PHYSIOLOGY 33: 281–297, 2018. Published June 13, 2018; doi:10.1152/physiol.00014.

2018
REVIEW
Carotid Bodies and the Integrated Bruce G. Lindsey, Sarah C. Nuding,
Lauren S. Segers, and
Cardiorespiratory Response to Hypoxia Kendall F. Morris
Department of Molecular Pharmacology and Physiology,
Advances in our understanding of brain mechanisms for the hypoxic ventila- Morsani College of Medicine, University of South Florida,
Tampa, Florida
blindsey@health.usf.edu
tory response, coordinated changes in blood pressure, and the long-term
consequences of chronic intermittent hypoxia as in sleep apnea, such as
hypertension and heart failure, are giving impetus to the search for therapies
to “erase” dysfunctional memories distributed in the carotid bodies and
central nervous system. We review current network models, open questions,
sex differences, and implications for translational research.

Introduction chemoreceptors (213). Repeated episodes of

Carotid body chemoreceptors are sensors of arte-
rial O2, CO2, and pH (31, 123, 143, 236). These
peripheral receptors operate cooperatively with
central chemoreceptors in the brain that monitor
CO2-pH or O2 (22, 43, 78, 87, 180, 195, 211, 259).
Carotid chemoreceptors contribute to the drive to
breathe. Their activity is enhanced during hypox-
emia, a reduction in the PO2 in the blood that
commonly occurs at high altitude, during apneas
associated with sleep disordered breathing or dys-
autonomia (80, 107, 214), with ventilation-perfu-
sion mismatching in the lungs, or as a
consequence of other disorders (201, 255). Numer-
ous medical conditions are associated with altered
carotid body function (see discussion in Refs. 143,
154).
Hypoxia stimulates oxygen-sensing mechanisms
in the carotid bodies, leading to reduced potas-
sium currents in type I glomus cells (29, 30, 123,
141–143, 208, 212). The resulting depolarization
and transmitter release evoke action potentials
in the glossopharyngeal nerve, exciting neurons in
the nucleus of the solitary tract (NTS). The brain
stem circuits targeted by these NTS neurons gen-
erate a ventilatory response, expressed as increases
in tidal volume and breathing frequency, along
with coordinated changes in sympathetic and
parasympathetic outflows that increase cardiac
output and vascular tone to maintain or reestab-
lish tissue PO2 sufficient to meet metabolic de-
mands (114, 152, 209, 236, 249, 260). Reciprocal
interactions between the respiratory and cardio-
vascular control systems through brain networks
and via sensory systems mediate this “cardiorespi-
ratory coupling” (14, 56, 91, 165, 265).
Carotid chemoreceptor activity evoked by hyp-
oxia is sufficient to cause the reemergence of
breathing during hypocapnic apneas (69, 185)
and to maintain ventilation under conditions as-
sociated with the congenital loss of central
transient hypoxia, as during sleep apneas, can
induce a distributed “memory” in circuits of the
brain stem and spinal cord, termed “long-term
facilitation” or LTF, expressed as increases in
respiratory drive and blood pressure that persist
well beyond the evoking perturbations (17, 51,
77, 113, 160, 161, 171, 172). Parallel mechanisms
evoked by disruption of vagal feedback during
repeated obstructive apneas, but independent of
hypoxia, can also trigger potentiated hypoglossal
motor neuron activity (243, 248).
Chronic intermittent hypoxia, depending on its
severity, duration, and patterning, can trigger a
time-dependent and escalating cascade of physio-
logical responses (206, 235) that, although initially
adaptive, can cause or exacerbate hypertension,
heart failure, and other disorders (143, 207, 209,
256). There is a growing body of preclinical and
clinical research targeting the carotid bodies with
the goal of developing therapies for these disorders
(45, 106, 153, 179, 237). Recent papers have de-
scribed hypoxia-sensing transduction mechanisms
in the carotid bodies (143, 208, 212, 236), the ven-
tilatory response to hypoxia (192, 249), adaptations
to chronic sustained or intermittent hypoxia (17,
72, 82, 84, 101, 143, 193, 196, 205, 220, 222), and
cardiorespiratory coupling (56, 91), including pul-
monary receptor-evoked cardiovascular effects
triggered by air pollution (12, 103).
This review focuses on the brain stem network
through which the carotid bodies enhance the
drive to breathe and blood pressure, and induce
LTF. Some open questions on mechanisms, sex
differences, and translational research are also
considered. The models and hypotheses reviewed
are based on results from many laboratories and
diverse experimental and computational ap-
proaches, as described in the cited literature and in
other recent complementary reviews (17, 56, 80,
81, 91, 131, 162, 164, 216, 265).

1548-9213/18 Copyright © 2018 Int. Union Physiol. Sci./Am. Physiol. Soc. 281

Downloaded from journals.physiology.org/journal/physiologyonline (095.252.059.005) on January 7, 2022.

