model. To mimic the progression of PD degeneration, rats
received a systemic injection of noradrenergic neurotoxin DSP-4, followed one week later by bilateral
intrastriatal injection of dopaminergic neurotoxin 6-hydroxydopamine. At this time, a subset of rats
also had vagus cuffs implanted. After eleven days, rats received a precise VNS regimen twice a day for
ten days, and locomotion was measured during each afternoon session. Immediately following final
stimulation, rats were euthanized, and left dorsal striatum, bilateral SN and LC were sectioned for
immunohistochemical detection of monoaminergic neurons (tyrosine hydroxylase, TH), Î±-synuclein,
astrocytes (GFAP) and microglia (Iba-1). VNS significantly increased locomotion of lesioned rats.
VNS also resulted in increased expression of TH in striatum, SN, and LC; decreased SN Î±-synuclein
expression; and decreased expression of glial markers in the SN and LC of lesioned rats. Additionally,
saline-treated rats after VNS, had higher LC TH and lower SN Iba-1. Our findings of increased
locomotion, beneficial effects on LC-NE and SN-DA neurons, decreased Î±-synuclein density in SN
TH-positive neurons, and neuroinflammation suggest VNS has potential as a novel PD therapeutic.
Copyright Â© 2017 Elsevier Inc. All rights reserved.
262. Designer Receptors Enhance Memory in a Mouse Model of Down Syndrome
PubMed Central
Fortress, Ashley M.; Hamlett, Eric D.; Vazey, Elena M.; Aston-Jones, Gary; Cass, Wayne A.; Boger,
Heather A.
2015-01-01
Designer receptors exclusively activated by designer drugs (DREADDs) are novel and powerful tools
to investigate discrete neuronal populations in the brain. We have used DREADDs to stimulate
degenerating neurons in a Down syndrome (DS) model, Ts65Dn mice. Individuals with DS develop
Alzheimer's disease (AD) neuropathology and have elevated risk for dementia starting in their 30s and
40s. Individuals with DS often exhibit working memory deficits coupled with degeneration of the
locus coeruleus (LC) norepinephrine (NE) neurons. It is thought that LC degeneration precedes other
AD-related neuronal loss, and LC noradrenergic integrity is important for executive function, working
memory, and attention. Previous studies have shown that LC-enhancing drugs can slow the
progression of AD pathology, including amyloid aggregation, oxidative stress, and inflammation. We
have shown that LC degeneration in Ts65Dn mice leads to exaggerated memory loss and neuronal
degeneration. We used a DREADD, hM3Dq, administered via adeno-associated virus into the LC
under a synthetic promoter, PRSx8, to selectively stimulate LC neurons by exogenous administration
of the inert DREADD ligand clozapine-N-oxide. DREADD stimulation of LC-NE enhanced
performance in a novel object recognition task and reduced hyperactivity in Ts65Dn mice, without
significant behavioral effects in controls. To confirm that the noradrenergic transmitter system was
responsible for the enhanced memory function, the NE prodrug l-threo-dihydroxyphenylserine was
administered in Ts65Dn and normosomic littermate control mice, and produced similar behavioral
results. Thus, NE stimulation may prevent memory loss in Ts65Dn mice, and may hold promise for
treatment in individuals with DS and dementia. PMID:25632113
263. Orexin neurons suppress narcolepsy via 2 distinct efferent pathways
PubMed Central
Hasegawa, Emi; Yanagisawa, Masashi; Sakurai, Takeshi; Mieda, Michihiro
2014-01-01
The loss of orexin neurons in humans is associated with the sleep disorder narcolepsy, which is
characterized by excessive daytime sleepiness and cataplexy. Mice lacking orexin peptides, orexin
neurons, or orexin receptors recapitulate human narcolepsy phenotypes, further highlighting a critical
role for orexin signaling in the maintenance of wakefulness. Despite the known role of orexin neurons
in narcolepsy, the precise neural mechanisms downstream of these neurons remain unknown. We
found that targeted restoration of orexin receptor expression in the dorsal raphe (DR) and in the locus
coeruleus (LC) of mice lacking orexin receptors inhibited cataplexy-like episodes and pathological
fragmentation of wakefulness (i.e., sleepiness), respectively. The suppression of cataplexy-like
episodes correlated with the number of serotonergic neurons restored with orexin receptor expression
in the DR, while the consolidation of fragmented wakefulness correlated with the number of
noradrenergic neurons restored in the LC. Furthermore, pharmacogenetic activation of these neurons
using designer receptor exclusively activated by designer drug (DREADD) technology ameliorated
narcolepsy in mice lacking orexin neurons. These results suggest that DR serotonergic and LC
noradrenergic neurons play differential roles in orexin neuronâ€“dependent regulation of
sleep/wakefulness and highlight a pharmacogenetic approach for the amelioration of narcolepsy.

PMID:24382351
264. Noradrenergic innervation of the hypothalamus of rhesus monkeys: distribution of dopamine-beta-

hydroxylase immunoreactive fibers and quantitative analysis of varicosities in the paraventricular
nucleus.
PubMed
Ginsberg, S D; Hof, P R; Young, W G; Morrison, J H
1993-01-22
The distribution of noradrenergic processes within the hypothalamus of rhesus monkeys (Macaca
mulatta) was examined by immunohistochemistry with an antibody against dopamine-beta-
hydroxylase. The results revealed that the pattern of dopamine-beta-hydroxylase immunoreactivity
varied systematically throughout the rhesus monkey hypothalamus. Extremely high densities of
dopamine-beta-hydroxylase-immunoreactive processes were observed in the paraventricular and
supraoptic nuclei, while relatively lower levels were found in the arcuate and dorsomedial nuclei and
in the medial preoptic, perifornical, and suprachiasmatic areas. Moderate levels of dopamine-beta-
hydroxylase immunoreactivity were found throughout the lateral hypothalamic area and in the internal
lamina of the median eminence. Very few immunoreactive processes were found in the ventromedial
nucleus or in the mammillary complex. Other midline diencephalic structures were found to have high
densities of dopamine-beta-hydroxylase immunoreactivity, including the paraventricular nucleus of the
thalamus and a discrete subregion of nucleus reuniens, the magnocellular subfascicular nucleus. A
moderate density of dopamine-beta-hydroxylase immunoreactive processes were found in the
rhomboid nucleus and zona incerta whereas little dopamine-beta-hydroxylase immunoreactivity was
found in the fields of Forel, nucleus reuniens, or subthalamic nucleus. The differential distribution of
dopamine-beta-hydroxylase-immunoreactive processes may reflect a potential role of norepinephrine
as a regulator of a variety of functions associated with the nuclei that are most heavily innervated, e.g.,
neuroendocrine release from the paraventricular and supraoptic nuclei, and gonadotropin release from
the medial preoptic area and mediobasal hypothalamus. Additionally, quantitative analysis of
dopamine-beta-hydroxylase-immunoreactive varicosities was performed on a laser scanning
microscope in both magnocellular and parvicellular regions of
265. Exploring Practical Responses of M3LC for Learning Literacy
Nasrullah; Baharman
2018-01-01
This study aims to explore the responses of participants toward Mathematics-Language Literacy
Learning Courseware (M3LC) for learning literacy. There are five practical aspects concerned by
involving 30 participants in the focus group discussion. In the beginning, participants were given some
response sheet and introduced to M3LC by watching learning video of M3LC. At the end, they were
asked to concern about response sheet and give comments related what they saw during the
introduction session. The results show that the responses of usersâ€™ agree and strongly agree are still
higher than those of usersâ€™ disagree or strongly disagree, with below 30% of responses are in the
fair category. It means that the participants tend to give a positive opinion that M3LC is a useful
courseware since it is qualified to satisfy 5 practical aspects, including knowledge use, knowledge
construction, evaluation practice, social programming, and valuing to support literacy learning. In
future, the implementation of using this courseware can be enhanced to further recognition of literacy
level so that students can be well-prepared before starting learning activities in the classroom.
266. LC-MS characterization of constituents of mesquite flour

Using an LC-MS method in conjunction with two complementary types of chromatographic retention
modesâ€”namely reversed phase and aqueous normal phase (ANP)â€”various compounds present in
mesquite flour extracts were identified. Because of the diverse types of chemical constituents found in
such natural ...
267. Data reduction of isotope-resolved LC-MS spectra.
PubMed
Du, Peicheng; Sudha, Rajagopalan; Prystowsky, Michael B; Angeletti, Ruth Hogue
2007-06-01
Data reduction of liquid chromatography-mass spectrometry (LC-MS) spectra can be a challenge due
to the inherent complexity of biological samples, noise and non-flat baseline. We present a new
algorithm, LCMS-2D, for reliable data reduction of LC-MS proteomics data. LCMS-2D can reliably
reduce LC-MS spectra with multiple scans to a list of elution peaks, and subsequently to a list of
peptide masses. It is capable of noise removal, and deconvoluting peaks that overlap in m/z, in
retention time, or both, by using a novel iterative peak-picking step, a 'rescue' step, and a modified
variable selection method. LCMS-2D performs well with three sets of annotated LC-MS spectra,
yielding results that are better than those from PepList, msInspect and the vendor software BioAnalyst.
The software LCMS-2D is available under the GNU general public license from
http://www.bioc.aecom.yu.edu/labs/angellab/as a standalone C program running on LINUX.
268. A computational psychiatry approach identifies how alpha-2A noradrenergic agonist Guanfacine
affects feature-based reinforcement learning in the macaque
PubMed Central
Hassani, S. A.; Oemisch, M.; Balcarras, M.; Westendorff, S.; Ardid, S.; van der Meer, M. A.; Tiesinga,
P.; Womelsdorf, T.
2017-01-01
Noradrenaline is believed to support cognitive flexibility through the alpha 2A noradrenergic receptor
(a2A-NAR) acting in prefrontal cortex. Enhanced flexibility has been inferred from improved working
memory with the a2A-NA agonist Guanfacine. But it has been unclear whether Guanfacine improves
specific attention and learning mechanisms beyond working memory, and whether the drug effects can
be formalized computationally to allow single subject predictions. We tested and confirmed these
suggestions in a case study with a healthy nonhuman primate performing a feature-based reversal
learning task evaluating performance using Bayesian and Reinforcement learning models. In an initial
dose-testing phase we found a Guanfacine dose that increased performance accuracy, decreased
distractibility and improved learning. In a second experimental phase using only that dose we
examined the faster feature-based reversal learning with Guanfacine with single-subject computational
modeling. Parameter estimation suggested that improved learning is not accounted for by varying a
single reinforcement learning mechanism, but by changing the set of parameter values to higher
learning rates and stronger suppression of non-chosen over chosen feature information. These findings
provide an important starting point for developing nonhuman primate models to discern the synaptic
mechanisms of attention and learning functions within the context of a computational neuropsychiatry
framework. PMID:28091572
269. Effects of selective serotonin reuptake and dual serotonergic-noradrenergic reuptake treatments on
attention and executive functions in patients with major depressive disorder.
PubMed
Herrera-GuzmÃ¡n, Ixchel; Herrera-Abarca, Jorge E; Gudayol-FerrÃ©, Esteve; Herrera-GuzmÃ¡n,

Daniel; GÃ³mez-Carbajal, Lizbeth; PeÃ±a-Olvira, Miriam; Villuendas-GonzÃ¡lez, Erwin; Joan,
GuÃ rdia-Olmos
2010-05-30
Several reports suggest that antidepressants may improve cognitive functioning in patients with major
depressive disorder (MDD). The present work aims to study the effects of selective serotonin reuptake
inhibitors (SSRIs) and serotonergic-noradrenergic reuptake inhibitors (SNRIs) treatments on the
performance of working memory, attention and executive functions in patients with MDD. A total of
73 subjects meeting the Diagnostic and Statistical Manual of Mental Disorders version IV (DSM-IV)
criteria for MDD, and 37 control subjects were assessed with the Hamilton Depression Rating Scale
and a neuropsychological battery. The subjects were medicated with escitalopram (n=36) or duloxetine
(n=37) for 24 weeks. At the end of the trial, the subjects were assessed again with the same tests. The
depressed subjects showed alterations in attention and cognitive functions when compared to the
control group. The administration of both treatments improved working memory, as well as attention
and all the executive functions, but the cognitive functions of depressed patients do not improve
enough to reach the levels of performance of the control subjects. Our results suggest that both SSRI
and SNRI treatments presented the same efficacy in improving attention and the remaining executive
functions. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.
270. Effects of selective serotonin reuptake and dual serotonergic-noradrenergic reuptake treatments on
memory and mental processing speed in patients with major depressive disorder.
PubMed
Herrera-GuzmÃ¡n, Ixchel; Gudayol-FerrÃ©, Esteve; Herrera-GuzmÃ¡n, Daniel; GuÃ rdia-Olmos,

Joan; Hinojosa-Calvo, Erika; Herrera-Abarca, Jorge E
2009-06-01
Patients with major depressive disorder (MDD) usually suffer from altered cognitive functions of
episodic memory, working memory, mental processing speed and motor response. Diverse studies
suggest that different antidepressant agents may improve cognitive functions in patients with MDD.
The aim of this work is to study the effects of serotonergic reuptake inhibitors (SSRIs) and
serotonergic-noradrenergic reuptake inhibitors (SNRIs) treatments to improve the performance on
memory tasks and mental processing speed in MDD. Seventy-three subjects meeting criteria for major
depressive disorder were assessed with the Hamilton depression rating scale and a neuropsychological
battery. The subjects were medicated with escitalopram (n=36) or duloxetine (n=37) for 24 weeks. At
the end of the trial, the subjects were assessed again with the same neuropsychological battery used
prior to the treatment. Both treatments improved importantly the episodic memory and to a lesser
extent, working memory, mental processing speed and motor performance. Our results suggest that
cognition is partially independent from improvement in clinical symptoms. Both groups achieved
remission rates in the HAM-D-17 after 24 weeks of treatment, but SNRI was superior to SSRI at
improving episodic and working memory. Our work indicates that the superiority of SNRI over the
SSRI at episodic memory improvement is clinically relevant.
271. The influence of botulinum toxin type A (BTX) on the immunohistochemical characteristics of
noradrenergic and cholinergic nerve fibers supplying the porcine urinary bladder wall.
PubMed
Lepiarczyk, E; Bossowska, A; Kaleczyc, J; Majewski, M
2011-01-01
Botulinum toxin (BTX) belongs to a family of neurotoxins which strongly influence the function of
autonomic neurons supplying the urinary bladder. Accordingly, BTX has been used as an effective
drug in experimental therapies of a range of neurogenic bladder disorders. However, there is no
detailed information dealing with the influence of BTX on the morphological and chemical properties
of nerve fibres supplying the urinary bladder wall. Therefore, the present study investigated, using
double-labeling immunohistochemistry, the distribution, relative frequency and chemical coding of
cholinergic and noradrenergic nerve fibers supplying the wall of the urinary bladder in normal female
pigs (n = 6) and in the pigs (n = 6) after intravesical BTX injections. In the pigs injected with BTX, the
number of adrenergic (DbetaH-positive) nerve fibers distributed in the bladder wall (urothelium,
submucosa and muscle coat) was distinctly higher while the number of cholinergic (VAChT-positive)
nerve terminals was lower than that found in the control animals. Moreover, the injections of BTX
resulted in some changes dealing with the chemical coding of the adrenergic nerve fibers. In contrast
to the normal pigs, in BTX injected animals the number of DbetaH/NPY- or DbetaH/CGRP-positive
axons was higher in the muscle coat, and some fibres distributed in the urothelium and submucosa
expressed immunoreactivity to CGRP. The results obtained suggest that the therapeutic effects of BTX
on the urinary bladder might be dependent on changes in the distribution and chemical coding of nerve
fibers supplying this organ.
272. Noradrenergic neurotransmission within the bed nucleus of the stria terminalis modulates the retention
of immobility in the rat forced swimming test.
PubMed
Nagai, Michelly M; Gomes, Felipe V; Crestani, Carlos C; Resstel, Leonardo B M; Joca, SÃ¢mia R L
2013-06-01
The bed nucleus of the stria terminalis (BNST) is a limbic structure that has a direct influence on the
autonomic, neuroendocrine, and behavioral responses to stress. It was recently reported that reversible
inactivation of synaptic transmission within this structure causes antidepressant-like effects, indicating
that activation of the BNST during stressful situations would facilitate the development of behavioral
changes related to the neurobiology of depression. Moreover, noradrenergic neurotransmission is
abundant in the BNST and has an important role in the regulation of emotional processes related to the
stress response. Thus, this study aimed to test the hypothesis that activation of adrenoceptors within
the BNST facilitates the development of behavioral consequences of stress. To investigate this
hypothesis, male Wistar rats were stressed (forced swimming, 15 min) and 24 h later received intra-
BNST injections of vehicle, WB4101, RX821002, CGP20712, or ICI118,551, which are selective
Î±(1), Î±(2), Î²(1), and Î²(2) adrenoceptor antagonists, respectively, 10 min before a 5-min forced
swimming test. It was observed that administration of WB4101 (10 and 15 nmol), CGP20712 (5 and
10 nmol), or ICI118,551 (5 nmol) into the BNST reduced the immobility time of rats subjected to
forced swimming test, indicating an antidepressant-like effect. These findings suggest that activation
of Î±(1), Î²(1), and Î²(2) adrenoceptors in the BNST could be involved in the development of the
behavioral consequences of stress. Â© 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.
273. Frequency jumps in single chip microwave LC oscillators
SciTech Connect
Gualco, Gabriele; Grisi, Marco; Boero, Giovanni, E-mail: giovanni.boero@epfl.ch
2014-12-15
We report on the experimental observation of oscillation frequency jumps in microwave LC oscillators

fabricated using standard complementary metal-oxide-semiconductor technologies. The LC oscillators,
operating at a frequency of about 20 GHz, consist of a single turn planar coil, a metal-oxide-metal
capacitor, and two cross-coupled metal-oxide-semiconductor field effect transistors used as negative
resistance network. At 300â€‰K as well as at 77â€‰K, the oscillation frequency is a continuous
function of the oscillator bias voltage. At 4â€‰K, frequency jumps as large as 30 MHz are
experimentally observed. This behavior is tentatively attributed to the emission and capture of single
electrons from defects andmoreÂ Â» dopant atoms.Â«Â less
274. Ecdysone triggered PGRP-LC expression controls Drosophila innate immunity.
PubMed
Rus, Florentina; Flatt, Thomas; Tong, Mei; Aggarwal, Kamna; Okuda, Kendi; Kleino, Anni; Yates,
Elisabeth; Tatar, Marc; Silverman, Neal
2013-05-29
Throughout the animal kingdom, steroid hormones have been implicated in the defense against
microbial infection, but how these systemic signals control immunity is unclear. Here, we show that
the steroid hormone ecdysone controls the expression of the pattern recognition receptor PGRP-LC in
Drosophila, thereby tightly regulating innate immune recognition and defense against bacterial
infection. We identify a group of steroid-regulated transcription factors as well as two GATA
transcription factors that act as repressors and activators of the immune response and are required for
the proper hormonal control of PGRP-LC expression. Together, our results demonstrate that
Drosophila use complex mechanisms to modulate innate immune responses, and identify a
transcriptional hierarchy that integrates steroid signalling and immunity in animals.
275. Data Treatment for LC-MS Untargeted Analysis.
PubMed
Riccadonna, Samantha; Franceschi, Pietro
2018-01-01
Liquid chromatography-mass spectrometry (LC-MS) untargeted experiments require complex

chemometrics strategies to extract information from the experimental data. Here we discuss "data
preprocessing", the set of procedures performed on the raw data to produce a data matrix which will be
the starting point for the subsequent statistical analysis. Data preprocessing is a crucial step on the path
to knowledge extraction, which should be carefully controlled and optimized in order to maximize the
output of any untargeted metabolomics investigation.
276. LC and ferromagnetic resonance in soft/hard magnetic microwires
Tian, Bin; Vazquez, Manuel
2015-12-01
The magnetic behavior of soft/hard biphase microwires is introduced here. The microwires consist of a
Co59.1Fe14.8Si10.2B15.9 soft magnetic nucleus and a Co90Ni10 hard outer shell separated by an
intermediate insulating Pyrex glass microtube. By comparing the resistance spectrums of welding the
ends of metallic core (CC) or welding the metallic core and outer shell (CS) to the connector, it is
found that one of the two peaks in the resistance spectrum is because the LC resonance depends on the
inductor and capacitors in which one is the capacitor between the metallic core and outer shell, and the
other is between the outer shell and connector. Correspondingly, another peak is for the ferromagnetic
resonance of metallic core. After changing the capacitance of the capacitors, the frequency of LC
resonance moves to high frequency band, and furthermore, the peak of LC resonance in the resistance
spectrum disappeared. These magnetostatically coupled biphase systems are thought to be of large
potential interest as sensing elements in sensor devices.
277. Delocalized periodic vibrations in nonlinear LC and LCR electrical chains
Chechin, G. M.; Shcherbinin, S. A.
2015-05-01
We consider electrical LC- and LCR-chains consisting of N cells. In the LC-chain each cell contains a
linear inductor L and a nonlinear capacitor C, while the cell in the LCR-chain include additionally a
resistor R and an voltage source. It is assumed that voltage dependence of capacitors represents an
even function. Such capacitors have implemented by some experimental groups studying propagation
of electrical signals in the lines constructed on MOS and CMOS substrates. In these chains, we study
dynamical regimes representing nonlinear normal modes (NNMs) by Rosenberg. We prove that
maximum possible number of symmetry-determined NNMs which can be excited in the considered
chains is equal to 5. The stability of these modes for different N is studied with the aid of the group-
theoretical method [Physical Review E 73 (2006) 36216] which allows to simplify radically the
variational systems appearing in the Floquet stability analysis. For NNMs in LC-chain, the scaling of
the voltage stability threshold in the thermodynamic limit (N â†’ âˆž) is determined. It is shown that
the above group theoretical method can be also used for studying stability of NNMs in the LCR-
chains.
278. Analytical Stability-Indicating Methods for Alogliptin in Tablets by LC-CAD and LC-UV.
PubMed
Bertol, Charise Dallazem; Friedrich, Maria Tereza; Carlos, Graciela; Froehlich, Pedro Eduardo
2017-03-01
Stability-indicating LC methods using a UV detector and a charged aerosol detector (CAD)

simultaneously were validated for the assessment of alogliptin (ALG) in tablets. The analysis was
performed on a C8 column (250 Ã— 4.6 mm, 5 Î¼m) at a flow of 0.8 mL/min, using acetonitrile-10
mM ammonium acetate buffer (pH 3.5; 90 + 10, v/v) as mobile phase and UV detection at 275 nm.
Validation followed the International Conference on Harmonization guidelines. The method was linear
over the range of 25-200 Î¼g/mL. Normality of the residuals showed a normal distribution, no
autocorrelation, and homoscedasticity. LODs were 6.25 and 2.65 Âµg/mL and LOQs were 20.85 and
8.84 Âµg/mL for the CAD and the UV detector, respectively. The methods were precise and accurate.
Excipients and degradation products did not interfere in the methods in studies of specificity. None of
the factors studied in the analysis of robustness had a significant effect on the quantification of the
ALG by the Pareto chart. The results of the assay obtained with LC-CAD and LC-UV were similar.
The methods could be considered interchangeable and stability-indicating, and can be applied as an
appropriate QC tool for analysis of ALG in tablets.
279. Effects of levomilnacipran ER on noradrenergic symptoms, anxiety symptoms, and functional

impairment in adults with major depressive disorder: Post hoc analysis of 5 clinical trials.
PubMed
Blier, Pierre; Gommoll, Carl; Chen, Changzheng; Kramer, Kenneth
2017-03-01
To evaluate the effects of levomilnacipran extended-release (LVM-ER; 40-120mg/day) on

noradrenergic (NA) and anxiety-related symptoms in adults with major depressive disorder (MDD)
and explore the relationship between these symptoms and functional impairment. Data were pooled
from 5 randomized, double-blind, placebo-controlled trials (N=2598). Anxiety and NA Cluster scores
were developed by adding selected item scores from the Montgomery-Ã…sberg Depression Rating
Scale (MADRS) and 17-item Hamilton Depression Rating Scale (HAMD 17 ). A path analysis was
conducted to estimate the direct effects of LVM-ER on functional impairment (Sheehan Disability
Scale [SDS] total score) and the indirect effects through changes in NA and Anxiety Cluster scores.
Mean improvements from baseline in NA and Anxiety Cluster scores were significantly greater with
LVM-ER versus placebo (both P<0.001), as were the response rates (â‰¥50% score improvement):
NA Cluster (44% vs 34%; odds ratio=1.56; P<0.0001); Anxiety Cluster (39% vs 36%; odds
ratio=1.19; P=0.041). Mean improvement in SDS total score was also significantly greater with LVM-
ER versus placebo (-7.3 vs -5.6; P<0.0001). LVM-ER had an indirect effect on change in SDS total
score that was mediated more strongly through NA Cluster score change (86%) than Anxiety Cluster
score change (18%); the direct effect was negligible. NA and Anxiety Cluster scores, developed based
on the face validity of individual MADRS and HAMD 17 items, were not predefined as efficacy
outcomes in any of the studies. In adults with MDD, LVM-ER indirectly improved functional
impairment mainly through improvements in NA symptoms and less so via anxiety symptoms.
Copyright Â© 2016 The Authors. Published by Elsevier B.V. All rights reserved.
280. Effects of single and simultaneous lesions of serotonergic and noradrenergic pathways on open-space
and bright-space anxiety-like behavior in two animal models.
PubMed
Sziray, NÃ³ra; Kuki, ZsÃ³fia; Nagy, Katalin M; MarkÃ³, Bernadett; Kompagne, Hajnalka; LÃ©vay,
GyÃ¶rgy
2010-05-01
The objective of the present study is to investigate the effects of single and simultaneous lesions of the
noradrenergic and serotonergic pathways (NA-X, 5-HT-X and XX, respectively) by
intracerebroventricular administration of selective neurotoxins N-(2-chloroethyl)-N-ethyl-2-
bromobenzylamine-HCl (DSP-4) and 5,7-dihydroxytryptamine (5,7-DHT) on anxiety-like behavior in
rats. To evaluate the effects of the various lesions, animals were tested in elevated plus-maze (EPM)
and light-dark (LD) paradigms. In EPM, single lesions produced strong, statistically significant
increase (p<0.001) of both time spent in the open arms (OT) and number of entries into the open arms
(OE) compared to sham-lesioned animals. Simultaneous lesion further strengthened this anxiolytic
effect causing an approximate 500% elevation of OT compared to sham-lesioned animals. In LD, 5-
HT lesion caused a significant (p<0.05) increase in both light movement time and light horizontal
activity parameters compared to intact, sham, and NA-lesioned groups. Neither of the lesions caused
any change in the spontaneous locomotor activity of the animals up to 15min as measured in activity
meter. These findings suggest that single and simultaneous lesions of 5-HT- and NA-pathways modify
anxiety-related state of experimental animals to different extents and these modifications alter the
behavior of animals differently in the two models used: NA-X and 5-HT-X reduce open space anxiety-
like behavior and XX further strengthens this effect in the EPM, while only 5-HT-X is resulting in
reduced bright-space anxiety-like behavior leaving the performance of NA-X and XX animals
unchanged.
«
12
13
14
15
16
»
«
13
14
15
16
17
»
281. Noradrenergic alpha-2 receptor modulators in the ventral bed nucleus of the stria terminalis: effects on
anxiety behavior in postpartum and virgin female rats.
PubMed
Smith, Carl D; Piasecki, Christopher C; Weera, Marcus; Olszewicz, Joshua; Lonstein, Joseph S
2013-08-01
Emotional hyperreactivity can inhibit maternal responsiveness in female rats and other animals.
Maternal behavior in postpartum rats is disrupted by increasing norepinephrine release in the ventral
bed nucleus of the stria terminalis (BSTv) with the Î±2-autoreceptor antagonist, yohimbine, or the
more selective Î±2-autoreceptor antagonist, idazoxan (Smith et al., 2012). Because high noradrenergic
activity in the BSTv can also increase anxiety-related behaviors, increased anxiety may underlie the
disrupted mothering of dams given yohimbine or idazoxan. To assess this possibility, anxiety-related
behaviors in an elevated plus maze were assessed in postpartum rats after administration of yohimbine
or idazoxan. It was further assessed if the Î±2-autoreceptor agonist clonidine (which decreases
norepinephrine release) would, conversely, reduce dams' anxiety. Groups of diestrous virgins were also
examined. It was found that peripheral or intra-BSTv yohimbine did increase anxiety-related behavior
in postpartum females. However, BSTv infusion of idazoxan did not reproduce yohimbine's
anxiogenic effects and anxiety was not reduced by peripheral or intra-BSTv clonidine. Because
yohimbine is a weak 5HT1A receptor agonist, other groups of females received BSTv infusion of the
5HT1A receptor agonist 8OH-DPAT, but it did not alter their anxiety-related behavior. Lastly, levels of
norepinephrine and serotonin in tissue punches from the BSTv did not differ between postpartum and
diestrous rats, but serotonin turnover was lower in mothers. These results suggest that the impaired
maternal behavior after BSTv infusion of yohimbine or idazoxan cannot both be readily explained by
an increase in dams' anxiety, and that BSTv Î±2-autoreceptor modulation alone has little influence on
anxiety-related behaviors in postpartum or diestrous rats.
282. Noradrenergic alpha-2 receptor modulators in the ventral bed nucleus of the stria terminalis â€“ effects
on anxiety behavior in postpartum and virgin female rats
PubMed Central
Smith, Carl D.; Piasecki, Christopher C.; Weera, Marcus; Olszewicz, Joshua; Lonstein, Joseph S.
2014-01-01
Emotional hyper-reactivity can inhibit maternal responsiveness in female rats and other animals.
Maternal behavior in postpartum rats is disrupted by increasing norepinephrine release in the ventral
bed nucleus of the stria terminalis (BSTv) with the Î±2-autoreceptor antagonist, yohimbine, or the
more selective Î±2-autoreceptor antagonist, idazoxan (Smith et al., 2012). Because high noradrenergic
activity in the BSTv can also increase anxiety-related behaviors, increased anxiety may underlie the
disrupted mothering of dams given yohimbine or idazoxan. To assess this possibility, anxiety-related
behaviors in an elevated plus maze were assessed in postpartum rats after administration of yohimbine
or idazoxan. It was further assessed if the Î±2-autoreceptor agonist clonidine (which decreases
norepinephrine release) would, conversely, reduce damsâ€™ anxiety. Groups of diestrous virgins were
also examined. It was found that peripheral or intra-BSTv yohimbine did increase anxiety-related
behavior in postpartum females. However, BSTv infusion of idazoxan did not reproduce
yohimbineâ€™s anxiogenic effects and anxiety was not reduced by peripheral or intra-BSTv
clonidine. Because yohimbine is a weak 5HT1A receptor agonist, other groups of females received
BSTv infusion of the 5HT1A receptor agonist 8OH-DPAT, but it did not alter their anxiety-related
behavior. Lastly, levels of norepinephrine and serotonin in tissue punches from the BSTv did not differ
between postpartum and diestrous rats, but serotonin turnover was lower in mothers. These results
suggest that the impaired maternal behavior after BSTv infusion of yohimbine or idazoxan cannot both
be readily explained by an increase in damsâ€™ anxiety, and that BSTv Î±2-autoreceptor modulation
alone has little influence anxiety-related behaviors in postpartum or diestrous rats. PMID:23796237
283. Cerebellar sub-divisions differ in exercise-induced plasticity of noradrenergic axons and in their
association with resilience to activity-based anorexia.
PubMed
Nedelescu, Hermina; Chowdhury, Tara G; Wable, Gauri S; Arbuthnott, Gordon; Aoki, Chiye
2017-01-01
The vermis or "spinocerebellum" receives input from the spinal cord and motor cortex for controlling
balance and locomotion, while the longitudinal hemisphere region or "cerebro-cerebellum" is
interconnected with non-motor cortical regions, including the prefrontal cortex that underlies decision-
making. Noradrenaline release in the cerebellum is known to be important for motor plasticity but less
is known about plasticity of the cerebellar noradrenergic (NA) system, itself. We characterized
plasticity of dopamine Î²-hydroxylase-immunoreactive NA fibers in the cerebellum of adolescent
female rats that are evoked by voluntary wheel running, food restriction (FR) or by both, in
combination. When 8Â days of wheel access was combined with FR during the last 4Â days, some
responded with excessive exercise, choosing to run even during the hours of food access: this
exacerbated weight loss beyond that due to FR alone. In the vermis, exercise, with or without FR,
shortened the inter-varicosity intervals and increased varicosity density along NA fibers, while
excessive exercise, due to FR, also shortened NA fibers. In contrast, the hemisphere required the FR-
evoked excessive exercise to evoke shortened inter-varicosity intervals along NA fibers and this
change was exhibited more strongly by rats that suppressed the FR-evoked excessive exercise, a
behavior that minimized weight loss. Presuming that shortened inter-varicosity intervals translate to
enhanced NA release and synthesis of norepinephrine, this enhancement in the cerebellar hemisphere
may contribute towards protection of individuals from the life-threatening activity-based anorexia via
relays with higher-order cortical areas that mediate the animal's decision to suppress the innate FR-
evoked hyperactivity.
284. Effects of atomoxetine on attention and impulsivity in the five-choice serial reaction time task in rats
with lesions of dorsal noradrenergic ascending bundle.
PubMed
Liu, Yia-Ping; Huang, Teng-Shun; Tung, Che-Se; Lin, Chen-Cheng
2015-01-02
Atomoxetine, a noradrenaline reuptake inhibitor (NRI), which is a non-stimulating medicine that is