REVIEW
Brain Stem Circuits for the
Integrated Cardiorespiratory
Response to Transient Hypoxia
Neurons in the NTS and adjacent medial medulla
have heterogeneous phenotypes and diverse re-
sponses to carotid body stimulation (2, 4, 36, 116,
120, 157, 194, 265). These “chemoresponsive” neu-
rons operate through multiple circuit pathways to
regulate the depth and frequency of breathing and,
concurrently, cardiac output and vascular tone
(FIGURE 1) (91, 177).
Inspiratory Drive and the Hypoxic
Ventilatory Response
A rostral cluster of pre-inspiratory “I-Driver” neu-
rons in the pre-Bötzinger complex (128, 131, 162,
229, 231, 240) of the ventral respiratory column
(VRC) excites a downstream “chain” of premotor
and motor neurons for the diaphragm, other in-
spiratory pump muscles, and muscles that influ-
ence airway resistance, such as those of the tongue
and oropharynx (FIGURE 1A) (19, 67, 73, 83, 246).
Carotid chemoreceptor stimulation can shorten
the inspiratory burst duration of some I-Driver
neurons, which otherwise exhibit little or no
change in their firing rate, whereas their targets,
including bulbospinal premotor neurons, exhibit
larger rate increases, enhancing inspiratory drive.
These observations led to a model with parallel
circuit mechanisms for tuning tidal volume and
breathing frequency (173, 177).
Chemoresponsive NTS neurons operate on a
subset of rostral I-Driver neurons and at multiple
sites along the inspiratory neuron chain to increase
neuronal firing rates (11, 171, 173). Evidence for
excitatory synaptic interactions between some re-
sponsive NTS and VRC neurons supports a model
for inspiratory drive amplification that includes
positive feedback circuits constrained by synaptic
depression in the recurrent arm of the loop
(FIGURE 1B; see Fig. 11B in Ref. 177). This model is
consistent with the observation that some chemo-
responsive NTS neurons have an evoked or
enhanced inspiratory-modulated firing pattern
during carotid body stimulation (194).
A second stage of amplification mediated by a
disinhibitory microcircuit downstream from the
pre-Bötzinger complex has also been proposed
(233). An efference copy of inspiratory drive excites
inhibitory inspiratory neurons, which in turn in-
hibit pericolumnar tonic expiratory (t-E) neurons.
This sequence results in disinhibition of their ex-
citatory inspiratory neuron targets (FIGURE 1C).
These t-E neurons operate as network “hubs” for
integration of convergent baroreceptor, peripheral
and central chemoreceptor, and motor efference
282 PHYSIOLOGY • Volume 33 • July 2018 • www.physiologyonline.org
Downloaded from journals.physiology.org/journal/physiologyonline (095.252.059.005) on January 7, 2022.
copy inputs that cooperatively tune inspiratory
drive and, as considered subsequently, autonomic
influences on cardiovascular function (135, 177,
190, 233). During exercise, carotid chemoreceptors
contribute to tonic vasoconstriction and locomotor
blood flow; their role in the enhancement of sym-
pathetic activity and their interactions with other
afferent and feed-forward central command mech-
anisms remain incompletely understood (46). The
convergence of chemoreceptor and efference copy
motor influences at VRC t-E hub neurons during
rhythmic behaviors like breathing and coughing
suggests that these hubs may have a role in the
generation of hyperpnea and other physiological
responses to exercise (186, 234).
Via NTS neurons, carotid chemoreceptors also
cooperate with central CO2-pH chemoreceptors
in the retrotrapezoid nucleus-parafacial region
(FIGURE 1D) (22, 89, 91, 94, 253, 259). Recent evi-
dence suggests that chemoresponsive neurons in
this area influence inspiratory drive via multi-path
modulation of t-E neuron nodes, supporting a
complex, partly hierarchical architecture for coop-
erative interactions between peripheral and central
chemoreceptor drives and a quasi-periodic tuning
of VRC circuits by coordinated clusters of adjacent
tegmental field neurons (177, 189, 190, 233).
Tuning Breathing Rate
Chemoresponsive NTS neurons evoke changes in
breathing frequency through mechanisms that re-
duce or limit the durations of both inspiratory
and expiratory phases (Ti and Te, respectively).
Truncation of I-Driver activity and the inspira-
tory phase is mediated in part by enhanced post-
inspiratory (decrementing expiratory) neuron
inhibition caused by carotid body stimulation
(FIGURE 1E) (125, 128, 138, 139, 173, 177, 216,
226). Teasing apart the physiological contexts
and respective contributions of inhibition and
intrinsic mechanisms for the I-Driver “off
switch” remains an active and controversial area
of research, in part because of the different prep-
arations and model systems studied and the
complex consequences of pharmacological ma-
nipulations used (7, 10, 37, 150, 216, 225).
A shortened expiratory phase, although not
obligatory, when present, may reflect enhanced
rostral Bötzinger complex augmenting expiratory
neuron inhibition of the relevant inhibitory decre-
menting expiratory (E-Dec) cells (FIGURE 1F) (129,
139, 140), overcoming chemoreceptor-driven en-
hancement of E-Dec neuron activity (11, 96, 170,
173, 187, 238). Regulation of the expiratory phase
of the respiratory cycle remains an area of active
research, and additional network mechanisms
proposed to tune breathing frequency, including

circuit loops through the pons, are considered
subsequently.
Enhancement of Expiratory Drive
Mechanisms for the enhanced expiratory effort as-
sociated with hypoxia are less well understood.
Active expiration, including excitation of abdomi-
nal and intercostal expiratory muscles, is present
during resting breathing under some conditions (1,
35, 42, 105, 185, 219) and dramatically enhanced
during hypoxia (140). It remains to be determined
whether this increased expiratory drive reflects, in
part, NTS chemoresponsive neurons acting directly
on caudal bulbospinal expiratory premotor neurons.
However, there is evidence for the recruitment of
both Bötzinger and adjacent RTN-parafacial neurons
during chemoreceptor stimulation (75, 108, 109,
191). The parafacial-lateral tegmental field region, a
site with complex neuronal interactions (177, 189,
190) and where peripheral and central chemorecep-
tor influences converge, as noted above, has been
strongly implicated as a source of expiratory drive
(20, 94, 131, 164). Hypercapnia leads to disinhibition
of non-chemosensitive late-E neurons proposed to
excite downstream expiratory neurons (41). This ob-
servation and other recent results collectively suggest
parallel push-pull excitatory and disinhibitory con-
trol circuits for expiratory drive tuning, including
tightly coordinated control of premotor inspiratory
and expiratory drives by shared RTN-pF region neu-
rons (FIGURE 1G) (104, 162, 177, 189, 190, 233).
Central Oxygen Sensing and Gasping
Selective stimulation of carotid chemoreceptors
may evoke somewhat different motor patterns and
autonomic responses than transient systemic hyp-
oxia, which stimulates oxygen sensors within the
carotid bodies and in the brain, all of which can
potentially contribute to the hypoxic ventilatory
response via parallel actions on pre-Bötzinger
complex I-Driver neurons (FIGURE 1H) and other
elements of the brain stem respiratory network (87,
236).
Under conditions of severe hypoxia, breathing is
first enhanced and then depressed until apnea or
the cessation of breathing (217, 218), followed by
the emergence of a simplified reconfigured respi-
ratory network that generates an autoresuscitative
gasping motor pattern. The network states and
biophysical processes required for this behavior
remain incompletely understood, as does the ex-
tent to which efferent copies of this drive engage
autonomic circuits (57, 64, 82, 122, 197, 226, 245,
251). Gasping is common in patients in cardiac
arrest with ventricular fibrillation and is associated
with successful resuscitation (61).
Downloaded from journals.physiology.org/journal/physiologyonline (095.252.059.005) on January 7, 2022.
REVIEW
Efference Copy and Hypoxia-Evoked
Changes in Autonomic Activity
The brain stem respiratory network has a profound
influence on the patterns (121) and magnitude (8) of
autonomic nervous system signaling that modulates
cardiac output and blood pressure in response to
hypoxia (FIGURE 1I). Carotid chemoreceptors evoke
coordinated changes through other routes, including
direct NTS neuron projections to pre-sympathetic C1
and non-C1 neurons in the rostral-ventrolateral me-
dulla (RVLM) (116, 120). These RVLM neurons excite
spinal pre-ganglionic sympathetic neurons that
drive vasoconstriction and stimulate the heart in
response to hypoxia (93, 156, 188, 265). The RVLM
C1 and non-C1 neurons are phenotypically heter-
ogeneous, with attributes including three distinct
classes of respiratory modulated discharge pat-
terns: inspiratory-excited [presumably excited by
pre-Bötzinger complex I-Driver neurons or down-
stream inspiratory chain follower neurons (166)],
inspiratory-inhibited, and those with a post-in-
spiratory modulation (166, 168). C1 neurons are
involved in inspiratory modulation of sympathetic
activity enhanced by carotid chemoreceptors
(167). The post-inspiratory subset includes neu-
rons that also exhibit late expiratory neuron exci-
tation following chronic intermittent hypoxia, an
example of plasticity considered further in a sub-
sequent section of this review (168). RVLM neurons
are modulated by baroreceptors indirectly through
inhibitory neurons (FIGURE 1I) in the intermediate
ventrolateral medulla (IVLM, “alias” caudal ventro-
lateral medulla) (93), which also receive post-in-
spiratory excitation during hypoxia (168).
Parasympathetic cardiac vagal pre-ganglionic
neurons in the nucleus ambiguus (NA) receive
convergent carotid chemoreceptor and barorecep-
tor influences via the NTS; they are inhibited dur-
ing inspiration, presumably by neurons in the VRC
(FIGURE 1J). The resulting respiratory sinus ar-
rhythmia (RSA) caused by reduced vagal inhibition
of the heart can contribute to increased cardiac
output (85, 88). Moderate hypoxia diminishes the
magnitude of the RSA (28, 60, 254, 262, 263). The
extent to which changes in the breathing pattern
and autonomic modulation of the heart and circu-
lation influence venous return and cardiac output
depends on various factors (147). Left ventricular
stroke volume decreases during inspiration, al-
though right ventricular filling pressure increases
(221). Moreover, venous flow from the legs dur-
ing inspiration varies, depending on the relative
contributions of the diaphragm and intercostal
and abdominal muscle activity (258). Respiratory
sinus arrhythmia does not appear to improve gas
exchange efficiency, but rather minimizes the
work done by the heart while maintaining
PHYSIOLOGY • Volume 33 • July 2018 • www.physiologyonline.org 283
REVIEW