used for the treatment of patients with attention deficit hyperactivity disorder (ADHD), has been found
to be effective in reducing behavioral impulsivity in rodents, but its efficacy in a dorsal noradrenergic
ascending bundle (DNAB)-lesioned condition has not been examined. The present study aimed to
investigate the effects of DNAB lesions on attention and impulsive control in the five-choice serial
reaction time task (5-CSRTT) in rats treated with atomoxetine. The drug-induced changes in
noradrenaline efflux in the medial prefrontal cortex were also measured. 5-CSRTT-trained rats were
included in one of the following groups: N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-
4)/Atomoxetine, Sham/Atomoxetine, DSP-4/Saline, or Sham/Saline. Acute atomoxetine (0.3 mg/kg)
was administered 14 days after the DSP-4 regime. The behavioral testing included manipulations of
the inter-trial interval (ITI), stimulation duration and food satiety. In vivo microdialysis of the
noradrenaline efflux in the medial prefrontal cortex and the expression of the noradrenaline transporter
(NAT) in the DNAB areas were examined. Atomoxetine reduced impulsivity and perseveration in the
long-ITI condition with no effects on any other variables. This phenomenon was not influenced by
DSP-4 pre-treatment. The DNAB-lesioned rats had lower noradrenaline efflux in the medial prefrontal
cortex. DSP-4 caused no change in NAT expression in the DNAB areas. These findings suggested that
noradrenaline reuptake may not be exclusively responsible for the atomoxetine effects in adjusting
impulsivity. The role of DNAB should also be considered, particularly in conditions requiring greater
behavioral inhibition. Copyright Â© 2014 Elsevier Inc. All rights reserved.
285. Measurement of endogenous noradrenaline release in the rat cerebral cortex in vivo by transcortical
dialysis: effects of drugs affecting noradrenergic transmission.
PubMed
L'Heureux, R; Dennis, T; Curet, O; Scatton, B
1986-06-01
The release of endogenous noradrenaline was measured in the cerebral cortex of the halothane-
anesthetized rat by using the technique of brain dialysis coupled to a radioenzymatic assay. A thin
dialysis tube was inserted transversally in the cerebral cortex (transcortical dialysis) and perfused with
Ringer medium (2 microliter min-1). Under basal conditions, the cortical output of noradrenaline was
stable over a period of at least 6 h and amounted to 8.7 pg/20 min (not corrected for recovery).
Histological control of the perfused area revealed very little damage and normal morphology in the
vicinity of the dialysis tube. Omission of calcium from the perfusion medium caused a marked drop in
cortical noradrenaline output. Bilateral electrical stimulation (for 10 min) of the ascending
noradrenergic pathways in the medial forebrain bundle caused a frequency-dependent increase in
cortical noradrenaline output over the range 5-20 Hz. Stimulation at a higher frequency (50 Hz)
resulted in a levelling off of the increase in cortical noradrenaline release. Systemic administration of
the dopamine-beta-hydroxylase inhibitor bis-(4-methyl-1-homopiperazinylthiocarbonyl) disulfide
(FLA 63) (25 mg/kg i.p.) markedly reduced, whereas injection of the monoamine oxidase inhibitor
pargyline (75 mg/kg i.p.) resulted in a progressive increase in, cortical noradrenaline output. d-
Amphetamine (2 mg/kg i.p.) provoked a sharp increase in cortical noradrenaline release (+450% over
basal values within 40 min). Desmethylimipramine (10 mg/kg i.p.) produced a twofold increase of
cortical noradrenaline release. Finally, idazoxan (20 mg/kg i.p.) and clonidine (0.3 mg/kg i.p.),
respectively, increased and decreased the release of noradrenaline from the cerebral cortex.
(ABSTRACT TRUNCATED AT 250 WORDS)
286. Quantitative RT-PCR and immunoblot analyses reveal acclimated A2 noradrenergic neuron substrate
fuel transporter, glucokinase, phospho-AMPK, and dopamine-Î²-hydroxylase responses to
hypoglycemia.
PubMed
Cherian, Ajeesh Koshy; Briski, Karen P
2011-07-01
Cellular metabolic stasis is monitored in discrete brain sites, including the dorsal vagal complex
(DVC), where A2 noradrenergic neurons perform this sensory function. Single-cell qPCR and high-
sensitivity immunoblotting were used to determine if A2 neurons adapt to chronic hypoglycemia by
increasing substrate fuel transporter expression, and whether such adjustments coincide with decreased
cellular energy instability during this systemic metabolic stress. Tyrosine hydroxylase-immunolabeled
neurons were laser-microdissected from the caudal DVC 2 hr after single or serial neutral protamine
Hagedorn insulin (NPH) dosing. Preceding hypoglycemia suppressed basal A2 MCT2, GLUT3, and
GLUT4 profiles and diminished MCT2, GLUT4, and glucokinase responses to recurring
hypoglycemia. Acute NPH caused a robust increase in A2 phospho-AMPK protein levels; baseline
phospho-AMPK expression was elevated after 3 days of insulin treatment but only slight augmented
after a fourth NPH injection. Transcripts encoding the catecholamine biosynthetic enzyme dopamine-
Î²-hydroxylase were unaffected by acute NPH but were diminished by serial insulin dosing. This
evidence for diminished basal A2 glucose and lactate uptake and attenuated phospho-AMPK-mediated
detection of hypoglycemia-associated energy deficits suggests that these cells acclimate to chronic
hypoglycemia by adopting a new metabolic steady state characterized by energy paucity and reduced
sensitivity to hypoglycemia. Because dopamine-Î²-hydroxylase mRNA was reduced after serial, but
not single NPH dosing, A2 neurotransmitter biosynthesis may be impervious to acute hypoglycemia
but inhibited when posthypoglycemic metabolic deficiency is exacerbated by recurring hypoglycemia.
This research suggests that chronic hypoglycemia-associated adjustments in A2-sensory
neurotransmission may reflect cellular energetic debilitation rather than adaptive attenuation of cellular
metabolic imbalance. Copyright Â© 2011 Wiley-Liss, Inc.
287. Resting-state functional connectivity of neurotransmitter producing sites in female patients with
borderline personality disorder.
PubMed
Wagner, Gerd; Krause-Utz, Annegret; de la Cruz, Feliberto; Schumann, Andy; Schmahl, Christian;
BÃ¤r, Karl-JÃ¼rgen
2018-04-20
Impulsive behavior, difficulties in controlling anger and suicidal behavior are typical patterns of
affective/behavioral dysregulation in patients with borderline personality disorder (BPD). Previous
functional MRI studies in the resting state condition demonstrated altered functional connectivity (FC)
between the anterior cingulate cortex (ACC) and the frontoparietal executive control network (ECN),
which was significantly associated with impulsivity in BPD. Impulsivity is often defined as a function
of inhibitory control, strongly relying on the proper functioning of the fronto-cingulo-striatal network.
Noradrenergic, dopaminergic and serotonergic neurotransmitter systems are assumed to be involved in
different forms of impulsive behavior and inhibitory control. In our previous study, we investigated the
FC of the main monoamine-producing nuclei within the midbrain and brainstem, which were
functionally integrated in specific resting-state networks. In the present study we investigated the
resting-state FC of midbrain/brainstem nuclei in 33 unmedicated female patients with BPD and 33
matched healthy controls. We further related altered functional connectivity of these nuclei to the
patient's degree of impulsivity. The main finding was that BPD patients showed stronger FC from the
noradrenergic locus coeruleus (LC) to the ACC. Functional connectivity between the LC and ACC
was positively associated with the degree of motor impulsivity in the total group. Controlling for
aggression, a stronger FC was also found between serotonergic nucleus centralis superior (NCS) and
the frontopolar cortex (FPC) in patients compared to controls. Furthermore, patients showed a weaker
"anti-correlation" from the substantia nigra (SNc) to the left dorsolateral prefrontal cortex (DLPFC).
The observed enhanced LC-ACC FC in BPD and its association with the motor impulsivity might be
indicative of a noradrenergic dysfunction in the neural inhibitory control network, whereas the
288. LC-MS/MS signal suppression effects in the analysis of pesticides in complex environmental matrices.
PubMed
Choi, B K; Hercules, D M; Gusev, A I
2001-02-01
The application of LC separation and mobile phase additives in addressing LC-MS/MS matrix signal
suppression effects for the analysis of pesticides in a complex environmental matrix was investigated.
It was shown that signal suppression is most significant for analytes eluting early in the LC-MS
analysis. Introduction of different buffers (e.g. ammonium formate, ammonium hydroxide, formic
acid) into the LC mobile phase was effective in improving signal correlation between the matrix and
standard samples. The signal improvement is dependent on buffer concentration as well as LC
separation of the matrix components. The application of LC separation alone was not effective in
addressing suppression effects when characterizing complex matrix samples. Overloading of the LC
column by matrix components was found to significantly contribute to analyte-matrix co-elution and
suppression of signal. This signal suppression effect can be efficiently compensated by 2D LC (LC-
LC) separation techniques. The effectiveness of buffers and LC separation in improving signal
correlation between standard and matrix samples is discussed.
289. Neurofeedback in ADHD and insomnia: vigilance stabilization through sleep spindles and circadian
networks.
PubMed
Arns, Martijn; Kenemans, J Leon
2014-07-01
In this review article an overview of the history and current status of neurofeedback for the treatment
of ADHD and insomnia is provided. Recent insights suggest a central role of circadian phase delay,
resulting in sleep onset insomnia (SOI) in a sub-group of ADHD patients. Chronobiological
treatments, such as melatonin and early morning bright light, affect the suprachiasmatic nucleus. This
nucleus has been shown to project to the noradrenergic locus coeruleus (LC) thereby explaining the
vigilance stabilizing effects of such treatments in ADHD. It is hypothesized that both Sensori-Motor
Rhythm (SMR) and Slow-Cortical Potential (SCP) neurofeedback impact on the sleep spindle circuitry
resulting in increased sleep spindle density, normalization of SOI and thereby affect the noradrenergic
LC, resulting in vigilance stabilization. After SOI is normalized, improvements on ADHD symptoms
will occur with a delayed onset of effect. Therefore, clinical trials investigating new treatments in
ADHD should include assessments at follow-up as their primary endpoint rather than assessments at
outtake. Furthermore, an implication requiring further study is that neurofeedback could be stopped
when SOI is normalized, which might result in fewer sessions. Copyright Â© 2012 Elsevier Ltd. All
rights reserved.
290. The E3 ubiquitin ligase NEDD4 is an LC3-interactive protein and regulates autophagy
PubMed Central
Sun, Aiqin; Wei, Jing; Childress, Chandra; Shaw, John H.; Peng, Ke; Shao, Genbao; Yang, Wannian;
Lin, Qiong
2017-01-01
ABSTRACT The MAP1LC3/LC3 family plays an essential role in autophagosomal biogenesis and
transport. In this report, we show that the HECT family E3 ubiquitin ligase NEDD4 interacts with LC3
and is involved in autophagosomal biogenesis. NEDD4 binds to LC3 through a conserved WXXL
LC3-binding motif in a region between the C2 and the WW2 domains. Knockdown of NEDD4
impaired starvation- or rapamycin-induced activation of autophagy and autophagosomal biogenesis
and caused aggregates of the LC3 puncta colocalized with endoplasmic reticulum membrane markers.
Electron microscopy observed gigantic deformed mitochondria in NEDD4 knockdown cells,
suggesting that NEDD4 might function in mitophagy. Furthermore, SQSTM1 is ubiquitinated by
NEDD4 while LC3 functions as an activator of NEDD4 ligase activity. Taken together, our studies
define an important role of NEDD4 in regulation of autophagy. PMID:28085563
291. The E3 ubiquitin ligase NEDD4 is an LC3-interactive protein and regulates autophagy.
PubMed
Sun, Aiqin; Wei, Jing; Childress, Chandra; Shaw, John H; Peng, Ke; Shao, Genbao; Yang, Wannian;
Lin, Qiong
2017-03-04
The MAP1LC3/LC3 family plays an essential role in autophagosomal biogenesis and transport. In this
report, we show that the HECT family E3 ubiquitin ligase NEDD4 interacts with LC3 and is involved
in autophagosomal biogenesis. NEDD4 binds to LC3 through a conserved WXXL LC3-binding motif
in a region between the C2 and the WW2 domains. Knockdown of NEDD4 impaired starvation- or
rapamycin-induced activation of autophagy and autophagosomal biogenesis and caused aggregates of
the LC3 puncta colocalized with endoplasmic reticulum membrane markers. Electron microscopy
observed gigantic deformed mitochondria in NEDD4 knockdown cells, suggesting that NEDD4 might
function in mitophagy. Furthermore, SQSTM1 is ubiquitinated by NEDD4 while LC3 functions as an
activator of NEDD4 ligase activity. Taken together, our studies define an important role of NEDD4 in
regulation of autophagy.
292. Are antidepressant drugs that combine serotonergic and noradrenergic mechanisms of action more
effective than the selective serotonin reuptake inhibitors in treating major depressive disorder? A meta-
analysis of studies of newer agents.
PubMed
Papakostas, George I; Thase, Michael E; Fava, Maurizio; Nelson, J Craig; Shelton, Richard C
2007-12-01
Recent studies suggest that the treatment of major depressive disorder (MDD) with newer
antidepressant drugs that simultaneously enhance norepinephrine and serotonin neurotransmission
might result in higher response and remission rates than the selective serotonin reuptake inhibitors
(SSRIs). The goal of our work was to compare response rates among patients with MDD treated with
either of these two broad categories of antidepressant drugs. Medline/Pubmed, EMBase, clinical trial
registries, program syllabi from major psychiatric meetings held since 1995, and documents from
relevant pharmaceutical companies were searched for double-blind, randomized trials comparing a
newer serotonergic-noradrenergic antidepressant drug (venlafaxine, duloxetine, milnacipran,
mirtazapine, mianserin, or moclobemide) with an SSRI for MDD. Ninety-three trials (n = 17,036)
were combined using a random-effects model. Treatment with serotonergic + noradrenergic
antidepressant drugs was more likely to result in clinical response than the SSRIs (risk ratio [RR] =
1.059; response rates 63.6% versus 59.3%; p = .003). There was no evidence for heterogeneity among
studies combined (p = 1.0). Excluding each individual agent did not significantly alter the pooled RR.
With the exception of duloxetine (.985), RRs for response for each individual serotonergic +
noradrenergic antidepressant drug were within the 95% confidence interval of the pooled RR (1.019-
1.101). Serotonergic-noradrenergic antidepressant drugs seem to have a modest efficacy advantage
compared with SSRIs in MDD. With the Number Needed to Treat (NNT) statistic as one indicator of
clinical significance, nearly 24 patients would need to be treated with dual-action antidepressant drugs
instead of SSRIs in order to obtain one additional responder. This difference falls well below the mark
of NNT = 10 suggested by the United Kingdom's National Institute of Clinical Excellence but
nonetheless might be of public health relevance given the
293. Improved profiling of estrogen metabolites by orbitrap LC/MS
PubMed Central
Li, Xingnan; Franke, Adrian A.
2015-01-01
Estrogen metabolites are important biomarkers to evaluate cancer risks and metabolic diseases. Due to
their low physiological levels, a sensitive and accurate method is required, especially for the
quantitation of unconjugated forms of endogenous steroids and their metabolites in humans. Here, we
evaluated various derivatives of estrogens for improved analysis by orbitrap LC/MS in human serum
samples. A new chemical derivatization reagent was applied modifying phenolic steroids to form 1-
methylimidazole-2-sulfonyl adducts. The method significantly improves the sensitivity 2â€“100 fold
by full scan MS and targeted selected ion monitoring MS over other derivatization methods including,
dansyl, picolinoyl, and pyridine-3-sulfonyl products. PMID:25543003
294. Voltage- and temperature- controlled LC:PDMS waveguide channels
Rutkowska, Katarzyna A.; Asquini, Rita; d'Alessandro, Antonio
2017-08-01
In this paper, we present our studies on electrical and thermal tuning of light propagation in waveguide
channels, made for the scope from a polydimethylsiloxane (PDMS) substrate infiltrated with nematic
liquid crystal (LC). We demonstrated, via numerical simulations, the changes of the waveguide optical
parameters when solicited by temperature changes or electric fields. Moreover, the paper goes through
the fabrication process of a waveguide channel sample and its characterization, as well as some
preliminary experimental trials of sputtering indium tin oxide (ITO) and chromium layers on PDMS
substrate to obtain flat electrodes.
295. Reduction of the nitro group to amine by hydroiodic acid to synthesize o-aminophenol derivatives as
putative degradative markers of neuromelanin.
PubMed
Wakamatsu, Kazumasa; Tanaka, Hitomi; Tabuchi, Keisuke; Ojika, Makoto; Zucca, Fabio A; Zecca,
Luigi; Ito, Shosuke
2014-06-16
Neuromelanin (NM) is produced in dopaminergic neurons of the substantia nigra (SN) and in
noradrenergic neurons of the locus coeruleus (LC). The synthesis of NM in those neurons is a
component of brain aging and there is the evidence that this pigment can be involved in the
pathogenesis of neurodegenerative diseases such as Parkinson's disease. NM is believed to derive from
the oxidative polymerization of dopamine (DA) or norepinephrine (NE) with the participation of
cysteine, dolichols and proteins. However, there are still unknown aspects in the chemical structure of
NM from SN (SN-NM) and LC (LC-NM). In this study, we designed a new method to synthesize o-
aminophenol compounds as putative degradation products of catecholamines and their metabolites
which may be incorporated into NM. Those compounds are aminohydroxyphenylethylamine
(AHPEA) isomers, aminohydroxyphenylacetic acid (AHPAA) isomers and
aminohydroxyethylbenzene (AHEB) isomers, which are expected to arise from DA or NE, 3,4-
dihydroxyphenylacetic acid (DOPAC) or 3,4-dihydroxyphenylmandelic acid (DOMA) and 3,4-
dihydroxyphenylethanol (DOPE) or 3,4-dihydroxyphenylethyleneglycol (DOPEG), respectively.
These o-aminophenol compounds were synthesized by the nitration of phenol derivatives followed by
reduction with hydroiodic acid (HI), and they could be identified by HPLC in HI hydrolysates of SN-
NM and LC-NM. This degradative approach by HI hydrolysis allows the identification of catecholic
precursors unique to SN-NM and LC-NM, which are present in catecholaminergic neurons.
296. GABAergic ventrolateral pre-optic nucleus neurons are involved in the mediation of the anesthetic
hypnosis induced by propofol
PubMed Central
Yuan, Jie; Luo, Zhuxin; Zhang, Yu; Zhang, Yi; Wang, Yuan; Cao, Song; Fu, Bao; Yang, Hao; Zhang,
Lin; Zhou, Wenjing; Yu, Tian
2017-01-01
Intravenous anesthetics have been used clinically to induce unconsciousness for seventeen decades,
however the mechanism of anesthetic-induced unconsciousness remains to be fully elucidated. It has
previously been demonstrated that anesthetics exert sedative effects by acting on endogenous sleep-
arousal circuits. However, few studies focus on the ventrolateral pre-optic (VLPO) to locus coeruleus
(LC) sleep-arousal pathway. The present study aimed to investigate if VLPO is involved in
unconsciousness induced by propofol. The present study additionally investigated if the inhibitory
effect of propofol on LC neurons was mediated by activating VLPO neurons. Microinjection, target
lesion and extracellular single-unit recordings were used to study the role of the VLPO-LC pathway in
propofol anesthesia. The results demonstrated that GABAA agonist (THIP) or GABAA antagonist
(gabazine) microinjections into VLPO altered the time of loss of righting reflex and the time of
recovery of righting reflex. Furthermore, propofol suppressed the spontaneous firing activity of LC
noradrenergic neurons. There was no significant difference observed in firing activity between VLPO
sham lesion and VLPO lesion rats. The findings indicate that VLPO neurons are important in
propofol-induced unconsciousness, however are unlikely to contribute to the inhibitory effect of
propofol on LC spontaneous firing activity. PMID:28765955
297. Method of preparing a tunable-focus liquid-crystal (LC) lens
Li, Xiaolong; Zhou, Zuowei; Ren, Hongwen
2018-02-01
A liquid crystal (LC) lens is prepared by controlling the alignment of a LC using a homogeneous
polyimide (PI) layer and a homeotropic PI layer. The rubbed homogeneous PI layer has a concave
surface and the homeotropic PI layer is flat. The LC sandwiched between the two PI layers obtains a
hybrid alignment which has the largest gradient of refractive index (GRIN) distribution. The LC layer
exhibits a lens character because of its convex shape. Since the effective refractive index of the LC is
larger than that of the homogeneous PI, the LC lens can focus a light with the shortest focal length in
the voltage-off state. By applying an external voltage, the LC molecules can be reoriented along the
electric field. As a result, the focal length of the LC lens is reduced. The focal length of the LC lens
can be tuned from 30 to 120 Î¼m when the voltage is changed from 0 to 7 Vrms. This LC lens has the
advantages of no threshold, low operating voltage, and simple fabrication.
298. Three Members of the LC8/DYNLL Family Are Required for Outer Arm Dynein Motor Function
PubMed Central
Tanner, Christopher A.; Rompolas, Panteleimon; Patel-King, Ramila S.; Gorbatyuk, Oksana;
Wakabayashi, Ken-ichi; Pazour, Gregory J.
2008-01-01
The highly conserved LC8/DYNLL family proteins were originally identified in axonemal dyneins
and subsequently found to function in multiple enzyme systems. Genomic analysis uncovered a third
member (LC10) of this protein class in Chlamydomonas. The LC10 protein is extracted from flagellar
axonemes with 0.6 M NaCl and cofractionates with the outer dynein arm in sucrose density gradients.
Furthermore, LC10 is specifically missing only from axonemes of those strains that fail to assemble
outer dynein arms. Previously, the oda12-1 insertional allele was shown to lack the Tctex2-related
dynein light chain LC2. The LC10 gene is located âˆ¼2 kb from that of LC2 and is also completely
missing from this mutant but not from oda12-2, which lacks only the 3â€² end of the LC2 gene.
Although oda12-1 cells assemble outer arms that lack only LC2 and LC10, this strain exhibits a
flagellar beat frequency that is consistently less than that observed for strains that fail to assemble the
entire outer arm and docking complex (e.g., oda1). These results support a key regulatory role for the
intermediate chain/light chain complex that is an integral and highly conserved feature of all
oligomeric dynein motors. PMID:18579685
299. Comprehensive Analysis of LC/MS Data Using Pseudocolor Plots
Crutchfield, Christopher A.; Olson, Matthew T.; Gourgari, Evgenia; Nesterova, Maria; Stratakis,
Constantine A.; Yergey, Alfred L.
2013-02-01
We have developed new applications of the pseudocolor plot for the analysis of LC/MS data. These
applications include spectral averaging, analysis of variance, differential comparison of spectra, and
qualitative filtering by compound class. These applications have been motivated by the need to better
understand LC/MS data generated from analysis of human biofluids. The examples presented use data
generated to profile steroid hormones in urine extracts from a Cushing's disease patient relative to a
healthy control, but are general to any discovery-based scanning mass spectrometry technique. In
addition to new visualization techniques, we introduce a new metric of variance: the relative maximum
difference from the mean. We also introduce the concept of substructure-dependent analysis of steroid
hormones using precursor ion scans. These new analytical techniques provide an alternative approach
to traditional untargeted metabolomics workflow. We present an approach to discovery using MS that
essentially eliminates alignment or preprocessing of spectra. Moreover, we demonstrate the concept
that untargeted metabolomics can be achieved using low mass resolution instrumentation.
300. Measuring FLOPS Using Hardware Performance Counter Technologies on LC systems
SciTech Connect
Ahn, D H
2008-09-05
FLOPS (FLoating-point Operations Per Second) is a commonly used performance metric for scientific
programs that rely heavily on floating-point (FP) calculations. The metric is based on the number of
FP operations rather than instructions, thereby facilitating a fair comparison between different
machines. A well-known use of this metric is the LINPACK benchmark that is used to generate the
Top500 list. It measures how fast a computer solves a dense N by N system of linear equations Ax=b,
which requires a known number of FP operations, and reports the result in millions of FP operations
per second (MFLOPS). While running amoreÂ Â» benchmark with known FP workloads can provide
insightful information about the efficiency of a machine's FP pipelines in relation to other machines,
measuring FLOPS of an arbitrary scientific application in a platform-independent manner is nontrivial.
The goal of this paper is twofold. First, we explore the FP microarchitectures of key processors that are
underpinning the LC machines. Second, we present the hardware performance monitoring counter-
based measurement techniques that a user can use to get the native FLOPS of his or her program,
which are practical solutions readily available on LC platforms. By nature, however, these native
FLOPS metrics are not directly comparable across different machines mainly because FP operations
are not consistent across microarchitectures. Thus, the first goal of this paper represents the base
reference by which a user can interpret the measured FLOPS more judiciously.Â«Â less
«
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14
15
16
17
»
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14
15
16
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18
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301. L-C Measurement Acquisition Method for Aerospace Systems
Woodard, Stanley E.; Taylor, B. Douglas; Shams, Qamar A.; Fox, Robert L.
2003-01-01
This paper describes a measurement acquisition method for aerospace systems that eliminates the need
for sensors to have physical connection to a power source (i.e., no lead wires) or to data acquisition
equipment. Furthermore, the method does not require the sensors to be in proximity to any form of
acquisition hardware. Multiple sensors can be interrogated using this method. The sensors consist of a
capacitor, C(p), whose capacitance changes with changes to a physical property, p, electrically
connected to an inductor, L. The method uses an antenna to broadcast electromagnetic energy that
electrically excites one or more inductive-capacitive sensors via Faraday induction. This method
facilitates measurements that were not previously possible because there was no practical means of
providing power and data acquisition electrical connections to a sensor. Unlike traditional sensors,
which measure only a single physical property, the manner in which the sensing element is
interrogated simultaneously allows measurement of at least two unrelated physical properties (e.g.,
displacement rate and fluid level) by using each constituent of the L-C element. The key to using the
method for aerospace applications is to increase the distance between the L-C elements and
interrogating antenna; develop all key components to be non-obtrusive and to develop sensing
elements that can easily be implemented. Techniques that have resulted in increased distance between
antenna and sensor will be presented. Fluid-level measurements and pressure measurements using the
acquisition method are demonstrated in the paper.
302. Metabolism of isorhynchophylline in rats detected by LC-MS.
PubMed
Wang, Wei; Ma, Chao-Mei; Hattori, Masao
2010-01-01
This paper investigates the metabolic fate of isorhynchophylline (ISOR) as a main bioactive oxindole
alkaloid in the traditional Chinese medicine. After oral administration of ISOR to rats, plasma, bile,
urine and feces were analyzed by LC-MS. Hydroxylation of ISOR and successive glucuronidation
proceeded in vitro by incubation with rat liver microsomes. ISOR was identified in plasma, 11-
hydroxyisorhynchophylline 11-O--D-glucuronide (MI1) and 10-hydroxyisorhynchophylline 10-O--D-
glucuronide (MI2) in bile, and free 11-hydroxyisorhynchophylline (MI3) and 10-
hydroxyisorhynchophylline (MI4) in urine and feces. Within 24 h, 71.6% of ISOR was excreted into
the feces (in 20.0 g) and 13.8% into the urine (in 20.0 ml) of rats after oral administration of 37.5
mg/kg. Monitoring by LC-MS showed that 8.5% of ISOR was metabolized to MI3 and MI4 in a ratio
of ca. 1:1. Specific inhibition of CYP isozymes indicated that CYP2D, CYP1A1/2 and CYP2C
participate in ISOR hydroxylation. ISOR was involved in the circulatory system after oral
administration. Cytochrome P450 (CYP) in rat liver microsomes played a key role in ISOR
hydroxylation.
303. The antinociceptive effect of intravenous imipramine in colorectal distension-induced visceral pain in
rats: the role of serotonergic and noradrenergic receptors.
PubMed
Ä°lkaya, Fatih; Bilge, S SÄ±rrÄ±; Bozkurt, Ayhan; BaÅŸ, Duygu B; Erdal, Arzu; Ã‡iftÃ§ioÄŸlu,
Engin; Kesim, YÃ¼ksel
2014-07-01
It has been shown that imipramine, a tricyclic antidepressant (TCA), is a potent analgesic agent.
However, the effect of imipramine on visceral pain has not been extensively investigated. In the
current study, our aim was to characterise the putative analgesic effect of intravenous imipramine on
visceral pain in rats. Our second aim was to assess the involvement of serotonergic (5-HTâ‚‚,â‚ƒ,â‚„)
and noradrenergic (Î±(2A, 2B, 2C)) receptor subtypes in this putative antinociceptive effect of
imipramine. Male Sprague Dawley rats (250-300 g) were implanted with venous catheters for drug
administration and implanted with enamelled nichrome electrodes for electromyography of the
external oblique muscles. Noxious visceral stimulation was applied via by colorectal distension
(CRD). The visceromotor responses (VMRs) to CRD were quantified electromyographically before
and after imipramine administration at 5, 15, 30, 60, 90 and 120 min. In the antagonist groups, the
agents were administered 10 min before imipramine. The administration of imipramine (5-40 mg/kg)
produced a dose-dependent reduction in VMR. The administration of yohimbine (a nonselective Î±â‚‚-
adrenoceptor antagonist, 1 mg/kg), BRL-44408 (an Î±(2A)-adrenoceptor antagonist, 1 mg/kg) or MK-
912 (an Î±2C-adrenoceptor antagonist, 300 Î¼g/kg) but not imiloxan (an Î±(2B)-adrenoceptor
antagonist, 1 mg/kg) inhibited the antinociceptive effect of imipramine (20 mg/kg). Additionally,
ketanserin (a 5-HTâ‚‚ receptor antagonist, 0.5, 1, and 2 mg/kg) and GR113808 (a 5-HTâ‚„ receptor
antagonist, 1 mg/kg) enhanced, and ondansetron (a 5-HTâ‚ƒ receptor antagonist, 0.5, 1, and 2 mg/kg)
failed to alter the imipramine-induced antinociceptive effect. Our data demonstrated that, in the CDR-
induced rat visceral pain model, intravenous imipramine appeared to have antinociceptive potential
and that Î±(2A)-/Î±(2C)-adrenoceptors and 5-HTâ‚‚/5-HTâ‚„ receptors may be responsible for the
antinociceptive effect of imipramine on visceral pain
304. Hypersensitivity of prediabetic JCR:LA-cp rats to fine airborne combustion particle-induced direct and
noradrenergic-mediated vascular contraction.
PubMed
Proctor, Spencer D; Dreher, Kevin L; Kelly, Sandra E; Russell, James C
2006-04-01
Particulate matter with mean aerodynamic diameter < or =2.5 microm (PM(2.5)), from diesel exhaust,
coal or residual oil burning, and from industrial plants, is a significant component of airborne
pollution. Type 2 diabetes is associated with enhanced risk of adverse cardiovascular events following
exposure to PM(2.5). Particle properties, sources, and pathophysiological mechanisms responsible are
unknown. We studied effects of residual oil fly ash (ROFA) from a large U.S. powerplant on vascular
function in a prediabetic, hyperinsulinemic model, the JCR:LA-cp rat. Residual oil fly ash leachate
(ROFA-L) was studied using aortic rings from young-adult, obese, insulin-resistant rats and lean
normal rats in vitro. Contractile response to phenylephrine and relaxant response to acetylcholine were
determined in the presence and absence of L-NAME (N(G)-nitro-L-arginine methyl ester). In a
separate series of studies, the direct contractile effects of ROFA-L on repeated exposure were
determined. ROFA-L (12.5 microg ml(-1)) increased phenylephrine-mediated contraction in obese (p <
0.05), but not in lean rat aortae, with the effect being exacerbated by L-NAME, and it reduced
acetylcholine-mediated relaxation of both obese and lean aortae (p < 0.0001). Initial exposure of aortae
to ROFA-L caused a small contractile response (<0.05 g), which was markedly greater on second
exposure in the obese (approximately 0.6 g, p < 0.0001) aortae but marginal in lean (approximately 0.1
g) aortae. Our data demonstrate that bioavailable constituents of oil combustion particles enhance
noradrenergic-mediated vascular contraction, impair endothelium-mediated relaxation, and induce
direct vasocontraction in prediabetic rats. These observations provide the first direct evidence of the
causal properties of PM(2.5) and identify the pathophysiological role of the early prediabetic state in
susceptibility to environmentally induced cardiovascular disease. These are important implications for
public
305. Norepinephrine ignites local hotspots of neuronal excitation: How arousal amplifies selectivity in
perception and memory.
PubMed
Mather, Mara; Clewett, David; Sakaki, Michiko; Harley, Carolyn W
2016-01-01
Emotional arousal enhances perception and memory of high-priority information but impairs
processing of other information. Here, we propose that, under arousal, local glutamate levels signal the
current strength of a representation and interact with norepinephrine (NE) to enhance high priority
representations and out-compete or suppress lower priority representations. In our "glutamate
amplifies noradrenergic effects" (GANE) model, high glutamate at the site of prioritized
representations increases local NE release from the locus coeruleus (LC) to generate "NE hotspots." At
these NE hotspots, local glutamate and NE release are mutually enhancing and amplify activation of
prioritized representations. In contrast, arousal-induced LC activity inhibits less active representations
via two mechanisms: 1) Where there are hotspots, lateral inhibition is amplified; 2) Where no hotspots
emerge, NE levels are only high enough to activate low-threshold inhibitory adrenoreceptors. Thus,
LC activation promotes a few hotspots of excitation in the context of widespread suppression,
enhancing high priority representations while suppressing the rest. Hotspots also help synchronize
oscillations across neural ensembles transmitting high-priority information. Furthermore, brain
structures that detect stimulus priority interact with phasic NE release to preferentially route such
information through large-scale functional brain networks. A surge of NE before, during, or after
encoding enhances synaptic plasticity at NE hotspots, triggering local protein synthesis processes that
enhance selective memory consolidation. Together, these noradrenergic mechanisms promote selective
attention and memory under arousal. GANE not only reconciles apparently contradictory findings in
the emotion-cognition literature but also extends previous influential theories of LC neuromodulation
by proposing specific mechanisms for how LC-NE activity increases neural gain.
306. Phase retardation vs. pretilt angle in liquid crystal cells with homogeneous and inhomogeneous LC
director configuration.
PubMed
Belyaev, Victor; Solomatin, Alexey; Chausov, Denis
2013-02-25
Phase retardation of both extraordinary and ordinary polarized rays passing through a liquid crystal
(LC) cell with homogeneous and inhomogeneous LC director distribution is calculated as a function of
the LC pretilt angle Î¸â‚€ on the cell substrates in the range 0 â‰¤ Î¸â‚€ â‰¤ 90Â°. The LC pretilt on
both substrates can have the same or opposite direction, thereby forming homogeneous, splay, or bend
director configurations. At the same pretilt angle value, the largest phase retardation Î”Î¦ is observed in
splay LC cells, whereas the smallest phase retardation is observed in bend cells. For the Î¸â‚€ values
close to 0, 45Â°, and 90Â°, analytical approximations are derived, showing that phase retardation
depends on LC birefringence variation.
307. Chip-LC-MS for label-free profiling of human serum.
PubMed
Horvatovich, Peter; Govorukhina, Natalia I; Reijmers, Theo H; van der Zee, Ate G J; Suits, Frank;
Bischoff, Rainer
2007-12-01
The discovery of biomarkers in easily accessible body fluids such as serum is one of the most
challenging topics in proteomics requiring highly efficient separation and detection methodologies.
Here, we present the application of a microfluidics-based LC-MS system (chip-LC-MS) to the label-
free profiling of immunodepleted, trypsin-digested serum in comparison to conventional capillary LC-
MS (cap-LC-MS). Both systems proved to have a repeatability of approximately 20% RSD for peak
area, all sample preparation steps included, while repeatability of the LC-MS part by itself was less
than 10% RSD for the chip-LC-MS system. Importantly, the chip-LC-MS system had a two times
higher resolution in the LC dimension and resulted in a lower average charge state of the tryptic
peptide ions generated in the ESI interface when compared to cap-LC-MS while requiring
approximately 30 times less (~5 pmol) sample. In order to characterize both systems for their
capability to find discriminating peptides in trypsin-digested serum samples, five out of ten
individually prepared, identical sera were spiked with horse heart cytochrome c. A comprehensive data
processing methodology was applied including 2-D smoothing, resolution reduction, peak picking,
time alignment, and matching of the individual peak lists to create an aligned peak matrix amenable
for statistical analysis. Statistical analysis by supervised classification and variable selection showed
that both LC-MS systems could discriminate the two sample groups. However, the chip-LC-MS
system allowed to assign 55% of the overall signal to selected peaks against 32% for the cap-LC-MS
system.
308. Nucleocytoplasmic Distribution and Dynamics of the Autophagosome Marker EGFP-LC3
PubMed Central
Drake, Kimberly R.; Kang, Minchul; Kenworthy, Anne K.
2010-01-01
The process of autophagy involves the formation of autophagosomes, double-membrane structures that
encapsulate cytosol. Microtubule-associated protein light chain 3 (LC3) was the first protein shown to
specifically label autophagosomal membranes in mammalian cells, and subsequently EGFP-LC3 has
become one of the most widely utilized reporters of autophagy. Although LC3 is currently thought to
function primarily in the cytosol, the site of autophagosome formation, EGFP-LC3 often appears to be
enriched in the nucleoplasm relative to the cytoplasm in published fluorescence images. However, the
nuclear pool of EGFP-LC3 has not been specifically studied in previous reports, and mechanisms by
which LC3 shuttles between the cytoplasm and nucleoplasm are currently unknown. In this study, we
therefore investigated the regulation of the nucleo-cytoplasmic distribution of EGFP-LC3 in living
cells. By quantitative fluorescence microscopy analysis, we demonstrate that soluble EGFP-LC3 is
indeed enriched in the nucleus relative to the cytoplasm in two commonly studied cell lines, COS-7
and HeLa. Although LC3 contains a putative nuclear export signal (NES), inhibition of active nuclear
export or mutation of the NES had no effect on the nucleo-cytoplasmic distribution of EGFP-LC3.
Furthermore, FRAP analysis indicates that EGFP-LC3 undergoes limited passive nucleo-cytoplasmic
transport under steady state conditions, and that the diffusional mobility of EGFP-LC3 was
substantially slower in the nucleus and cytoplasm than predicted for a freely diffusing monomer.
Induction of autophagy led to a visible decrease in levels of soluble EGFP-LC3 relative to
autophagosome-bound protein, but had only modest effects on the nucleo-cytoplasmic ratio or
diffusional mobility of the remaining soluble pools of EGFP-LC3. We conclude that the enrichment of
soluble EGFP-LC3 in the nucleus is maintained independently of active nuclear export or induction of
autophagy. Instead, incorporation of soluble
309. Anti-LC1 autoantibodies in patients with chronic hepatitis C virus infection.
PubMed
BÃ©land, Kathie; Lapierre, Pascal; Marceau, Gabriel; Alvarez, Fernando
2004-03-01
Various autoantibodies have been reported in patients chronically infected by hepatitis C virus. 2% to
10% of theses patients have anti-liver-kidney microsome type 1 (anti-LKM1) autoantibodies. In type 2
autoimmune hepatitis, anti-LKM1 autoantibodies are frequently associated with anti-liver-cytosol type
1 (anti-LC1) autoantibodies. To determine the prevalence of anti-LC1 autoantibodies in a hepatitis C-
positive population and characterize their reactivity. 146 patients suffering from liver diseases, of
which 99 were chronically infected by hepatitis C virus, were tested by Western blotting and
immunoprecipitation to detect and characterize anti-LC1 autoantibodies. 12% of this hepatitis C
population had anti-LC1 autoantibodies. LC1 positivity by Western blotting was 30% of LC1+ sera.
Epitopes were found throughout the protein but linear epitopes were situated in the 395-541 amino
acid region of formiminotransferase cyclodeaminase. Three putative conformational epitopes were
identified by phage display. Anti-LC1 autoantibodies are as prevalent as anti-LKM1 autoantibodies in
patients infected with hepatitis C virus and their production is not dependent of anti-LKM1
autoantibodies formation. Autoantibody reactivity against the anti-LC1 antigen is different in hepatitis
C than in type 2 autoimmune hepatitis. Anti-LC1 autoantibodies can now be regarded as a serological
marker of autoimmunity in chronic hepatitis C infection.
310. The Linked System Project : a network interconnection project between three major bibliographic
utilities and LC
Kurihara, Shin'ichi
The Linked Systems Project (LSP) is the first network project based on the Open Systems
Interconnection (OSI) in the world. The purpose of the project is to interconnect between three major
bibliographic utilities and LC, and to perform as one system on the whole. The first application
developed for the LSP is the sharing of name authority data based on the Name Authority Cooperative
(NACO) Project. In 1985, LC began to send name authority records to RLG/RLIN. Since 1987,
RLG/RLIN and OCLC send name authority records to LC. Bibliographic records will be sent mutually
between three major bibliographic utilities and LC near future.
311. Therapeutic drug monitoring of tamoxifen using LC-MS/MS.
PubMed
Tchu, Simone M; Lynch, Kara L; Wu, Alan H B
2012-01-01
Tamoxifen is a selective estrogen receptor modulator (SERM) that is used widely in the treatment of
estrogen receptor positive breast cancer (ER+). Therapeutic monitoring of tamoxifen, and its
metabolites N-desmethyltamoxifen (NDTam) and 4-hydroxy-N-desmethyltamoxifen (endoxifen), may
be clinically useful for guiding treatment decisions. Two significant barriers to tamoxifen efficacy are:
(1) variability in conversion of tamoxifen into the potent antiestrogenic metabolite, endoxifen, and (2)
poor compliance and adherence to tamoxifen therapy. Therapeutic monitoring can be used to address
both of these issues. Low levels of endoxifen indicate either poor compliance or poor metabolism of
tamoxifen. Low tamoxifen levels would suggest poor compliance while a low ratio of endoxifen to
NDTam would be indicative of poor metabolism. Solid phase extraction of patient serum followed by
liquid chromatography tandem mass spectrometry (LC-MS/MS) detection enables rapid, accurate,
detection of tamoxifen, N-desmethyltamoxifen, and endoxifen.
312. Overexpression of maize anthocyanin regulatory gene Lc affects rice fertility.
PubMed
Li, Yuan; Zhang, Tao; Shen, Zhong-Wei; Xu, Yu; Li, Jian-Yue
2013-01-01
Seventeen independent transgenic rice plants with the maize anthocyanin regulatory gene Lc under
control of the CaMV 35S promoter were obtained and verified by molecular identification. Ten plants
showed red spikelets during early development of florets, and the degenerate florets were still red after
heading. Additionally, these plants exhibited intense pigmentation on the surface of the anther and the
bottom of the ovary. They were unable to properly bloom and were completely sterile. Following
pollination with normal pollen, these plants yielded red caryopses but did not mature normally. QRT-
PCR analysis indicated that mRNA accumulation of the CHS-like gene encoding a chalcone synthase-
related protein was increased significantly in the sterile plant. This is the first report to suggest that
upregulation of the CHS gene expression may result in rice sterility and affect the normal development
of rice seeds.
313. [Determination of Butroxydim in Agricultural Products by LC-MS].
PubMed
Minatani, Tomiaki; Nagai, Hiroyuki; Tada, Hiroyuki; Goto, Kotaro; Nemoto, Satoru
2015-01-01
An analytical method for the determination of butroxydim in agricultural products by LC-MS was
developed. Butroxydim was extracted with acetonitrile and an aliquot of the crude extract was cleaned
up on an octadecyl silanized silica gel (C18) cartridge column (1,000 mg), followed by a salting-out
step to remove water. Before purification on a silica gel (SI) cartridge column (690 mg), polar matrices
were precipitated by adding ethyl acetate, n-hexane and anhydrous sodium sulfate successively. This
process effectively removed caffeine and catechins and improved recovery when analyzing residual
butroxydim in tea leaves. Recovery and repeatability were good; the relative standard deviations were
less than 5% for all 12 tested agricultural products (brown rice, soybean, potato, spinach, cabbage,
apple, orange, grapefruit, lemon, tomato, peas with pods, and tea). Average recoveries for 11
agricultural products, except for lemon, were 74-92%.
314. Ethinyl estradiol and levonorgestrel alter cognition and anxiety in rats concurrent with a decrease in
tyrosine hydroxylase expression in the locus coeruleus and brain-derived neurotrophic factor
expression in the hippocampus.
PubMed
Simone, Jean; Bogue, Elizabeth A; Bhatti, Dionnet L; Day, Laura E; Farr, Nathan A; Grossman, Anna
M; Holmes, Philip V
2015-12-01
In the United States, more than ten million women use contraceptive hormones. Ethinyl estradiol and
levonorgestrel have been mainstay contraceptive hormones for the last four decades. Surprisingly,
there is scant information regarding their action on the central nervous system and behavior. Intact
female rats received three weeks of subcutaneous ethinyl estradiol (10 or 30Î¼g/rat/day),
levonorgestrel (20 or 60Î¼g/rat/day), a combination of both (10/20Î¼g/rat/day and 30/60Î¼g/rat/day),
or vehicle. Subsequently, the rats were tested in three versions of the novel object recognition test to
assess learning and memory, and a battery of tests for anxiety-like behavior. Serum estradiol and
ovarian weights were measured. All treatment groups exhibited low endogenous 17Î²-estradiol levels
at the time of testing. Dose-dependent effects of drug treatment manifested in both cognitive and
anxiety tests. All low dose drugs decreased anxiety-like behavior and impaired performance on novel
object recognition. In contrast, the high dose ethinyl estradiol increased anxiety-like behavior and
improved performance in cognitive testing. In the cell molecular analyses, low doses of all drugs
induced a decrease in tyrosine hydroxylase mRNA and protein in the locus coeruleus. At the same
time, low doses of ethinyl estradiol and ethinyl estradiol/levonorgestrel increased galanin protein in
this structure. Consistent with the findings above, the low dose treatments of ethinyl estradiol and
combination ethinyl estradiol/levonorgestrel reduced brain-derived neurotrophic factor mRNA in the
hippocampus. These effects of ethinyl estradiol 10Î¼g alone and in combination with levonorgestrel
20Î¼g suggest a diminution of norepinephrine input into the hippocampus resulting in a decline in
learning and memory. Copyright Â© 2015 Elsevier Ltd. All rights reserved.
315. Chronic nandrolone decanoate exposure during adolescence affects emotional behavior and
monoaminergic neurotransmission in adulthood.
PubMed
Rainer, Quentin; Speziali, Simona; Rubino, Tiziana; Dominguez-Lopez, Sergio; Bambico, Francis
Rodriguez; Gobbi, Gabriella; Parolaro, Daniela
2014-08-01
Nandrolone decanoate, an anabolic androgen steroid (AAS) illicitly used by adult and adolescent
athletes to enhance physical performance and body image, induces psychiatric side effects, such as
aggression, depression as well as a spectrum of adverse physiological impairments. Since adolescence
represents a neurodevelopmental window that is extremely sensitive to the detrimental effects of drug
abuse, we investigated the long-term behavioral and neurophysiological consequences of nandrolone
abuse during adolescence. Adolescent rats received daily injections of nandrolone decanoate
(15Â mg/kg, i.m.) for 14 days (PND 40-53). At early adulthood (PND 68), forced swim, sucrose
preference, open field and elevated plus maze tests were performed to assess behavioral changes.
InÂ vivo electrophysiological recordings were carried out to monitor changes in electrical activity of
serotonergic neurons of the dorsal raphe nucleus (DRN) and noradrenergic neurons of the locus
coeruleus (LC). Our results show that after early exposure to nandrolone, rats display depression-
related behavior, characterized by increased immobility in the forced swim test and reduced sucrose
intake in the sucrose preference test. In addition, adult rats presented anxiety-like behavior
characterized by decreased time and number of entries in the central zone of the open field and
decreased time spent in the open arms of the elevated plus maze. Nandrolone decreased the firing rate
of spontaneously active serotonergic neurons in the DRN while increasing the firing rate of
noradrenergic neurons in the LC. These results provide evidence that nandrolone decanoate exposure
during adolescence alters the emotional profile of animals in adulthood and significantly modifies both
serotonergic and noradrenergic neurotransmission. Copyright Â© 2014 Elsevier Ltd. All rights
reserved.
316. Structural features of LC8-induced self-association of swallow.
PubMed
Kidane, Ariam I; Song, Yujuan; Nyarko, Afua; Hall, Justin; Hare, Michael; LÃ¶hr, Frank; Barbar,
Elisar
2013-09-03
Cell functions depend on the collective activity of protein networks within which a few proteins, called
hubs, participate in a large number of interactions. Dynein light chain LC8, first discovered as a
subunit of the motor protein dynein, is considered to have a role broader than that of dynein, and its
participation in diverse systems fits the description of a hub. Among its partners is Swallow with
which LC8 is essential for proper localization of bicoid mRNA at the anterior cortex of Drosophila
oocytes. Why LC8 is essential in this process is not clear, but emerging evidence suggests that LC8
functions by promoting self-association and/or structural organization of its diverse binding partners.
This work addresses the energetics and structural features of LC8-induced Swallow self-association
distant from LC8 binding. Mutational design based on a hypothetical helical wheel, intermonomer
nuclear Overhauser effects assigned to residues expected at interface positions, and circular dichroism
spectral characteristics indicate that the LC8-promoted dimer of Swallow is a coiled coil. Secondary
chemical shifts and (15)N backbone relaxation identify the boundaries and distinguishing structural
features of the coiled coil. Thermodynamic analysis of Swallow polypeptides designed to decouple
self-association from LC8 binding reveals that the higher binding affinity of the engineered bivalent
Swallow is of purely entropic origin and that the linker separating the coiled coil from the LC8 binding
site remains disordered. We speculate that the LC8-promoted coiled coil is critical for bicoid mRNA
localization because it favors structural organization of Swallow, which except for the central LC8-
promoted coiled coil is primarily disordered.
317. Lattice-patterned LC-polymer composites containing various nanoparticles as additives
PubMed Central
2012-01-01
In this study, we show the effect of various nanoparticle additives on phase separation behavior of a
lattice-patterned liquid crystal [LC]-polymer composite system and on interfacial properties between
the LC and polymer. Lattice-patterned LC-polymer composites were fabricated by exposing to UV
light a mixture of a prepolymer, an LC, and SiO2 nanoparticles positioned under a patterned
photomask. This resulted in the formation of an LC and prepolymer region through phase separation.
We found that the incorporation of SiO2 nanoparticles significantly affected the electro-optical
properties of the lattice-patterned LC-polymer composites. This effect is a fundamental characteristic
of flexible displays. The electro-optical properties depend on the size and surface functional groups of
the SiO2 nanoparticles. Compared with untreated pristine SiO2 nanoparticles, which adversely affect
the performance of LC molecules surrounded by polymer walls, SiO2 nanoparticles with surface
functional groups were found to improve the electro-optical properties of the lattice-patterned LC-
polymer composites by increasing the quantity of SiO2 nanoparticles. The surface functional groups of
the SiO2 nanoparticles were closely related to the distribution of SiO2 nanoparticles in the LC-
polymer composites, and they influenced the electro-optical properties of the LC molecules. It is clear
from our work that the introduction of nanoparticles into a lattice-patterned LC-polymer composite
provides a method for controlling and improving the composite's electro-optical properties. This
technique can be used to produce flexible substrates for various flexible electronic devices.
PMID:22222011
318. Proteome analysis of excretory-secretory proteins of Entamoeba histolytica HM1:IMSS via LC-ESI-
MS/MS and LC-MALDI-TOF/TOF.
PubMed
Ujang, Jorim Anak; Kwan, Soon Hong; Ismail, Mohd Nazri; Lim, Boon Huat; Noordin, Rahmah;
Othman, Nurulhasanah
2016-01-01
Excretory-secretory (ES) proteins of E. histolytica are thought to play important roles in the host
invasion, metabolism, and defence. Elucidation of the types and functions of E. histolytica ES proteins
can further our understanding of the disease pathogenesis. Thus, the aim of this study is to use
proteomics approach to better understand the complex ES proteins of the protozoa. E. histolytica ES
proteins were prepared by culturing the trophozoites in protein-free medium. The ES proteins were
identified using two mass spectrometry tools, namely, LC-ESI-MS/MS and LC-MALDI-TOF/TOF.
The identified proteins were then classified according to their biological processes, molecular
functions, and cellular components using the Panther classification system (PantherDB). A
complementary list of 219 proteins was identified; this comprised 201 proteins detected by LC-ESI-
MS/MS and 107 proteins by LC-MALDI-TOF/TOF. Of the 219 proteins, 89 were identified by both
mass-spectrometry systems, while 112 and 18 proteins were detected exclusively by LC-ESI-MS/MS
and LC-MALDI-TOF/TOF respectively. Biological protein functional analysis using PantherDB
showed that 27% of the proteins were involved in metabolic processes. Using molecular functional and
cellular component analyses, 35% of the proteins were found to be involved in catalytic activity, and
21% were associated with the cell parts. This study showed that complementary use of LC-ESI-
MS/MS and LC-MALDI-TOF/TOF has improved the identification of ES proteins. The results have
increased our understanding of the types of proteins excreted/secreted by the amoeba and provided
further evidence of the involvement of ES proteins in intestinal colonisation and evasion of the host
immune system, as well as in encystation and excystation of the parasite.
319. Silver ion chromatography for peak resolution enhancement: Application to the preparative separation
of two sesquiterpenes using online heart-cutting LC-LC technique.
PubMed
Yang, Yang; Zhang, Yongmin; Wei, Chong; Li, Jing; Sun, Wenji
2018-09-01
Silver ion chromatography, utilizing columns packed with silver ions bonded to silica gel, has proved
to be an invaluable technique for the analysis of some positional isomers. In this work, silver ion
chromatography by combination with online heart-cutting LC-LC technique for the preparative
separation of two sesquiterpenes positional isomers from a natural product was investigated. On the
basis of the evaluation that silver ion content impacts on the separation, the laboratory-made silver ion
columns, utilizing silica gel impregnated with 15% silver nitrate as column packing materials, were
used for peak resolution improvement of these two isomers and the preparative separation of them in
heart-cutting LC-LC. The relationship among the maximal sample load, flow rate and peak resolution
in the silver ion column were optimized, and the performance of the silver ion column was compared
with conventional C 18 column and silica gel column. Based on the developed chromatographic
conditions, online heart-cutting LC-LC chromatographic separation system in combination with a
silica gel column and a silver ion column that was applied to preparative separation of these two
isomers from a traditional Chinese medicine, Inula racemosa Hook.f., was established. The results
showed that the online heart-cutting LC-LC technique by combination of a silica gel column and a
silver ion column for the preparative separation of these two positional isomers from this natural plant
was superior to the preparative separation performed on a single-column system with C 18 column or
silica gel column. Copyright Â© 2018 Elsevier B.V. All rights reserved.
320. Determination of Insecticidal Effect (LC50 and LC90) of Organic Fatty Acids Mixture
(C8910+Silicone) Against Aedes aegypti and Aedes albopictus (Diptera: Culicidae).
PubMed
Dunford, James C; Falconer, Aneika; Leite, Laura N; Wirtz, Robert A; Brogdon, William G
2016-05-01
Emerging and re-emerging vector-borne diseases such as chikungunya and dengue and associated
Aedes vectors are expanding their historical ranges; thus, there is a need for the development of novel
insecticides for use in vector control programs. The mosquito toxicity of a novel insecticide and
repellent consisting of medium-chain carbon fatty acids (C8910) was examined. Determination of LC
50 and LC 90 was made against colony-reared Aedes aegypti (L.) and Aedes albopictus (Skuse) using
probit analysis on mortality data generated by Centers for Disease Control and Prevention bottle
bioassays. Six different concentrations of C8910â€‰+â€‰silicone oil yielded an LC 50 of 160.3â€
‰Âµg a.i/bottle (147.6-182.7) and LC 90 of 282.8 (233.2-394.2) in Ae. aegypti; five concentrations
yielded an LC 50 of 125.4 (116.1-137.6) and LC 90 of 192.5 (165.0-278.9) in Ae. albopictus. Further
development of C8910 and similar compounds could provide vector control specialists novel
insecticides for controlling insect disease vectors. Published by Oxford University Press on behalf of
Entomological Society of America 2015. This work is written by US Government employees and is in
the public domain in the US.
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321. The noradrenaline precursor L-DOPS reduces pathology in a mouse model of Alzheimerâ€™s disease
PubMed Central
Kalinin, Sergey; Polak, Paul E.; Lin, Shao Xia; Sakharkar, Amul J.; Pandey, Subhash C.; Feinstein,
Douglas L.
2013-01-01
Damage to noradrenergic neurons in the locus coeruleus (LC) is a hallmark of Alzheimerâ€™s disease
(AD) and may contribute to disease progression. In 5xFAD transgenic mice, which accumulate
amyloid burden at early ages, the LC undergoes stress as evidenced by increased astrocyte activation,
neuronal hypertrophy, reduced levels of LC-enriched messenger RNAs (mRNAs), and increased
inflammatory gene expression. Central nervous system (CNS) noradrenaline (NA) levels in 5-month-
old male 5xFAD mice were increased using the NA precursor L-threo-3,4-dihydroxyphenylserine (L-
DOPS). After 1 month, L-DOPS treatment improved learning in the Morris water maze test compared
with vehicle-treated mice. L-DOPS increased CNS NA levels, and average latency times in the water
maze test were inversely correlated to NA levels. L-DOPS reduced astrocyte activation and
Thioflavin-S staining; increased mRNA levels of neprilysin and insulin degrading enzyme, and of
several neurotrophins; and increased brain-derived neurotrophic factor protein levels. These data
demonstrate the presence of LC stress in a robust mouse model of AD, and suggest that raising CNS
NA levels could provide benefit in AD. PMID:21705113
322. The noradrenaline precursor L-DOPS reduces pathology in a mouse model of Alzheimer's disease.
PubMed
Kalinin, Sergey; Polak, Paul E; Lin, Shao Xia; Sakharkar, Amul J; Pandey, Subhash C; Feinstein,
Douglas L
2012-08-01
Damage to noradrenergic neurons in the locus coeruleus (LC) is a hallmark of Alzheimer's disease
(AD) and may contribute to disease progression. In 5xFAD transgenic mice, which accumulate
amyloid burden at early ages, the LC undergoes stress as evidenced by increased astrocyte activation,
neuronal hypertrophy, reduced levels of LC-enriched messenger RNAs (mRNAs), and increased
inflammatory gene expression. Central nervous system (CNS) noradrenaline (NA) levels in 5-month-
old male 5xFAD mice were increased using the NA precursor L-threo-3,4-dihydroxyphenylserine (L-
DOPS). After 1 month, L-DOPS treatment improved learning in the Morris water maze test compared
with vehicle-treated mice. L-DOPS increased CNS NA levels, and average latency times in the water
maze test were inversely correlated to NA levels. L-DOPS reduced astrocyte activation and
Thioflavin-S staining; increased mRNA levels of neprilysin and insulin degrading enzyme, and of
several neurotrophins; and increased brain-derived neurotrophic factor protein levels. These data
demonstrate the presence of LC stress in a robust mouse model of AD, and suggest that raising CNS
NA levels could provide benefit in AD. Copyright Â© 2012 Elsevier Inc. All rights reserved.
323. Short-Term Effects of Chewing on Task Performance and Task-Induced Mydriasis: Trigeminal
Influence on the Arousal Systems
PubMed Central
Tramonti Fantozzi, Maria Paola; De Cicco, Vincenzo; Barresi, Massimo; Cataldo, Enrico; Faraguna,
Ugo; Bruschini, Luca; Manzoni, Diego
2017-01-01
Trigeminal input to the ascending activating system is important for the maintenance of arousal and
may affect the discharge of the noradrenergic neurons of the locus coeruleus (LC), whose activity
influences both vigilance state and pupil size, inducing mydriasis. For this reason, pupil size evaluation
is now considered an indicator of LC activity. Since mastication activates trigeminal afferent neurons,
the aims of the present study, conducted on healthy adult participants, were to investigate whether
chewing a bolus of different hardness may: (1) differentially affect the performance on a cognitive task
(consisting in the retrieval of specific target numbers within numerical matrices) and (2) increase the
dilatation of the pupil (mydriasis) induced by a haptic task, suggesting a change in LC activation.
Results show that chewing significantly increased both the velocity of number retrieval (without
affecting the number of errors) and the mydriasis associated with the haptic task, whereas simple task
repetition did not modify either retrieval or mydriasis. Handgrip exercise, instead, significantly
decreased both parameters. Effects were significantly stronger and longer lasting when subjects
chewed hard pellets. Finally, chewing-induced improvements in performance and changes in mydriasis
were positively correlated, which suggests that trigeminal signals enhanced by chewing may boost the
cognitive performance by increasing LC activity. PMID:28848404
324. An analysis of the effects of acute and chronic fluoxetine on extracellular norepinephrine in the rat
hippocampus during stress.
PubMed
Page, M E; Abercrombie, E D
1997-06-01
The locus coeruleus (LC) noradrenergic system is activated by a range of arousing and stressful
stimuli. The serotonergic inputs to this structure have been shown to attenuate LC activation under
some conditions. The present study examined the effect of fluoxetine, a selective serotonin reuptake
inhibitor (SSRI) known to be a clinically effective antidepressant, on basal and stress-induced
norepinephrine (NE) release. Basal and stress-induced NE efflux in the rat hippocampus were assessed
using in vivo microdialysis techniques. The effect of a 30 minute tailpinch stressor on extracellular
concentration of NE was compared in rats treated with fluoxetine either once prior to tailpinch or twice
daily for 14 days and, respectively, in unhandled controls and vehicle-treated control animals. A single
fluoxetine injection prior to tailpinch did not significantly alter the tailpinch-induced increase of
extracellular NE as compared to naive controls. However, there was an enhanced NE response to
tailpinch in chronic fluoxetine versus chronic vehicle-treated control rats. Thus, acute blockade of 5-
HT uptake by fluoxetine does not affect NE release in response to tailpinch stress. Chronic fluoxetine
administration, however, results in a potentiated evoked response of the LC-NE system. One action of
chronic fluoxetine, which may relate to therapeutic efficacy, is an increase in responsivity of LC
neurons.
325. STS-30 Atlantis, OV-104, on the mobile launcher platform heads to KSC LC pad
1989-01-01
STS-30 Atlantis, Orbiter Vehicle (OV) 104, riding atop the mobile launcher platform and the crawler
transporter approaches Kennedy Space Center (KSC) Launch Complex (LC) pad 39B. This backlit
view highlights OV-104's profile, the external tank (ET), and one of the two solid rocket boosters
(SRBs) as it moves up LC pad 39B incline.
326. Simultaneous Quantitation of Atenolol, Metoprolol, and Propranolol in Biological Matrices Via
LC/MS
2005-05-01
Simultaneous Quantitation of Atenolol, Metoprolol , and Propranolol in Biological Matrices Via