FIGURE 1. Continued

physiological levels of arterial carbon dioxide or
PaCO2 (23, 24). An enhancement of firing rate
during the post-inspiratory interval also has
been observed in vivo, supporting the hypothesis
that slow breathing, which increases the post-
inspiratory phase duration, slows the heart rate
by increasing the firing rate of cardiac vagal pre-
ganglionic neurons (65, 88).
Cardiorespiratory coupling is also apparent in
the arterial pulse modulation of respiratory

284 PHYSIOLOGY • Volume 33 • July 2018 • www.physiologyonline.org

Downloaded from journals.physiology.org/journal/physiologyonline (095.252.059.005) on January 7, 2022.

 REVIEW

FIGURE 1. Medullary circuit mechanisms in contemporary models of carotid chemoreceptor and baroreceptor modulation of
breathing and cardiovascular functions
A–K: schematic representations of specific functional interactions described in the text. Neuron populations are grouped by brain stem location and
labeled by their respiratory modulated firing rates: inspiratory (I), post-inspiratory (post-I), or expiratory (E), according to the phase of greatest aver-
age activity, and as decrementing (Dec) or augmenting (Aug) if the average peak firing rate occurs during the first or second half of the phase, re-
spectively. I-Driver neuron activity begins slightly before phrenic nerve discharge, with firing rates that peak in the early I phase and then slowly
decrease before abruptly decreasing at the end of inspiration. Tonic E cells (t-E) are active throughout the respiratory cycle, with their greatest rate
during expiration. Black lines and “synapses” indicate inferred functional connectivity discussed in the text. 1, Cross-correlogram with offset peak
consistent with RTN-pF region neuron exciting a putative premotor caudal VRC augmenting expiratory neuron. Figure adapted from Fig. 5D in Ref.
190 with permission from Journal of Neurophysiology. Both neurons responded to transient hypoxia with increased firing rates (177). Bin-
width ⫽ 15.5 ms, 71,132 trigger neuron spikes, 25,541 target neuron spikes. Böt, Bötzinger complex; BS, bulbospinal; FTL/RTN-pF, lateral tegmen-
tal field/retrotrapezoid n.-parafacial n; IML, intermediolateral column of the spinal cord; IVLM, intermediate ventrolateral medulla; Lum, lumbar
nerve; NA, n. ambiguus; NTS-DMM, n. tractus solitarius-dorsal medial medulla; Phr, phrenic nerve; pre-Böt, pre-Bötzinger complex; RVLM, rostral
ventrolateral medulla; VRC, ventral respiratory column.

premotor and motor neurons (52, 74). Barore-
ceptors provide a major coordinating influence
on cardiorespiratory coupling during hypoxia
through their actions on breathing and via coor-
dinated feedback regulation of cardiovascular
function. Functional connectivity of medullary ra-
phe circuits supports baroreceptor modulation of
inspiratory drive and expiratory phase duration via
push-pull tuning of VRC t-E and E-Dec neurons,
respectively (9, 135). Raphe circuits are dynami-
cally reconfigured over the course of the respira-
tory cycle and baroreceptor and carotid
chemoreceptor stimulation (6, 32, 127, 172). These
circuits (FIGURE 1K) have been proposed to incor-
porate internal equilibrium-seeking mechanisms
that help to stabilize breathing and regulate reflex
gain during perturbations of blood pressure, for
example, during cough (130, 134, 135, 202), and to
contribute to the respiratory modulation of the
sympathetic baroreceptor reflex (9).

PHYSIOLOGY • Volume 33 • July 2018 • www.physiologyonline.org 285

Downloaded from journals.physiology.org/journal/physiologyonline (095.252.059.005) on January 7, 2022.