LC/MS Robert D. Johnson Russell J. Lewis Civil...authorized 1 SIMULTANEOUS QUANTITATION
OF ATENOLOL, METOPROLOL , AND PROPRANOLOL IN BIOLOGICAL MATRICES VIA
LC/MS INTRODUCTION The Federal Aviation...detect beta-blocker compounds such as atenolol,
metoprolol , or propranolol in the submitted biological samples. In forensic toxicol- ogy laboratories
327. STS-26 Discovery, Orbiter Vehicle (OV) 103, at KSC LC pad 39B
NASA Image and Video Library
1988-07-04
S88-42101 (15 July 1988) --- STS-26 Discovery, Orbiter Vehicle (OV) 103, awaits further processing
at Kennedy Space Center (KSC) launch complex (LC) pad 39B. OV-103 arrived at LC pad 39B after a
six-hour journey from the vehicle assembly building (VAB). The rotating service structure is retracted.
328. LC-lens array with light field algorithm for 3D biomedical applications
Huang, Yi-Pai; Hsieh, Po-Yuan; Hassanfiroozi, Amir; Martinez, Manuel; Javidi, Bahram; Chu, Chao-
Yu; Hsuan, Yun; Chu, Wen-Chun
2016-03-01
In this paper, liquid crystal lens (LC-lens) array was utilized in 3D bio-medical applications including
3D endoscope and light field microscope. Comparing with conventional plastic lens array, which was
usually placed in 3D endoscope or light field microscope system to record image disparity, our LC-
lens array has higher flexibility of electrically changing its focal length. By using LC-lens array, the
working distance and image quality of 3D endoscope and microscope could be enhanced. Furthermore,
the 2D/3D switching ability could be achieved if we turn off/on the electrical power on LClens array.
In 3D endoscope case, a hexagonal micro LC-lens array with 350um diameter was placed at the front
end of a 1mm diameter endoscope. With applying electric field on LC-lens array, the 3D specimen
would be recorded as from seven micro-cameras with different disparity. We could calculate 3D
construction of specimen with those micro images. In the other hand, if we turn off the electric field on
LC-lens array, the conventional high resolution 2D endoscope image would be recorded. In light field
microscope case, the LC-lens array was placed in front of the CMOS sensor. The main purpose of LC-
lens array is to extend the refocusing distance of light field microscope, which is usually very narrow
in focused light field microscope system, by montaging many light field images sequentially focusing
on different depth. With adjusting focal length of LC-lens array from 2.4mm to 2.9mm, the refocusing
distance was extended from 1mm to 11.3mm. Moreover, we could use a LC wedge to electrically shift
the optics axis and increase the resolution of light field.
329. Simulating multiprimary LCDs on standard tri-stimulus LC displays
Lebowsky, Fritz; Vonneilich, Katrin; Bonse, Thomas
2008-01-01
Large-scale, direct view TV screens, in particular those based on liquid crystal technology, are
beginning to use subpixel structures with more than three subpixels to implement a multi-primary
display with up to six primaries. Since their input color space is likely to remain tri-stimulus RGB we
first focus on some fundamental constraints. Among them, we elaborate simplified gamut mapping
architectures as well as color filter geometry, transparency, and chromaticity coordinates in color
space. Based on a 'display centric' RGB color space tetrahedrization combined with linear interpolation
we describe a simulation framework which enables optimization for up to 7 primaries. We evaluated
the performance through mapping the multi-primary design back onto a RGB LC display gamut
without building a prototype multi-primary display. As long as we kept the RGB equivalent output
signal within the display gamut we could analyze all desirable multi-primary configurations with
regard to colorimetric variance and visually perceived quality. Not only does our simulation tool
enable us to verify a novel concept it also demonstrates how carefully one needs to design a
multiprimary display for LCD TV applications.
330. LC-MS-based quantification method for Achyranthes root saponins.
PubMed
Kawahara, Yuki; Hoshino, Tatsuro; Morimoto, Hidetaka; Shinizu, Tomofumi; Narukawa, Yuji;
Fuchino, Hiroyuki; Kawahara, Nobuo; Kiuchi, Fumiyuki
2016-01-01
A liquid chromatography mass spectrometry (LC-MS) method was developed for simultaneous
quantitative analysis of Achyranthes root saponins: chikusetsusaponins IVa (1) and V (2),
achyranthosides B (3), C (4), D (5), E (6), and G (7), sulfachyranthosides B (8) and D (9), and
betavulgarosides II (10) and IV (11). Satisfactory separation of the saponins was achieved with the use
of a volatile ion-pair reagent (dihexyl ammonium acetate) on a phenyl-hexylated silica gel column, and
the amounts of saponins extracted under three different conditions were determined. When
Achyranthes root was extracted with water at room temperature, achyranthosides B (3) and D (5) were
the major saponins, and smaller amounts of other saponins (4, 6-11) were present. However, the
amounts of chikusetsusaponins (1 and 2) were negligible. Under the condition to make a standard
decoction of a Kampo formula, the major saponins were achyranthosides B (3), C (4), and D (5), and
small amounts of chikusetsusaponins IVa (1) and V (2) appeared, whereas prolonged heating largely
increased the amounts of chikusetsusaponins. This method can be used for quality control of
Achyranthes root.
331. Measurement of "total" microcystins using the MMPB/LC/MS ...
The detection and quantification of microcystins, a family of toxins associated with harmful algal
blooms, is complicated by their structural diversity and a lack of commercially available analytical
standards for method development. As a result, most detection methods have focused on either a
subset of microcystin congeners, as in US EPA Method 544, or on techniques which are sensitive to
structural features common to most microcystins, as in the anti-ADDA ELISA method. A recent
development has been the use of 2-methyl-3-methoxy-4-phenylbutyric acid (MMPB), which is
produced by chemical oxidation the ADDA moiety in most microcystin congeners, as a proxy for the
sum of congeners present. Conditions for the MMPB derivatization were evaluated and applied to
water samples obtained from various HAB impacted surface waters, and results were compared with
congener-based LC/MS/MS and ELISA methods. The detection and quantification of microcystins, a
family of toxins associated with harmful algal blooms, is complicated by their structural diversity and
a lack of commercially available analytical standards for method development. As a result, most
detection methods have focused on either a subset of microcystin congeners, as in US EPA Method
544, or on techniques which are sensitive to structural features common to most microcystins, as in the
anti-ADDA ELISA method. A recent development has been the use of 2-methyl-3-methoxy-4-
phenylbutyric acid (MMPB), which is produce
332. Neural substrates linking balance control and anxiety
Balaban, Carey D.
2002-01-01
This communication provides an update of our understanding of the neurological bases for the close
association between balance control and anxiety. New data suggest that a vestibulo-recipient region of
the parabrachial nucleus (PBN) contains cells that respond to body rotation and position relative to
gravity. The PBN, with its reciprocal relationships with the extended central amygdaloid nucleus,
infralimbic cortex, and hypothalamus, appears to be an important node in a primary network that
processes convergent vestibular, somatic, and visceral information processing to mediate avoidance
conditioning, anxiety, and conditioned fear responses. Noradrenergic and serotonergic projections to
the vestibular nuclei also have parallel connections with anxiety pathways. The coeruleo-vestibular
pathway originates in caudal locus coeruleus (LC) and provides regionally specialized noradrenergic
input to the vestibular nuclei, which likely mediate effects of alerting and vigilance on the sensitivity
of vestibulo-motor circuits. Both serotonergic and nonserotonergic pathways from the dorsal raphe
nucleus and the nucleus raphe obscurus also project differentially to the vestibular nuclei, and 5-
HT(2A) receptors are expressed in amygdaloid and cortical targets of the PBN. It is proposed that the
dorsal raphe nucleus pathway contributes to both (a) a tradeoff between motor and sensory
(information gathering) aspects of responses to self-motion and (b) a calibration of the sensitivity of
affective responses to aversive aspects of motion. This updated neurologic model continues to be a
synthetic schema for investigating the neurological and neurochemical bases for comorbidity of
balance disorders and anxiety disorders.
333. Characterization of a mixture of lobster digestive cysteine proteinases by ionspray mass spectrometry
and tryptic mapping with LC--MS and LC--MS--MS
Thibault, P.; Pleasance, S.; Laycock, M. V.; Mackay, R. M.; Boyd, R. K.
1991-12-01
An inseparable mixture of two cysteine proteinases, isolated from the digestive tract of the American
lobster, was investigated by ionspray mass spectrometry (ISP-MS), using a combination of infusion of
intact proteins with on-line liquid chromatography--mass spectrometry (LC--MS) and LC--MS--MS
analyses of tryptic digests. These data were interpreted by comparisons with predictions from results
of molecular cloning of cysteine-proteinase-encoding messenger RNA sequences previously isolated
from the lobster hepatopancreas. Investigations of the numbers of free thiol groups and of disulfide
bonds were made by measuring the molecular weights of the alkylated proteins with and without prior
reduction of disulfide bonds, and comparison with the corresponding data for the native proteins.
Identification of tyrptic fragment peptides containing cysteine residues was facilitated by comparing
LC--MS analyses of tryptic digests of denatured and of denatured and alkylated proteins, since such
tryptic peptides are subject to shifts in both mass and retention time upon reduction and alkylation.
Confirmation of amino acid sequences was obtained from fragment ion spectra of each tryptic peptide
(alkylated or not) as it eluted from the column. Acquisition of such on-line LC--MS data was possible
through use of the entire effluent from a standard 1 mm high performance liquid chromatography
(HPLC) column by an IonsSprayÂ® LC--MS interface (pneumatically assisted electrospray).
334. LC-MS metabolic profiling of Arabidopsis thaliana plant leaves and cell cultures: optimization of pre-
LC-MS procedure parameters.
PubMed
t'Kindt, Ruben; De Veylder, Lieven; Storme, Michael; Deforce, Dieter; Van Bocxlaer, Jan
2008-08-01
This study treats the optimization of methods for homogenizing Arabidopsis thaliana plant leaves as
well as cell cultures, and extracting their metabolites for metabolomics analysis by conventional liquid
chromatography electrospray ionization mass spectrometry (LC-ESI/MS). Absolute recovery, process
efficiency and procedure repeatability have been compared between different pre-LC-MS
homogenization/extraction procedures through the use of samples fortified before extraction with a
range of representative metabolites. Hereby, the magnitude of the matrix effect observed in the ensuing
LC-MS based metabolomics analysis was evaluated. Based on relative recovery and repeatability of
key metabolites, comprehensiveness of extraction (number of m/z-retention time pairs) and clean-up
potential of the approach (minimum matrix effects), the most appropriate sample pre-treatment was
adopted. It combines liquid nitrogen homogenization for plant leaves with thermomixer based
extraction using MeOH/H(2)O 80/20. As such, an efficient and highly reproducible LC-MS plant
metabolomics set-up is achieved, as illustrated by the obtained results for both LC-MS (8.88%+/-5.16
versus 7.05%+/-4.45) and technical variability (12.53%+/-11.21 versus 9.31%+/-6.65) data in a
comparative investigation of A. thaliana plant leaves and cell cultures, respectively.
335. [Establishment of RAW264.7 cell strain stably expressing RFP-GFP-LC3].
PubMed
Wang, Wan; Zhang, Qing; Zhao, Runpeng; Xu, Xuewei; Xing, Yingru; Zhang, Rongbo; Wu, Jing; Hu,
Dong
2015-09-01
To establish murine macrophage RAW264.7 cell strain with stable expression of red fluorescent
protein-green fluorescent protein-microtubule associated protein light chain 3 (RFP-GFP-LC3). A
lentiviral vector containing RFP-GFP-LC3 gene was constructed and then packaged in HEK293T cells
with the packaging plasmids. The viral supernatant was collected to infect RAW264.7 cells. The
RAW264.7 cell strain with stable expression of RFP-GFP-LC3 was screened with puromycin and
analyzed with flow cytometry and fluorescent microscopy for infection efficiency. The number of
RFP-GFP-LC3 puncta was observed using florescence microscopy following starvation treatment. The
recombinant lentivirus pLV-CMV-RFP-GFP-LC3 was successfully constructed. The RAW264.7 cells
with stable expression of RFP-GFP-LC3 were obtained by viral infection and puromycin screening.
Fluorescent microscopy and flow cytometry demonstrated the expression rates of RFP and GFP
reached to 100%. The number of autophagic puncta significantly increased after starvation treatment.
The RAW264.7 cell strain with stable expression of RFP-GFP-LC3 has been successfully constructed,
which provides a reliable cellular platform for autophagy research.
336. Immunohistochemical assessment of ATG7, LC3, and p62 in ameloblastomas.
PubMed
Okada, Miwa; Oikawa, Mariko; Miki, Yasuhiro; Shimizu, Yoshinaka; Echigo, Seishi; Takahashi,
Tetsu; Kumamoto, Hiroyuki
2014-09-01
To investigate the roles of autophagy in tumorigenesis, cytodifferentiation, and prognosis of

odontogenic tumors, we analyzed the immunohistochemical expression of ATG7, LC3, and p62 in
odontogenic tissues. Tissue specimens of nine dental follicles and 69 ameloblastomas were
immunohistochemically examined with antibodies against ATG7, LC3, and p62.
Immunohistochemical reactivity for ATG7, LC3, and p62 was detected in many odontogenic epithelial
cells and several endothelial cells and fibroblasts in dental follicles and ameloblastomas. ATG7
reactivity in ameloblatomas was significantly higher than that in dental follicles. Expression of ATG7,
LC3, and p62 was found markedly in neoplastic cells near the basement membrane rather than central
polyhedral cells in ameloblastomas. Reactivity for these molecules was significantly higher in
unicystic ameloblastomas than in solid ameloblastomas. Granular cells in granular cell
ameloblastomas showed obvious reactivity for the autophagy- related molecules, and LC3 reactivity in
granular cell ameloblastomas was significantly higher than in other ameloblastoma variations.
Recurrent ameloblastomas showed significantly lower reactivity of LC3 and p62 than primary
ameloblastomas. Expression of ATG7, LC3, and p62 in dental follicles and ameloblastomas suggests
that autophagy regulation might be affected by microenvironment alterations during tumorigenesis.
The molecular machinery for autophagy is possibly involved in tissue architecture, neoplastic cell
differentiation, and prognosis of the benign epithelial odontogenic tumor. Â© 2014 John Wiley & Sons
A/S. Published by John Wiley & Sons Ltd.
337. Dissecting the involvement of LC3B and GATE-16 in p62 recruitment into autophagosomes.
PubMed
Shvets, Elena; Abada, Adi; Weidberg, Hilla; Elazar, Zvulun
2011-07-01
Autophagy is a major intracellular trafficking pathway that delivers proteins and organelles from the
cytoplasm into lysosomes for consequential degradation and recycling. Mammalian Atg8s are key
autophagic factors that undergo a unique ubiquitin-like conjugation to the lipid phase of the
autophagosomal membrane. In addition to their activity in autophagosome formation, several Atg8s
directly bind p62/SQSTM1. Here we show that LC3 and GATE-16 differ in their mode of p62 binding.
While the soluble form of both LC3 and GATE-16 bind p62, only the lipidated form of LC3 is directly
involved in p62 recruitment into autophagosomes. Moreover, by utilizing chimeras of LC3 and GATE-
16 where their N-terminus was swapped, we determined the regions responsible for this differential
binding. Accordingly, we found that the chimera of GATE-16 containing the LC3 N-terminal region
acts similarly to wild-type LC3 in recruiting p62 into autophagosomes. We therefore propose that LC3
is responsible for the final stages of p62 incorporation into autophagosomes, a process selectively
mediated by its N-terminus.
338. Chlorosilane acute inhalation toxicity and development of an LC50 prediction model.
PubMed
Jean, Paul A; Gallavan, Robert H; Kolesar, Gary B; Siddiqui, Waheed H; Oxley, Jon A; Meeks, Robert
G
2006-07-01
The acute inhalation toxicity of 10 chlorosilanes was investigated in Fischer 344 rats using a 1-h
whole-body vapor inhalation exposure and a 14-day recovery period. The median lethal concentration
(LC50(1)) for each material was calculated from the nominal exposure concentrations and mortality.
Experimentally derived LC50(1) values for monochlorosilanes (4257-4478 ppm) were greater than
those for dichlorosilanes (1785-2092 ppm), which were greater than those for trichlorosilanes (1257-
1611 ppm). Apparent was a strong structure-activity relationship (r2 = .97) between chlorine content
and LC50(1) value. Estimated LC50(1) values for mono-, di-, and trichlorosilanes were determined to
be 3262, 1639, and 1066 ppm, respectively, utilizing this relationship and the lower limit of the 95%
prediction interval. The LC50(1) values determined in this series of studies were greater than that
reported for hydrogen chloride (3124 ppm), when expressed on a chlorine equivalence basis (3570-
5248 ppm), demonstrating that the acute toxicity of these chlorosilanes is similar to or less than that
for hydrogen chloride. The good correlation between chlorine content and LC50(1) provides a sound
basis for estimation of LC50(1) for chlorosilanes not already evaluated. The use of structure-activity
relationships is consistent with the chemical industry and federal agency initiatives to reduce, refine,
and/or replace the use of animals in testing without compromising the quality of health and safety
assessments.
339. The transcription factor Lc-Maf participates in Col27a1 regulation during chondrocyte maturation
SciTech Connect
Mayo, Jaime L.; Holden, Devin N.; Barrow, Jeffery R.
2009-08-01
The transcription factor Lc-Maf, which is a splice variant of c-Maf, is expressed in cartilage
undergoing endochondral ossification and participates in the regulation of type II collagen through a
cartilage-specific Col2a1 enhancer element. Type XXVII and type XI collagens are also expressed in
cartilage during endochondral ossification, and so enhancer/reporter assays were used to determine
whether Lc-Maf could regulate cartilage-specific enhancers from the Col27a1 and Col11a2 genes. The
Col27a1 enhancer was upregulated over 4-fold by Lc-Maf, while the Col11a2 enhancer was
downregulated slightly. To confirm the results of these reporter assays, rat chondrosarcoma (RCS)
cells were transiently transfected with anmoreÂ Â» Lc-Maf expression plasmid, and quantitative RT-
PCR was performed to measure the expression of endogenous Col27a1 and Col11a2 genes.
Endogenous Col27a1 was upregulated 6-fold by Lc-Maf overexpression, while endogenous Col11a2
was unchanged. Finally, in situ hybridization and immunohistochemistry were performed in the radius
and ulna of embryonic day 17 mouse forelimbs undergoing endochondral ossification. Results
demonstrated that Lc-Maf and Col27a1 mRNAs are coexpressed in proliferating and prehypertrophic
regions, as would be predicted if Lc-Maf regulates Col27a1 expression. Type XXVII collagen protein
was also most abundant in prehypertrophic and proliferating chondrocytes. Others have shown that
mice that are null for Lc-Maf and c-Maf have expanded hypertrophic regions with reduced ossification
and delayed vascularization. Separate studies have indicated that Col27a1 may serve as a scaffold for
ossification and vascularization. The work presented here suggests that Lc-Maf may affect the process
of endochondral ossification by participating in the regulation of Col27a1 expression.Â«Â less
340. Expression of Anthocyanins and Proanthocyanidins after Transformation of Alfalfa with Maize Lc12
PubMed Central
Ray, Heather; Yu, Min; Auser, Patricia; Blahut-Beatty, Laureen; McKersie, Brian; Bowley, Steve;
Westcott, Neil; Coulman, Bruce; Lloyd, Alan; Gruber, Margaret Y.
2003-01-01
Three anthocyanin regulatory genes of maize (Zea mays; Lc, B-Peru, and C1) were introduced into
alfalfa (Medicago sativa) in a strategy designed to stimulate the flavonoid pathway and alter the
composition of flavonoids produced in forage. Lc constructs included a full-length gene and a gene
with a shortened 5â€²-untranslated region. Lc RNA was strongly expressed in Lc transgenic alfalfa
foliage, but accumulation of red-purple anthocyanin was observed only under conditions of high light
intensity or low temperature. These stress conditions induced chalcone synthase and flavanone 3-
hydroxylase expression in Lc transgenic alfalfa foliage compared with non-transformed plants.
Genotypes containing the Lc transgene construct with a full-length 5â€²-untranslated region responded
more quickly to stress conditions and with a more extreme phenotype. High-performance liquid
chromatography analysis of field-grown tissue indicated that flavone content was reduced in forage of
the Lc transgenic plants. Leucocyanidin reductase, the enzyme that controls entry of metabolites into
the proanthocyanidin pathway, was activated both in foliage and in developing seeds of the Lc
transgenic alfalfa genotypes. Proanthocyanidin polymer was accumulated in the forage, but (+)-
catechin monomers were not detected. B-Peru transgenic and C1 transgenic populations displayed no
visible phenotypic changes, although these transgenes were expressed at detectable levels. These
results support the emerging picture of Lc transgene-specific patterns of expression in different
recipient species. These results demonstrate that proanthocyanidin biosynthesis can be stimulated in
alfalfa forage using an myc-like transgene, and they pave the way for the development of high quality,
bloat-safe cultivars with ruminal protein bypass. PMID:12857826
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341. Two fatal intoxication cases with imidacloprid: LC/MS analysis.
PubMed
ProenÃ§a, Paula; Teixeira, Helena; Castanheira, Fernando; Pinheiro, JoÃ£o; Monsanto, Paula V;
Marques, Estela P; Vieira, Duarte Nuno
2005-10-04
Imidacloprid [1-(6-chloro-3pyridylmethyl)-N-nitroimidazolidin-2-ylideneamine] is a new and potent

nitromethylene insecticide with high insecticidal activity at very low application rates. It is the first
highly effective insecticide that, like nicotine, acts on the nervous system, causing blockage of
postsynaptic nicotinergic acetylcholine receptors. Two fatal cases with this insecticide in two male
individuals, of 33 and 66 years old, are presented. An LC/MS with electrospray method for measuring
imidacloprid and its metabolites in post-mortem samples is described. In the chromatographic
separation, a reverse-phase column XTerra MS C18 (2.1mm i.d.x 150 mm, 5 microm) was used and
the mobile phase composed with acetonitrile and 0.1% formic acid (15:85), at a 0.25 mL/min flow
rate. Samples were prepared with a liquid-liquid extraction procedure with dichloromethane.
Calibration curves for imidacloprid in blood and urine samples were linear from 0.2 to 15 microg/mL.
The mean recovery was 86% with a coefficient of variation of +/-5.9%. The detection limit was 0.002
microg/mL. Quantitative results were obtained for all post-mortem matrices available of the two fatal
cases: blood, urine, stomach contents, lung, liver and kidney. The imidacloprid blood concentrations
found in two-cases were 12.5 and 2.05 microg/mL. The authors validated a method to detect and
quantify imidacloprid in post-mortem samples, and to our knowledge for the first time a post-mortem
tissue distribution was performed on various samples for this insecticide.
342. Angiotensin II AT1 receptors mediate neuronal sensitization and sustained blood pressure response
induced by a single injection of amphetamine.
PubMed
Marchese, N A; Paz, M C; Caeiro, X; Dadam, F M; Baiardi, G; Perez, M F; Bregonzio, C
2017-01-06
A single exposure to amphetamine induces neurochemical sensitization in striatal areas. The

neuropeptide angiotensin II, through AT 1 receptors (AT 1 -R) activation, is involved in these
responses. However, amphetamine-induced alterations can be extended to extra-striatal areas involved
in blood pressure control and their physiological outcomes. Our aim for the present study was to
analyze the possible role for AT 1 -R in these events using a two-injection protocol and to further
characterize the proposed AT 1 -R antagonism protocol. Central effect of orally administered AT 1 -R
blocker (Candesartan, 3mg/kg p.o.Ã—5days) in male Wistar rats was analyzed by spontaneous activity
of neurons within locus coeruleus. In another group of animals pretreated with the AT 1 -R blocker or
vehicle, sensitization was achieved by a single administration of amphetamine (5mg/kg i.p. - day 6)
followed by a 3-week period off drug. On day 27, after receiving an amphetamine challenge (0.5mg/kg
i.p.), we evaluated: (1) the sensitized c-Fos expression in locus coeruleus (LC), nucleus of the solitary
tract (NTS), caudal ventrolateral medulla (A1) and central amygdala (CeAmy); and (2) the blood
pressure response. AT 1 -R blockade decreased LC neurons' spontaneous firing rate. Moreover,
sensitized c-Fos immunoreactivity in TH+neurons was found in LC and NTS; and both responses were
blunted by the AT 1 -R blocker pretreatment. Meanwhile, no differences were found neither in CeAmy
nor A1. Sensitized blood pressure response was observed as sustained changes in mean arterial
pressure and was effectively prevented by AT 1 -R blockade. Our results extend AT 1 -R role in
amphetamine-induced sensitization over noradrenergic nuclei and their cardiovascular output.
Copyright Â© 2016 IBRO. Published by Elsevier Ltd. All rights reserved.
343. Stability of omega-3 LC-PUFA-rich photoautotrophic microalgal oils compared to commercially

available omega-3 LC-PUFA oils.
PubMed
Ryckebosch, Eline; Bruneel, Charlotte; Termote-Verhalle, Romina; Lemahieu, Charlotte; Muylaert,

Koenraad; Van Durme, Jim; Goiris, Koen; Foubert, Imogen
2013-10-23
Microalgae are the primary producers of omega-3 LC-PUFA, which are known for their health
benefits. Their oil may thus be a potential alternative for fish oil. However, oxidative and hydrolytic
stability of omega-3 LC-PUFA oils are important parameters. The purpose of this work was therefore
to evaluate these parameters in oils from photoautotrophic microalgae (Isochrysis, Phaeodactylum,
Nannochloropsis gaditana, and Nannochloropsis sp.) obtained with hexane/isopropanol (HI) and
hexane (H) and compare them with commercial omega-3 LC-PUFA oils. When the results of both the
primary and secondary oxidation parameters were put together, it was clear that fish, tuna, and
heterotrophic microalgae oil are the least oxidatively stable oils, whereas krill oil and the microalgae
oils performed better. The microalgal HI oils were shown to be more oxidatively stable than the
microalgal H oils. The hydrolytic stability was shown not to be a problem during the storage of any of
the oils.
344. Analytical determination of virginiamycin drug residues in edible porcine tissues by LC-MS with
confirmation by LC-MS/MS.
PubMed
Boison, Joe; Lee, Stephen; Gedir, Ron
2009-01-01
A liquid chromatographic-mass spectrometric (LC-MS) method was developed and validated for the
determination and confirmation of virginiamycin (VMY) M1 residues in porcine liver, kidney, and
muscle tissues at concentrations > or =2 ng/g. Porcine liver, kidney, or muscle tissue is homogenized
with methanol-acetonitrile. After centrifugation, the supernatant is diluted with phosphate buffer and
cleaned up on a C18 solid-phase extraction cartridge. VMY in the eluate is partitioned into chloroform
and the aqueous upper layer is removed by aspiration. After evaporating the chloroform in the residual
mixture to dryness, the dried extract is reconstituted in mobile phase and VMY is quantified by LC-
MS. Any samples eliciting quantifiable levels of VMY M1 (i.e., at concentrations > or =2 ng/g) are
subjected to confirmatory analysis by LC-MSIMS. VMY S1, a minor component of the VMY
complex, is monitored but not quantified or confirmed.
345. LC3 fluorescent puncta in autophagosomes or in protein aggregates can be distinguished by FRAP
analysis in living cells
PubMed Central
Wang, Liang; Chen, Min; Yang, Jie; Zhang, Zhihong
2013-01-01
LC3 is a marker protein that is involved in the formation of autophagosomes and autolysosomes,
which are usually characterized and monitored by fluorescence microscopy using fluorescent protein-
tagged LC3 probes (FP-LC3). FP-LC3 and even endogenous LC3 can also be incorporated into
intracellular protein aggregates in an autophagy-independent manner. However, the dynamic process
of LC3 associated with autophagosomes and autolysosomes or protein aggregates in living cells
remains unclear. Here, we explored the dynamic properties of the two types of FP-LC3-containing
puncta using fluorescence microscopy techniques, including fluorescence recovery after
photobleaching (FRAP) and fluorescence resonance energy transfer (FRET). The FRAP data revealed
that the fluorescent signals of FP-LC3 attached to phagophores or in mature autolysosomes showed
either minimal or no recovery after photobleaching, indicating that the dissociation of LC3 from the
autophagosome membranes may be very slow. In contrast, FP-LC3 in the protein aggregates exhibited
nearly complete recovery (more than 80%) and rapid kinetics of association and dissociation (half-time
< 1 sec), indicating a rapid exchange occurs between the aggregates and cytoplasmic pool, which is
mainly due to the transient interaction of LC3 and SQSTM1/p62. Based on the distinct dynamic
properties of FP-LC3 in the two types of punctate structures, we provide a convenient and useful
FRAP approach to distinguish autophagosomes from LC3-involved protein aggregates in living cells.
Using this approach, we find the FP-LC3 puncta that adjacently localized to the phagophore marker
ATG16L1 were protein aggregate-associated LC3 puncta, which exhibited different kinetics compared
with that of autophagic structures. PMID:23482084
346. Microfluidic LC Device with Orthogonal Sample Extraction for On-Chip MALDI-MS Detection
PubMed Central
Lazar, Iulia M.; Kabulski, Jarod L.
2013-01-01
A microfluidic device that enables on-chip matrix assisted laser desorption ionization-mass
spectrometry (MALDI-MS) detection for liquid chromatography (LC) separations is described. The
device comprises an array of functional elements to carry out LC separations, integrates a novel
microchip-MS interface to facilitate the orthogonal transposition of the microfluidic LC channel into
an array of reservoirs, and enables sensitive MALDI-MS detection directly from the chip. Essentially,
the device provides a snapshot MALDI-MS map of the content of the separation channel present on
the chip. The detection of proteins with biomarker potential from MCF10A breast epithelial cell
extracts, and detection limits in the low fmol range, are demonstrated. In addition, the design of the
novel LC-MALDI-MS chip entices the promotion of a new concept for performing sample separations
within the limited time-frame that accompanies the dead-volume of a separation channel.
PMID:23592150
347. 9. Photocopy of engineering drawing. LC17 LOX STORAGE TANK PAD: ...
Survey
9. Photocopy of engineering drawing. LC-17 LOX STORAGE TANK PAD: ELECTRICAL,

OCTOBER 1966. - Cape Canaveral Air Station, Launch Complex 17, Facility 28405, East end of
Lighthouse Road, Cape Canaveral, Brevard County, FL
348. 41. Photocopy of engineering drawing. LC17B LONG TANK DELTA UPBUILD ...
Survey
41. Photocopy of engineering drawing. LC-17B LONG TANK DELTA UPBUILD UMBILICAL
MAST: ELEVATIONS AND DETAILS, MECHANICAL, APRIL 1969 - Cape Canaveral Air Station,
Launch Complex 17, Facility 28402, East end of Lighthouse Road, Cape Canaveral, Brevard County,
FL
349. 5. Photocopy of engineering drawing. LC17 HIGH PRESSURE GAS INSTALLATION: ...
Survey
5. Photocopy of engineering drawing. LC-17 HIGH PRESSURE GAS INSTALLATION: PLANS

AND DETAILS (CHANGE HOUSE)-STRUCTURAL, APRIL 1969. - Cape Canaveral Air Station,
Launch Complex 17, Facility 28409, East end of Lighthouse Road, Cape Canaveral, Brevard County,
FL
350. 6. Photocopy of engineering drawing. LC17 HIGH PRESSURE GAS INSTALLATION: ...
Survey
6. Photocopy of engineering drawing. LC-17 HIGH PRESSURE GAS INSTALLATION: PLANS,

SCHEDULES AND ELEVATIONS (CHANGE HOUSE)-ARCHITECTURAL, APRIL 1969. - Cape
Canaveral Air Station, Launch Complex 17, Facility 28409, East end of Lighthouse Road, Cape
Canaveral, Brevard County, FL
351. The clinical impact of recent advances in LC-MS for cancer biomarker discovery and verification.
PubMed
Wang, Hui; Shi, Tujin; Qian, Wei-Jun; Liu, Tao; Kagan, Jacob; Srivastava, Sudhir; Smith, Richard D;
Rodland, Karin D; Camp, David G
2016-01-01
Mass spectrometry (MS) -based proteomics has become an indispensable tool with broad applications
in systems biology and biomedical research. With recent advances in liquid chromatography (LC) and
MS instrumentation, LC-MS is making increasingly significant contributions to clinical applications,
especially in the area of cancer biomarker discovery and verification. To overcome challenges
associated with analyses of clinical samples (for example, a wide dynamic range of protein
concentrations in bodily fluids and the need to perform high throughput and accurate quantification of
candidate biomarker proteins), significant efforts have been devoted to improve the overall
performance of LC-MS-based clinical proteomics platforms. Reviewed here are the recent advances in
LC-MS and its applications in cancer biomarker discovery and quantification, along with the
potentials, limitations and future perspectives.
352. Profiling cytosine oxidation in DNA by LC-MS/MS.
PubMed
Samson-Thibault, Francois; Madugundu, Guru S; Gao, Shanshan; Cadet, Jean; Wagner, J Richard
2012-09-17
Spontaneous and oxidant-induced damage to cytosine is probably the main cause of CG to TA

transition mutations in mammalian genomes. The reaction of hydroxyl radical (Â·OH) and one-
electron oxidants with cytosine derivatives produces numerous oxidation products, which have been
identified in large part by model studies with monomers and short oligonucleotides. Here, we
developed an analytical method based on LC-MS/MS to detect 10 oxidized bases in DNA, including 5
oxidation products of cytosine. The utility of this method is demonstrated by the measurement of base
damage in isolated calf thymus DNA exposed to ionizing radiation in aerated aqueous solutions (0-200
Gy) and to well-known Fenton-like reactions (Fe(2+) or Cu(+) with H(2)O(2) and ascorbate). The
following cytosine modifications were quantified as modified 2'-deoxyribonucleosides upon exposure
of DNA to ionizing radiation in aqueous aerated solution: 5-hydroxyhydantoin (Hyd-Ura) > 5-
hydroxyuracil (5-OHUra) > 5-hydroxycytosine (5-OHCyt) > 5,6-dihydroxy-5,6-dihydrouracil (Ura-
Gly) > 1-carbamoyl-4,5-dihydroxy-2-oxoimidazolidine (Imid-Cyt). The total yield of cytosine
oxidation products was comparable to that of thymine oxidation products (5,6-dihydroxy-5,6-
dihydrothymine (Thy-Gly), 5-hydroxy-5-methylhydantotin (Hyd-Thy), 5-(hydroxymethyl)uracil (5-
HmUra), and 5-formyluracil (5-ForUra)) as well as the yield of 8-oxo-7,8-dihydroguanine (8-oxoGua).
The major oxidation product of cytosine in DNA was Hyd-Ura. In contrast, the formation of Imid-Cyt
was a minor pathway of DNA damage, although it is the major product arising from irradiation of the
monomers, cytosine, and 2'-deoxycytidine. The reaction of Fenton-like reagents with DNA gave a
different distribution of cytosine derived products compared to ionizing radiation, which likely reflects
the reaction of metal ions with intermediate peroxyl radicals or hydroperoxides. The analysis of the
main cytosine oxidation products will help elucidate the complex
353. Application of Generalized Feynman-Hellmann Theorem in Quantization of LC Circuit in Thermo

Bath
Fan, Hong-Yi; Tang, Xu-Bing
For the quantized LC electric circuit, when taking the Joule thermal effect into account, we think that
physical observables should be evaluated in the context of ensemble average. We then use the
generalized Feynman-Hellmann theorem for ensemble average to calculate them, which seems
convenient. Fluctuation of observables in various LC electric circuits in the presence of thermo bath
growing with temperature is exhibited.
354. Exploring on the Sensitivity Changes of the LC Resonance Magnetic Sensors Affected by Superposed
Ringing Signals.
PubMed
Lin, Tingting; Zhou, Kun; Yu, Sijia; Wang, Pengfei; Wan, Ling; Zhao, Jing
2018-04-25
LC resonance magnetic sensors are widely used in low-field nuclear magnetic resonance (LF-NMR)
and surface nuclear magnetic resonance (SNMR) due to their high sensitivity, low cost and simple
design. In magnetically shielded rooms, LC resonance magnetic sensors can exhibit sensitivities at the
fT/√Hz level in the kHz range. However, since the equivalent magnetic field noise of this type of
sensor is greatly affected by the environment, weak signals are often submerged in practical
applications, resulting in relatively low signal-to-noise ratios (SNRs). To determine why noise
increases in unshielded environments, we analysed the noise levels of an LC resonance magnetic
sensor ( L ≠ 0) and a Hall sensor ( L ≈ 0) in different environments. The experiments and simulations
indicated that the superposed ringing of the LC resonance magnetic sensors led to the observed
increase in white noise level caused by environmental interference. Nevertheless, ringing is an inherent
characteristic of LC resonance magnetic sensors. It cannot be eliminated when environmental
interference exists. In response to this problem, we proposed a method that uses matching resistors
with various values to adjust the quality factor Q of the LC resonance magnetic sensor in different
measurement environments to obtain the best sensitivity. The LF-NMR experiment in the laboratory
showed that the SNR is improved significantly when the LC resonance magnetic sensor with the best
sensitivity is selected for signal acquisition in the light of the test environment. (When the matching
resistance is 10 kΩ, the SNR is 3.46 times that of 510 Ω). This study improves LC resonance magnetic
sensors for nuclear magnetic resonance (NMR) detection in a variety of environments.
355. High-Throughput Quantification of GFP-LC3+ Dots by Automated Fluorescence Microscopy.
PubMed
Bravo-San Pedro, J M; Pietrocola, F; Sica, V; Izzo, V; Sauvat, A; Kepp, O; Maiuri, M C; Kroemer, G;

Galluzzi, L
2017-01-01
Macroautophagy is a specific variant of autophagy that involves a dedicated double-membraned

organelle commonly known as autophagosome. Various methods have been developed to quantify the
size of the autophagosomal compartment, which is an indirect indicator of macroautophagic responses,
based on the peculiar ability of microtubule-associated protein 1 light chain 3 beta (MAP1LC3B; best
known as LC3) to accumulate in forming autophagosomes upon maturation. One particularly
convenient method to monitor the accumulation of mature LC3 within autophagosomes relies on a
green fluorescent protein (GFP)-tagged variant of this protein and fluorescence microscopy. In
physiological conditions, cells transfected temporarily or stably with a GFP-LC3-encoding construct
exhibit a diffuse green fluorescence over the cytoplasm and nucleus. Conversely, in response to
macroautophagy-promoting stimuli, the GFP-LC3 signal becomes punctate and often (but not always)
predominantly cytoplasmic. The accumulation of GFP-LC3 in cytoplasmic dots, however, also ensues
the blockage of any of the steps that ensure the degradation of mature autophagosomes, calling for the
implementation of strategies that accurately discriminate between an increase in autophagic flux and
an arrest in autophagic degradation. Various cell lines have been engineered to stably express GFP-
LC3, which-combined with the appropriate controls of flux, high-throughput imaging stations, and
automated image analysis-offer a relatively straightforward tool to screen large chemical or biological
libraries for inducers or inhibitors of autophagy. Here, we describe a simple and robust method for the
high-throughput quantification of GFP-LC3 + dots by automated fluorescence microscopy. Â© 2017
Elsevier Inc. All rights reserved.
356. Placing Tactical Data into the MIST and LC2IEDM Systems
2003-10-01
Defence R& D Canada DEFENCE DÃ‰FENSE & Placing Tactical Data into the MIST and
LC2IEDM Systems Anthony W. Isenor Technical Memorandum DRDC Atlantic TM...intentionally
left blank. Copy No: Placing Tactical Data into the MIST and LC2IEDM Systems Anthony W. Isenor
Defence R& D Canada â€“ Atlantic Technical...currently underway at Defence R& D Canada â€“
Atlantic, as well as international efforts with The Technical Cooperation Program (TTCP). Both
groups
357. Host and Bacterial Proteins That Repress Recruitment of LC3 to Shigella Early during Infection
PubMed Central
Baxt, Leigh A.; Goldberg, Marcia B.
2014-01-01
Shigella spp. are intracytosolic gram-negative pathogens that cause disease by invasion and spread
through the colonic mucosa, utilizing host cytoskeletal components to form propulsive actin tails. We
have previously identified the host factor Toca-1 as being recruited to intracellular S. flexneri and
being required for efficient bacterial actin tail formation. We show that at early times during infection
(40 min.), the type three-secreted effector protein IcsB recruits Toca-1 to intracellular bacteria and that
recruitment of Toca-1 is associated with repression of recruitment of LC3, as well as with repression of
recruitment of the autophagy marker NDP52, around these intracellular bacteria. LC3 is best
characterized as a marker of autophagosomes, but also marks phagosomal membranes in the process
LC3-associated phagocytosis. IcsB has previously been demonstrated to be required for S. flexneri
evasion of autophagy at late times during infection (4â€“6 hr) by inhibiting binding of the autophagy
protein Atg5 to the Shigella surface protein IcsA (VirG). Our results suggest that IcsB and Toca-1
modulation of LC3 recruitment restricts LC3-associated phagocytosis and/or LC3 recruitment to
vacuolar membrane remnants. Together with published results, our findings suggest that IcsB inhibits
innate immune responses in two distinct ways, first, by inhibiting LC3-associated phagocytosis and/or
LC3 recruitment to vacuolar membrane remnants early during infection, and second, by inhibiting
autophagy late during infection. PMID:24722587
358. Neuromelanin detection by magnetic resonance imaging (MRI) and its promise as a biomarker for
Parkinson's disease.
PubMed
Sulzer, David; Cassidy, Clifford; Horga, Guillermo; Kang, Un Jung; Fahn, Stanley; Casella, Luigi;
Pezzoli, Gianni; Langley, Jason; Hu, Xiaoping P; Zucca, Fabio A; Isaias, Ioannis U; Zecca, Luigi
2018-01-01
The diagnosis of Parkinson's disease (PD) occurs after pathogenesis is advanced and many substantia
nigra (SN) dopamine neurons have already died. Now that therapies to block this neuronal loss are
under development, it is imperative that the disease be diagnosed at earlier stages and that the response
to therapies is monitored. Recent studies suggest this can be accomplished by magnetic resonance
imaging (MRI) detection of neuromelanin (NM), the characteristic pigment of SN dopaminergic, and
locus coeruleus (LC) noradrenergic neurons. NM is an autophagic product synthesized via oxidation of
catecholamines and subsequent reactions, and in the SN and LC it increases linearly during normal
aging. In PD, however, the pigment is lost when SN and LC neurons die. As shown nearly 25 years
ago by Zecca and colleagues, NM's avid binding of iron provides a paramagnetic source to enable
electron and nuclear magnetic resonance detection, and thus a means for safe and noninvasive measure
in living human brain. Recent technical improvements now provide a means for MRI to differentiate
between PD patients and age-matched healthy controls, and should be able to identify changes in SN
NM with age in individuals. We discuss how MRI detects NM and how this approach might be
improved. We suggest that MRI of NM can be used to confirm PD diagnosis and monitor disease
progression. We recommend that for subjects at risk for PD, and perhaps generally for older people,
that MRI sequences performed at regular intervals can provide a pre-clinical means to detect
presymptomatic PD.
359. Spatiotemporal alterations of autophagy marker LC3 in rat skin fibroblasts during wound healing
process
PubMed Central
Asai, Emiko; Yamamoto, Masaya; Ueda, Kazuki; Waguri, Satoshi
2018-01-01
Abstract To investigate the possible implications of autophagy, one of the degradation pathways
induced by metabolic stress, in the dynamic reconstructive process of wound healing, the appearance
and changes of punctate structures for microtubule-associated protein 1 light chain 3 (LC3), an
autophagosome marker, were examined in a rat skin wound healing model. Although the ratio of LC3-
II/LC3-I in Western blotting was not evidently changed during the wound healing process, LC3-
positive dots were clearly observed in fibroblasts and myofibroblasts, and occasionally in
macrophages, by immunohistofluorescence microscopy. Some of the LC3-positive dots were
colocalized with Atg16L signal, an isolation membrane marker, and electron microscopy revealed the
presence of typical autophagosomes in fibroblasts near the margin of the wound. The number of LC3-
positive dots per fibroblast increased during the later period of the proliferation phase, and
interestingly, it was higher in the margin than the center of the wound. It was also high in the
periwound skin area. These results suggest that drastic functional changes in fibroblasts during wound
healing process are accompanied by the alteration of the autophagy-lysosomal degradation system.
PMID:29343655
360. Glycoproteins Enrichment and LC-MS/MS Glycoproteomics in Central Nervous System Applications.
PubMed
Zhu, Rui; Song, Ehwang; Hussein, Ahmed; Kobeissy, Firas H; Mechref, Yehia
2017-01-01
Proteins and glycoproteins play important biological roles in central nervous systems (CNS).
Qualitative and quantitative evaluation of proteins and glycoproteins expression in CNS is critical to
reveal the inherent biomolecular mechanism of CNS diseases. This chapter describes proteomic and
glycoproteomic approaches based on liquid chromatography/tandem mass spectrometry (LC-MS or
LC-MS/MS) for the qualitative and quantitative assessment of proteins and glycoproteins expressed in
CNS. Proteins and glycoproteins, extracted by a mass spectrometry friendly surfactant from CNS
samples, were subjected to enzymatic (tryptic) digestion and three down-stream analyses: (1) a nano
LC system coupled with a high-resolution MS instrument to achieve qualitative proteomic profile, (2)
a nano LC system combined with a triple quadrupole MS to quantify identified proteins, and (3)
glycoprotein enrichment prior to LC-MS/MS analysis. Enrichment techniques can be applied to
improve coverage of low abundant glycopeptides/glycoproteins. An example described in this chapter
is hydrophilic interaction liquid chromatographic (HILIC) enrichment to capture glycopeptides,
allowing efficient removal of peptides. The combination of three LC-MS/MS-based approaches is
capable of the investigation of large-scale proteins and glycoproteins from CNS with an in-depth
coverage, thus offering a full view of proteins and glycoproteins changes in CNS.
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361. Bayesian Normalization Model for Label-Free Quantitative Analysis by LC-MS
PubMed Central
Nezami Ranjbar, Mohammad R.; Tadesse, Mahlet G.; Wang, Yue; Ressom, Habtom W.
2016-01-01
We introduce a new method for normalization of data acquired by liquid chromatography coupled with
mass spectrometry (LC-MS) in label-free differential expression analysis. Normalization of LC-MS
data is desired prior to subsequent statistical analysis to adjust variabilities in ion intensities that are
not caused by biological differences but experimental bias. There are different sources of bias
including variabilities during sample collection and sample storage, poor experimental design, noise,
etc. In addition, instrument variability in experiments involving a large number of LC-MS runs leads
to a significant drift in intensity measurements. Although various methods have been proposed for
normalization of LC-MS data, there is no universally applicable approach. In this paper, we propose a
Bayesian normalization model (BNM) that utilizes scan-level information from LC-MS data.
Specifically, the proposed method uses peak shapes to model the scan-level data acquired from
extracted ion chromatograms (EIC) with parameters considered as a linear mixed effects model. We
extended the model into BNM with drift (BNMD) to compensate for the variability in intensity
measurements due to long LC-MS runs. We evaluated the performance of our method using synthetic
and experimental data. In comparison with several existing methods, the proposed BNM and BNMD
yielded significant improvement. PMID:26357332
362. Definitive screening design enables optimization of LC-ESI-MS/MS parameters in proteomics.
PubMed
Aburaya, Shunsuke; Aoki, Wataru; Minakuchi, Hiroyoshi; Ueda, Mitsuyoshi
2017-12-01
In proteomics, more than 100,000 peptides are generated from the digestion of human cell lysates.
Proteome samples have a broad dynamic range in protein abundance; therefore, it is critical to
optimize various parameters of LC-ESI-MS/MS to comprehensively identify these peptides. However,
there are many parameters for LC-ESI-MS/MS analysis. In this study, we applied definitive screening
design to simultaneously optimize 14 parameters in the operation of monolithic capillary LC-ESI-
MS/MS to increase the number of identified proteins and/or the average peak area of MS1. The
simultaneous optimization enabled the determination of two-factor interactions between LC and MS.
Finally, we found two parameter sets of monolithic capillary LC-ESI-MS/MS that increased the
number of identified proteins by 8.1% or the average peak area of MS1 by 67%. The definitive
screening design would be highly useful for high-throughput analysis of the best parameter set in LC-
ESI-MS/MS systems.
363. Classical autophagy proteins LC3B and ATG4B facilitate melanosome movement on cytoskeletal
tracks.
PubMed
Ramkumar, Amrita; Murthy, Divya; Raja, Desingu Ayyappa; Singh, Archana; Krishnan, Anusha;
Khanna, Sangeeta; Vats, Archana; Thukral, Lipi; Sharma, Pushkar; Sivasubbu, Sridhar; Rani, Rajni;
Natarajan, Vivek T; Gokhale, Rajesh S
2017-08-03
Macroautophagy/autophagy is a dynamic and inducible catabolic process that responds to a variety of

hormonal and environmental cues. Recent studies highlight the interplay of this central pathway in a
variety of pathophysiological diseases. Although defective autophagy is implicated in melanocyte
proliferation and pigmentary disorders, the mechanistic relationship between the 2 pathways has not
been elucidated. In this study, we show that autophagic proteins LC3B and ATG4B mediate
melanosome trafficking on cytoskeletal tracks. While studying melanogenesis, we observed spatial
segregation of LC3B-labeled melanosomes with preferential absence at the dendritic ends of
melanocytes. This LC3B labeling of melanosomes did not impact the steady-state levels of these
organelles but instead facilitated their intracellular positioning. Melanosomes primarily traverse on
microtubule and actin cytoskeletal tracks and our studies reveal that LC3B enables the assembly of
microtubule translocon complex. At the microtubule-actin crossover junction, ATG4B detaches LC3B
from melanosomal membranes by enzymatic delipidation. Further, by live-imaging we show that
melanosomes transferred to keratinocytes lack melanocyte-specific LC3B. Our study thus elucidates a
new role for autophagy proteins in directing melanosome movement and reveal the unconventional use
of these proteins in cellular trafficking pathways. Such crosstalk between the central cellular function
and housekeeping pathway may be a crucial mechanism to balance melanocyte bioenergetics and
homeostasis.
364. Serological responses in humans to the smallpox vaccine LC16m8
PubMed Central
Johnson, Benjamin F.; Kanatani, Yasuhiro; Fujii, Tatsuya; Saito, Tomoya; Yokote, Hiroyuki
2011-01-01
In response to potential bioterrorism with smallpox, members of the Japanese Self-Defense Forces
were vaccinated with vaccinia virus (VACV) strain LC16m8, an attenuated smallpox vaccine derived
from VACV strain Lister. The serological response induced by LC16m8 to four virion-surface proteins
and the intracellular mature virus (IMV) and extracellular enveloped virus (EEV) was investigated.
LC16m8 induced antibody response against the IMV protein A27 and the EEV protein A56. LC16m8
also induced IMV-neutralizing antibodies, but unlike the VACV strain Lister, did not induce either
EEV-neutralizing antibody or antibody to EEV protein B5, except after revaccination. Given that B5 is
the only target for EEV-neutralizing antibody and that neutralization of both IMV and EEV give
optimal protection against orthopoxvirus challenge, these data suggest that immunity induced by
LC16m8 might be less potent than that deriving from strain Lister. This potential disadvantage should
be balanced against the advantage of the greater safety of LC16m8. PMID:21715598
365. Lactobacillus paracasei subsp. paracasei LC01 positively modulates intestinal microflora in healthy
young adults.
PubMed
Zhang, Hao; Sun, Jing; Liu, Xianting; Hong, Chuan; Zhu, Yuanbo; Liu, Aiping; Li, Siqi; Guo,
Huiyuan; Ren, Fazheng
2013-12-01
Lactobacillus paracasei subsp. paracasei LC01 (LC01) can tolerate intestinal stresses and has
antioxidant activity. To evaluate the effect of the bacterium on human intestinal microflora, a
randomized, double-blind, placebo-controlled human trial was carried out. Fifty-two healthy adult
volunteers were randomized equally to two groups. One group consumed 12% (wt/vol) skimmed milk
supplemented with 10(10) CFU of LC01 each day for the 4-week treatment period, and then consumed
placebo in the next treatment period, separated by a 2-week washout. The other group followed the
reverse order. Group-specific real-time PCR and biochemical analyses was used to determine the
intestinal bacterial composition of fecal samples collected at the end of every period, and the
concentration of short-chain fatty acids and ammonia. A significant inhibition in fecal Escherichia coli
and increase in Lactobacillus, Bifidobacterium, and Roseburia intestinalis were observed after
consumption of LC01. Acetic acid and butyric acid were significantly higher in the probiotic stage and
fecal ammonia was significantly lower. The results indicated a modulation effect of LC01 on the
intestinal microflora of young adults, suggesting a beneficial effect on bowel health. LC01 may have
potential value as a probiotic.
366. The change of nuclear LC3 distribution in acute myeloid leukemia cells.
PubMed
Guo, Wenjian; Jin, Jingrui; Pan, Jiajia; Yao, Rongxing; Li, Xia; Huang, Xin; Ma, Zhixing; Huang,
Sujuan; Yan, Xiao; Jin, Jie; Dong, Aishu
2018-05-09
Making sure the change of nuclear LC3 distribution in the autophagy of acute myeloid leukemia
(AML) cell and finding out the regulation mechanism may lead to a breakthrough for killing AML
cells. Western blots were performed to assess the expression of autophagy proteins. Changes in the
LC3 distribution were monitored by immunofluorescence assays together with western blots, and the
expression levels of Sirt1, DOR, Beclin1, HMGB1, and AMPK mRNA were detected via fluorescent
quantitative PCR. The effects of Sirt1 and DOR on cell proliferation and survival were analyzed by
MTT, flow cytometry, and western blotting assays. We found that treating AML cells with Ara-c or
Sorafenib resulted in autophagy enhancement, and when autophagy was enhanced, nuclear LC3
moved into the cytoplasm. Notably, when autophagy was inhibited by blocking the nuclear LC3 shift,
the cytotoxicity of drugs was enhanced. Our results also identified Sirt1 and DOR as regulatory
molecules for the observed nuclear LC3 shift, and these molecules further affected the expression of
Beclin1, HMGB1, and AMPK. Our results suggest the distribution of nuclear LC3 can be a novel way
for further studying death of AML cells,and the regulatory molecules may be new targets for treating
AML. Copyright Â© 2018 Elsevier Inc. All rights reserved.
367. Screening Antioxidants Using LC-MS: A Case Study with Cocoa
PubMed Central
CalderÃ³n, Angela I.; Wright, Brian J.; Hurst, W. Jeffrey; van Breemen, Richard B.
2009-01-01
Oxidative stress enhances pathological processes contributing to cancer, cardiovascular disease and
neurodegenerative diseases, and dietary antioxidants may counteract these deleterious processes. Since
rapid methods to evaluate and compare food products for antioxidant benefits are needed, a new assay
based on liquid chromatography-mass spectrometry (LC-MS) was developed for the identification and
quantitative analysis of antioxidants in complex natural product samples such as food extracts. This
assay is based on the comparison of electrospray LC-MS profiles of sample extracts before and after
treatment with reactive oxygen species such as hydrogen peroxide or DPPH (2,2-diphenyl-1-
picrylhydrazyl radical). Using this assay, methanolic extracts of cocoa powder were analyzed, and
procyanidins were found to be the most potent antioxidant species. These species were identified using
LC-MS, LC-MS-MS, accurate mass measurement, and comparison with reference standards.
Furthermore, LC-MS was used to determine the levels of these species in cocoa samples. Catechin and
epicatechin were the most abundant antioxidants followed by their dimers and trimers. The most
potent antioxidants in cocoa were trimers and dimers of catechin and epicatechin, such as procyanidin
B2, followed by catechin and epicatechin. This new LC-MS assay facilitates the rapid identification
and then the determination of the relative antioxidant activities of individual antioxidant species in
complex natural product samples and food products such as cocoa. PMID:19489609
368. V-ATPase and osmotic imbalances activate endolysosomal LC3 lipidation.
PubMed
Florey, Oliver; Gammoh, Noor; Kim, Sung Eun; Jiang, Xuejun; Overholtzer, Michael
2015-01-01
Recently a noncanonical activity of autophagy proteins has been discovered that targets lipidation of
microtubule-associated protein 1 light chain 3 (LC3) onto macroendocytic vacuoles, including
macropinosomes, phagosomes, and entotic vacuoles. While this pathway is distinct from canonical
autophagy, the mechanism of how these nonautophagic membranes are targeted for LC3 lipidation
remains unclear. Here we present evidence that this pathway requires activity of the vacuolar-type
H(+)-ATPase (V-ATPase) and is induced by osmotic imbalances within endolysosomal compartments.
LC3 lipidation by this mechanism is induced by treatment of cells with the lysosomotropic agent
chloroquine, and through exposure to the Heliobacter pylori pore-forming toxin VacA. These data add
novel mechanistic insights into the regulation of noncanonical LC3 lipidation and its associated
processes, including LC3-associated phagocytosis (LAP), and demonstrate that the widely and
therapeutically used drug chloroquine, which is conventionally used to inhibit autophagy flux, is an
inducer of LC3 lipidation.
369. Spatiotemporal alterations of autophagy marker LC3 in rat skin fibroblasts during wound healing
process.
PubMed
Asai, Emiko; Yamamoto, Masaya; Ueda, Kazuki; Waguri, Satoshi
2018-04-17
To investigate the possible implications of autophagy, one of the degradation pathways induced by
metabolic stress, in the dynamic reconstructive process of wound healing, the appearance and changes
of punctate structures for microtubule-associated protein 1 light chain 3 (LC3), an autophagosome
marker, were examined in a rat skin wound healing model. Although the ratio of LC3-II/LC3-I in
Western blotting was not evidently changed during the wound healing process, LC3-positive dots were
clearly observed in fibroblasts and myofibroblasts, and occasionally in macrophages, by
immunohistofluorescence microscopy. Some of the LC3-positive dots were colocalized with Atg16L
signal, an isolation membrane marker, and electron microscopy revealed the presence of typical
autophagosomes in fibroblasts near the margin of the wound. The number of LC3-positive dots per
fibroblast increased during the later period of the proliferation phase, and interestingly, it was higher in
the margin than the center of the wound. It was also high in the periwound skin area. These results
suggest that drastic functional changes in fibroblasts during wound healing process are accompanied
by the alteration of the autophagy-lysosomal degradation system.
370. The evolutionarily conserved interaction between LC3 and p62 selectively mediates autophagy-
dependent degradation of mutant huntingtin.
PubMed
Tung, Ying-Tsen; Hsu, Wen-Ming; Lee, Hsinyu; Huang, Wei-Pang; Liao, Yung-Feng
2010-07-01
Mammalian p62/sequestosome-1 protein binds to both LC3, the mammalian homologue of yeast Atg8,
and polyubiquitinated cargo proteins destined to undergo autophagy-mediated degradation. We
previously identified a cargo receptor-binding domain in Atg8 that is essential for its interaction with
the cargo receptor Atg19 in selective autophagic processes in yeast. We, thus, sought to determine
whether this interaction is evolutionally conserved from yeast to mammals. Using an amino acid
replacement approach, we demonstrate that cells expressing mutant LC3 (LC3-K30D, LC3-K51A, or
LC3-L53A) all exhibit defective lipidation of LC3, a disrupted LC3-p62 interaction, and impaired
autophagic degradation of p62, suggesting that the p62-binding site of LC3 is localized within an
evolutionarily conserved domain. Importantly, whereas cells expressing these LC3 mutants exhibited
similar overall autophagic activity comparable to that of cells expressing wild-type LC3, autophagy-
mediated clearance of the aggregation-prone mutant Huntingtin was defective in the mutant-expressing
cells. Together, these results suggest that p62 directly binds to the evolutionarily conserved cargo
receptor-binding domain of Atg8/LC3 and selectively mediates the clearance of mutant Huntingtin.
371. Norepinephrine ignites local hot spots of neuronal excitation: How arousal amplifies selectivity in
perception and memory
PubMed Central
Mather, Mara; Clewett, David; Sakaki, Michiko; Harley, Carolyn W.
2018-01-01
Long Abstract Existing brain-based emotion-cognition theories fail to explain arousalâ€™s ability to
both enhance and impair cognitive processing. In the Glutamate Amplifies Noradrenergic Effects
(GANE) model outlined in this paper, we propose that arousal-induced norepinephrine (NE) released
from the locus coeruleus (LC) biases perception and memory in favor of salient, high priority
representations at the expense of lower priority representations. This increase in gain under phasic
arousal occurs via synaptic self-regulation of NE based on glutamate levels. When the LC is phasically
active, elevated levels of glutamate at the site of prioritized representations increase local NE release,
creating â€œNE hot spots.â€ At these local hot spots, glutamate and NE release are mutually
enhancing and amplify activation of prioritized representations. This excitatory effect contrasts with
widespread NE suppression of weaker representations via lateral and auto-inhibitory processes. On a
broader scale, hot spots increase oscillatory synchronization across neural ensembles transmitting high
priority information. Furthermore, key brain structures that detect or pre-determine stimulus priority
interact with phasic NE release to preferentially route such information through large-scale functional
brain networks. A surge of NE before, during or after encoding enhances synaptic plasticity at sites of
high glutamate activity, triggering local protein synthesis processes that enhance selective memory
consolidation. Together, these noradrenergic mechanisms increase perceptual and memory selectivity
under arousal. Beyond explaining discrepancies in the emotion-cognition literature, GANE reconciles
and extends previous influential theories of LC neuromodulation by highlighting how NE can produce
such different outcomes in processing based on priority. PMID:26126507
372. Quantitation of melatonin and n-acetylserotonin in human plasma by nanoflow LC-MS/MS and
electrospray LC-MS/MS.
PubMed
Carter, Melissa D; Calcutt, M Wade; Malow, Beth A; Rose, Kristie L; Hachey, David L
2012-03-01
Melatonin (MEL) and its chemical precursor N-acetylserotonin (NAS) are believed to be potential
biomarkers for sleep-related disorders. Measurement of these compounds, however, has proven to be
difficult due to their low circulating levels, especially that of NAS. Few methods offer the sensitivity,
specificity and dynamic range needed to monitor MEL and its precursors and metabolites in small
blood samples, such as those obtained from pediatric patients. In support of our ongoing study to
determine the safety, tolerability and PK dosing strategies for MEL in treating insomnia in children
with autism spectrum disorder, two highly sensitive LC-MS/MS assays were developed for the
quantitation of MEL and precursor NAS at pg/mL levels in small volumes of human plasma. A
validated electrospray ionization (ESI) method was used to quantitate high levels of MEL in PK
studies, and a validated nanospray (nESI) method was developed for quantitation of MEL and NAS at
endogenous levels. In both assays, plasma samples were processed by centrifugal membrane dialysis
after addition of stable isotopic internal standards, and the components were separated by either
conventional LC using a Waters SymmetryShield RP18 column (2.1â€‰Ã—â€‰100 â€‰mm, 3.5â€
‰Âµm) or on a polyimide-coated, fused-silica capillary self-packed with 17â€‰cm AquaC18 (3â€
‰Âµm, 125â€‰Ã…). Quantitation was done using the SRM transitions m/z 233â€‰â†’â€‰174 and
m/z 219â€‰â†’â€‰160 for MEL and NAS, respectively. The analytical response ratio versus
concentration curves were linear for MEL (nanoflow LC: 11.7-1165â€‰ pg/mL, LC: 1165-116,500 â€
‰pg/mL) and for NAS (nanoflow LC: 11.0-1095 â€‰pg/mL). Copyright Â© 2012 John Wiley &
Sons, Ltd.
373. Quantitation of Melatonin and N-acetylserotonin in Human Plasma by Nanoflow LC-MS/MS and
Electrospray LC-MS/MS
PubMed Central
Carter, Melissa D.; Calcutt, M. Wade; Malow, Beth A.; Rose, Kristie L.; Hachey, David L.
2012-01-01
Melatonin (MEL) and its chemical precursor N-acetylserotonin (NAS) are believed to be potential
biomarkers for sleep-related disorders. Measurement of these compounds, however, has proven to be
difficult due to their low circulating levels, especially that of NAS. Few methods offer the sensitivity,
specificity and dynamic range needed to monitor MEL and its precursors and metabolites in small
blood samples, such as those obtained from pediatric patients. In support of our ongoing study to
determine the safety, tolerability, and PK dosing strategies for MEL in treating insomnia in children
with autism spectrum disorder, two highly sensitive LC-MS/MS assays were developed for the
quantitation of MEL and precursor NAS at pg/mL levels in small volumes of human plasma. A
validated electrospray ionization (ESI) method was used to quantitate high levels of MEL in PK
studies and a validated nanospray (nESI) method was developed for quantitation of MEL and NAS at
endogenous levels. In both assays plasma samples were processed by centrifugal membrane dialysis
after addition of stable isotopic internal standards, and the components were separated by either
conventional LC using a Waters SymmetryShield RP18 column (2.1Ã—100 mm, 3.5 Î¼m) or on a
polyimide-coated, fused-silica capillary self-packed with 17 cm AquaC18 (3 Î¼m, 125 Ã…).
Quantitation was done using the SRM transitions m/z 233â†’174 and m/z 219â†’160 for MEL and
NAS, respectively. The analytical response ratio vs. concentration curves were linear for MEL
(nanoflow LC: 11.7â€“1165 pg/mL, LC: 1165â€“116500 pg/mL) and for NAS (nanoflow LC:
11.0â€“1095 pg/mL). PMID:22431453
374. Online structural elucidation of alkaloids and other constituents in crude extracts and cultured cells of
Nandina domestica by combination of LC-MS/MS, LC-NMR, and LC-CD analyses.
PubMed
Iwasa, Kinuko; Takahashi, Teturo; Nishiyama, Yumi; Moriyasu, Masataka; Sugiura, Makiko;
Takeuchi, Atsuko; Tode, Chisato; Tokuda, Harukuni; Takeda, Kazuyoshi
2008-08-01
The combination of NMR, MS, and CD data permitted the structural elucidation including the absolute
configuration of the known alkaloids and unknown components in the extract matrix solution of
Nandina domestica without isolation and sample purification prior to the coupling experiments.
Unstable natural stereoisomers were identified by LC-NMR and LC-MS. Five known alkaloids, (S)-
isoboldine, (S)-domesticine, (S)-nantenine, sinoacutine, and menispermine, were identified from N.
domestica. O-Methylpallidine and (E, E)-, (E, Z)-, and (Z, Z)-terrestribisamide were also characterized
for the first time from this plant. Known jatrorrhizine, palmatine, and berberine and unknown (R)-
carnegine and (E, E)-, (E, Z)-, and (Z, Z)-terrestribisamide were identified in the callus of N.
domestica.
375. LC-MS/MS imaging with thermal film-based laser microdissection.
PubMed
Oya, Michiko; Suzuki, Hiromi; Anas, Andrea Roxanne J; Oishi, Koichi; Ono, Kenji; Yamaguchi,
Shun; Eguchi, Megumi; Sawada, Makoto
2018-01-01
Mass spectrometry (MS) imaging is a useful tool for direct and simultaneous visualization of specific
molecules. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is used to evaluate the
abundance of molecules in tissues using sample homogenates. To date, however, LC-MS/MS has not
been utilized as an imaging tool because spatial information is lost during sample preparation. Here we
report a new approach for LC-MS/MS imaging using a thermal film-based laser microdissection
(LMD) technique. To isolate tissue spots, our LMD system uses a 808-nm near infrared laser, the
diameter of which can be freely changed from 2.7 to 500 Î¼m; for imaging purposes in this study, the
diameter was fixed at 40 Î¼m, allowing acquisition of LC-MS/MS images at a 40-Î¼m resolution. The
isolated spots are arranged on a thermal film at 4.5-mm intervals, corresponding to the well spacing on
a 384-well plate. Each tissue spot is handled on the film in such a manner as to maintain its spatial
information, allowing it to be extracted separately in its individual well. Using analytical LC-MS/MS
in combination with the spatial information of each sample, we can reconstruct LC-MS/MS images.
With this imaging technique, we successfully obtained the distributions of pilocarpine, glutamate, Î³-
aminobutyric acid, acetylcholine, and choline in a cross-section of mouse hippocampus. The protocol
we established in this study is applicable to revealing the neurochemistry of pilocarpine model of
epilepsy. Our system has a wide range of uses in fields such as biology, pharmacology, pathology, and
neuroscience. Graphical abstract Schematic Indication of LMD-LC-MS/MS imaging.
376. Methods for Studying Interactions Between Atg8/LC3/GABARAP and LIR-Containing Proteins.
PubMed
Johansen, T; Birgisdottir, Ã… B; Huber, J; Kniss, A; DÃ¶tsch, V; Kirkin, V; Rogov, V V
2017-01-01
LC3/GABARAP proteins (LC3/GABARAPs) are mammalian orthologues of yeast Atg8, small