REVIEW
The Role of the Pons in the Hypoxic
Ventilatory Response and Cardiorespiratory
Coupling
The Kölliker-Fuse/parabrachial complex of the
dorsolateral pons receives inputs from NTS neu-
rons that relay signals from carotid body afferents
(FIGURE 2A) (98, 244). Neurons of the Kölliker-
Fuse (K-F) region contribute to cardiorespiratory
coupling and are activated during hypoxia and ca-
rotid sinus nerve stimulation (63). They project to
several brain stem sites that participate in the con-
trol of tidal volume and breathing frequency and
directly to brain stem sympathetic circuits that
regulate the cardiovascular network (13, 15, 16, 53,
59). Pharmacological perturbations of K-F neurons
disrupt the hypoxic ventilatory response (38), pos-
sibly, in part, through reciprocal connections with
the RTN and parafacial region (59, 223, 239).
The dorsolateral pons influences breathing fre-
quency during hypoxia through inspiratory-expira-
tory phase switching mechanisms. These circuits
remain incompletely understood; models (5, 17,
178, 203) include pontine neurons that operate
to shorten inspiration and expiration (e.g.,
FIGURE 2B). Inhibition of the K-F region with
muscimol, a GABA-A receptor agonist, reduces
the enhancement of phrenic and sympathetic
drive (FIGURE 2C) and breathing frequency
responses to hypoxia (39). The Kölliker-Fuse nu-
cleus also provides a pathway for post-inspira-
tory modulation of cardiac vagal parasympathetic
activity (FIGURE 2D) (65). K-F connectivity to post-
inspiratory or E-Dec neurons could also contribute
to modulation of augmenting or late expiratory
neuron activity and the enhancement of active ex-
piration with increased chemical drive (18).
Neurons of the lateral parabrachial nucleus
(LPBN) may also enhance breathing frequency
during hypoxia by reducing expiratory phase du-
ration (242). Bilateral lesions of K-F nuclei provoke
apnea, suggesting that neurons there promote in-
spiration (204). This conclusion is supported by the
finding that both pharmacological and patterned
electrical microstimulation within the pontine me-
dial parabrachial nucleus promote inspiratory
burst onset (FIGURE 2E) and can evoke a prema-
ture onset of the next inspiratory phase, thereby
shortening Te and increasing breathing frequency
(266).
The A5 cell group of noradrenergic and glutama-
tergic neurons in the ventrolateral pons modulates
FIGURE 2. Simplified functional connectivity of hypoxia-responsive pontine neurons
A–E: interactions inferred from various experimental approaches reviewed in the text that contribute to the hypoxic ventilatory response and
changes in cardiorespiratory coupling during hypoxia in current models. F and G: MWRO-triggered firing rate histograms of a pontine neuron be-
fore and after bilateral vagotomy and phase resetting of MWROs by withholding lung inflation in vagus-intact cat. Figure derived from Fig. 5A in
Ref. 176 with permission. See text for details. KF, Kölliker-Fuse n.; LPBM, lateral parabrachial n.; MWRO, Mayer wave-related oscillations; NPBM,
medial parabrachial n.; Ti (Te), duration of inspiratory (expiratory) phase.
286 PHYSIOLOGY • Volume 33 • July 2018 • www.physiologyonline.org
Downloaded from journals.physiology.org/journal/physiologyonline (095.252.059.005) on January 7, 2022.
breathing frequency and cardiovascular function
during and following hypoxia (118, 119). Neurons
in the A5 group project to the VRC, have post-
inspiratory and expiratory modulated firing pat-
terns, and are responsive to hypoxia (50, 59, 92).
Micro-injections of muscimol into the ventrolat-
eral pons prolongs inspiration (110), whereas ap-
plication of glutamate prolongs expiration (111).
This expiratory-facilitating function is apparent
during and following episodes of transient severe
hypoxia: respiratory frequency first increases, then
slows in a “post-hypoxic frequency decline,” fol-
lowed by a gradual return to control levels. A sim-
ilar sequence is observed during and following
carotid sinus nerve stimulation under hyperoxic
conditions, suggesting that the frequency decline is
of central origin (97).
Raphe-Pontine Circuits, Slow Breathing,
and Mayer Wave-Related Oscillations
Slow (~0.1 Hz) oscillations in respiratory drive and
blood pressure, termed Mayer waves, can be trig-
gered by hypoxia or hemorrhage, conditions that
increase carotid body chemoreceptor activity and
sympathetic drive (3, 33, 68, 124, 262). Oscillations
evoked by carotid artery occlusion with hemor-
rhage can be eliminated by section of the carotid
sinus nerves or destruction of carotid body chemo-
receptors, suggesting that hypoxia or under-perfu-
sion of the carotid body can evoke this category of
cardiorespiratory coupling (3).
Bilateral vagotomy commonly results in a pro-
longation of the inspiratory phase. The loss of
the Breuer-Hering reflex (96) together with the
aforementioned inspiratory off-switch function
of the pons (55) contributes to this slowing of
breathing frequency. A second mechanism
involving cardiorespiratory coupling has been
proposed to play a role in the generation of the
slower breathing rhythm. The VRC is embedded
in a highly interconnected pontomedullary net-
work with medullary raphe circuits providing
parallel signaling routes between the pons and
the VRC (184, 230, 232). Pontine and raphe neu-
rons with Mayer wave-related oscillations
(MWROs) can become synchronized 1:1 with the
breathing rhythm after vagotomy (FIGURE 2F)
(176). Computational models show that neurons
with inspiratory efference copy input and feed-
forward inhibition produce similar rate profiles
(55). Prior to vagotomy, withholding lung inflation
 REVIEW

PHYSIOLOGY • Volume 33 • July 2018 • www.physiologyonline.org 287

Downloaded from journals.physiology.org/journal/physiologyonline (095.252.059.005) on January 7, 2022.