ubiquitin (Ub)-like proteins (UBLs) whose covalent attachment to lipid membranes is crucial for the
growth and closure of the double membrane vesicle called the autophagosome. In the past decade, it
was demonstrated that Atg8/LC3/GABARAPs are also required for autophagic degradation of cargos
in a selective fashion. Cargo selectivity is ensured by receptor proteins, such as p62/SQSTM1, NBR1,
Cue5, Atg19, NIX, Atg32, NCOA4, and FAM134B, which simultaneously bind
Atg8/LC3/GABARAPs and the cargo together, thereby linking the core autophagic machinery to the
target structure: a protein, an organelle, or a pathogen. LC3-interacting regions (LIRs) are short linear
motifs within selective autophagy receptors and some other structural and signaling proteins (e.g.,
ULK1, ATG13, FIP200, and Dvl2), which mediate binding to Atg8/LC3/GABARAPs. Identification
and characterization of LIR-containing proteins have provided important insights into the biology of
the autophagy pathway, and studying their interactions with the core autophagy machinery represents a
growing area of autophagy research. Here, we present protocols for the identification of LIR-
containing proteins, i.e., by yeast-two-hybrid screening, glutathione S-transferase (GST) pulldown
experiments, and peptide arrays. The use of two-dimensional peptide arrays also represents a powerful
method to identify the residues of the LIR motif that are critical for binding. We also describe a
biophysical method for studying interactions between Atg8/LC3/GABARAP and LIR-containing
proteins and a protocol for preparation and purification of LIR peptides. Â© 2017 Elsevier Inc. All
rights reserved.
377. An LC-IMS-MS Platform Providing Increased Dynamic Range for High-Throughput Proteomic
Studies
SciTech Connect
Baker, Erin Shammel; Livesay, Eric A.; Orton, Daniel J.
2010-02-05
A high-throughput approach and platform using 15 minute reversed-phase capillary liquid

chromatography (RPLC) separations in conjunction with ion mobility spectrometry-mass spectrometry
(IMS-MS) measurements was evaluated for the rapid analysis of complex proteomics samples. To test
the separation quality of the short LC gradient, a sample was prepared by spiking twenty reference
peptides at varying concentrations from 1 ng/mL to 10 Âµg/mL into a tryptic digest of mouse blood
plasma and analyzed with both a LC-Linear Ion Trap Fourier Transform (FT) MS and LC-IMS-TOF
MS. The LC-FT MS detected thirteen out of the twenty spiked peptides that had concentrations â‰
¥100 ng/mL.moreÂ Â» In contrast, the drift time selected mass spectra from the LC-IMS-TOF MS
analyses yielded identifications for nineteen of the twenty peptides with all spiking level present. The
greater dynamic range of the LC-IMS-TOF MS system could be attributed to two factors. First, the
LC-IMS-TOF MS system enabled drift time separation of the low concentration spiked peptides from
the high concentration mouse peptide matrix components, reducing signal interference and
background, and allowing species to be resolved that would otherwise be obscured by other
components. Second, the automatic gain control (AGC) in the linear ion trap of the hybrid FT MS
instrument limits the number of ions that are accumulated to reduce space charge effects, but in turn
limits the achievable dynamic range compared to the TOF detector.Â«Â less
378. LC-MSsim â€“ a simulation software for liquid chromatography mass spectrometry data
PubMed Central
Schulz-Trieglaff, Ole; Pfeifer, Nico; GrÃ¶pl, Clemens; Kohlbacher, Oliver; Reinert, Knut
2008-01-01
Background Mass Spectrometry coupled to Liquid Chromatography (LC-MS) is commonly used to

analyze the protein content of biological samples in large scale studies. The data resulting from an LC-
MS experiment is huge, highly complex and noisy. Accordingly, it has sparked new developments in
Bioinformatics, especially in the fields of algorithm development, statistics and software engineering.
In a quantitative label-free mass spectrometry experiment, crucial steps are the detection of peptide
features in the mass spectra and the alignment of samples by correcting for shifts in retention time. At
the moment, it is difficult to compare the plethora of algorithms for these tasks. So far, curated
benchmark data exists only for peptide identification algorithms but no data that represents a ground
truth for the evaluation of feature detection, alignment and filtering algorithms. Results We present
LC-MSsim, a simulation software for LC-ESI-MS experiments. It simulates ESI spectra on the MS
level. It reads a list of proteins from a FASTA file and digests the protein mixture using a user-defined
enzyme. The software creates an LC-MS data set using a predictor for the retention time of the
peptides and a model for peak shapes and elution profiles of the mass spectral peaks. Our software also
offers the possibility to add contaminants, to change the background noise level and includes a model
for the detectability of peptides in mass spectra. After the simulation, LC-MSsim writes the simulated
data to mzData, a public XML format. The software also stores the positions (monoisotopic m/z and
retention time) and ion counts of the simulated ions in separate files. Conclusion LC-MSsim generates
simulated LC-MS data sets and incorporates models for peak shapes and contaminations. Algorithm
developers can match the results of feature detection and alignment algorithms against the simulated
ion lists and meaningful error rates can be computed. We anticipate that LC-MSsim will be
379. Simultaneous analysis of 17 diuretics in dietary supplements by HPLC and LC-MS/MS.
PubMed
Woo, H; Kim, J W; Han, K M; Lee, J H; Hwang, I S; Lee, J H; Kim, J; Kweon, S J; Cho, S; Chae, K
R; Han, S Y; Kim, J
2013-01-01
In order to test health foods for illegally added diuretics for weight loss, we developed simple, rapid,
selective, and sensitive methods using HPLC and LC-MS/MS for the simultaneous analysis of 17
diuretics in dietary supplements. HPLC conditions were set with a Capcell-pak C18, using a mobile
phase consisting of gradient conditions, UV detection at 254 nm and validated for linearity (r(2)>
0.999), precision (CV â‰¤ 3%), recoveries (90.4-102.8%) and reproducibility. Identification and
quantification of 17 diuretics were accomplished by ion-spray LC-MS/MS using multiple reaction
monitoring (MRM). The chromatographic separation was carried out under the reversed-phase
mechanism on an HSS-T3 column. The LC-MS/MS method was validated for linearity (r(2)> 0.99)
and precision (CV < 13%). Sixteen dietary supplements were tested with the developed methods.
Diuretics were not detected in all samples. Extraction recovery was also investigated and the extraction
recoveries in different formulations were from 88% to 110% and from 81% to 116% using HPLC and
LC-MS/MS, respectively. There was no significant difference in recoveries in the type of dietary
supplements. Based on this result, the developed methods to monitor illegal drug adulterations in
dietary supplements using HPLC and LC-MS/MS are simple, fast and reliable. Therefore, it is
applicable to routine drug-adulteration screening.
380. 2016 ASMS Workshop Review: Next Generation LC/MS: Critical Insights and Future Perspectives
SciTech Connect
Gao, Hongying; Makarov, Alexander; Smith, Richard D.
The pilot workshop on BNext Generation LC/MS: Critical Insights and Future Perspectives was held
on the evening of June 6, 2016 at the 64th ASMS Conference on Mass Spectrometry and Allied Topics
held in San Antonio, TX. The workshop, chaired by Hongying Gao (Pfizer), consisted of stimulating
talks from distinguished speakers and open discussion among the audience and invited presenters.The
objectives of this workshop were to better understand the advances and limitations of current
technologies; to exchange perspectives on the next generation LC/MS; and to discuss/debate the
features of next generation LC/MS focusing on the following three questions: (1) WhatmoreÂ Â»
would the next generation LC/MS look like? (2) How would it change the way we do analysis? and (3)
What fundamental issues need to be resolved? A real-world case in the biopharmaceutical industry
was presented by Hongying Gao on the needs by industry for LC/MS innovation and technology
advancements. The primary invited speakers were Alexander Makarov (Thermo Fisher Scientific) and
Richard (Dick) Smith (Pacific Northwest National Laboratory). The open discussions started with
Q&A and comments for Alexander Makarov and Dick Smith, followed by insights and perspectives
from members of the audience and other invited presenters who shared their thoughts addressing the
above questions.Â«Â less
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381. ICPD-a new peak detection algorithm for LC/MS.
PubMed
Zhang, Jianqiu; Haskins, William
2010-12-01
The identification and quantification of proteins using label-free Liquid Chromatography/Mass

Spectrometry (LC/MS) play crucial roles in biological and biomedical research. Increasing evidence
has shown that biomarkers are often low abundance proteins. However, LC/MS systems are subject to
considerable noise and sample variability, whose statistical characteristics are still elusive, making
computational identification of low abundance proteins extremely challenging. As a result, the
inability of identifying low abundance proteins in a proteomic study is the main bottleneck in protein
biomarker discovery. In this paper, we propose a new peak detection method called Information
Combining Peak Detection (ICPD ) for high resolution LC/MS. In LC/MS, peptides elute during a
certain time period and as a result, peptide isotope patterns are registered in multiple MS scans. The
key feature of the new algorithm is that the observed isotope patterns registered in multiple scans are
combined together for estimating the likelihood of the peptide existence. An isotope pattern matching
score based on the likelihood probability is provided and utilized for peak detection. The performance
of the new algorithm is evaluated based on protein standards with 48 known proteins. The evaluation
shows better peak detection accuracy for low abundance proteins than other LC/MS peak detection
methods.
382. Design and analysis of quantitative differential proteomics investigations using LC-MS technology.
PubMed
Bukhman, Yury V; Dharsee, Moyez; Ewing, Rob; Chu, Peter; Topaloglou, Thodoros; Le Bihan,
Thierry; Goh, Theo; Duewel, Henry; Stewart, Ian I; Wisniewski, Jacek R; Ng, Nancy F
2008-02-01
Liquid chromatography-mass spectrometry (LC-MS)-based proteomics is becoming an increasingly

important tool in characterizing the abundance of proteins in biological samples of various types and
across conditions. Effects of disease or drug treatments on protein abundance are of particular interest
for the characterization of biological processes and the identification of biomarkers. Although state-of-
the-art instrumentation is available to make high-quality measurements and commercially available
software is available to process the data, the complexity of the technology and data presents challenges
for bioinformaticians and statisticians. Here, we describe a pipeline for the analysis of quantitative LC-
MS data. Key components of this pipeline include experimental design (sample pooling, blocking, and
randomization) as well as deconvolution and alignment of mass chromatograms to generate a matrix of
molecular abundance profiles. An important challenge in LC-MS-based quantitation is to be able to
accurately identify and assign abundance measurements to members of protein families. To address
this issue, we implement a novel statistical method for inferring the relative abundance of related
members of protein families from tryptic peptide intensities. This pipeline has been used to analyze
quantitative LC-MS data from multiple biomarker discovery projects. We illustrate our pipeline here
with examples from two of these studies, and show that the pipeline constitutes a complete workable
framework for LC-MS-based differential quantitation. Supplementary material is available at
http://iec01.mie.utoronto.ca/~thodoros/Bukhman/.
383. LC-MSMS assays of urinary cortisol, a comparison between four in-house assays.
PubMed
Brossaud, Julie; Leban, Monique; Corcuff, Jean-Benoit; Boux de Casson, Florence; Leloupp, Anne-
GaÃ«lle; Masson, Damien; Moal, ValÃ©rie; Bach-Ngohou, Kalyane
2018-06-27
Twenty-four hour urinary free cortisol (UFC) determination can be used for screening and follow-up of
Cushing syndrome (CS). As immunoassay methods lack specificity for UFC measurement, the use of
high-performance liquid chromatography coupled to mass spectrometer (LC-MSMS) is recommended.
The aim of our study was to compare UFC results using four LC-MSMS methods performed in four
independent laboratories in order to evaluate interlaboratory agreement. Frozen aliquots of 24-h urine
samples (78 healthy volunteers and 20 patients with CS) were sent to four different laboratories for
analysis. Following liquid-liquid or solid-liquid extraction, UFC were determined using four different
LC-MSMS assay. UFC intra- and interassays variation coefficients were lower than 10% for each
centre. External quality control results were not significantly different. UFC normal ranges
(established from healthy volunteers) were 17-126, 15-134, 12-118 and 27-157 nmol/day, respectively.
Classification of UFC from healthy volunteers and patients with CS using a 95th percentile threshold
was similar. However, for extreme UFC values (<50 or >270 nmol/day), negative or positive bias was
noted. Even for highly specific methods such as LC-MSMS, variations of results can be found
depending on analytical process. Validation of LC-MSMS methods including determination of the
reference range is essential.
384. ICPD-A New Peak Detection Algorithm for LC/MS
PubMed Central
2010-01-01
Background The identification and quantification of proteins using label-free Liquid

Chromatography/Mass Spectrometry (LC/MS) play crucial roles in biological and biomedical
research. Increasing evidence has shown that biomarkers are often low abundance proteins. However,
LC/MS systems are subject to considerable noise and sample variability, whose statistical
characteristics are still elusive, making computational identification of low abundance proteins
extremely challenging. As a result, the inability of identifying low abundance proteins in a proteomic
study is the main bottleneck in protein biomarker discovery. Results In this paper, we propose a new
peak detection method called Information Combining Peak Detection (ICPD ) for high resolution
LC/MS. In LC/MS, peptides elute during a certain time period and as a result, peptide isotope patterns
are registered in multiple MS scans. The key feature of the new algorithm is that the observed isotope
patterns registered in multiple scans are combined together for estimating the likelihood of the peptide
existence. An isotope pattern matching score based on the likelihood probability is provided and
utilized for peak detection. Conclusions The performance of the new algorithm is evaluated based on
protein standards with 48 known proteins. The evaluation shows better peak detection accuracy for
low abundance proteins than other LC/MS peak detection methods. PMID:21143790
385. The autophagy marker LC3 strongly predicts immediate mortality after surgical resection for
hepatocellular carcinoma.
PubMed
Lin, Chih-Wen; Lin, Chih-Che; Lee, Po-Huang; Lo, Gin-Ho; Hsieh, Pei-Min; Koh, Kah Wee; Lee,
Chih-Yuan; Chen, Yao-Li; Dai, Chia-Yen; Huang, Jee-Fu; Chuang, Wang-Long; Chen, Yaw-Sen; Yu,
Ming-Lung
2017-11-03
The remnant liver's ability to regenerate may affect post-hepatectomy immediate mortality. The
promotion of autophagy post-hepatectomy could enhance liver regeneration and reduce mortality. This
study aimed to identify predictive factors of immediate mortality after surgical resection for
hepatocellular carcinoma (HCC). A total of 535 consecutive HCC patients who had undergone their
first surgical resection in Taiwan were enrolled between 2010 and 2014. Clinicopathological data and
immediate mortality, defined as all cause-mortality within three months after surgery, were analyzed.
The expression of autophagy proteins (LC3, Beclin-1, and p62) in adjacent non-tumor tissues was
scored by immunohistochemical staining. Approximately 5% of patients had immediate mortality after
surgery. The absence of LC3, hypoalbuminemia (<3.5 g/dl), high alanine aminotransferase, and major
liver surgery were significantly associated with immediate mortality in univariate analyses.
Multivariate logistic regression demonstrated that absence of LC3 (hazard ratio/95% confidence
interval: 40.8/5.14-325) and hypoalbuminemia (2.88/1.11-7.52) were significantly associated with
immediate mortality. The 3-month cumulative incidence of mortality was 12.1%, 13.0%, 21.4% and
0.4%, respectively, among patients with absence of LC3 expression, hypoalbuminemia, both, or
neither of the two. In conclusion, the absence of LC3 expression in adjacent non-tumor tissues and
hypoalbuminemia were strongly predictive of immediate mortality after resection for HCC.
386. Targeted and non-targeted detection of lemon juice adulteration by LC-MS and chemometrics.
PubMed
Wang, Zhengfang; Jablonski, Joseph E
2016-01-01
Economically motivated adulteration (EMA) of lemon juice was detected by LC-MS and principal
component analysis (PCA). Twenty-two batches of freshly squeezed lemon juice were adulterated by
adding an aqueous solution containing 5% citric acid and 6% sucrose to pure lemon juice to obtain
30%, 60% and 100% lemon juice samples. Their total titratable acidities, Â°Brix and pH values were
measured, and then all the lemon juice samples were subject to LC-MS analysis. Concentrations of
hesperidin and eriocitrin, major phenolic components of lemon juice, were quantified. The PCA score
plots for LC-MS datasets were used to preview the classification of pure and adulterated lemon juice
samples. Results showed a large inherent variability in the chemical properties among 22 batches of
100% lemon juice samples. Measurement or quantitation of one or several chemical properties
(targeted detection) was not effective in detecting lemon juice adulteration. However, by using the LC-
MS datasets, including both chromatographic and mass spectrometric information, 100% lemon juice
samples were successfully differentiated from adulterated samples containing 30% lemon juice in the
PCA score plot. LC-MS coupled with chemometric analysis can be a complement to existing methods
for detecting juice adulteration.
387. LC-MS based analysis of endogenous steroid hormones in human hair.
PubMed
Gao, Wei; Kirschbaum, Clemens; Grass, Juliane; Stalder, Tobias
2016-09-01
The quantification of endogenous steroid hormone concentrations in hair is increasingly used as a

method for obtaining retrospective information on long-term integrated hormone exposure. Several
different analytical procedures have been employed for hair steroid analysis, with liquid
chromatography-mass spectrometry (LC-MS) being recognized as a particularly powerful analytical
tool. Several methodological aspects affect the performance of LC-MS systems for hair steroid
analysis, including sample preparation and pretreatment, steroid extraction, post-incubation
purification, LC methodology, ionization techniques and MS specifications. Here, we critically review
the differential value of such protocol variants for hair steroid hormones analysis, focusing on both
analytical quality and practical feasibility issues. Our results show that, when methodological
challenges are adequately addressed, LC-MS protocols can not only yield excellent sensitivity and
specificity but are also characterized by relatively simple sample processing and short run times. This
makes LC-MS based hair steroid protocols particularly suitable as a high-quality option for routine
application in research contexts requiring the processing of larger numbers of samples. Copyright Â©
2016 Elsevier Ltd. All rights reserved.
388. The future of liquid chromatography-mass spectrometry (LC-MS) in metabolic profiling and
metabolomic studies for biomarker discovery
PubMed Central
Metz, Thomas O.; Zhang, Qibin; Page, Jason S.; Shen, Yufeng; Callister, Stephen J.; Jacobs, Jon M.;
Smith, Richard D.
2008-01-01
SUMMARY The future utility of liquid chromatography-mass spectrometry (LC-MS) in metabolic

profiling and metabolomic studies for biomarker discover will be discussed, beginning with a brief
description of the evolution of metabolomics and the utilization of the three most popular analytical
platforms in such studies: NMR, GC-MS, and LC-MS. Emphasis is placed on recent developments in
high-efficiency LC separations, sensitive electrospray ionization approaches, and the benefits to
incorporating both in LC-MS-based approaches. The advantages and disadvantages of various
quantitative approaches are reviewed, followed by the current LC-MS-based tools available for
candidate biomarker characterization and identification. Finally, a brief prediction on the future path of
LC-MS-based methods in metabolic profiling and metabolomic studies is given. PMID:19177179
389. Effects of chronic sleep fragmentation on wake-active neurons and the hypercapnic arousal response.
PubMed
Li, Yanpeng; Panossian, Lori A; Zhang, Jing; Zhu, Yan; Zhan, Guanxia; Chou, Yu-Ting; Fenik, Polina;
Bhatnagar, Seema; Piel, David A; Beck, Sheryl G; Veasey, Sigrid
2014-01-01
Delayed hypercapnic arousals may occur in obstructive sleep apnea. The impaired arousal response is
expected to promote more pronounced oxyhemoglobin desaturations. We hypothesized that long-term
sleep fragmentation (SF) results in injury to or dysfunction of wake-active neurons that manifests, in
part, as a delayed hypercapnic arousal response. Adult male mice were implanted for behavioral state
recordings and randomly assigned to 4 weeks of either orbital platform SF (SF4wk, 30 events/h) or
control conditions (Ct4wk) prior to behavioral, histological, and locus coeruleus (LC) whole cell
electrophysiological evaluations. SF was successfully achieved across the 4 week study, as evidenced
by a persistently increased arousal index, P < 0.01 and shortened sleep bouts, P < 0.05, while total
sleep/wake times and plasma corticosterone levels were unaffected. A multiple sleep latency test
performed at the onset of the dark period showed a reduced latency to sleep in SF4wk mice (P < 0.05).
The hypercapnic arousal latency was increased, Ct4wk 64 Â± 5 sec vs. SF4wk 154 Â± 6 sec, P <
0.001, and remained elevated after a 2 week recovery (101 Â± 4 sec, P < 0.001). C-fos activation in
noradrenergic, orexinergic, histaminergic, and cholinergic wake-active neurons was reduced in
response to hypercapnia (P < 0.05-0.001). Catecholaminergic and orexinergic projections into the
cingulate cortex were also reduced in SF4wk (P < 0.01). In addition, SF4wk resulted in impaired LC
neuron excitability (P < 0.01). Four weeks of sleep fragmentation (SF4wk) impairs arousal responses
to hypercapnia, reduces wake neuron projections and locus coeruleus neuronal excitability, supporting
the concepts that some effects of sleep fragmentation may contribute to impaired arousal responses in
sleep apnea, which may not reverse immediately with therapy.
390. Metabolic profiling of Vitex agnus castus leaves, fruits and sprouts: analysis by LC/ESI/(QqQ)MS and
(HR) LC/ESI/(Orbitrap)/MS n.
PubMed
Mari, Angela; Montoro, Paola; D'Urso, Gilda; Macchia, Mario; Pizza, Cosimo; Piacente, Sonia
2015-01-01
Food supplements based on Vitex agnus castus L. (Verbenaceae) fruits, also known as chasteberry, are
routinely used by women against somatic and psychic premenstrual symptoms such as depression,
sadness or irritability. With the aim of highlighting the differences in the chemical profiles of
cultivated fruits and different parts of wild plants (fruits, leaves and sprouts) of V. agnus castus, a
method concerning with the quali-quantitative study of the derived hydroalcoholic extracts was carried
out by using high-performance liquid chromatography coupled to electrospray negative ionization
Orbitrap multicollisional high resolution mass spectrometry (LC/ESI/(Orbitrap)MS(n)) and high-
performance liquid chromatography coupled to electrospray negative ionization triple quadrupole
tandem mass spectrometry (LC/ESI/(QqQ)MS) in multiple reaction monitoring (MRM) mode.
Copyright Â© 2014 Elsevier B.V. All rights reserved.
391. G2LC: Resources Autoscaling for Real Time Bioinformatics Applications in IaaS.
PubMed
Hu, Rongdong; Liu, Guangming; Jiang, Jingfei; Wang, Lixin
2015-01-01
Cloud computing has started to change the way how bioinformatics research is being carried out.
Researchers who have taken advantage of this technology can process larger amounts of data and
speed up scientific discovery. The variability in data volume results in variable computing
requirements. Therefore, bioinformatics researchers are pursuing more reliable and efficient methods
for conducting sequencing analyses. This paper proposes an automated resource provisioning method,
G2LC, for bioinformatics applications in IaaS. It enables application to output the results in a real time
manner. Its main purpose is to guarantee applications performance, while improving resource
utilization. Real sequence searching data of BLAST is used to evaluate the effectiveness of G2LC.
Experimental results show that G2LC guarantees the application performance, while resource is saved
up to 20.14%.
392. G2LC: Resources Autoscaling for Real Time Bioinformatics Applications in IaaS
PubMed Central
Hu, Rongdong; Liu, Guangming; Jiang, Jingfei; Wang, Lixin
2015-01-01
Cloud computing has started to change the way how bioinformatics research is being carried out.
Researchers who have taken advantage of this technology can process larger amounts of data and
speed up scientific discovery. The variability in data volume results in variable computing
requirements. Therefore, bioinformatics researchers are pursuing more reliable and efficient methods
for conducting sequencing analyses. This paper proposes an automated resource provisioning method,
G2LC, for bioinformatics applications in IaaS. It enables application to output the results in a real time
manner. Its main purpose is to guarantee applications performance, while improving resource
utilization. Real sequence searching data of BLAST is used to evaluate the effectiveness of G2LC.
Experimental results show that G2LC guarantees the application performance, while resource is saved
up to 20.14%. PMID:26504488
393. Pharmacological modulators of autophagy activate a parallel noncanonical pathway driving

unconventional LC3 lipidation.
PubMed
Jacquin, Elise; Leclerc-Mercier, StÃ©phanie; Judon, Celine; Blanchard, Emmanuelle; Fraitag, Sylvie;
Florey, Oliver
2017-05-04
The modulation of canonical macroautophagy/autophagy for therapeutic benefit is an emerging

strategy of medical and pharmaceutical interest. Many drugs act to inhibit autophagic flux by targeting
lysosome function, while others were developed to activate the pathway. Here, we report the surprising
finding that many therapeutically relevant autophagy modulators with lysosomotropic and ionophore
properties, classified as inhibitors of canonical autophagy, are also capable of activating a parallel
noncanonical autophagy pathway that drives MAP1LC3/LC3 lipidation on endolysosomal membranes.
Further, we provide the first evidence supporting drug-induced noncanonical autophagy in vivo using
the local anesthetic lidocaine and human skin biopsies. In addition, we find that several published
inducers of autophagy and mitophagy are also potent activators of noncanonical autophagy. Together,
our data raise important issues regarding the interpretation of LC3 lipidation data and the use of
autophagy modulators, and highlight the need for a greater understanding of the functional
consequences of noncanonical autophagy.
394. Application of LC/MS/MS Techniques to Development of US ...
This presentation will describe the U.S. EPAâ€™s drinking water and ambient water method
development program in relation to the process employed and the typical challenges encountered in
developing standardized LC/MS/MS methods for chemicals of emerging concern. The EPAâ€™s
Drinking Water Contaminant Candidate List and Unregulated Contaminant Monitoring Regulations,
which are the driving forces behind drinking water method development, will be introduced. Three
drinking water LC/MS/MS methods (Methods 537, 544 and a new method for nonylphenol) and two
ambient water LC/MS/MS methods for cyanotoxins will be described that highlight some of the
challenges encountered during development of these methods. This presentation will provide the
audience with basic understanding of EPA's drinking water method development program and an
introduction to two new ambient water EPA methods.
395. The clinical impact of recent advances in LC-MS for cancer biomarker discovery and verification
SciTech Connect
Wang, Hui; Shi, Tujin; Qian, Wei-Jun
2015-12-04
Mass spectrometry-based proteomics has become an indispensable tool in biomedical research with
broad applications ranging from fundamental biology, systems biology, and biomarker discovery.
Recent advances in LC-MS have made it become a major technology in clinical applications,
especially in cancer biomarker discovery and verification. To overcome the challenges associated with
the analysis of clinical samples, such as extremely wide dynamic range of protein concentrations in
biofluids and the need to perform high throughput and accurate quantification, significant efforts have
been devoted to improve the overall performance of LC-MS bases clinical proteomics. In this review,
we summarize the recent advances inmoreÂ Â» LC-MS in the aspect of cancer biomarker discovery
and quantification, and discuss its potentials, limitations, and future perspectives.Â«Â less
396. [Domino principle--monoamines in bottom-view].
PubMed
SÃ¼megi, AndrÃ¡s
2008-06-01
involved, in the noradrenergic innervation spreading from the locus coeruleus (LC). Dysregulation of
the LC projection activities may lead in turn to malfunction of serotonergic and dopaminergic
neurotransmission. Failure of the LC function could explain the basic impairments in the processing of
novel information, intensive processing of irrational beliefs, and anxiety. Consecutive deficits in the
serotonergic neurotransmission may contribute to the mood changes and reduction in the
mesotelencephalic dopaminergic activity to loss of motivation, and anhedonia. Malfunction and
dysregulation of CRF and other neuropeptides such as neuropeptide Y, galanin and substance P may
reinforce the LC dysfunction and thus further weaken the adaptive ability to stressful stimuli. The new
SNRI antidepressants seem to be more superior and effective in the treatment of major depression and
in the prophylaxis of recurrent depressive episodes because of their coexistent noradrenergic activity.
397. Contaminant screening of wastewater with HPLC-IM-qTOF-MS and LC+LC-IM-qTOF-MS using a

CCS database.
PubMed
Stephan, Susanne; Hippler, Joerg; KÃ¶hler, Timo; Deeb, Ahmad A; Schmidt, Torsten C; Schmitz,
Oliver J
2016-09-01
Non-target analysis has become an important tool in the field of water analysis since a broad variety of
pollutants from different sources are released to the water cycle. For identification of compounds in
such complex samples, liquid chromatography coupled to high resolution mass spectrometry are often
used. The introduction of ion mobility spectrometry provides an additional separation dimension and
allows determining collision cross sections (CCS) of the analytes as a further physicochemical
constant supporting the identification. A CCS database with more than 500 standard substances
including drug-like compounds and pesticides was used for CCS data base search in this work. A non-
target analysis of a wastewater sample was initially performed with high performance liquid
chromatography (HPLC) coupled to an ion mobility-quadrupole-time of flight mass spectrometer (IM-
qTOF-MS). A database search including exact mass (Â±5Â ppm) and CCS (Â±1Â %) delivered 22
different compounds. Furthermore, the same sample was analyzed with a two-dimensional LC method,
called LC+LC, developed in our group for the coupling to IM-qTOF-MS. This four dimensional
separation platform revealed 53 different compounds, identified over exact mass and CCS, in the
examined wastewater sample. It is demonstrated that the CCS database can also help to distinguish
between isobaric structures exemplified for cyclophosphamide and ifosfamide. Graphical Abstract
Scheme of sample analysis and database screening.
398. Separation and identification of selenotrisulfides in epithelial cell homogenates by LC-ICP-MS and
LC-ESI-MS after incubation with selenite.
PubMed
Gabel-Jensen, Charlotte; Gammelgaard, Bente; Bendahl, Lars; StÃ¼rup, Stefan; JÃ¸ns, Ole
2006-02-01
To elucidate how selenite is metabolised in the intestine after oral intake, it was incubated with
homogenized epithelial cells from pigs. When the metabolites were analysed by LC-ICP-MS, two
major selenium metabolites were separated in the supernatant from the homogenate. These metabolites
were formed instantly but disappeared within 15 min. No other selenium-containing compounds
appeared during this time. Hence, the secondary reaction products were either volatilised or
precipitated. To verify the identity of the compounds, a larger amount of selenite was incubated with
epithelial cells. The presence of Cys-Se-SG and GS-Se-SG was verified by LC-ESI-MS.
Selenotrisulfides were synthesized by reaction of L-cysteine and L-glutathione with sodium selenite.
The reaction mixture contained three main products: selenodicysteine (Cys-Se-Cys), selenocysteine
glutathione (Cys-Se-SG), and selenodiglutathione (GS-Se-SG). The two transient selenium compounds
in the epithelial cell incubation mixture co-eluted with the synthesized Cys-Se-SG and GS-Se-SG,
respectively. The identities of these compounds were verified by LC-ESI-MS. Hence, these selenium
metabolites have now been identified by ESI-MS after isolation from epithelial cells.
399. Smooth muscle myosin isoform expression and LC20 phosphorylation in innate rat airway
hyperresponsiveness.
PubMed
Gil, Fulvio R; Zitouni, Nedjma B; Azoulay, Eric; Maghni, Karim; Lauzon, Anne-Marie
2006-11-01
Four smooth muscle myosin heavy chain (SMMHC) isoforms are generated by alternative mRNA
splicing of a single gene. Two of these isoforms differ by the presence [(+)insert] or absence [(-)insert]
of a 7-amino acid insert in the motor domain. The rate of actin filament propulsion of the (+)insert
SMMHC isoform, as measured in the in vitro motility assay, is twofold greater than that of the (-)insert
isoform. We hypothesized that a greater expression of the (+)insert SMMHC isoform and greater
regulatory light chain (LC(20)) phosphorylation contribute to airway hyperresponsiveness. We
measured airway responsiveness to methacholine in Fischer hyperresponsive and Lewis
normoresponsive rats and determined SMMHC isoform mRNA and protein expression, as well as
essential light chain (LC(17)) isoforms, h-caldesmon, and alpha-actin protein expression in their
tracheae. We also measured tracheal muscle strip contractility in response to methacholine and
corresponding LC(20) phosphorylation. We found Fischer rats have more (+)insert mRNA (69.4 +/-
2.0%) (mean +/- SE) than Lewis rats (53.0 +/- 2.4%; P < 0.05) and a 44% greater content of (+)insert
isoform relative to total myosin protein. No difference was found for LC(17) isoform, h-caldesmon,
and alpha-actin expression. The contractility experiments revealed a greater isometric force for Fischer
trachealis segments (4.2 +/- 0.8 mN) than Lewis (1.9 +/- 0.4 mN; P < 0.05) and greater LC(20)
phosphorylation level in Fischer (55.1 +/- 6.4) than in Lewis (41.4 +/- 6.1; P < 0.05) rats. These results
further support the contention that innate airway hyperresponsiveness is a multifactorial disorder in
which increased expression of the fast (+)insert SMMHC isoform and greater activation of LC(20)
lead to smooth muscle hypercontractility.
400. The Short Cosyntropin Test Revisited: New Normal Reference Range Using LC-MS/MS.
PubMed
Ueland, Grethe Ã…; Methlie, Paal; Ã˜ksnes, Marianne; Thordarson, Hrafnkell B; Sagen, JÃ¸rn;
Kellmann, Ralf; Mellgren, Gunnar; RÃ¦der, Maria; Dahlqvist, Per; Dahl, Sandra R; Thorsby, Per M;
LÃ¸vÃ¥s, Kristian; Husebye, Eystein S
2018-04-01
The cosyntropin test is used to diagnose adrenal insufficiency (AI) and nonclassical congenital adrenal
hyperplasia (NCCAH). Current cutoffs for cortisol and 17-hydroxyprogesterone (17-OHP) are derived
from nonstandardized immunoassays. Liquid chromatography tandem mass spectrometry (LC-
MS/MS) offers direct measurement of steroids, prompting the need to re-establish normal ranges. The
goal of this study was to define cutoff values for cortisol and 17-OHP in serum by LC-MS/MS 30 and
60 minutes after intravenous administration of 250 Âµg tetracosactide acetate to healthy volunteers
and to compare the results with LC-MS/MS with routine immunoassays. Cosyntropin testing was
performed in healthy subjects (n = 138) and in patients referred for evaluation of adrenocortical
function (n = 94). Steroids were assayed by LC-MS/MS and compared with two immunoassays used
in routine diagnostics (Immulite and Roche platforms). The cutoff level for cortisol was defined as the
2.5% percentile in healthy subjects not using oral estrogens (n = 121) and for 17-OHP as the 97.5%
percentile. Cortisol cutoff levels for LC-MS/MS were 412 and 485 nmol/L at 30 and 60 minutes,
respectively. Applying the new cutoffs, 13 of 60 (22%) subjects who had AI according to conventional
criteria now had a normal test result. For 17-OHP, the cutoff levels were 8.9 and 9.0 nmol/L at 30 and
60 minutes, respectively. LC-MS/MS provides cutoff levels for cortisol and 17-OHP after cosyntropin
stimulation that are lower than those based on immunoassays, possibly because cross-reactivity
between steroid intermediates and cortisol is eliminated. This reduces the number of false-positive
tests for AI and false-negative tests for NCCAH.
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401. Cerebellar Norepinephrine Modulates Learning of Delay Classical Eyeblink Conditioning: Evidence
for Post-Synaptic Signaling via PKA
Fister, Mathew; Bickford, Paula C.; Cartford, M. Claire; Samec, Amy
2004-01-01
The neurotransmitter norepinephrine (NE) has been shown to modulate cerebellar-dependent learning
and memory. Lesions of the nucleus locus coeruleus or systemic blockade of noradrenergic receptors
has been shown to delay the acquisition of several cerebellar-dependent learning tasks. To date, no
studies have shown a direct involvement ofâ€¦
402. Human Atg8-cardiolipin interactions in mitophagy: Specific properties of LC3B, GABARAPL2 and
GABARAP.
PubMed
AntÃ³n, ZuriÃ±e; Landajuela, Ane; HervÃ¡s, Javier H; Montes, L Ruth; HernÃ¡ndez-Tiedra, Sonia;
Velasco, Guillermo; GoÃ±i, Felix M; Alonso, Alicia
2016-12-01
The phospholipid cardiolipin (CL) has been proposed to play a role in selective mitochondrial
autophagy, or mitophagy. CL externalization to the outer mitochondrial membrane would act as a
signal for the human Atg8 ortholog subfamily, MAP1LC3 (LC3). The latter would mediate both
mitochondrial recognition and autophagosome formation, ultimately leading to removal of damaged
mitochondria. We have applied quantitative biophysical techniques to the study of CL interaction with
various Atg8 human orthologs, namely LC3B, GABARAPL2 and GABARAP. We have found that
LC3B interacts preferentially with CL over other di-anionic lipids, that CL-LC3B binding occurs with
positive cooperativity, and that the CL-LC3B interaction relies only partially on electrostatic forces.
CL-induced increased membrane fluidity appears also as an important factor helping LC3B to bind
CL. The LC3B C terminus remains exposed to the hydrophilic environment after protein binding to
CL-enriched membranes. In intact U87MG human glioblastoma cells rotenone-induced autophagy
leads to LC3B translocation to mitochondria and subsequent delivery of mitochondria to lysosomes.
We have also observed that GABARAP, but not GABARAPL2, interacts with CL in vitro. However
neither GABARAP nor GABARAPL2 were translocated to mitochondria in rotenone-treated U87MG
cells. Thus the various human Atg8 orthologs might play specific roles in different autophagic
processes.
403. LC3-mediated fibronectin mRNA translation induces fibrosarcoma growth by increasing connective
tissue growth factor
PubMed Central
Ying, Lihua; Lau, Agatha; Alvira, Cristina M.; West, Robert; Cann, Gordon M.; Zhou, Bin; Kinnear,
Caroline; Jan, Eric; Sarnow, Peter; Van de Rijn, Matt; Rabinovitch, Marlene
2009-01-01
Summary Previously, we related fibronectin (Fn1) mRNA translation to an interaction between an AU-
rich element in the Fn1 3â€² UTR and light chain 3 (LC3) of microtubule-associated proteins 1A and
1B. Since human fibrosarcoma (HT1080) cells produce little fibronectin and LC3, we used these cells
to investigate how LC3-mediated Fn1 mRNA translation might alter tumor growth. Transfection of
HT1080 cells with LC3 enhanced fibronectin mRNA translation. Using polysome analysis and RNA-
binding assays, we show that elevated levels of translation depend on an interaction between a triple
arginine motif in LC3 and the AU-rich element in Fn1 mRNA. Wild-type but not mutant LC3
accelerated HT1080 cell growth in culture and when implanted in SCID mice. Comparison of WT
LC3 with vector-transfected HT1080 cells revealed increased fibronectin-dependent proliferation,
adhesion and invasion. Microarray analysis of genes differentially expressed in WT and vector-
transfected control cells indicated enhanced expression of connective tissue growth factor (CTGF).
Using siRNA, we show that enhanced expression of CTGF is fibronectin dependent and that LC3-
mediated adhesion, invasion and proliferation are CTGF dependent. Expression profiling of soft tissue
tumors revealed increased expression of both LC3 and CTGF in some locally invasive tumor types.
PMID:19366727
404. Rugged LC-MS/MS survey analysis for acrylamide in foods.
PubMed
Roach, John A G; Andrzejewski, Denis; Gay, Martha L; Nortrup, David; Musser, Steven M
2003-12-17
The described liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the
detection of acrylamide in food entails aqueous room temperature extraction, SPE cleanup, and
analysis by LC-MS/MS. The method is applicable to a wide variety of foods. [(13)C(3)]acrylamide is
the internal standard. The limit of quantitation is 10 ppb (microg/kg). Data were obtained in duplicate
from >450 products representing >35 different food types. The variability in analyte levels in certain
food types suggests that it may be possible to reduce acrylamide levels in those foods.
405. A computer method of finding valuations forcing validity of LC formulae
Godlewski, Åukasz; Åšwietorzecka, Kordula; Mulawka, Jan
2014-11-01
The purpose of this paper is to present the computer implementation of a system known as LC
temporal logic [1]. Firstly, to become familiar with some theoretical issues, a short introduction to this
logic is discussed. The algorithms allowing a deep analysis of the formulae of LC logic are considered.
In particular we discuss how to determine if a formula is a tautology, contrtautology or it is satisfable.
Next, we show how to find all valuations to satisfy the formula. Finally, we consider finding histories
generated by the formula and transforming these histories into the state machine. Moreover, a
description of the experiments that verify the implementation are briefly presented.
406. STS-29 Discovery, Orbiter Vehicle (OV) 103, roll out to KSC LC Pad 39B
1989-01-01
In the early morning hours, STS-29 Discovery, Orbiter Vehicle (OV) 103, mated to the external tank
(ET) and solid rocket boosters (SRBs) is rolled out to Kennedy Space Center (KSC) Launch Complex
(LC) Pad 39B atop the mobile launcher platform. Trees, shrubs, and a light mist surround the mobile
launcher platform as it makes its way to LC Pad 39B. OV-103 will fly on Mission STS-29 scheduled
for launch in mid-March. View provided by KSC with alternate KSC number KSC-89PC-50.
407. Review of Research Status and Development Trends of Wireless Passive LC Resonant Sensors for
Harsh Environments
PubMed Central
Li, Chen; Tan, Qiulin; Jia, Pinggang; Zhang, Wendong; Liu, Jun; Xue, Chenyang; Xiong, Jijun
2015-01-01
Measurement technology for various key parameters in harsh environments (e.g., high-temperature
and biomedical applications) continues to be limited. Wireless passive LC resonant sensors offer long
service life and can be suitable for harsh environments because they can transmit signals without
battery power or wired connections. Consequently, these devices have become the focus of many
current research studies. This paper addresses recent research, key technologies, and practical
applications relative to passive LC sensors used to monitor temperature, pressure, humidity, and
harmful gases in harsh environments. The advantages and disadvantages of various sensor types are
discussed, and prospects and challenges for future development of these sensors are presented.
PMID:26053753
408. Ebola Virus VP35 Interaction with Dynein LC8 Regulates Viral RNA Synthesis
SciTech Connect
Luthra, Priya; Jordan, David S.; Leung, Daisy W.
2015-03-04
Ebola virus VP35 inhibits alpha/beta interferon production and functions as a viral polymerase
cofactor. Previously, the 8-kDa cytoplasmic dynein light chain (LC8) was demonstrated to interact
with VP35, but the functional consequences were unclear. Here we demonstrate that the interaction is
direct and of high affinity and that binding stabilizes the VP35 N-terminal oligomerization domain and
enhances viral RNA synthesis. Mutational analysis demonstrates that VP35 interaction is required for
the functional effects of LC8.
409. Review of Research Status and Development Trends of Wireless Passive LC Resonant Sensors for
Harsh Environments.
PubMed
Li, Chen; Tan, Qiulin; Jia, Pinggang; Zhang, Wendong; Liu, Jun; Xue, Chenyang; Xiong, Jijun
2015-06-04
Measurement technology for various key parameters in harsh environments (e.g., high-temperature
and biomedical applications) continues to be limited. Wireless passive LC resonant sensors offer long
service life and can be suitable for harsh environments because they can transmit signals without
battery power or wired connections. Consequently, these devices have become the focus of many
current research studies. This paper addresses recent research, key technologies, and practical
applications relative to passive LC sensors used to monitor temperature, pressure, humidity, and
harmful gases in harsh environments. The advantages and disadvantages of various sensor types are
discussed, and prospects and challenges for future development of these sensors are presented.
410. Dependence between LD50 for Rodents and LC50 for Adult Fish and Fish Embryos.
PubMed
Zolotarev, K V; Belyaeva, N F; Mikhailov, A N; Mikhailova, M V
2017-02-01
We revealed empirical dependences between common logarithm of a ratio of rat oral LD 50 to LC a 50

for adult fish and lgP for 50 different chemicals; and common logarithm of a ratio of the oral LD 50 in
rodents to LC e 50 for fish embryos and lgP for 30 different chemicals. The dependences were
obtained by constructing a trend line between experimental points and calculation of Pearson's R
correlation coefficient as a measure of regression significance. These dependences can show the
influence of substance lipophilicity on its toxicity for aquatic organisms comparing to mammals.
411. Elevated mu-opioid receptor expression in the nucleus of the solitary tract accompanies attenuated
withdrawal signs after chronic low dose naltrexone in opiate-dependent rats.
PubMed
Van Bockstaele, E J; Rudoy, C; Mannelli, P; Oropeza, V; Qian, Y
2006-02-15
We previously described a decrease in withdrawal behaviors in opiate-dependent rats that were

chronically treated with very low doses of naltrexone in their drinking water. Attenuated expression of
withdrawal behaviors correlated with decreased c-Fos expression and intracellular signal transduction
elements [protein kinase A regulatory subunit II (PKA) and phosphorylated cAMP response element
binding protein (pCREB)] in brainstem noradrenergic nuclei. In this study, to determine whether
similar cellular changes occurred in forebrain nuclei associated with drug reward, expressions of PKA
and pCREB were analyzed in the ventral tegmental area, frontal cortex, striatum, and amygdala of
opiate-treated rats that received low doses of naltrexone in their drinking water. No significant
difference in PKA or pCREB was detected in these regions following drug treatment. To examine
further the cellular mechanisms in noradrenergic nuclei that could underlie attenuated withdrawal
behaviors following low dose naltrexone administration, the nucleus of the solitary tract (NTS) and
locus coeruleus (LC) were examined for opioid receptor (OR) protein expression. Results showed a
significant increase in muOR expression in the NTS of morphine-dependent rats that received low
doses of naltrexone in their drinking water, and increases in muOR expression were also found to be
dose dependent. Protein expression of muOR in the LC and deltaOR in either brain region remained
unchanged. In conclusion, our previously reported decreases in c-Fos and PKA expression in the NTS
following pretreatment with low doses of naltrexone may be partially explained by a greater inhibition
of NTS neurons resulting from increased muOR expression in this region.
412. Monoaminergic Neuropathology in Alzheimer's disease
PubMed Central
Å imiÄ‡, Goran; Leko, Mirjana BabiÄ‡; Wray, Selina; Harrington, Charles; Delalle, Ivana; Jovanov-
MiloÅ¡eviÄ‡, NataÅ¡a; BaÅ¾adona, Danira; BuÃ©e, Luc; de Silva, Rohan; Di Giovanni, Giuseppe;
Wischik, Claude; Hof, Patrick R.
2016-01-01
None of the proposed mechanisms of Alzheimerâ€™s disease (AD) fully explains the distribution
patterns of the neuropathological changes at the cellular and regional levels, and their clinical
correlates. One aspect of this problem lies in the complex genetic, epigenetic, and environmental
landscape of AD: early-onset AD is often familial with autosomal dominant inheritance, while the vast
majority of AD cases are late-onset, with the Îµ4 variant of the gene encoding apolipoprotein E
(APOE) known to confer a 5â€“20 fold increased risk with partial penetrance. Mechanisms by which
genetic variants and environmental factors influence the development of AD pathological changes,
especially neurofibrillary degeneration, are not yet known. Here we review current knowledge of the
involvement of the monoaminergic systems in AD. The changes in the serotonergic, noradrenergic,
dopaminergic, histaminergic, and melatonergic systems in AD are briefly described. We also
summarize the possibilities for monoamine-based treatment in AD. Besides neuropathologic AD
criteria that include the noradrenergic locus coeruleus (LC), special emphasis is given to the
serotonergic dorsal raphe nucleus (DRN). Both of these brainstem nuclei are among the first to be
affected by tau protein abnormalities in the course of sporadic AD, causing behavioral and cognitive
symptoms of variable severity. The possibility that most of the tangle-bearing neurons of the LC and
DRN may release amyloid Î² as well as soluble monomeric or oligomeric tau protein trans-synaptically
by their diffuse projections to the cerebral cortex emphasizes their selective vulnerability and warrants
further investigations of the monoaminergic systems in AD. PMID:27084356
413. Application of survival analysis methodology to the quantitative analysis of LC-MS proteomics data.
PubMed
Tekwe, Carmen D; Carroll, Raymond J; Dabney, Alan R
2012-08-01
Protein abundance in quantitative proteomics is often based on observed spectral features derived from
liquid chromatography mass spectrometry (LC-MS) or LC-MS/MS experiments. Peak intensities are
largely non-normal in distribution. Furthermore, LC-MS-based proteomics data frequently have large
proportions of missing peak intensities due to censoring mechanisms on low-abundance spectral
features. Recognizing that the observed peak intensities detected with the LC-MS method are all
positive, skewed and often left-censored, we propose using survival methodology to carry out
differential expression analysis of proteins. Various standard statistical techniques including non-
parametric tests such as the Kolmogorov-Smirnov and Wilcoxon-Mann-Whitney rank sum tests, and
the parametric survival model and accelerated failure time-model with log-normal, log-logistic and
Weibull distributions were used to detect any differentially expressed proteins. The statistical operating
characteristics of each method are explored using both real and simulated datasets. Survival methods
generally have greater statistical power than standard differential expression methods when the
proportion of missing protein level data is 5% or more. In particular, the AFT models we consider
consistently achieve greater statistical power than standard testing procedures, with the discrepancy
widening with increasing missingness in the proportions. The testing procedures discussed in this
article can all be performed using readily available software such as R. The R codes are provided as
supplemental materials. ctekwe@stat.tamu.edu.
414. Gas barrier properties of bio-inspired Laponite-LC polymer hybrid films.
PubMed
Tritschler, Ulrich; Zlotnikov, Igor; Fratzl, Peter; Schlaad, Helmut; GrÃ¼ner, Simon; CÃ¶lfen, Helmut
2016-05-26
Bio-inspired Laponite (clay)-liquid crystal (LC) polymer composite materials with high clay fractions
(>80%) and a high level of orientation of the clay platelets, i.e. with structural features similar to the
ones found in natural nacre, have been shown to exhibit a promising behavior in the context of reduced
oxygen transmission. Key characteristics of these bio-inspired composite materials are their high
inorganic content, high level of exfoliation and orientation of the clay platelets, and the use of a LC
polymer forming the organic matrix in between the Laponite particles. Each single feature may be
beneficial to increase the materials gas barrier property rendering this composite a promising system
with advantageous barrier capacities. In this detailed study, Laponite/LC polymer composite coatings
with different clay loadings were investigated regarding their oxygen transmission rate. The obtained
gas barrier performance was linked to the quality, respective Laponite content and the underlying
composite micro- and nanostructure of the coatings. Most efficient oxygen barrier properties were
observed for composite coatings with 83% Laponite loading that exhibit a structure similar to sheet-
like nacre. Further on, advantageous mechanical properties of these Laponite/LC polymer composites
reported previously give rise to a multifunctional composite system.
415. A multiclass multiresidue LC-MS/MS method for analysis of veterinary drugs in bovine kidney
The increased efficiency permitted by multiclass, multiresidue methods has made such approaches
very attractive to laboratories involved in monitoring veterinary drug residues in animal tissues. In this
current work, evaluation of a multiclass multiresidue LC-MS/MS method in bovine kidney is describ...
416. MEASUREMENT OF OXIDATIVE STRESS PARAMETERS USING LIQUID

CHROMATOGRAPHY - TANDEM MASS SPECTROSCOPY (LC-MS/MS)
What is the study?

An invited review article. Measurement of oxidative stress parameters using liquid chromatography-
tandem mass spectroscopy (LC-MS/MS)
Why was it done?
Although oxidative stress is frequently cited as a cause of various adverse biological eff...
417. LC-MSn Analysis of Isomeric Chondroitin Sulfate Oligosaccharides Using a Chemical Derivatization
Strategy
PubMed Central
Huang, Rongrong; Pomin, Vitor H.; Sharp, Joshua S.
2011-01-01
Improved methods for structural analyses of glycosaminoglycans (GAGs) are required to understand
their functional roles in various biological processes. Major challenges in structural characterization of
complex GAG oligosaccharides using liquid chromatography-mass spectrometry (LC-MS) include the
accurate determination of the patterns of sulfation due to gas-phase losses of the sulfate groups upon
collisional activation and inefficient on-line separation of positional sulfation isomers prior to MS/MS
analyses. Here, a sequential chemical derivatization procedure including permethylation, desulfation,
and acetylation was demonstrated to enable both on-line LC separation of isomeric mixtures of
chondroitin sulfate (CS) oligosaccharides and accurate determination of sites of sulfation by MSn. The
derivatized oligosaccharides have sulfate groups replaced with acetyl groups, which are sufficiently
stable to survive MSn fragmentation and reflect the original sulfation patterns. A standard reversed-
phase LC-MS system with a capillary C18 column was used for separation, and MSn experiments
using collision-induced dissociation (CID) were performed. Our results indicate that the combination
of this derivatization strategy and MSn methodology enables accurate identification of the sulfation
isomers of CS hexasaccharides with either saturated or unsaturated nonreducing ends. Moreover,
derivatized CS hexasaccharide isomer mixtures become separable by LC-MS method due to different
positions of acetyl modifications. PMID:21953261
418. ANALYTICAL METHODS AND QUALITY ASSURANCE CRITERIA FOR LC/ES/MS

DETERMINATION OF PFOS IN FISH
PFOS, perfluorooctanesulfonate, has recently received much attention from environmental researchers.
Previous analytical methods were based upon complexing with a strong ion-pairing reagent and
extraction into MTBE. Detection was done on a concentrate using negative ion LC/ES/MS/...
419. 40. Photocopy of engineering drawing. LC17B LONG TANK DELTA UPBUILD ...
Survey
40. Photocopy of engineering drawing. LC-17B LONG TANK DELTA UPBUILD LAUNCH DECK:
NEW PLATE AT LAUNCH MOUNT AREA-STRUCTURAL, APRIL 1969. - Cape Canaveral Air
Station, Launch Complex 17, Facility 28402, East end of Lighthouse Road, Cape Canaveral, Brevard
County, FL
420. STS-30 Atlantis, OV-104, at KSC LC Pad 39B atop mobile launcher platform
1989-01-01
STS-30 Atlantis, Orbiter Vehicle (OV) 104, arrives at Kennedy Space Center (KSC) Launch Complex
(LC) Pad 39B atop mobile launcher platform. The fixed service structure (FSS) towers above OV-104,
its external tank (ET), and its solid rocket boosters (SRBs). The rotating service structure (RSS) is
retracted. The launch tower catwalks are also retracted.
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421. Development of Immunocapture-LC/MS Assay for Simultaneous ADA Isotyping and

Semiquantitation
PubMed Central
2016-01-01
Therapeutic proteins and peptides have potential to elicit immune responses resulting in anti-drug
antibodies that can pose problems for both patient safety and product efficacy. During drug
development immunogenicity is usually examined by risk-based approach along with specific
strategies for developing â€œfit-for-purposeâ€ bioanalytical approaches. Enzyme-linked
immunosorbent assays and electrochemiluminescence immunoassays are the most widely used
platform for ADA detection due to their high sensitivity and throughput. During the past decade,
LC/MS has emerged as a promising technology for quantitation of biotherapeutics and protein
biomarkers in biological matrices, mainly owing to its high specificity, selectivity, multiplexing, and
wide dynamic range. In fully taking these advantages, we describe here an immunocapture-LC/MS
methodology for simultaneous isotyping and semiquantitation of ADA in human plasma. Briefly,
ADA and/or drug-ADA complex is captured by biotinylated drug or anti-drug Ab, immobilized on
streptavidin magnetic beads, and separated from human plasma by a magnet. ADA is then released
from the beads and subjected to trypsin digestion followed by LC/MS detection of specific universal
peptides for each ADA isotype. The LC/MS data are analyzed using cut-point and calibration curve.
The proof-of-concept of this methodology is demonstrated by detecting preexisting ADA in human
plasma. PMID:27034966
422. Development of Immunocapture-LC/MS Assay for Simultaneous ADA Isotyping and

Semiquantitation.
PubMed
Chen, Lin-Zhi; Roos, David; Philip, Elsy
2016-01-01
Therapeutic proteins and peptides have potential to elicit immune responses resulting in anti-drug
antibodies that can pose problems for both patient safety and product efficacy. During drug
development immunogenicity is usually examined by risk-based approach along with specific
strategies for developing "fit-for-purpose" bioanalytical approaches. Enzyme-linked immunosorbent
assays and electrochemiluminescence immunoassays are the most widely used platform for ADA
detection due to their high sensitivity and throughput. During the past decade, LC/MS has emerged as
a promising technology for quantitation of biotherapeutics and protein biomarkers in biological
matrices, mainly owing to its high specificity, selectivity, multiplexing, and wide dynamic range. In
fully taking these advantages, we describe here an immunocapture-LC/MS methodology for
simultaneous isotyping and semiquantitation of ADA in human plasma. Briefly, ADA and/or drug-
ADA complex is captured by biotinylated drug or anti-drug Ab, immobilized on streptavidin magnetic
beads, and separated from human plasma by a magnet. ADA is then released from the beads and
subjected to trypsin digestion followed by LC/MS detection of specific universal peptides for each
ADA isotype. The LC/MS data are analyzed using cut-point and calibration curve. The proof-of-
concept of this methodology is demonstrated by detecting preexisting ADA in human plasma.
423. Video-microscopy of NCAP films: the observation of LC droplets in real time
Reamey, Robert H.; Montoya, Wayne; Wong, Abraham
1992-06-01
We have used video-microscopy to observe the behavior of liquid crystal (LC) droplets within nematic
droplet-polymer films (NCAP) as the droplets respond to an applied electric field. The textures
observed at intermediate fields yielded information about the process of liquid crystal orientation
dynamics within droplets. The nematic droplet-polymer films had low LC content (less than 1 percent)
to allow the observation of individual droplets in a 2 - 6 micrometers size range. The aqueous
emulsification technique was used to prepare the films as it allows the straightforward preparation of
low LC content films with a controlled droplet size range. Standard electro-optical (E-O) tests were
also performed on the films, allowing us to correlate single droplet behavior with that of the film as a
whole. Hysteresis measured in E-O tests was visually confirmed by droplet orientation dynamics; a
film which had high hysteresis in E-O tests exhibited distinctly different LC orientations within the
droplet when ramped up in voltage than when ramped down in voltage. Ramping the applied voltage
to well above saturation resulted in some droplets becoming `stuck'' in a new droplet structure which
can be made to revert back to bipolar with high voltage pulses or with heat.
424. Identification of RIP-II toxins by affinity enrichment, enzymatic digestion and LC-MS.
PubMed
Fredriksson, Sten-Ã…ke; Artursson, Elisabet; BergstrÃ¶m, Tomas; Ã–stin, Anders; Nilsson, Calle;
Ã…stot, Crister
2015-01-20
Type 2 ribosome-inactivating protein toxins (RIP-II toxins) were enriched and purified prior to
enzymatic digestion and LC-MS analysis. The enrichment of the RIP-II family of plant proteins, such
as ricin, abrin, viscumin, and volkensin was based on their affinity for galactosyl moieties. A
macroporous chromatographic material was modified with a galactose-terminated substituent and
packed into miniaturized columns that were used in a chromatographic system to achieve up to 1000-
fold toxin enrichment. The galactose affinity of the RIP-II proteins enabled their selective enrichment
from water, beverages, and extracts of powder and wipe samples. The enriched fractions were digested
with trypsin and RIP-II peptides were identified based on accurate mass LC-MS data. Their identities
were unambiguously confirmed by LC-MS/MS product ion scans of peptides unique to each of the
toxins. The LC-MS detection limit achieved for ricin target peptides was 10 amol and the
corresponding detection limit for the full method was 10 fmol/mL (0.6 ng/mL). The affinity
enrichment method was applied to samples from a forensic investigation into a case involving the
illegal production of ricin and abrin toxins.
425. LC-MS and MS/MS in the analysis of recombinant proteins
Coulot, M.; Domon, B.; Grossenbacher, H.; Guenat, C.; Maerki, W.; MÃ¼ller, D. R.; Richter, W. J.
1993-03-01
Applicability and performance of electrospray ionization mass spectrometry (ESIMS) is demonstrated

for protein analysis. ESIMS is applied in conjunction with on-line HPLC (LC-ESlMS) and direct
tandem mass spectrometry (positive and negative ion mode ESlMS/MS) to the structural
characterization of a recombinant protein (r-hirudin variant 1) and a congener phosphorylated at
threonine 45 (RP-1).
426. Measurement of deuterium-labeled phylloquinone in plasma by LC-APCI-MS
Deuterium-labeled vegetables were fed to humans for the measurement of both unlabeled and
deuterium-labeled phylloquinone in plasma. We developed a technique to determine the quantities of
these compounds using liquid chromatography/mass spectrometry with atmospheric pressure chemical
ionization (LC...
427. Determination of toxins involved in ciguatera fish poisoning in the Pacific by LC/MS.
PubMed
Yogi, Kentaro; Sakugawa, Satsuki; Oshiro, Naomasa; Ikehara, Tsuyoshi; Sugiyama, Kiminori;
Yasumoto, Takeshi
2014-01-01
Ciguatera fish poisoning is the most extensive and difficult to control of the seafood poisonings. To
facilitate monitoring of fish toxicity, toxin profiles were investigated by an LC/MS/MS method using
14 reference toxins on eight representative species of fish collected in four different areas of the
Pacific. Snappers and groupers from Okinawa contained ciguatoxin-1B (CTX1B) and two deoxy
congeners at variable but species-specific ratios, while red snapper, Lutjanus bohar, from
Minamitorishima, and amberjack, Seriola dumerili, from Hawaii, contained both CTX1B-type and
CTX3C-type toxins. Spotted knifejaw, Oplegnathus punctatus, from Okinawan waters, contained
mainly CTX4A and CTX4B, but the same species caught at Miyazaki was contaminated primarily
with the CTX3C-type toxins. Otherwise, the toxin profiles were consistently species-specific in fish
collected from various locations around Okinawa over 20 years. The LC/MS/MS and mouse bioassay
results agreed well, indicating the LC/MS/MS method is a promising alternative to the mouse
bioassay. Pure CTX1B and CTX3C were prepared for use in future LC/MS/MS analysis.
428. A LC/MS METHOD FOR THE DETERMINATION OF CYANOBACTERIA TOXINS IN WATER
The cyanobacteria toxins anatoxin-a, microcystin-LR, microcystin-RR, microcystin-YR, and nodularin

were separated in less than 30 minutes on several 1 mm x 15 cm reverse phase liquid chromatography
(LC) columns, and their electrospray mass spectra were measured with 50 ng or less...
429. 25. Photocopy of engineering drawing. LC17B LONG TANK DELTA UPBUILD: ...
Survey
25. Photocopy of engineering drawing. LC-17B LONG TANK DELTA UPBUILD: MOBILE
SERVICE TOWER, WEATHER CURTAINS SECTION 1 AND PLANS LEVELS 4 & 4A, 3, 2X, &
1A-ARCHITECTURAL, APRIL 1969. - Cape Canaveral Air Station, Launch Complex 17, Facility
28417, East end of Lighthouse Road, Cape Canaveral, Brevard County, FL
430. LC-MS n Analysis of Isomeric Chondroitin Sulfate Oligosaccharides Using a Chemical Derivatization
Strategy
Huang, Rongrong; Pomin, Vitor H.; Sharp, Joshua S.
2011-09-01
Improved methods for structural analyses of glycosaminoglycans (GAGs) are required to understand
their functional roles in various biological processes. Major challenges in structural characterization of
complex GAG oligosaccharides using liquid chromatography-mass spectrometry (LC-MS) include the
accurate determination of the patterns of sulfation due to gas-phase losses of the sulfate groups upon
collisional activation and inefficient on-line separation of positional sulfation isomers prior to MS/MS
analyses. Here, a sequential chemical derivatization procedure including permethylation, desulfation,
and acetylation was demonstrated to enable both on-line LC separation of isomeric mixtures of
chondroitin sulfate (CS) oligosaccharides and accurate determination of sites of sulfation by MS n .
The derivatized oligosaccharides have sulfate groups replaced with acetyl groups, which are
sufficiently stable to survive MS n fragmentation and reflect the original sulfation patterns. A standard
reversed-phase LC-MS system with a capillary C18 column was used for separation, and MS n
experiments using collision-induced dissociation (CID) were performed. Our results indicate that the
combination of this derivatization strategy and MS n methodology enables accurate identification of
the sulfation isomers of CS hexasaccharides with either saturated or unsaturated nonreducing ends.
Moreover, derivatized CS hexasaccharide isomer mixtures become separable by LC-MS method due to
different positions of acetyl modifications.
431. MassCascade: Visual Programming for LC-MS Data Processing in Metabolomics.
PubMed
Beisken, Stephan; Earll, Mark; Portwood, David; Seymour, Mark; Steinbeck, Christoph
2014-04-01
Liquid chromatography coupled to mass spectrometry (LC-MS) is commonly applied to investigate

the small molecule complement of organisms. Several software tools are typically joined in custom
pipelines to semi-automatically process and analyse the resulting data. General workflow
environments like the Konstanz Information Miner (KNIME) offer the potential of an all-in-one
solution to process LC-MS data by allowing easy integration of different tools and scripts. We describe
MassCascade and its workflow plug-in for processing LC-MS data. The Java library integrates
frequently used algorithms in a modular fashion, thus enabling it to serve as back-end for graphical
front-ends. The functions available in MassCascade have been encapsulated in a plug-in for the
workflow environment KNIME, allowing combined use with e.g. statistical workflow nodes from
other providers and making the tool intuitive to use without knowledge of programming. The design of
the software guarantees a high level of modularity where processing functions can be quickly replaced
or concatenated. MassCascade is an open-source library for LC-MS data processing in metabolomics.
It embraces the concept of visual programming through its KNIME plug-in, simplifying the process of
building complex workflows. The library was validated using open data.
432. Data Dependent Peak Model Based Spectrum Deconvolution for Analysis of High Resolution LC-MS
Data
PubMed Central
2015-01-01
A data dependent peak model (DDPM) based spectrum deconvolution method was developed for
analysis of high resolution LC-MS data. To construct the selected ion chromatogram (XIC), a
clustering method, the density based spatial clustering of applications with noise (DBSCAN), is
applied to all m/z values of an LC-MS data set to group the m/z values into each XIC. The DBSCAN
constructs XICs without the need for a user defined m/z variation window. After the XIC construction,
the peaks of molecular ions in each XIC are detected using both the first and the second derivative
tests, followed by an optimized chromatographic peak model selection method for peak deconvolution.
A total of six chromatographic peak models are considered, including Gaussian, log-normal, Poisson,
gamma, exponentially modified Gaussian, and hybrid of exponential and Gaussian models. The
abundant nonoverlapping peaks are chosen to find the optimal peak models that are both data- and
retention-time-dependent. Analysis of 18 spiked-in LC-MS data demonstrates that the proposed
DDPM spectrum deconvolution method outperforms the traditional method. On average, the DDPM
approach not only detected 58 more chromatographic peaks from each of the testing LC-MS data but
also improved the retention time and peak area 3% and 6%, respectively. PMID:24533635
433. A Guideline to Univariate Statistical Analysis for LC/MS-Based Untargeted Metabolomics-Derived

Data
PubMed Central
Vinaixa, Maria; Samino, Sara; Saez, Isabel; Duran, Jordi; Guinovart, Joan J.; Yanes, Oscar
2012-01-01
Several metabolomic software programs provide methods for peak picking, retention time alignment
and quantification of metabolite features in LC/MS-based metabolomics. Statistical analysis, however,
is needed in order to discover those features significantly altered between samples. By comparing the
retention time and MS/MS data of a model compound to that from the altered feature of interest in the
research sample, metabolites can be then unequivocally identified. This paper reports on a
comprehensive overview of a workflow for statistical analysis to rank relevant metabolite features that
will be selected for further MS/MS experiments. We focus on univariate data analysis applied in
parallel on all detected features. Characteristics and challenges of this analysis are discussed and
illustrated using four different real LC/MS untargeted metabolomic datasets. We demonstrate the
influence of considering or violating mathematical assumptions on which univariate statistical test rely,
using high-dimensional LC/MS datasets. Issues in data analysis such as determination of sample size,
analytical variation, assumption of normality and homocedasticity, or correction for multiple testing
are discussed and illustrated in the context of our four untargeted LC/MS working examples.
PMID:24957762
434. A Guideline to Univariate Statistical Analysis for LC/MS-Based Untargeted Metabolomics-Derived

Data.
PubMed
Vinaixa, Maria; Samino, Sara; Saez, Isabel; Duran, Jordi; Guinovart, Joan J; Yanes, Oscar
2012-10-18
Several metabolomic software programs provide methods for peak picking, retention time alignment
and quantification of metabolite features in LC/MS-based metabolomics. Statistical analysis, however,
is needed in order to discover those features significantly altered between samples. By comparing the
retention time and MS/MS data of a model compound to that from the altered feature of interest in the
research sample, metabolites can be then unequivocally identified. This paper reports on a
comprehensive overview of a workflow for statistical analysis to rank relevant metabolite features that
will be selected for further MS/MS experiments. We focus on univariate data analysis applied in
parallel on all detected features. Characteristics and challenges of this analysis are discussed and
illustrated using four different real LC/MS untargeted metabolomic datasets. We demonstrate the
influence of considering or violating mathematical assumptions on which univariate statistical test rely,
using high-dimensional LC/MS datasets. Issues in data analysis such as determination of sample size,
analytical variation, assumption of normality and homocedasticity, or correction for multiple testing
are discussed and illustrated in the context of our four untargeted LC/MS working examples.
435. Transitioning Students out of College: The Senior LC in Psychology at Wagner College
Nolan, Laurence J.; Jenkins, Steve M.
2012-01-01
At Wagner College, students are required to participate in a series of three curriculum-based learning
communities (C-BLCs) as the core of the undergraduate curriculum known as the Wagner Plan for the
Practical Liberal Arts. This article describes the senior learning community (LC) in psychology at
Wagner College, which is an example of aâ€¦
436. Crystallization and preliminary crystallographic analysis of human Atg4Bâ€“LC3 complex
SciTech Connect
Satoo, Kenji; Suzuki, Nobuo N.; Fujioka, Yuko
2007-02-01
Human Atg4B and LC3 were expressed, purified and crystallized as a complex. Diffraction data were
collected to a resolution of 1.9 Ã…. The reversible modification of Atg8 with
phosphatidylethanolamine (PE) is crucial for autophagy, the bulk degradation process of cytoplasmic
components by the vacuolar/lysosomal system. Atg4 is a cysteine protease that is responsible for the
processing and deconjugation of Atg8. Human Atg4B (HsAtg4B; a mammalian orthologue of yeast
Atg4) and LC3 (a mammalian orthologue of yeast Atg8) were expressed and purified and two
complexes, one consisting of HsAtg4B(1â€“354) and LC3(1â€“120) (complex I; the product complex)
and the other consisting ofmoreÂ Â» HsAtg4B(1â€“354) and LC3(1â€“124) (complex II; the substrate
complex), were crystallized using polyethylene glycol 3350 as a precipitant. In both complexes His280
of HsAtg4B was mutated to alanine. The crystals belong to the same space group P2{sub 1}2{sub
1}2{sub 1}, with unit-cell parameters a = 47.5, b = 91.8, c = 102.6 Ã… for complex I and a = 46.9, b
= 90.9, c = 102.5 Ã… for complex II. Diffraction data were collected to a resolution of 1.9 Ã… from
both crystals.Â«Â less
437. Trans Ova Genetics, L.C. - Clean Water Act Public Notice
The EPA is providing notice of a proposed Administrative Penalty Assessment against Trans Ova
Genetics, L.C., a business located at 2938 380th Street Sioux Center, IA 51250, for alleged violations
at the Trans Ova Genetics, L.C.â€™s facility located in 12425
438. User Guide to the 1981 LC (Language Census) Database. Version 1.2.
Kimbrough, Kenneth L.
This guide is designed to introduce potential users of the California Language Census data to a means
of accessing that data using an online, interactive computer system known as "1981 LC." The language
census is an actual count of the numbers of pupils with a primary language other than English in
California public schools as of March 1â€¦
439. NMR Characterization of Self-Association Domains Promoted by Interactions with LC8 Hub Protein
PubMed Central
Barbar, Elisar; Nyarko, Afua
2014-01-01
Most proteins in interaction networks have a small number of partners, while a few, called hubs,
participate in a large number of interactions and play a central role in cell homeostasis. One highly
conserved hub is a protein called LC8 that was originally identified as an essential component of the
multi-subunit complex dynein but later shown to be also critical in multiple protein complexes in
diverse systems. What is intriguing about this hub protein is that it does not passively bind its various
partners but emerging evidence suggests that LC8 acts as a dimerization engine that promotes self-
association and/or higher order organization of its primarily disordered monomeric partners. This
structural organization process does not require ATP but is triggered by long-range allosteric
regulation initiated by LC8 binding a pair of disordered chains forming a bivalent or polybivalent
scaffold. This review focuses on the role of LC8 in promoting self-association of two of its binding
partners, a dynein intermediate chain and a non dynein protein called Swallow. PMID:24757501
440. LC-MS analysis of glycoalkaloid diversity among seven potato genotypes
Secondary metabolites in potato tubers include both phytonutrients and plant defense compounds. The
extent of variation in these small molecules among different potato genotypes is not well
characterized. LC-MS analysis of tuber extracts from seven potato genotypes showed that one large
source of sm...
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441. LC-MS Analysis of Phenolic Compounds in Tubers Showing Zebra Chip Symptoms
A new potato disorder called zebra chip (ZC) has been identified in the United States and has been
especially problematic in Texas where substantial economic losses have been incurred. Upon frying,
ZC tubers develop a dark â€œzebra chipâ€ pattern of discoloration. LC-MS analysis of symptomatic
tubers...
442. Myosins and DYNLL1/LC8 in the honey bee (Apis mellifera L.) brain.
PubMed
CalÃ¡bria, Luciana Karen; Peixoto, Pablo Marco Veras; Passos Lima, Andreia Barcelos; Peixoto,
Leonardo Gomes; de Moraes, Viviane Rodrigues Alves; Teixeira, Renata Roland; Dos Santos, Claudia
Tavares; E Silva, LetÃcia Oliveira; da Silva, Maria de FÃ¡tima Rodrigues; dos Santos, Ana Alice
Diniz; Garcia-Cairasco, Norberto; Martins, AntÃ´nio Roberto; Espreafico, Enilza Maria; Espindola,
Foued Salmen
2011-09-01
Honey bees have brain structures with specialized and developed systems of communication that
account for memory, learning capacity and behavioral organization with a set of genes homologous to
vertebrate genes. Many microtubule- and actin-based molecular motors are involved in
axonal/dendritic transport. Myosin-Va is present in the honey bee Apis mellifera nervous system of the
larvae and adult castes and subcastes. DYNLL1/LC8 and myosin-IIb, -VI and -IXb have also been
detected in the adult brain. SNARE proteins, such as CaMKII, clathrin, syntaxin, SNAP25, munc18,
synaptophysin and synaptotagmin, are also expressed in the honey bee brain. Honey bee myosin-Va
displayed ATP-dependent solubility and was associated with DYNLL1/LC8 and SNARE proteins in
the membrane vesicle-enriched fraction. Myosin-Va expression was also decreased after the
intracerebral injection of melittin and NMDA. The immunolocalization of myosin-Va and -IV,
DYNLL1/LC8, and synaptophysin in mushroom bodies, and optical and antennal lobes was compared
with the brain morphology based on Neo-Timm histochemistry and revealed a distinct and punctate
distribution. This result suggested that the pattern of localization is associated with neuron function.
Therefore, our data indicated that the roles of myosins, DYNLL1/LC8, and SNARE proteins in the
nervous and visual systems of honey bees should be further studied under different developmental,
caste and behavioral conditions. Copyright Â© 2011 Elsevier Ltd. All rights reserved.
443. Arsenic speciation and fucoxanthin analysis from seaweed dietary supplements using LC-MS
Inorganic species are considered more toxic to humans than organic arsenic and total arsenic. Analysis
of total arsenic in metallic form, organic and inorganic arsenic species from seaweeds and dietary
supplements using LC-ICP-MS was developed. Solvent extraction with sonication and microwave
extr...
444. Activation of beta- and alpha-2-adrenoceptors in the basolateral amygdala has opposing effects on
hippocampal-prefrontal long-term potentiation.
PubMed
Lim, Ee Peng; Dawe, Gavin S; Jay, ThÃ©rÃ¨se M
2017-01-01
Noradrenaline (NA), released by the locus coeruleus (LC), plays a key role in mediating the effects of
stress on memory functions. The LC provides diffuse projections to many forebrain nuclei including
the hippocampus, the prefrontal cortex (PFC), and the basolateral amygdala (BLA). These three
structures are intricately interlinked. The hippocampal-prefrontal (H-PFC) pathway is involved in
various cognitive functions. The first aim of this study was to examine the role of BLA in H-PFC
plasticity by infusion of drugs to activate and inactivate the BLA and studying the effects on H-PFC
long-term potentiation (LTP) in the rat in vivo. Activation of the BLA with glutamate impaired, while
inactivation with muscimol augmented, H-PFC LTP. This study also aimed to demonstrate how
directly applying noradrenaline and other noradrenergic agents in the BLA can affect H-PFC LTP.
Noradrenaline at 1Î¼g/0.2Î¼l enhanced H-PFC LTP. Stimulating alpha-2-adrenoceptors in the BLA
with clonidine enhanced LTP while blocking alpha-2 adrenoceptors with idazoxan impaired it.
Propranolol, a non-selective beta antagonist, enhanced H-PFC LTP while isoprenaline, a non-selective
beta agonist, decreased H-PFC LTP. These results suggest that the BLA regulates H-PFC plasticity
negatively and also provide a mechanism by which noradrenaline in the BLA can affect H-PFC
plasticity via alpha-2 and beta adrenoceptors. Copyright Â© 2016 Elsevier Inc. All rights reserved.
445. Systemic administration of WIN 55,212-2 increases norepinephrine release in the rat frontal cortex.
PubMed
Oropeza, V C; Page, M E; Van Bockstaele, E J
2005-06-07
Cannabinoid agonists modulate a variety of behavioral functions by activating cannabinoid receptors