REVIEW

FIGURE 3. Distributed network sites for induction and expression of carotid body- and intermittent hypoxia-induced long-term
facilitation
A: responses of raphe neurons and integrated phrenic nerve activity during repeated selective stimulation of carotid chemoreceptors and induction
of long-term facilitation (LTF). Figure is derived from Ref. 174 with permission from Respiration Physiology. B: raphe circuit mechanism proposed to
contribute to ratchet-like incremental induction of LTF (171, 172). C: firing rate histogram and by-cycle rate plots show opposite responses of a ra-
phe neuron to selective stimulation of central and peripheral carotid chemoreceptors. Figure derived from Fig. 2A, C in Ref. 183 with permission
from The Royal Society. D: increased number of black bins in the top right quadrant along the diagonal of the joint peri-stimulus time histogram
(JPSTH) documents a significant increase in spike synchrony and effective connectivity for two raphe cells following induction of LTF. Figure
adapted from Fig. 4A in Ref. 171 with permission from Journal of Physiology. E: offset cross-correlogram peak shows effective connectivity between
a pre-Bötzinger I-Driver neuron and a VRG inspiratory target cell; binwidth ⫽ 0.5 ms, 8,216 trigger neuron spikes, 4,569 target neuron spikes. F:
non-uniform distribution of statistically significant black bins along the diagonal of the JPSTH for the same neurons shown in E documents en-
hanced effective connectivity between this pair of neurons following induction of LTF. Figure derived from Fig. 3, B and C, in Ref. 171 with permis-
sion from Journal of Physiology. G–L: additional sites for distributed LTF expression following repeated episodes of intermittent hypoxia. See text
for details.

during inspiration both prolongs the inspiratory (54). Functional connectivity inferred from multi-
phase and resets the MWROs (FIGURE 2G) (176). array recordings suggests that pontine-raphe cir-
Increased cardiorespiratory coupling can persist cuits contribute to this aspect of cardiorespiratory
following slow deep breathing in human subjects coupling (176).

288 PHYSIOLOGY • Volume 33 • July 2018 • www.physiologyonline.org

Downloaded from journals.physiology.org/journal/physiologyonline (095.252.059.005) on January 7, 2022.