that are widely distributed throughout the central nervous system. In the present study, norepinephrine
efflux was assessed in the frontal cortex of rats that received a systemic administration of the
cannabinoid agonist, WIN 55,212-2. The synthetic cannabinoid agonist dose-dependently increased
the release of norepinephrine in this brain region. Pretreatment with the cannabinoid receptor
antagonist, SR 141716A, blocked the increase in norepinephrine release. To identify sites of cellular
activation, immunocytochemical detection of c-Fos was combined with detection of the catecholamine
synthesizing enzyme, tyrosine hydroxylase (TH), in the brainstem nucleus locus coeruleus (LC), a
region that is the sole source of norepinephrine to the frontal cortex. Systemic administration of WIN
55,212-2 significantly increased the number of c-Fos immunoreactive cells within TH-containing
neurons in the LC compared to vehicle-treated rats. Pretreatment with SR 141716A inhibited the WIN
55,212-2 induced c-Fos expression, while the antagonist alone did not affect c-Fos expression. Taken
together, these data indicate that systemically administered cannabinoid agonists stimulate
norepinephrine release in the frontal cortex by activating noradrenergic neurons in the coeruleo-frontal
cortex pathway. These effects may partially underlie changes in attention, arousal and anxiety
observed following exposure to cannabis-based drugs.
446. LcMCII-1 is involved in the ROS-dependent senescence of the rudimentary leaves of Litchi chinensis.
PubMed
Wang, Congcong; LÃ¼, Peitao; Zhong, Silin; Chen, Houbin; Zhou, Biyan
2017-01-01
LcMCII - 1 is a type II metacaspase. Over-expression of LcMCII- 1 in Arabidopsis promoted ROS-

dependent and natural senescence. Virus-induced LcMCII- 1 silencing delayed the ROS-dependent
senescence of the rudimentary leaves of Litchi chinensis . Litchi is an evergreen woody fruit tree that
is widely cultivated in subtropical and tropical regions. Its floral buds are mixed with axillary or apical
panicle primordia, leaf primordia and rudimentary leaves. A low spring temperature is vital for litchi
production as it promotes the abscission of the rudimentary leaves, which could otherwise prevent
panicle development. Hence, climate change could present additional challenges for litchi production.
We previously reported that reactive oxygen species (ROS) can substitute low-temperature treatment
to induce the senescence of rudimentary leaves. We have now identified from RNA-Seq data a litchi
type II metacaspase gene, LcMCII-1, that is responsive to ROS. Silencing LcMCII-1 by virus-induced
gene silencing delayed ROS-dependent senescence. The ectopic over-expression of LcMCII-1 in
transgenic Arabidopsis promoted ROS-dependent and natural senescence. Consistently, the transient
expression of LcMCII-1 in tobacco leaf by agroinfiltration resulted in leaf yellowing. Our findings
demonstrate that LcMCII-1 is positively involved in the regulation of rudimentary leaf senescence in
litchi and provide a new target for the future molecular breeding of new cultivars that can set fruit in
warmer climates.
447. 78 FR 11169 - Virginia Hydrogeneration and Historical Society's, L.C.; Notice of Termination of
License by...
Federal Register 2010, 2011, 2012, 2013, 2014
2013-02-15
... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Project No. 8657-064]
Virginia Hydrogeneration and Historical Society's, L.C.; Notice of Termination of License by Implied
Surrender and... Hydrogeneration and Historical Society's, L.C. e. Name and Location of Project: The
Harvell Hydroelectric Project...
448. Elucidation of the anti-autophagy mechanism of the Legionella effector RavZ using semisynthetic LC3
proteins
PubMed Central
Yang, Aimin; Pantoom, Supansa; Wu, Yao-Wen
2017-01-01
Autophagy is a conserved cellular process involved in the elimination of proteins and organelles. It is
also used to combat infection with pathogenic microbes. The intracellular pathogen Legionella
pneumophila manipulates autophagy by delivering the effector protein RavZ to deconjugate Atg8/LC3
proteins coupled to phosphatidylethanolamine (PE) on autophagosomal membranes. To understand
how RavZ recognizes and deconjugates LC3-PE, we prepared semisynthetic LC3 proteins and
elucidated the structures of the RavZ:LC3 interaction. Semisynthetic LC3 proteins allowed the
analysis of structure-function relationships. RavZ extracts LC3-PE from the membrane before
deconjugation. RavZ initially recognizes the LC3 molecule on membranes via its N-terminal LC3-
interacting region (LIR) motif. The RavZ Î±3 helix is involved in extraction of the PE moiety and
docking of the acyl chains into the lipid-binding site of RavZ that is related in structure to that of the
phospholipid transfer protein Sec14. Thus, Legionella has evolved a novel mechanism to specifically
evade host autophagy. DOI: http://dx.doi.org/10.7554/eLife.23905.001 PMID:28395732
449. The N-terminus and Phe52 residue of LC3 recruit p62/SQSTM1 into autophagosomes.
PubMed
Shvets, Elena; Fass, Ephraim; Scherz-Shouval, Ruthie; Elazar, Zvulun
2008-08-15
LC3 belongs to a novel ubiquitin-like protein family that is involved in different intracellular
trafficking processes, including autophagy. All members of this family share a unique three-
dimensional structure composed of a C-terminal ubiquitin core and two N-terminal alpha-helices.
Here, we focus on the specific contribution of these regions to autophagy induced by amino acid
deprivation. We show that the ubiquitin core by itself is sufficient for LC3 processing through the
conjugation machinery and for its consequent targeting to the autophagosomal membrane. The N-
terminal region was found to be important for interaction between LC3 and p62/SQSTM1 (hereafter
termed p62). This interaction is dependent on the first 10 amino acids of LC3 and on specific residues
located within the ubiquitin core. Knockdown of LC3 isoforms and overexpression of LC3 mutants
that fail to interact with p62 blocked the incorporation of p62 into autophagosomes. The accumulation
of p62 was accompanied by elevated levels of polyubiquitylated detergent-insoluble structures. p62,
however, is not required for LC3 lipidation, autophagosome formation and targeting to lysosomes. Our
results support the proposal that LC3 is responsible for recruiting p62 into autophagosomes, a process
mediated by phenylalanine 52, located within the ubiquitin core, and the N-terminal region of the
protein.
450. THE DEVELOPMENT AND INTER-LABORATORY VERIFICATION OF LC-MS LIBRARIES

FOR ORGANIC CHEMICALS OF ENVIRONMENTAL CONCERN
The development, verification, and comparison study between LC-MS libraries for two
manufacturersâ€™ instruments and a verified protocol are discussed. The LC-MS library protocol was
verified through an inter-laboratory study that involved Federal, State, and private laboratories. ...
451. The autophagy-related marker LC3 can predict prognosis in human hepatocellular carcinoma.
PubMed
Lee, Yoo Jin; Hah, Yu Jin; Ha, Yu Jin; Kang, Yu Na; Kang, Koo Jeong; Hwang, Jae Seok; Chung, Woo
Jin; Cho, Kwang Bum; Park, Kyung Sik; Kim, Eun Soo; Seo, Hye-Young; Kim, Mi-Kyung; Park,
Keun-Gyu; Jang, Byoung Kuk
2013-01-01
Defects of autophagy and endoplasmic reticulum (ER) stress are related to many diseases and tumors.
However, only a few studies have examined hepatocellular carcinoma (HCC) as related to these
processes. Therefore, in this study, we investigated the expression and extent of autophagy and ER
stress-related markers in HCC and their influence on clinical characteristics and prognosis for each
protein. The expression of autophagy-related markers (LC3 and Beclin-1) and ER stress-related
markers (GRP78 and CHOP) was analyzed by immunohistochemistry on tissues from completely
resected specimens of 190 HCC patients. Their influence on clinicopathologic features and prognosis
were evaluated using the chi-square test and Kaplan-Meier analysis. Correlations of each protein were
determined by Spearman's correlation analysis. LC3 expression was not correlated with TNM, BCLC
stage, or Edmonson-Steiner grading, whereas it was correlated with longer overall survival (OS) (p =
0.039) and tended to be related with longer time to recurrence (TTR) (p=0.068) although it did not
show statistical significance. Multivariate analysis indicated that LC3 expression was a significantly
independent prognostic factor of OS (HR, 0.42; 95% CI, 0.22-0.80; p-value=0.009) and TTR (HR,
0.54; 95% CI, 0.33-0.90; p=0.017). Expression of LC3 in advanced stages of TNM (III) (p=0.045) and
Edmonson-Steiner Grades (III and IV) (p=0.043) was correlated with longer survival, but not in the
early stages. A positive correlation was not observed between the expression of autophagy-related
markers and ER stress-related markers. Our results suggest that the expression and extent of LC3
might be a strong prognostic factor of HCC, especially in patients with surgical resection.
452. Differential diagnosis of vacuolar muscle biopsies: use of p62, LC3 and LAMP2
immunohistochemistry.
PubMed
Vittonatto, Elisa; Boschi, Silvia; CHIADÃ²-Piat, Loredana; Ponzalino, Valentina; Bortolani, Sara;
Brusa, Chiara; Rainero, Innocenzo; Ricci, Federica; Vercelli, Liliana; Mongini, Tiziana
2017-12-01
Intrafibral vacuoles are the morphological hallmark in a wide variety of human skeletal muscle
disorders with different etiology. In most cases, differential diagnosis is feasible with a routine
histochemical work up of muscle biopsy. Ultrastructural analysis is an important confirmatory tool, but
it is not widely available. Immunohistochemical stainings for p62, LAMP2 and LC3 are commonly
available as tissutal marker for autophagy. We compared the immunohistochemical patterns for
autophagic markers p62, LC3 and LAMP2 with routine histochemical markers in 39 biopsies from
patients with definite diagnoses of glycogen storage disease type 2 (LOPD or Pompe disease, PD),
sporadic inclusion body myositis (sIBM), oculo-pharyngeal muscular dystrophy (OPMD) and
necrotizing myopathy (NM). Moreover, we also analyzed muscles of 10 normal controls. In PD group,
LC3 and LAMP2 showed an higher percentage of positive fibers, whereas p62 was limited to a
minority of fibers, thus paralleling the results of histochemical stainings; in NM group, LAMP2 and
LC-3 were diffusely and unspecifically expressed in necrotic fibers, with p62 significantly expressed
only in two cases. OPMD biopsies did not reveal any significant positivity. The most interesting results
were observed in sIBM group, where p62 was expressed in all cases, even in fibers without other
markers positivity. There results, although limited to a small number of cases, suggest that the
contemporary use of p62, LAMP2 and LC-3 staining may have an adjunctive role in characterizing
muscle fiber vacuoles, revealing autophagic pathway activation and providing further clues for the
understanding of pathogenetic mechanisms.s.
453. Identification of four new degradation products of epirubicin through forced degradation, LC-UV,
MSn and LC-MS-TOF studies.
PubMed
Kaushik, Dheeraj; Saini, Balraj; Bansal, Gulshan
2015-01-01
Epirubicin (EPI) was subjected to International Conference on Harmonization recommended forced

degradation under the conditions of hydrolysis, oxidation, dry heat and photolysis to characterize its
possible impurities and/or degradation products. The drug was found highly unstable to alkaline
hydrolysis even at room temperature, unstable to acid hydrolysis at 80Â°C and to oxidation at room
temperature. The hydrolytic and oxidative degradation products were resolved on an Agilent RP8 (150
mm Ã— 4.6 mm; 5 Âµm) column with isocratic elution using mobile phase composed of ammonium
formate (10 mM, pH 3.0), acetonitrile and methanol. The drug degraded to four oxidative products (O-
I, O-II, O-III and O-IV) and to one acid hydrolyzed product (A-I). Purity of each peak in liquid
chromatography-ultraviolet (LC-UV) chromatogram was ascertained through photodiode array (LC-
PDA) analysis. The products were characterized through electrospray ionization-mass spectrometry
(+ESI-MS(n)) studies on EPI and liquid chromatography-time of flight mass spectrometry (LC-MS-
TOF) studies on degraded drug solutions. The products, O-I-O-IV, were characterized as 2-hydroxy-8-
desacetylepirubicin-8-hydroperoxide, 4-hydroxy-8-desacetylepirubicin-8-hydroperoxide, 8-
desacetylepirubicin-8-hydroperoxide and 8-desacetylepirubicin, respectively, and product A-I was
characterized as deglucosaminylepirubicin. While A-I was found to be a pharmacopoeial impurity, all
oxidative products were found to be new degradation impurities. The mechanisms and pathways of
degradation of EPI were discussed and outlined. Â© The Author 2015. Published by Oxford
University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
454. Identification of alkyl dimethylbenzylammonium surfactants in water samples by solid-phase

extraction followed by ion trap LC/MS and LC/MS/MS
USGS Publications Warehouse
Ferrer, I.; Furlong, E.T.
2001-01-01
A novel methodology was developed for the determination of alkyl (C12, C14, and C16)
dimethylbenzylammonium chloride (benzalkonium chloride or BAC, Chemical Abstract Service
number: 8001-54-5) in water samples. This method is based on solid-phase extraction (SPE) using
polymeric cartridges, followed by high-performance liquid chromatography/ion trap mass
spectrometry (LC/MS) and tandem mass spectrometry(MS/MS) detection, equipped with an
electrospray interface in positive ion mode. Chromatographic separation was achieved for three BAC
homologues by using a C18 column and a gradient of acetonitrile/10 millimolar aqueous ammonium
formate. Total method recoveries were higher than 71% in different water matrices. The main ions
observed by LC/MS were at mass-to-charge ratios (m/z) of 304, 332, and 360, which correspond to the
molecular ions of the C12, C14, and C16 alkyl BAC, respectively. The unequivocal structural
identification of these compounds in water samples was performed by LC/MS/MS after isolation and
subsequent fragmentation of each molecular ion. The main fragmentation observed for the three
different homologues corresponded to the loss of the toluyl group in the chemical structure, which
leads to the fragment ions at m/z 212, 240, and 268 and a tropylium ion, characteristic of all
homologues, at m/z 91. Detection limits for the methodology developed in this work were in the low
nanogram-per-liter range. Concentration levels of BAC - ranging from 1.2 to 36.6 micrograms per liter
- were found in surface-water samples collected downstream from different wastewater-treatment
discharges, thus indicating its input and persistence through the wastewater-treatment process.
455. Comparison of the anti-inflammatory active constituents and hepatotoxic pyrrolizidine alkaloids in two
Senecio plants and their preparations by LC-UV and LC-MS.
PubMed
Chen, Pinghong; Wang, Yi; Chen, Lulin; Jiang, Wei; Niu, Yan; Shao, Qing; Gao, Lu; Zhao,
Quancheng; Yan, Licheng; Wang, Shufang
2015-11-10
Two Senecio plants, Senecio cannabifolius Less. and its variety S. cannabifolius Less. var. integrifolius
(Kiodz.) Kidam., were both used as the raw material of Feining granule, a traditional Chinese medicine
product for treating respiratory diseases. In this study, the chemical profiles of these two plants were
investigated and compared by liquid chromatography-mass spectrometry (LC-MS) and nuclear
magnetic resonance (NMR). A total number of 83 constituents, including 55 organic acids, 11
flavonoids, 4 alkaloids, 3 terpenes and 10 other types of compounds, were characterized. The results
indicated that the levels of most flavonoids were higher in S. cannabifolius than in S. cannabifolius
var. integrifolius, however, the levels of hepatotoxic pyrrolizidine alkaloids (PAs) were higher in S.
cannabifolius var. integrifolius than in S. cannabifolius. Fifteen constituents were evaluated on
lipopolysaccharides (LPS) induced RAW 264.7 cells, and eleven of them showed inhibition effect
against nitric oxide (NO) production. Finally, the levels of ten major constituents (including seven
anti-inflammatory active ones) and two PAs in Feining granule from two Senecio plants were
determined and compared by the LC-UV and LC-MS methods, respectively. It was found that one
organic acid (homogentisic acid) and two PAs (seneciphylline and senecionine) had higher contents in
the preparation of S. cannabifolius var. integrifolius than in that of S. cannabifolius, however, the
situations were inverse for the levels of four organic acids and flavonoids (chlorogenic acid,
hyperoside, isoquercitrin, and isochlorogenic acid B). Based on the above results, S. cannabifolius
might be a better raw material for Feining granule than S. cannabifolius var. integrifolius, because it
contained more anti-inflammatory constituents and less hepatotoxic PAs than the latter. However, more
pharmacological evaluations should be carried out to support the selection. The results in this study
were helpful
456. mRNA and protein dataset of autophagy markers (LC3 and p62) in several cell lines.
PubMed
GÃ³mez-SÃ¡nchez, RubÃ©n; Yakhine-Diop, Sokhna M S; RodrÃguez-Arribas, Mario; Bravo-San

Pedro, JosÃ© M; MartÃnez-ChacÃ³n, Guadalupe; Uribe-Carretero, Elisabet; Pinheiro de Castro,
Diana C J; Pizarro-Estrella, Elisa; Fuentes, JosÃ© M; GonzÃ¡lez-Polo, Rosa A
2016-06-01
We characterized the dynamics of autophagy in vitro using four different cell systems and analyzing
markers widely used in this field, i.e. LC3 (microtubule-associated protein 1 light chain 3; protein
recruited from the cytosol (LC3-I) to the autophagosomal membrane where it is lipidated (LC3-II))
and p62/SQSTM1 (adaptor protein that serves as a link between LC3 and ubiquitinated substrates),
(Klionsky et al., 2016) [1]. Data provided include analyses of protein levels of LC3 and p62 by
Western-blotting and endogenous immunofluorescence experiments, but also p62 mRNA levels
obtained by quantitative PCR (qPCR). To monitor the turnover of these autophagy markers and, thus,
measure the flux of this pathway, cells were under starvation conditions and/or treated with
bafilomycin A1 (Baf. A1) to block fusion of autophagosomes with lysosomes.
457. The LC Domain of hnRNPA2 Adopts Similar Conformations in Hydrogel Polymers, Liquid-like
Droplets and Nuclei
PubMed Central
Xiang, Siheng; Kato, Masato; Wu, Leeju; Lin, Yi; Ding, Ming; Zhang, Yajie; Yu, Yonghao; McKnight,
Steven L.
2016-01-01
SUMMARY Many DNA and RNA regulatory proteins contain polypeptide domains that are
unstructured when analyzed in cell lysates. These domains are typified by an over-representation of a
limited number of amino acids and have been termed prion-like, intrinsically disordered or low
complexity (LC) domains. When incubated at high concentration, certain of these LC domains
polymerize into labile, amyloid-like fibers. Here we report methods allowing the generation of a
molecular footprint of the polymeric state of the LC domain of hnRNPA2. By deploying this
footprinting technique to probe the structure of the native hnRNPA2 protein present in isolated nuclei,
we offer evidence that its LC domain exists in a similar conformation as that described for
recombinant polymers of the protein. These observations favor biologic utility to the polymerization of
LC domains in the pathway of information transfer from gene to message to protein. PMID:26544936
458. Nano-LC/MALDI-MS using a column-integrated spotting probe for analysis of complex biomolecule
samples.
PubMed
Hioki, Yusaku; Tanimura, Ritsuko; Iwamoto, Shinichi; Tanaka, Koichi
2014-03-04
Nanoflow liquid chromatography (nano-LC) is an essential technique for highly sensitive analysis of
complex biological samples, and matrix-assisted laser desorption/ionization mass spectrometry
(MALDI-MS) is advantageous for rapid identification of proteins and in-depth analysis of post-
translational modifications (PTMs). A combination of nano-LC and MALDI-MS (nano-LC/MALDI-
MS) is useful for highly sensitive and detailed analysis in life sciences. However, the existing system
does not fully utilize the advantages of each technique, especially in the interface of eluate transfer
from nano-LC to a MALDI plate. To effectively combine nano-LC with MALDI-MS, we integrated a
nano-LC column and a deposition probe for the first time (column probe) and incorporated it into a
nano-LC/MALDI-MS system. Spotting nanoliter eluate droplets directly from the column onto the
MALDI plate prevents postcolumn diffusion and preserves the chromatographic resolution. A DHB
prespotted plate was prepared to suit the fabricated column probe to concentrate the droplets of nano-
LC eluate. The performance of the advanced nano-LC/MALDI-MS system was substantiated by
analyzing protein digests. When the system was coupled with multidimensional liquid chromatography
(MDLC), trace amounts of glycopeptides that spiked into complex samples were successfully detected.
Thus, a nano-LC/MALDI-MS direct-spotting system that eliminates postcolumn diffusion was
constructed, and the efficacy of the system was demonstrated through highly sensitive analysis of the
protein digests or spiked glycopeptides.
459. Reduction of Solvent Effect in Reverse Phase Gradient Elution LC-ICP-MS
SciTech Connect
Sullivan, Patrick Allen
2005-12-17
Quantification in liquid chromatography (LC) is becoming very important as more researchers are
using LC, not as an analytical tool itself, but as a sample introduction system for other analytical
instruments. The ability of LC instrumentation to quickly separate a wide variety of compounds makes
it ideal for analysis of complex mixtures. For elemental speciation, LC is joined with inductively
coupled plasma mass spectrometry (ICP-MS) to separate and detect metal-containing, organic
compounds in complex mixtures, such as biological samples. Often, the solvent gradients required to
perform complex separations will cause matrix effects within the plasma. This limits the sensitivity
ofmoreÂ Â» the ICP-MS and the quantification methods available for use in such analyses.
Traditionally, isotope dilution has been the method of choice for LC-ICP-MS quantification. The use
of naturally abundant isotopes of a single element in quantification corrects for most of the effects that
LC solvent gradients produce within the plasma. However, not all elements of interest in speciation
studies have multiple naturally occurring isotopes; and polyatomic interferences for a given isotope
can develop within the plasma, depending on the solvent matrix. This is the case for reverse phase LC
separations, where increasing amounts of organic solvent are required. For such separations, an
alternative to isotope dilution for quantification would be is needed. To this end, a new method was
developed using the Apex-Q desolvation system (ESI, Omaha, NE) to couple LC instrumentation with
an ICP-MS device. The desolvation power of the system allowed greater concentrations of methanol to
be introduced to the plasma prior to destabilization than with direct methanol injection into the plasma.
Studies were performed, using simulated and actual linear methanol gradients, to find analyte-internal
standard (AIS) pairs whose ratio remains consistent (deviations {+-} 10%) over methanol
concentration ranges
460. Methods for the analysis of organophosphorus flame retardants-Comparison of GC-EI-MS, GC-NCI-
MS, LC-ESI-MS/MS, and LC-APCI-MS/MS.
PubMed
Tokumura, Masahiro; Miyake, Yuichi; Wang, Qi; Nakayama, Hayato; Amagai, Takashi; Ogo, Sayaka;
Kume, Kazunari; Kobayashi, Takeshi; Takasu, Shinji; Ogawa, Kumiko
2018-04-16
Organophosphorus flame retardants (PFRs) are extensively used as alternatives to banned

polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecane (HBCD). In this study, we
analyzed 14 PFRs by means of four mass-spectrometry-based methods: gas chromatography combined
with electron-impact mass spectrometry (GC-EI-MS) or negative-chemical-ionization mass
spectrometry (GC-NCI-MS) and liquid chromatography combined with tandem mass spectrometry
using electrospray ionization (LC-ESI-MS/MS) or atmospheric pressure chemical ionization (LC-
APCI-MS/MS). The limits of quantification (LOQs) for LC-ESI-MS/MS and LC-APCI-MS/MS (0.81-
970Â pg) were 1-2 orders of magnitude lower than the LOQs for GC-EI-MS and GC-NCI-MS (2.3-
3900Â pg). LC-APCI-MS/MS showed the lowest LOQs (mean = 41Â pg; median = 3.4Â pg) for all
but two of the PFRs targeted in this study. For LC-APCI-MS/MS, the lowest LOQ was observed for
tributyl phosphate (TBP) (0.81Â pg), and the highest was observed for tris(butoxyethyl) phosphate
(TBOEP) (36Â pg). The results of this study indicate that LC-APCI-MS/MS is the optimum analytical
method for the target PFRs, at least in terms of LOQ.
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461. Identification of BVT.2938 metabolites by LC/MS and LC/MS/MS after in vitro incubations with liver
microsomes and hepatocytes.
PubMed
Edlund, Per Olof; Baranczewski, Pawel
2004-03-10
The metabolism of the 5HT2c agonist BVT.2938, 1-(3-[2-[(2-ethoxy-3-pyridinyl)oxy]ethoxy]-2-

pyrazinyl)-2(R)-methylpiperazine, was studied in vitro by incubation with rat, monkey and human
liver microsomes as well as cryopreserved hepatocytes, followed by liquid chromatography/mass
spectrometry (LC/MS) and LC/MS/MS analysis on a quadrupole-time of flight mass spectrometer for
structural elucidation. Deuterium exchange on column was used to differentiate between hydroxylation
and N-oxidation. Liver microsomes were incubated in two different buffer systems with optimum
conditions for cytochrome P450 activity or UDP-glucuronosyltransferase activity. The major phase I
metabolites of BVT.2938 originated from O-deethylation of the pyridine ring, O-dealkylation of the
ethylene bridge, pyrazine ring hydroxylation, hydroxylation of pyridine ring and piperazine ring N-
hydroxylation. When a hydrogen carbonate buffer system was supplemented with UDPGA, the
piperazine carbamoyl-glucuronide from the parent compound was identified together with several
glucuronides of the phase I metabolites. The metabolite pattern in hepatocytes was similar to
microsomes except that the sulphate at the N-position of the piperazine ring of BVT.2938 was
identified, while the carbamoyl-glucuronide was missing. Excellent correlation was obtained between
radioactivity detection and the chemiluminescent nitrogen detector when the nitrogen content of the
analytes was taken into account.
462. Direct-injection screening for acidic drugs in plasma and neutral drugs in equine urine by differential-
gradient LC-LC coupled MS/MS.
PubMed
Stanley, Shawn M R; Wee, Wei Khee; Lim, Boon Huat; Foo, Hsiao Ching
2007-04-01
Direct-injection LC-LC hybrid tandem MS methods have been developed for undertaking broad-based
screening for acidic drugs in protein-precipitated plasma and neutral doping agents in equine urine. In
both analyses, analytes present in the matrix were trapped using a HLB extraction column before being
refocused and separated on a Chromolith RP-18e monolithic analytical column using a controlled
differential gradient generated by proportional dilution of the first column's eluent with water. Each
method has been optimised by the adoption of a mobile phase and gradient that was tailored to
enhance ionisation in the MS source while maintaining good chromatographic behaviour for the
majority of the target drugs. The analytical column eluent was fed into the heated nebulizer (HN) part
of the Duospray interface attached to a 4000 QTRAP mass spectrometer. Information dependent
acquisition (IDA) with dynamic background subtraction (DBS) was configured to trigger a sensitive
enhanced product ion (EPI) scan when a multiple reaction monitoring (MRM) survey scan signal
exceeded the defined criteria. Ninety-one percent of acidic drugs in protein-precipitated plasma and
80% of the neutral compounds in equine urine were detected when spiked at 10 ng/ml.
463. 4-hydroxyphenylacetic acid derivatives of inositol from dandelion (Taraxacum officinale) root
characterised using LC-SPE-NMR and LC-MS techniques.
PubMed
Kenny, O; Smyth, T J; Hewage, C M; Brunton, N P; McLoughlin, P
2014-02-01
The combination of hyphenated techniques, LC-SPE-NMR and LC-MS, to isolate and identify minor
isomeric compounds from an ethyl acetate fraction of Taraxacum officinale root was employed in this
study. Two distinct fractions of 4-hydroxyphenylacetic acid derivatives of inositol were isolated and
characterised by spectroscopic methods. The (1)H NMR spectra and MS data revealed two groups of
compounds, one of which were derivatives of the di-4-hydroxyphenylacetic acid derivative of the
inositol compound tetrahydroxy-5-[2-(4-hydroxyphenyl)acetyl] oxycyclohexyl-2-(4-hydroxyphenyl)
acetate, while the other group consisted of similar tri-substituted inositol derivatives. For both fractions
the derivatives of inositols vary in the number of 4-hydroxyphenylacetic acid groups present and their
position and geometry on the inositol ring. In total, three di-substituted and three tri-substituted 4-
hydroxyphenylacetic acid inositol derivates were identified for the first time along with a further two
previously reported di-substituted inositol derivatives. Copyright Â© 2013 Elsevier Ltd. All rights
reserved.
464. Multi-profile Bayesian alignment model for LC-MS data analysis with integration of internal standards
PubMed Central
Tsai, Tsung-Heng; Tadesse, Mahlet G.; Di Poto, Cristina; Pannell, Lewis K.; Mechref, Yehia; Wang,
Yue; Ressom, Habtom W.
2013-01-01
Motivation: Liquid chromatography-mass spectrometry (LC-MS) has been widely used for profiling
expression levels of biomolecules in various â€˜-omicâ€™ studies including proteomics,
metabolomics and glycomics. Appropriate LC-MS data preprocessing steps are needed to detect true
differences between biological groups. Retention time (RT) alignment, which is required to ensure that
ion intensity measurements among multiple LC-MS runs are comparable, is one of the most important
yet challenging preprocessing steps. Current alignment approaches estimate RT variability using either
single chromatograms or detected peaks, but do not simultaneously take into account the
complementary information embedded in the entire LC-MS data. Results: We propose a Bayesian
alignment model for LC-MS data analysis. The alignment model provides estimates of the RT
variability along with uncertainty measures. The model enables integration of multiple sources of
information including internal standards and clustered chromatograms in a mathematically rigorous
framework. We apply the model to LC-MS metabolomic, proteomic and glycomic data. The
performance of the model is evaluated based on ground-truth data, by measuring correlation of
variation, RT difference across runs and peak-matching performance. We demonstrate that Bayesian
alignment model improves significantly the RT alignment performance through appropriate integration
of relevant information. Availability and implementation: MATLAB code, raw and preprocessed LC-
MS data are available at http://omics.georgetown.edu/alignLCMS.html Contact: hwr@georgetown.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
PMID:24013927
465. During cooled storage the extender influences processed autophagy marker light chain 3 (LC3B) of
stallion spermatozoa.
PubMed
BolaÃ±os, J M Gallardo; MorÃ¡n, A MirÃ³; da Silva, C M Balao; DÃ¡vila, M Plaza; MuÃ±oz, P

MartÃn; Aparicio, I M; Tapia, J A; Ferrusola, C Ortega; PeÃ±a, F J
2014-02-01
To investigate the role of the processed autophagy marker light chain 3 (LC3B) protein in sperm
survival in stallion semen processing during cooled storage, split ejaculates were diluted in two
different extenders, KMT and INRA 96, and LC3B processing and sperm quality evaluated during
incubation at 5Â°C for five days. After 3 days of incubation there was a drop in total motility in both
extenders, although the percentage of progressive motile sperm was greater (P<0.05) in samples
extended in INRA96. On Day 5 of cooled storage all sperm parameters decreased significantly
independent of the extender, however, samples extended in INRA 96 maintained motility values while
those extended in KMT had a further decrease in motility compared with data collected on Day 3 of
incubation. The percentage of live sperm decreased over the time of incubation, but only in samples
incubated in KMT. The extender had a marked effect in LC3B processing during cooled storage.
Spermatozoa maintained in KMT extender did not exhibit LC3B processing, while in spermatozoa
incubated in INRA96 there was an increase (P<0.01) in LC3B processing after 5 days of cooled
storage. Stallion spermatozoa experience LC3B turnover during cooled storage, however, the extent
depends on the extender used. Apparently LC3B turnover is associated with enhanced survival.
466. BAG3 regulates total MAP1LC3B protein levels through a translational but not transcriptional
mechanism.
PubMed
RodrÃguez, Andrea E; LÃ³pez-Crisosto, Camila; PeÃ±a-OyarzÃºn, Daniel; Salas, Daniela; Parra,

Valentina; Quiroga, Clara; Morawe, Tobias; Chiong, Mario; Behl, Christian; Lavandero, Sergio
2016-01-01
Autophagy is mainly regulated by post-translational and lipid modifications of ATG proteins. In some
scenarios, the induction of autophagy is accompanied by increased levels of certain ATG mRNAs such
as MAP1LC3B/LC3B, ATG5 or ATG12. However, little is known about the regulation of ATG protein
synthesis at the translational level. The cochaperone of the HSP70 system BAG3 (BCL2-associated
athanogene 3) has been associated to LC3B lipidation through an unknown mechanism. In the present
work, we studied how BAG3 controls autophagy in HeLa and HEK293 cells. Our results showed that
BAG3 regulates the basal amount of total cellular LC3B protein by controlling its mRNA translation.
This effect was apparently specific to LC3B because other ATG protein levels were not affected.
BAG3 knockdown did not affect LC3B lipidation induced by nutrient deprivation or proteasome
inhibition. We concluded that BAG3 maintains the basal amount of LC3B protein by controlling the
translation of its mRNA in HeLa and HEK293 cells.
467. BAG3 regulates total MAP1LC3B protein levels through a translational but not transcriptional
mechanism
PubMed Central
RodrÃguez, Andrea E.; LÃ³pez-Crisosto, Camila; PeÃ±a-OyarzÃºn, Daniel; Salas, Daniela; Parra,
Valentina; Quiroga, Clara; Morawe, Tobias; Chiong, Mario; Behl, Christian; Lavandero, Sergio
2016-01-01
ABSTRACT Autophagy is mainly regulated by post-translational and lipid modifications of ATG

proteins. In some scenarios, the induction of autophagy is accompanied by increased levels of certain
ATG mRNAs such as MAP1LC3B/LC3B, ATG5 or ATG12. However, little is known about the
regulation of ATG protein synthesis at the translational level. The cochaperone of the HSP70 system
BAG3 (BCL2-associated athanogene 3) has been associated to LC3B lipidation through an unknown
mechanism. In the present work, we studied how BAG3 controls autophagy in HeLa and HEK293
cells. Our results showed that BAG3 regulates the basal amount of total cellular LC3B protein by
controlling its mRNA translation. This effect was apparently specific to LC3B because other ATG
protein levels were not affected. BAG3 knockdown did not affect LC3B lipidation induced by nutrient
deprivation or proteasome inhibition. We concluded that BAG3 maintains the basal amount of LC3B
protein by controlling the translation of its mRNA in HeLa and HEK293 cells. PMID:26654586
468. Automated DBS microsampling, microscale automation and microflow LC-MS for therapeutic protein
PK.
PubMed
Zhang, Qian; Tomazela, Daniela; Vasicek, Lisa A; Spellman, Daniel S; Beaumont, Maribel; Shyong,
BaoJen; Kenny, Jacqueline; Fauty, Scott; Fillgrove, Kerry; Harrelson, Jane; Bateman, Kevin P
2016-04-01
Reduce animal usage for discovery-stage PK studies for biologics programs using microsampling-
based approaches and microscale LC-MS. We report the development of an automated DBS-based
serial microsampling approach for studying the PK of therapeutic proteins in mice. Automated sample
preparation and microflow LC-MS were used to enable assay miniaturization and improve overall
assay throughput. Serial sampling of mice was possible over the full 21-day study period with the first
six time points over 24 h being collected using automated DBS sample collection. Overall, this
approach demonstrated comparable data to a previous study using single mice per time point liquid
samples while reducing animal and compound requirements by 14-fold. Reduction in animals and drug
material is enabled by the use of automated serial DBS microsampling for mice studies in discovery-
stage studies of protein therapeutics.
469. Authentication of Trappist beers by LC-MS fingerprints and multivariate data analysis.
PubMed
Mattarucchi, Elia; Stocchero, Matteo; Moreno-Rojas, JosÃ© Manuel; Giordano, Giuseppe; Reniero,
Fabiano; Guillou, Claude
2010-12-08
The aim of this study was to asses the applicability of LC-MS profiling to authenticate a selected
Trappist beer as part of a program on traceability funded by the European Commission. A total of 232
beers were fingerprinted and classified through multivariate data analysis. The selected beer was
clearly distinguished from beers of different brands, while only 3 samples (3.5% of the test set) were
wrongly classified when compared with other types of beer of the same Trappist brewery. The
fingerprints were further analyzed to extract the most discriminating variables, which proved to be
sufficient for classification, even using a simplified unsupervised model. This reduced fingerprint
allowed us to study the influence of batch-to-batch variability on the classification model. Our results
can easily be applied to different matrices and they confirmed the effectiveness of LC-MS profiling in
combination with multivariate data analysis for the characterization of food products.
470. LC-MS Data Processing with MAVEN: A Metabolomic Analysis and Visualization Engine
PubMed Central
Clasquin, Michelle F.; Melamud, Eugene; Rabinowitz, Joshua D.
2014-01-01
MAVEN is an open-source software program for interactive processing of LC-MS-based

metabolomics data. MAVEN enables rapid and reliable metabolite quantitation from multiple reaction
monitoring data or high-resolution full-scan mass spectrometry data. It automatically detects and
reports peak intensities for isotope-labeled metabolites. Menu-driven, click-based navigation allows
visualization of raw and analyzed data. Here we provide a User Guide for MAVEN. Step-by-step
instructions are provided for data import, peak alignment across samples, identification of metabolites
that differ strongly between biological conditions, quantitation and visualization of isotope-labeling
patterns, and export of tables of metabolite-specific peak intensities. Together, these instructions
describe a workflow that allows efficient processing of raw LC-MS data into a form ready for
biological analysis. PMID:22389014
471. Visualization of LC-MS/MS proteomics data in MaxQuant.
PubMed
Tyanova, Stefka; Temu, Tikira; Carlson, Arthur; Sinitcyn, Pavel; Mann, Matthias; Cox, Juergen
2015-04-01
Modern software platforms enable the analysis of shotgun proteomics data in an automated fashion
resulting in high quality identification and quantification results. Additional understanding of the
underlying data can be gained with the help of advanced visualization tools that allow for easy
navigation through large LC-MS/MS datasets potentially consisting of terabytes of raw data. The
updated MaxQuant version has a map navigation component that steers the users through mass and
retention time-dependent mass spectrometric signals. It can be used to monitor a peptide feature used
in label-free quantification over many LC-MS runs and visualize it with advanced 3D graphic models.
An expert annotation system aids the interpretation of the MS/MS spectra used for the identification of
these peptide features. Â© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
472. A 500-600 MHz GaN power amplifier with RC-LC stability network
Ma, Xinyu; Duan, Baoxing; Yang, Yintang
2017-08-01
A 500-600 MHz high-efficiency, high-power GaN power amplifier is designed and realized on the
basis of the push-pull structure. The RC-LC stability network is proposed and applied to the power
amplifier circuit for the first time. The RC-LC stability network can significantly reduce the high gain
out the band, which eliminates the instability of the power amplifier circuit. The developed power
amplifier exhibits 58.5 dBm (700 W) output power with a 17 dB gain and 85% PAE at 500-600 MHz,
300 Î¼s, 20% duty cycle. It has the highest PAE in P-band among the products at home and abroad.
Project supported by the National Key Basic Research Program of China (No. 2014CB339901).
473. LC-MS data processing with MAVEN: a metabolomic analysis and visualization engine.
PubMed
Clasquin, Michelle F; Melamud, Eugene; Rabinowitz, Joshua D
2012-03-01
MAVEN is an open-source software program for interactive processing of LC-MS-based

metabolomics data. MAVEN enables rapid and reliable metabolite quantitation from multiple reaction
monitoring data or high-resolution full-scan mass spectrometry data. It automatically detects and
reports peak intensities for isotope-labeled metabolites. Menu-driven, click-based navigation allows
visualization of raw and analyzed data. Here we provide a User Guide for MAVEN. Step-by-step
instructions are provided for data import, peak alignment across samples, identification of metabolites
that differ strongly between biological conditions, quantitation and visualization of isotope-labeling
patterns, and export of tables of metabolite-specific peak intensities. Together, these instructions
describe a workflow that allows efficient processing of raw LC-MS data into a form ready for
biological analysis.
474. DBS-LC-MS/MS assay for caffeine: validation and neonatal application.
PubMed
Bruschettini, Matteo; Barco, Sebastiano; Romantsik, Olga; Risso, Francesco; Gennai, Iulian; Chinea,
Benito; Ramenghi, Luca A; Tripodi, Gino; Cangemi, Giuliana
2016-09-01
DBS might be an appropriate microsampling technique for therapeutic drug monitoring of caffeine in
infants. Nevertheless, its application presents several issues that still limit its use. This paper describes
a validated DBS-LC-MS/MS method for caffeine. The results of the method validation showed an
hematocrit dependence. In the analysis of 96 paired plasma and DBS clinical samples, caffeine levels
measured in DBS were statistically significantly lower than in plasma but the observed differences
were independent from hematocrit. These results clearly showed the need for extensive validation with
real-life samples for DBS-based methods. DBS-LC-MS/MS can be considered to be a good alternative
to traditional methods for therapeutic drug monitoring or PK studies in preterm infants.
475. Quantification of Free Phenytoin by Liquid Chromatography Tandem Mass Spectrometry

(LC/MS/MS).
PubMed
Peat, Judy; Frazee, Clint; Garg, Uttam
2016-01-01
Phenytoin (diphenylhydantoin) is an anticonvulsant drug that has been used for decades for the
treatment of many types of seizures. The drug is highly protein bound and measurement of free-active
form of the drug is warranted particularly in patients with conditions that can affect drug protein
binding. Here, we describe a LC/MS/MS method for the measurement of free phenytoin. Free drug is
separated by ultrafiltration of serum or plasma. Ultrafiltrate is treated with acetonitrile containing
internal standard phenytoin d-10 to precipitate proteins. The mixture is centrifuged and supernatant is
injected onto LC-MS-MS, and analyzed using multiple reaction monitoring. This method is linear
from 0.1 to 4.0 Î¼g/mL and does not demonstrate any significant ion suppression or enhancement.
476. LC Data QUEST: A Technical Architecture for Community Federated Clinical Data Sharing.
PubMed
Stephens, Kari A; Lin, Ching-Ping; Baldwin, Laura-Mae; Echo-Hawk, Abigail; Keppel, Gina A;
Buchwald, Dedra; Whitener, Ron J; Korngiebel, Diane M; Berg, Alfred O; Black, Robert A; Tarczy-
Hornoch, Peter
2012-01-01
The University of Washington Institute of Translational Health Sciences is engaged in a project, LC

Data QUEST, building data sharing capacity in primary care practices serving rural and tribal
populations in the Washington, Wyoming, Alaska, Montana, Idaho region to build research
infrastructure. We report on the iterative process of developing the technical architecture for
semantically aligning electronic health data in primary care settings across our pilot sites and tools that
will facilitate linkages between the research and practice communities. Our architecture emphasizes
sustainable technical solutions for addressing data extraction, alignment, quality, and metadata
management. The architecture provides immediate benefits to participating partners via a clinical
decision support tool and data querying functionality to support local quality improvement efforts. The
FInDiT tool catalogues type, quantity, and quality of the data that are available across the LC Data
QUEST data sharing architecture. These tools facilitate the bi-directional process of translational
research.
477. [Simultaneous determination of pesticide residues in agricultural products by LC-MS/MS].
PubMed
Watanabe, Minae; Ueno, Eiji; Inoue, Tomomi; Ohno, Haruka; Ikai, Yoshitomo; Morishita, Toshio;
Oshima, Harumi; Hayashi, Rumiko
2013-01-01
A method for the simultaneous determination of multiple pesticide residues in agricultural products
was developed by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). The
sample was extracted with acetonitrile. Co-extractives were removed by GPC/graphitized carbon
column SPE, and silica gel/PSA cartridge column SPE. Pesticides in the test solution were determined
by LC-MS/MS using scheduled MRM. Recoveries of 124 pesticides from spinach, brown rice,
soybean, orange and tomato were tested at the level of 0.1 Âµg/g, and those of 121 pesticides ranged
from 70 to 120% (RSDâ‰¤15%). Pesticide residues in 239 agricultural products were investigated by
this method, and residues of 49 pesticides were detected in 98 agricultural products.
478. STS-55 Columbia, OV-102, mated to ET and SRBs, heads to KSC LC during rollout
1993-01-01
German payload processing team members watch as STS-55 Columbia, Orbiter Vehicle (OV) 102,
mated to the external tank (ET) and solid rocket boosters (SRBs), heads to Kennedy Space Center
(KSC) Launch Complex (LC) Pad 39A. OV-102, the ET, and SRBs ride atop the mobile launch
platform and the crawler transporter. A spectator in the foreground is wearing an STS-55 t-shirt. The
German-managed Spacelab Deutsche 2 (SL-D2) and the Unique Support Structure (USS) are already
integrated in OV-102's payload bay as it makes its way to LC Pad 39A. OV-102 is targeted for liftoff
on Space Shuttle Mission STS-55 in late February. View provided by KSC with alternate KSC number
KSC-93PC-283.
479. Rugged large volume injection for sensitive capillary LC-MS environmental monitoring
Roberg-Larsen, Hanne; Abele, Silvija; Demir, Deniz; Dzabijeva, Diana; Amundsen, Sunniva F.;
Wilson, Steven R.; Bartkevics, Vadims; Lundanes, Elsa
2017-08-01
A rugged and high throughput capillary column (cLC) LC-MS switching platform using large volume
injection and on-line automatic filtration and filter back-flush (AFFL) solid phase extraction (SPE) for
analysis of environmental water samples with minimal sample preparation is presented. Although
narrow columns and on-line sample preparation are used in the platform, high ruggedness is achieved
e.g. injection of 100 non-filtrated water samples would did not result in a pressure rise/clogging of the
SPE/capillary columns (inner diameter 300 Âµm). In addition, satisfactory retention time stability and
chromatographic resolution were also features of the system. The potential of the platform for
environmental water samples was demonstrated with various pharmaceutical products, which had
detection limits (LOD) in the 0.05 - 12.5 ng/L range. Between-day and within-day repeatability of
selected analytes were < 20% RSD.
480. A survey of free glutamic acid in foods using a robust LC-MS/MS method.
PubMed
Cebi, Nur; Dogan, Canan Ekinci; Olgun, Elmas Oktem; Sagdic, Osman
2018-05-15
An effective and simultaneous liquid chromatography-tandem mass spectrometry (LC-MS/MS)

method was used with the aim of quantifying monosodium glutamate (MSG) in foodstuffs, such as
chips, taste cubes, sauces and soups. The results were linear (R 2 â€¯=â€¯1), with very low LOD and
LOQ values, 1.0â€¯Âµg/kg, 5.0â€¯Âµg/kg, respectively. Excellent repeatability and reproducibility
were also achieved. This highly sensitive and robust LC-MS/MS technique was applied successfully
for the detection and quantification of MSG in a wide variety of foodstuffs. MSG contents ranged from
0.01â€¯g/100â€¯g to 15.39â€¯g/100â€¯g in food samples. Importantly, determination of free glutamic
acid in the daily diet could also prevent various side effects associated with consumption of excess free
glutamic acid. Copyright Â© 2017 Elsevier Ltd. All rights reserved.
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481. Coupled LC-GC techniques for the characterisation of polycyclic aromatic compounds in fuel
materials
SciTech Connect
Askey, S.A.; Holden, K.M.L.; Bartle, K.D.
1995-12-31
Exposure to polycyclic aromatic compounds (PAC) has long been identified as of considerable
environmental concern. Originating from both natural and anthropogenic sources, many PAC exhibit
significant carcinogenic and mutagenic properties. Multi-dimensional chromatographic techniques
which provide separation by virtue of chemical class (group-type) or by molecular mass greatly
simplifies the analysis of inherently complex fuel materials. In this study, on-line LC-GC techniques in
which high resolution gas chromatography (HPLC) have been investigated. Comprehensive
characterisation of fuel feedstocks and post-pyrolysis and combustion products was achieved by
coupling LC-GC to low resolution ion trap mass spectrometry (ITD-MS) and atomic emission
detection (AED). ThemoreÂ Â» identification of PAC in diesel and coal materials, as well as urban air
and diesel exhaust particulate extracts has provided valuable insight into the source, formation and
distribution of such compounds pre- and post processing.Â«Â less
482. Renilla Luciferase-LC3 Based Reporter Assay for Measuring Autophagic Flux.
PubMed
Farkas, T; JÃ¤Ã¤ttelÃ¤, M
2017-01-01
Macroautophagy (autophagy) is a dynamic intracellular degradation pathway. Monitoring the flux

through the autophagy pathway is experimentally challenging but obviously a prerequisite for the
proper investigation of the process. Here, we present an indirect autophagy flux assay based on
monitoring the degradation of an autophagosome-associated fusion protein Rluc-LC3 by luminescence
detection. The method is suitable for screening purposes with a high number of parallel samples and
can be used for measurements in cell lysates as well as in living cells. The Rluc-LC3 assay has proven
useful for the identification of genes, miRNAs, and small molecules that regulate autophagy flux in
mammalian cells. Â© 2017 Elsevier Inc. All rights reserved.
483. Turnover of Lipidated LC3 and Autophagic Cargoes in Mammalian Cells.
PubMed
RodrÃguez-Arribas, M; Yakhine-Diop, S M S; GonzÃ¡lez-Polo, R A; Niso-Santano, M; Fuentes, J M
2017-01-01
Macroautophagy (usually referred to as autophagy) is the most important degradation system in

mammalian cells. It is responsible for the elimination of protein aggregates, organelles, and other
cellular content. During autophagy, these materials (i.e., cargo) must be engulfed by a double-
membrane structure called an autophagosome, which delivers the cargo to the lysosome to complete its
degradation. Autophagy is a very dynamic pathway called autophagic flux. The process involves all
the steps that are implicated in cargo degradation from autophagosome formation. There are several
techniques to monitor autophagic flux. Among them, the method most used experimentally to assess
autophagy is the detection of LC3 protein processing and p62 degradation by Western blotting. In this
chapter, we provide a detailed and straightforward protocol for this purpose in cultured mammalian
cells, including a brief set of notes concerning problems associated with the Western-blotting detection
of LC3 and p62. Â© 2017 Elsevier Inc. All rights reserved.
484. How much separation for LC-MS/MS quantitative bioanalysis of drugs and metabolites?
PubMed
Tan, Aimin; Fanaras, John C
2018-05-01
LC-MS/MS has been the dominant analytical technology for quantitative bioanalysis of drugs and
metabolites for more than two decades. Despite this, a very fundamental question like how much
separation is required for LC-MS/MS quantitative bioanalysis of drugs and metabolites has not been
adequately addressed. Some think that no or only very limited separation is necessary thanks to the
unparalleled selectivity offered by tandem mass spectrometry. Others think that the more separation,
the better, because of the potential detrimental impact of matrix effect (ion suppression or
enhancement). Still others just use a rule-of-thumb approach by keeping the adjusted
retention/capacity factor always between 2 and 5. The purpose of this article is to address this
fundamental question through rational thinking together with various real case examples drawn from
regulated bioanalytical laboratories. Copyright Â© 2018 Elsevier B.V. All rights reserved.
485. LC Data QUEST: A Technical Architecture for Community Federated Clinical Data Sharing
PubMed Central
Stephens, Kari A.; Lin, Ching-Ping; Baldwin, Laura-Mae; Echo-Hawk, Abigail; Keppel, Gina A.;
Buchwald, Dedra; Whitener, Ron J.; Korngiebel, Diane M.; Berg, Alfred O.; Black, Robert A.; Tarczy-
Hornoch, Peter
2012-01-01
The University of Washington Institute of Translational Health Sciences is engaged in a project, LC

Data QUEST, building data sharing capacity in primary care practices serving rural and tribal
populations in the Washington, Wyoming, Alaska, Montana, Idaho region to build research
infrastructure. We report on the iterative process of developing the technical architecture for
semantically aligning electronic health data in primary care settings across our pilot sites and tools that
will facilitate linkages between the research and practice communities. Our architecture emphasizes
sustainable technical solutions for addressing data extraction, alignment, quality, and metadata
management. The architecture provides immediate benefits to participating partners via a clinical
decision support tool and data querying functionality to support local quality improvement efforts. The
FInDiT tool catalogues type, quantity, and quality of the data that are available across the LC Data
QUEST data sharing architecture. These tools facilitate the bi-directional process of translational
research. PMID:22779052
486. LC-MS guided isolation of ent-kaurane diterpenoids from Nouelia insignis.
PubMed
Sun, Chang-Li; Geng, Chang-An; Chen, Xing-Long; Yang, Tong-Hua; Yin, Xiu-Juan; Huang, Xiao-
Yan; Peng, Hua; Chen, Ji-Jun
2016-06-01
The preliminary LC-MS investigation on the stems of Nouelia insignis manifested the existence of
diterpenoids. As a result, 15 ent-kaurane diterpenoids, including 7 new glycosides (nouelosides A-G,
1-7), were isolated under the direction of LC-MS analysis. The new compounds were determined by
extensive spectroscopic analysis including HRESIMS, 1D and 2D NMR data and chemical methods.
Compounds 6 and 15 with the exo-methylene cyclopentanone functional group exhibited obvious
nitric oxide production inhibitory activity with IC50 values of 3.84Â±0.20 and 3.19Â±0.25Î¼M.
487. Liquid Chromatography Electrospray Ionization Mass Spectrometric (LC-ESI-MS) and Desorption
Electrospray Ionization Mass Spectrometric (DESI-MS) Identification of Chemical Warfare Agents in
Consumer Products
2007-06-01
T ACanadaY Approved for PublicR Distribution Uln& Liquid Chromatography Electrospray

Ionization Mass Spectrometric ( LC -ESI- MS) and Desorption...consumer products with chemical
warfare agents or other toxic chemicals. Liquid chromatography electrospray ionization mass
spectrometry ( LC -ESI-MS) and...house LC -ESI-MS and LC -ESI-MS/MS methods were evaluated
for the determination of chemical warfare agents in spiked bottled water samples. The
488. Fermentation, degradation and microbial nitrogen partitioning for three forage colour phenotypes
within anthocyanidin-accumulating Lc-alfalfa progeny.
PubMed
Jonker, Arjan; Gruber, Margaret Y; Wang, Yuxi; Narvaez, Nelmy; Coulman, Bruce; McKinnon, John J;
Christensen, David A; Azarfar, Arash; Yu, Peiqiang
2012-08-30
Alfalfa has the disadvantage of having a rapid initial rate of protein degradation, which results in
pasture bloat, low efficiency of protein utilisation and excessive nitrogen (N) pollution into the
environment for cattle. Introducing a gene that stimulates the accumulation of monomeric/polymeric
anthocyanidins might reduce the ruminal protein degradation rate (by fixing protein and/or direct
interaction with microbes) and additionally reduce methane emission. The objectives of this study
were to evaluate in vitro fermentation, degradation and microbial N partitioning of three forage colour
phenotypes (green, light purple-green (LPG) and purple-green (PG)) within newly developed Lc-
progeny and to compare them with those of parental green non-transgenic (NT) alfalfa. PG-Lc
accumulated more anthocyanidin compared with Green-Lc (P < 0.05), with LPG-Lc intermediate.
Volatile fatty acids and potentially degradable dry matter (DM) and N were similar among the four
phenotypes. Gas, methane and ammonia accumulation rates were slower for the two purple-Lc
phenotypes compared with NT-alfalfa (P < 0.05), while Green-Lc was intermediate. Effective
degradable DM and N were lower in the three Lc-phenotypes (P < 0.05) compared with NT-alfalfa.
Anthocyanidin concentration was negatively correlated (P < 0.05) with gas and methane production
rates and effective degradability of DM and N. The Lc-alfalfa phenotypes accumulated anthocyanidin.
Fermentation and degradation parameters indicated a reduced rate of fermentation and effective
degradability for both purple anthocyanidin-accumulating Lc-alfalfa phenotypes compared with NT-
alfalfa. Copyright Â© 2012 Society of Chemical Industry.
489. Quantifying MMA by SLE LC-MS/MS: Unexpected challenges in assay development.
PubMed
Lo, Sheng-Ying; Gordon, Cindy; Sadilkova, Katerina; Jack, Rhona M; Dickerson, Jane A
2016-09-01
Analysis of serum/plasma methylmalonic acid (MMA) is important for the diagnosis and management
of methylmalonic acidemia in pediatric populations. This work focuses on developing and validating a
liquid chromatography tandem mass spectrometry (LC-MS/MS) method to monitor methylmalonic
acidemia using a simple method preparation. MMA and stable isotope labeled d3-MMA was extracted
using supported liquid extraction (SLE). Assay imprecision, bias, linearity, recovery and carryover
were determined. The relationship between MMA and propionyl acylcarnitine (C3-acylcarnitine) was
also evaluated using historical paired results from 51 unique individuals. Baseline separation between
MMA and succinic acid was completed in 7min. The assay was linear from 0.1 to 500Î¼M. The intra-
day and inter-day imprecision CV ranged from 4.1 to 13.2% (0.3 to 526Î¼M) and 5.0 to 15.7% (0.3 to
233Î¼M), respectively. Recovery ranged from 93 to 125%. The correlation with a national reference
laboratory LC-MS/MS assay showed a Deming regression of 1.026 and intercept of -1.335. Carryover
was determined to be <0.04%. Patient-specific correlation was observed between MMA and C3-
acylcarnitine. This report describes the first LC-MS/MS method using SLE for MMA extraction. In
addition, we illustrate the challenges encountered during this method development that should be
assessed and resolved by any laboratory implementing a SLE LC-MS/MS assay designed to quantify
analytes across several orders of magnitude. Copyright Â© 2016 The Canadian Society of Clinical
Chemists. Published by Elsevier Inc. All rights reserved.
490. Comprehensive Optimization of LC-MS Metabolomics Methods Using Design of Experiments

(COLMeD)
PubMed Central
Rhoades, Seth D.
2017-01-01
Introduction Both reverse-phase and HILIC chemistries are deployed for liquid-chromatography mass
spectrometry (LC-MS) metabolomics analyses, however HILIC methods lag behind reverse-phase
methods in reproducibility and versatility. Comprehensive metabolomics analysis is additionally
complicated by the physiochemical diversity of metabolites and array of tunable analytical parameters.
Objective Our aim was to rationally and efficiently design complementary HILIC-based polar
metabolomics methods on multiple instruments using Design of Experiments (DoE). Methods We
iteratively tuned LC and MS conditions on ion-switching triple quadrupole (QqQ) and quadrupole-
time-of-flight (qTOF) mass spectrometers through multiple rounds of a workflow we term COLMeD
(Comprehensive optimization of LC-MS metabolomics methods using design of experiments).
Multivariate statistical analysis guided our decision process in the method optimizations. Results LC-
MS/MS tuning for the QqQ method on serum metabolites yielded a median response increase of
161.5% (p<0.0001) over initial conditions with a 13.3% increase in metabolite coverage. The
COLMeD output was benchmarked against two widely used polar metabolomics methods,
demonstrating total ion current increases of 105.8% and 57.3%, with median metabolite response
increases of 106.1% and 10.3% (p<0.0001 and p<0.05 respectively). For our optimized qTOF method,
22 solvent systems were compared on a standard mix of physiochemically diverse metabolites,
followed by COLMeD optimization, yielding a median 29.8% response increase (p<0.0001) over
initial conditions. Conclusions The COLMeD process elucidated response tradeoffs, facilitating
improved chromatography and MS response without compromising separation of isobars. COLMeD is
efficient, requiring no more than 20 injections in a given DoE round, and flexible, capable of class-
specific optimization as demonstrated through acylcarnitine optimization within the QqQ method.
PMID:28348510
491. GeLC-MRM quantitation of mutant KRAS oncoprotein in complex biological samples.
PubMed
Halvey, Patrick J; Ferrone, Cristina R; Liebler, Daniel C
2012-07-06
Tumor-derived mutant KRAS (v-Ki-ras-2 Kirsten rat sarcoma viral oncogene) oncoprotein is a critical
driver of cancer phenotypes and a potential biomarker for many epithelial cancers. Targeted mass
spectrometry analysis by multiple reaction monitoring (MRM) enables selective detection and
quantitation of wild-type and mutant KRAS proteins in complex biological samples. A recently
described immunoprecipitation approach (Proc. Nat. Acad. Sci.2011, 108, 2444-2449) can be used to
enrich KRAS for MRM analysis, but requires large protein inputs (2-4 mg). Here, we describe sodium
dodecyl sulfate-polyacrylamide gel electrophoresis-based enrichment of KRAS in a low molecular
weight (20-25 kDa) protein fraction prior to MRM analysis (GeLC-MRM). This approach reduces
background proteome complexity, thus, allowing mutant KRAS to be reliably quantified in low protein
inputs (5-50 Î¼g). GeLC-MRM detected KRAS mutant variants (G12D, G13D, G12V, G12S) in a
panel of cancer cell lines. GeLC-MRM analysis of wild-type and mutant was linear with respect to
protein input and showed low variability across process replicates (CV = 14%). Concomitant analysis
of a peptide from the highly similar HRAS and NRAS proteins enabled correction of KRAS-targeted
measurements for contributions from these other proteins. KRAS peptides were also quantified in fluid
from benign pancreatic cysts and pancreatic cancers at concentrations from 0.08 to 1.1 fmol/Î¼g
protein. GeLC-MRM provides a robust, sensitive approach to quantitation of mutant proteins in
complex biological samples.
492. STS-27 Atlantis, Orbiter Vehicle (OV) 104, at KSC Launch Complex (LC) pad 39B
1988-01-01
STS-27 Atlantis, Orbiter Vehicle (OV) 104, sits atop the mobile launcher platform at Kennedy Space
Center (KSC) Launch Complex (LC) pad 39B. Profile of OV-104 mounted on external tank and
flanked by solid rocket boosters (SRBs) is obscured by a flock of seagulls in the foreground. The fixed
service structure (FSS) with rotating service structure (RSS) retracted appears in the background.
Water resevoir is visible at the base of the launch pad concrete structure.
493. Screening of veterinary drug residues in food by LC-MS/MS. Background and challenges.
PubMed
Delatour, Thierry; Racault, Lucie; Bessaire, Thomas; Desmarchelier, AurÃ©lien
2018-04-01
Regulatory agencies and government authorities have established maximum residue limits (MRL) in
various food matrices of animal origin for supporting governments and food operators in the
monitoring of veterinary drug residues in the food chain, and ultimately in the consumer's plate. Today,
about 200 veterinary drug residues from several families, mainly with antibiotic, antiparasitic or
antiinflammatory activities, are regulated in a variety of food matrices such as milk, meat or egg. This
article provides a review of the regulatory framework in milk and muscle including data from Codex
Alimentarius, Europe, the U.S.A., Canada and China for about 220 veterinary drugs. The article also
provides a comprehensive overview of the challenge for food control, and emphasizes the pivotal role
of liquid chromatography-mass spectrometry (LC-MS), either in tandem with quadrupoles (LC-
MS/MS) or high resolution MS (LC-HRMS), for ensuring an adequate consumer protection combined
with an affordable cost. The capability of a streamlined LC-MS/MS platform for screening 152
veterinary drug residues in a broad range of raw materials and finished products is highlighted in a
production line perspective. The rationale for a suite of four methods intended to achieve appropriate
performance in terms of scope and sensitivity is presented. Overall, the platform encompasses one
stream for the determination of 105 compounds in a run (based on acidic QuEChERS-like), plus two
streams for 23 Î²-lactams (alkaline QuEChERS-like) and 10 tetracyclines (low-temperature
partitioning), respectively, and a dedicated stream for 14 aminoglycosides (molecularly-imprinted
polymer).
494. An improved method for fast and selective separation of carotenoids by LC-MS.
PubMed
Abate-Pella, Daniel; Freund, Dana M; Slovin, Janet P; Hegeman, Adrian D; Cohen, Jerry D
2017-11-01
Carotenoids are a large class of compounds that are biosynthesized by condensation of isoprene units
in plants, fungi, bacteria, and some animals. They are characteristically highly conjugated through
double bonds, which lead to many isomers as well susceptibility to oxidation and other chemical
modifications. Carotenoids are important because of their potent antioxidant activity and are the
pigments responsible for color in a wide variety of foods. Human consumption is correlated to many
health benefits including prevention of cancer, cardiovascular disease, and age-related disease.
Extreme hydrophobicity, poor stability, and low concentration in biological samples make these
compounds difficult to analyze and difficult to develop analytical methods for aimed towards
identification and quantification. Examples in the literature frequently report the use of exotic
stationary phases, solvents, and additives, such as ethyl acetate, dichloromethane, and methyl tert-butyl
ether that are incompatible with liquid chromatography mass spectrometry (LC-MS). In order to
address these issues, we implemented the use of LC-MS friendly conditions using a low-
hydrophobicity cyano-propyl column (Agilent Zorbax SB-CN). We successfully differentiated
between isomeric carotenoids by optimizing two gradient methods and using a mixture of 11 standards
and LC-MS in positive ionization mode. Three complex biological samples from strawberry leaf,
chicken feed supplement, and the photosynthetic bacterium Chloroflexus aurantiacus were analyzed
and several carotenoids were resolved in these diverse backgrounds. Our results show this
methodology is a significant improvement over other alternatives for analyzing carotenoids because of
its ease of use, rapid analysis time, high selectivity, and, most importantly, its compatibility with
typical LC-MS conditions. Copyright Â© 2017 Elsevier B.V. All rights reserved.
495. EasyLCMS: an asynchronous web application for the automated quantification of LC-MS data
PubMed Central
2012-01-01
Background Downstream applications in metabolomics, as well as mathematical modelling, require

data in a quantitative format, which may also necessitate the automated and simultaneous
quantification of numerous metabolites. Although numerous applications have been previously
developed for metabolomics data handling, automated calibration and calculation of the concentrations
in terms of Î¼mol have not been carried out. Moreover, most of the metabolomics applications are
designed for GC-MS, and would not be suitable for LC-MS, since in LC, the deviation in the retention
time is not linear, which is not taken into account in these applications. Moreover, only a few are web-
based applications, which could improve stand-alone software in terms of compatibility, sharing
capabilities and hardware requirements, even though a strong bandwidth is required. Furthermore,
none of these incorporate asynchronous communication to allow real-time interaction with pre-
processed results. Findings Here, we present EasyLCMS (http://www.easylcms.es/), a new application
for automated quantification which was validated using more than 1000 concentration comparisons in
real samples with manual operation. The results showed that only 1% of the quantifications presented
a relative error higher than 15%. Using clustering analysis, the metabolites with the highest relative
error distributions were identified and studied to solve recurrent mistakes. Conclusions EasyLCMS is a
new web application designed to quantify numerous metabolites, simultaneously integrating LC
distortions and asynchronous web technology to present a visual interface with dynamic interaction
which allows checking and correction of LC-MS raw data pre-processing results. Moreover, quantified
data obtained with EasyLCMS are fully compatible with numerous downstream applications, as well
as for mathematical modelling in the systems biology field. PMID:22884039
496. Study of Designing BPF by Using LC Tap-Coupling Resonators
Yasuzumi, Takenori; Wada, Kouji; Nakajima, Naoko; Hashimoto, Osamu
The resonance characteristics of short-ended half-wavelength coplanar waveguide(CPW) LC tap-

coupling resonators are examined theoretically and experimentally. The characteristics near the
passband have been improved by applying the presented CPW resonator to a design of a bandpass
filter(BPF). Moreover, the difference between the calculation and the measurement results is examined
by using the equivalent circuit about the presented BPF.
497. Reassessment of the Access Testosterone chemiluminescence assay and comparison with LC-MS
method.
PubMed
Dittadi, Ruggero; Matteucci, Mara; Meneghetti, Elisa; Ndreu, Rudina
2018-03-01
To reassess the imprecision and Limit of Quantitation, to evaluate the cross-reaction with
dehydroepiandrosterone-sulfate (DHEAS), the accuracy toward liquid chromatography-mass
spectrometry (LC-MS) and the reference interval of the Access Testosterone method, performed by
DxI immunoassay platform (Beckman Coulter). Imprecision was evaluated testing six pool samples
assayed in 20 different run using two reagents lots. The cross-reaction with DHEAS was studied both
by a displacement curve and by spiking DHEAS standard in two serum samples with known amount
of testosterone. The comparison with LC-MS was evaluated by Passing-Bablock analysis in 21 routine
serum samples and 19 control samples from an External Quality Assurance (EQA) scheme. The
reference interval was verified by an indirect estimation on 2445 male and 2838 female outpatients.
The imprecision study showed a coefficient of variation (CV) between 2.7% and 34.7% for serum
pools from 16.3 and 0.27Â nmol/L. The value of Limit of Quantitation at 20% CV was 0.53Â nmol/L.
The DHEAS showed a cross-reaction of 0.0074%. A comparison with LC-MS showed a trend toward
a slight underestimation of immunoassay vs LC-MS (Passing-Bablock equations: DxI=-0.24+0.906
LCMS in serum samples and DxI=-0.299+0.981 LCMS in EQA samples). The verification of
reference interval showed a 2.5th-97.5th percentile distribution of 6.6-24.3Â nmol/L for male over
14Â years and <0.5-2.78Â nmol/L for female subjects, in accord with the reference intervals reported
by the manufacturer. The Access Testosterone method could be considered an adequately reliable tool
for the testosterone measurement. Â© 2017 Wiley Periodicals, Inc.
498. Absolute configuration of a tetrahydrophenanthrene from Heliotropium ovalifolium by LC-NMR of its

Mosher esters.
PubMed
Guilet, David; Guntern, Alain; Ioset, Jean-Robert; Queiroz, Emerson F; Ndjoko, Karine; Foggin, Chris
M; Hostettmann, Kurt
2003-01-01
A new tetrahydrophenanthrene (1, (1R,2R)-1-hydroxy-2-methoxy-6,9-dimethyl-2,3-

dihydrophenanthren-4(1H)-one (heliophenanthrone)) has been isolated from the aerial parts of
Heliotropium ovalifolium. Its structure was elucidated on the basis of spectroscopic data, and the
absolute configuration of the asymmetric centers was determined from LC-NMR data of the Mosher
ester derivatives.
499. Improved LC-MS/MS method for the quantification of hepcidin-25 in clinical samples.
PubMed
Abbas, Ioana M; Hoffmann, Holger; Montes-BayÃ³n, MarÃa; Weller, Michael G
2018-06-01
Mass spectrometry-based methods play a crucial role in the quantification of the main iron metabolism
regulator hepcidin by singling out the bioactive 25-residue peptide from the other naturally occurring
N-truncated isoforms (hepcidin-20, -22, -24), which seem to be inactive in iron homeostasis. However,
several difficulties arise in the MS analysis of hepcidin due to the "sticky" character of the peptide and
the lack of suitable standards. Here, we propose the use of amino- and fluoro-silanized autosampler
vials to reduce hepcidin interaction to laboratory glassware surfaces after testing several types of vials
for the preparation of stock solutions and serum samples for isotope dilution liquid chromatography-
tandem mass spectrometry (ID-LC-MS/MS). Furthermore, we have investigated two sample
preparation strategies and two chromatographic separation conditions with the aim of developing a
LC-MS/MS method for the sensitive and reliable quantification of hepcidin-25 in serum samples. A
chromatographic separation based on usual acidic mobile phases was compared with a novel approach
involving the separation of hepcidin-25 with solvents at high pH containing 0.1% of ammonia. Both
methods were applied to clinical samples in an intra-laboratory comparison of two LC-MS/MS
methods using the same hepcidin-25 calibrators with good correlation of the results. Finally, we
recommend a LC-MS/MS-based quantification method with a dynamic range of 0.5-40Â Î¼g/L for the
assessment of hepcidin-25 in human serum that uses TFA-based mobile phases and silanized glass
vials. Graphical abstract Structure of hepcidin-25 (Protein Data Bank, PDB ID 2KEF).
500. Choline dehydrogenase interacts with SQSTM1/p62 to recruit LC3 and stimulate mitophagy.
PubMed
Park, Sungwoo; Choi, Seon-Guk; Yoo, Seung-Min; Son, Jin H; Jung, Yong-Keun
2014-01-01
CHDH (choline dehydrogenase) is an enzyme catalyzing the dehydrogenation of choline to betaine

aldehyde in mitochondria. Apart from this well-known activity, we report here a pivotal role of CHDH
in mitophagy. Knockdown of CHDH expression impairs CCCP-induced mitophagy and
PARK2/parkin-mediated clearance of mitochondria in mammalian cells, including HeLa cells and
SN4741 dopaminergic neuronal cells. Conversely, overexpression of CHDH accelerates PARK2-
mediated mitophagy. CHDH is found on both the outer and inner membranes of mitochondria in
resting cells. Interestingly, upon induction of mitophagy, CHDH accumulates on the outer membrane
in a mitochondrial potential-dependent manner. We found that CHDH is not a substrate of PARK2 but
interacts with SQSTM1 independently of PARK2 to recruit SQSTM1 into depolarized mitochondria.
The FB1 domain of CHDH is exposed to the cytosol and is required for the interaction with SQSTM1,
and overexpression of the FB1 domain only in cytosol reduces CCCP-induced mitochondrial
degradation via competitive interaction with SQSTM1. In addition, CHDH, but not the CHDH FB1
deletion mutant, forms a ternary protein complex with SQSTM1 and MAP1LC3 (LC3), leading to
loading of LC3 onto the damaged mitochondria via SQSTM1. Further, CHDH is crucial to the
mitophagy induced by MPP+ in SN4741 cells. Overall, our results suggest that CHDH is required for
PARK2-mediated mitophagy for the recruitment of SQSTM1 and LC3 onto the mitochondria for cargo
recognition.
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1. Chlorotoxin-mediated disinhibition of noradrenergic locus coeruleus neurons using a conditional

4. Locus coeruleus to basolateral amygdala noradrenergic projections promote anxiety-like behavior.

5. Locus coeruleus to basolateral amygdala noradrenergic projections promote anxiety-like behavior

7. The Longevity of Hippocampus-Dependent Memory Is Orchestrated by the Locus Coeruleus-

Torres-Sanchez, Sonia; Borges, Gisela Da Silva; Mico, Juan A; Berrocoso, Esther

9. Functional neuroanatomy of the central noradrenergic system.

Peterson, Andrew C; Li, Chiang-Shan R

Noradrenergic dysfunction contributes to cognitive impairment in Alzheimer's Disease (AD) and

Uematsu, Akira; Tan, Bao Zhen

16. Locus coeruleus activation accelerates perceptual learning.

Parkinson's disease (PD) is a neurodegenerative disease characterized by the loss of dopaminergic

FernÃ¡ndez-Pastor, BegoÃ±a; Mateo, Yolanda; GÃ³mez-Urquijo, Sonia; Javier Meana, J

of NA release through local alpha2A-adrenoceptors. The selective NA reuptake inhibitor desipramine

Scavone, Jillian L; Van Bockstaele, Elisabeth J

21. Noradrenergic Regulation of Central Amygdala in Aversive Pavlovian-to-Instrumental Transfer

22. Cholecystokinin-8 induces brain-derived neurotrophic factor expression in noradrenergic neuronal

Hwang, Cheol Kyu; Kim, Do Kyung; Chun, Hong Sung

23. A noradrenergic lesion exacerbates neurodegeneration in a Down syndrome mouse model.

24. A Noradrenergic Lesion Exacerbates Neurodegeneration in a Down Syndrome Mouse Model

Roberts, D C; Price, M T; Fibiger, H C

the present study, we used a noradrenergic toxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine

Bangasser, Debra A; Wiersielis, Kimberly R; Khantsis, Sabina

Desvignes, C; Robert, F; Vachette, C; Chouvet, G; Cespuglio, R; Renaud, B; LambÃ¡s-SeÃ±as, L

Rorabaugh, Jacki M; Chalermpalanupap, Termpanit; Botz-Zapp, Christian A; Fu, Vanessa M;

Medrano, M C; Gerrikagoitia, I; MartÃnez-MillÃ¡n, L; Mendiguren, A; Pineda, J

Hansen, Niels; Manahan-Vaughan, Denise

Retson, T A; Reyes, B A; Van Bockstaele, E J

Sciolino, Natale R.; Holmes, Philip V.

43. The Memory Function of Noradrenergic Activity in Non-REM Sleep

ERIC Educational Resources Information Center

ERIC Educational Resources Information Center

Shelkar, Gajanan P; Gakare, Sukanya G; Chakraborty, Suwarna; Dravid, Shashank M

Bueno-Nava, Antonio; Montes, Sergio; DelaGarza-Montano, Paloma; Alfaro-Rodriguez, Alfonso;

51. A53T-Î±-synuclein overexpression in murine locus coeruleus induces Parkinson's disease-like

52. The Role of the Central Noradrenergic System in Behavioral Inhibition

Stone, Eric A.; Lin, Yan; Sarfraz, Yasmeen; Quartermain, David

Masilamoni, Gunasingh Jeyaraj; Groover, Olivia; Smith, Yoland

Choudhary, Pooja; Pacholko, Anthony G; Palaschuk, Josh; Bekar, Lane K

62. Locus coeruleus and dopaminergic consolidation of everyday memory

Ruiz-DurÃ¡ntez, E; Ruiz-Ortega JA; Pineda, J; Ugedo, L

DTIC Science & Technology

67. The Effects of Locus Coeruleus and Norepinephrine in Methamphetamine Toxicity

Chalermpalanupap, Termpanit; Weinshenker, David

Degeneration of locus coeruleus (LC) is an underappreciated hallmark of Alzheimer's disease (AD).

Young, Elizabeth A; Abelson, James L; Cameron, Oliver G

70. A role for locus coeruleus in Parkinson tremor

Mather, Mara; Harley, Carolyn W

Simson, P G; Weiss, J M; Hoffman, L J; Ambrose, M J

Jacobs, Heidi I L; MÃ¼ller-Ehrenberg, Lisa; Priovoulos, Nikos; Roebroeck, Alard

76. Pharmacological Modulation of Noradrenergic Arousal Circuitry Disrupts Functional Connectivity of

Zhou, Fu-Wen; Dong, Hong-Wei; Ennis, Matthew

Snow, P J; Andre, P; Pompeiano, O

79. Individual differences in the locus coeruleus-norepinephrine system: relevance to stress-induced

Wood, Christopher S.; Valentino, Rita J.; Wood, Susan K.

Chapman, C Richard; Bradshaw, David H; Donaldson, Gary W; Jacobson, Robert C; Nakamura,

82. On the Origin of Cortical Dopamine: Is it a Co-Transmitter in Noradrenergic Neurons?

Devoto, Paola; Flore, Giovanna

83. On the origin of cortical dopamine: is it a co-transmitter in noradrenergic neurons?

Devoto, Paola; Flore, Giovanna

85. Noradrenergic dysregulation in the pathophysiology of PTSD.