Distributed Memories Induced by
Intermittent Hypoxia
In 1980, David Millhorn and colleagues reported
that episodic stimulation of carotid body chemo-
receptors can induce a respiratory memory ex-
pressed as an increase in phrenic nerve inspiratory
burst amplitude and breathing frequency. This
“long-term facilitation” (LTF) persists well beyond
the period of stimulation (160, 161) and can also be
evoked by direct electrical stimulation of n. raphe
obscurus but not by central CO2 chemoreceptors;
it is prevented or attenuated by serotonin (5-HT)
antagonists (76, 159, 160). Hypoxia and electrical
stimulation of the carotid sinus nerve also induces
Fos-like immunoreactivity in serotoninergic and
catecholaminergic neurons at multiple sites within
the brain stem (63). Raphe stimulation releases
5-HT in the cervical ventral horn of the spinal cord,
the site of phrenic motor neurons (27, 215). Sub-
sequent research has identified stimulus parame-
ters and conditions necessary for enhancement of
specific motor and autonomic outflows by inter-
mittent hypoxia (76, 117, 169, 257), along with in-
sights into the network, and cellular and molecular
mechanisms for a memory system distributed
among multiple sites in the brain stem (26, 77, 126,
137, 174, 175), spinal cord (34, 70, 247), and carotid
Downloaded from journals.physiology.org/journal/physiologyonline (095.252.059.005) on January 7, 2022.
REVIEW
FIGURE 3. Continued
bodies (236). These multi-scale mechanisms for
adaptive physiological responses alter cardiorespi-
ratory coordination and can exacerbate or result in
various pathophysiological conditions (143, 207,
209, 256, 261).
Cardiorespiratory-related neurons of the med-
ullary raphe nuclei have dynamic functional
associations and interact with the VRC, pons,
RTN, and other brain stem sites for the coordi-
nated regulation of breathing and the cardiovas-
cular system (6, 32, 91, 132–134, 136, 172, 173,
177, 184, 210). Some raphe neurons respond to
repeated stimulation of the carotid chemorecep-
tors with step-like increases in firing rate
(FIGURE 3A). A “ratchet-like” circuit mechanism
has been proposed to contribute to this incremen-
tal induction of respiratory LTF: periods of evoked
high firing rate in some neurons are limited by the
delayed inhibitory actions of other neurons
(FIGURE 3B), until the firing rates of the early re-
sponders increase and “saturate” (149, 171, 172).
Some raphe neurons excited by peripheral carotid
chemoreceptor stimulation are functionally inh-
ibited by central chemoreceptor activation
(FIGURE 3C) (183), a result consistent with the
inability of central chemoreceptor stimulation to
evoke LTF (159). Indeed, repeated episodes of hy-
percapnia have been shown to induce a long-term
PHYSIOLOGY • Volume 33 • July 2018 • www.physiologyonline.org 289
REVIEW
depression of phrenic nerve activity (115) through
processes involving activation of 5-HT1A and ␣2-
adrenergic receptors (227).
Intermittent or sustained hypercapnia can have
a profound effect on the responses to intermittent
hypoxia (155). Although intermittent hypercapnia
may depress ventilatory LTF, sustained hypercap-
nia facilitates it (90, 95). Sustained hypocapnia pre-
vents the occurrence of LTF, hence LTF can be
difficult to observe during sleep-disordered
breathing. Such breathing is made up of cycles of
hyperventilation followed by apneic hypoxic hy-
percapnia followed by arousal, hyperventilation,
etc. (155).
In rats, both intermittent and sustained hypoxia
increase sympathetic nerve activity after 2 wk, but
they affect sympatho-respiratory coupling differen-
tially (56). Intermittent hypoxia enhances sympatho-
respiratory coupling and decreases ventilatory
variability. Constant hypobaric hypoxia replaces nor-
mal 1-to-1 coupling between bursts of sympathetic
and phrenic nerve activity with 2-to-3 coupling with
increased ventilatory variability. Even a single session
of hypoxic exposure is capable of increasing tonic
sympathetic nerve output (sympathetic long-term fa-
cilitation) and altering chemo- and baroreflexes
(260).
Several lines of evidence collectively support an
important role for distributed brain stem circuits in
the induction and expression of LTF, including
carotid chemoreceptor-evoked responses, changes
in functional connectivity among raphe neurons
(FIGURE 3D), and evidence of increased effective
connectivity among I-Driver neurons and their
premotor targets (FIGURE 3, E–G) (17, 62, 79, 127,
171, 172, 257). How chronic intermittent hypoxia
impacts different states of inspiratory activity in
the pre-Bötzinger complex remains an active area
of research (81). Cell signaling pathways for LTF of
inspiratory drive have been most thoroughly inves-
tigated in the spinal cord (FIGURE 3H), where se-
rotonin-dependent induction of facilitation in
phrenic motor neurons depends on competing cell
signaling mechanisms that interact conditionally
with adenosine-dependent pathways for motor fa-
cilitation (47– 49, 71, 77, 200, 252).
Serotonergic mechanisms are also implicated in
the induction of expiratory LTF (126) at sites in the
RTN-pF respiratory group (FIGURE 3I) (91). This en-
hanced expiratory drive, together with sensitization
to central CO2 chemoreception with chronic inter-
mittent hypoxia, contribute to increased sympathetic
nerve activity (51, 163, 264). A subset of non-C1
RVLM presympathetic neurons (FIGURE 3J) has
been implicated as a source of this enhancement
(168). Recruitment of 5-HT systems by hypoxia and
hypercapnia also modulates the excitability of para-
sympathetic cardiac vagal neurons (FIGURE 3K)
290 PHYSIOLOGY • Volume 33 • July 2018 • www.physiologyonline.org
Downloaded from journals.physiology.org/journal/physiologyonline (095.252.059.005) on January 7, 2022.
(113). An altered balance of hypoxia-inducible fac-
tor-␣ isoforms and redox state were identified in the
NTS, RVLM, and adrenal medulla of rats exposed to
chronic intermittent hypoxia. These changes were
prevented by carotid body ablation, suggesting that
carotid-evoked changes in neural activity lead to
these alterations and the associated development of
hypertension and elevated sympathetic activity (199).
Chronic intermittent hypoxia enhances the
sensitivity and gain of carotid body chemorecep-
tors in an age- and history-dependent manner
(FIGURE 3L). Hypoxic sensitization requires ~10
times the number of episodes of intermittent
hypoxia in adult compared with neonatal rats.
Moreover, subsequent acute intermittent hyp-
oxia evokes LTF in the carotid body of previously
exposed adults but not of neonates (196, 198).
Hypoxia-induced changes in the redox state of
the carotid bodies via an altered balance of HIF-
1␣-dependent pro-oxidant and HIF-2␣-dependent
anti-oxidant activities may play a role in the induc-
tion of these changes (235, 236); a recent study
reports that HIF-2␣ is essential for carotid body
function and development (146). Acute hypoxia
with concurrent hypercapnia also evokes sensory
LTF in carotid bodies (224).
The hypoxemic carotid body expands far beyond
its normal size (142). Adult neural stem cells contrib-
ute to carotid body growth during hypoxia acclima-
tization, and these new cells contain voltage-
dependent ion channels (193). This adaptation to
chronic hypoxia requires HIF-2␣ for oxygen-sensitive
glomus cells to develop and survive within the ca-
rotid body (146) and for normal responses to hypoxia
(101). Contrary to maladaptive responses outlined
previously, other studies have suggested therapeutic
benefits of hypoxic or hypercapnic regimes in spinal
cord injury (34, 181), obstructive sleep apnea (153),
and other cardiovascular, respiratory, cognitive, and
metabolic consequences of intermittent hypoxia
(154).
Future Directions for Basic and
Translational Science
Sex Differences in Responses to Hypoxia
Further research is needed to better understand
sex differences in the hypoxic ventilatory re-
sponse and their impact during development.
Prenatal nicotine exposure alters the postnatal
heart rate response to hypoxia and respiratory
sinus arrhythmias in young male but not female
rats (25). The hypoxic ventilatory response is
greater in men than in women (86), and is dif-
ferentially depressed more in women by mor-
phine (228). Age- and sex-dependent differences
in serotonin-dependent hypoxia-evoked neural
plasticity have also been identified: LTF in-

creases with age in female rats but declines in
male rats (21).
The “Erasure” of Dysfunctional
Cardiorespiratory Network Memories
An emerging goal of contemporary translational
research is to identify safe and effective therapeutic
strategies for management and treatment of the
long-term consequences of adaptations to chronic
intermittent hypoxia (106, 143, 153, 236). Pharma-
cological and immunological approaches and gene
therapy are being actively considered (145, 148,
182, 236, 243). Ablation or denervation of the ca-
rotid bodies for resistant hypertension is also being
evaluated in preclinical research (106). A prospec-
tive human feasibility and safety trial on unilateral
ablation has been reported (179), and similar ap-
proaches for heart failure are being explored (44,
151).
The ablation approach is controversial. Carotid
body ablation was used in humans as an experi-
mental treatment for bronchial asthma and
chronic obstructive pulmonary disease but did not
produce significant benefits for patients (112). Pa-
tients with previous bilateral carotid body abla-
tions to treat asthma were subsequently evaluated
for responses to hypoxia and hypercapnia; whereas
ventilation in room air was normal, hyperpnea in
response to hypoxia was absent, and the response
to hypercapnia was reduced (144). These observa-
tions suggest that central hypoxia-sensing mecha-
nisms cannot fully compensate for the loss of
carotid O2 chemoreception (78, 87), and it remains
an open question as to whether central mecha-
nisms can “appropriate” network mechanisms
used by carotid chemoreceptors to reestablish
adaptive (or maladaptive) set points and system
gains (100, 158, 241). Several recent reviews and
perspectives (112, 143) and preclinical studies (58,
66, 102, 237) have noted potential risks and adverse
consequences of carotid body removal, including
baroreceptor failure, exacerbation of co-morbidi-
ties, altered blood glucose regulation, reduced abil-
ity for acclimatization to high altitude, and
irregular breathing rhythms.
Significant gaps remain in our understanding of
brain networks and cell signaling mechanisms for
cardiorespiratory regulation and hypoxia sensing.
The development, organization, plasticity, and
state-dependent functionality of these systems and
the integration of peripheral and central chemore-
ceptor influences are areas of active investigation
(259). These lines of inquiry also have a broader
relevance beyond cardiorespiratory integration
with the growing appreciation that other brain re-
gions, rhythms, and functions are influenced by
breathing (40, 99, 233, 250). 䡲
Downloaded from journals.physiology.org/journal/physiologyonline (095.252.059.005) on January 7, 2022.
REVIEW
Work from the authors’ laboratory reviewed herein was
supported by National Institute of Neurological Disorders
and Stroke Grants R01/37 NS-019814 and R01 NS-046062
as part of the NSF/NIH Collaborative Research in Compu-
tational Neuroscience (CRCNS) Program.
No conflicts of interest, financial or otherwise, are de-
clared by the author(s).
Author contributions: B.G.L. and L.S.S. prepared figures;
B.G.L., S.C.N., and L.S.S. drafted manuscript; B.G.L.,
S.C.N., L.S.S., and K.F.M. edited and revised manuscript;
B.G.L., S.C.N., L.S.S., and K.F.M. approved final version of
manuscript.
References
1. Abe T, Kusuhara N, Yoshimura N, Tomita T, Easton PA.
Differential respiratory activity of four abdominal muscles in
humans. J Appl Physiol (1985) 80: 1379 –1389, 1996. doi:10.
1152/jappl.1996.80.4.1379.
2. Accorsi-Mendonça D, Machado BH. Synaptic transmission of
baro- and chemoreceptors afferents in the NTS second order
neurons. Auton Neurosci 175: 3– 8, 2013. doi:10.1016/j.
autneu.2012.12.002.
3. Andersson B, Kenney RA, Neil E. The role of the chemocep-
tors of the carotid and aortic regions in the production of the
Mayer waves. Acta Physiol Scand 20: 203–220, 1950. doi:10.
1111/j.1748-1716.1950.tb00699.x.
4. Andresen MC, Kunze DL. Nucleus tractus solitarius--gateway
to neural circulatory control. Annu Rev Physiol 56: 93–116,
1994. doi:10.1146/annurev.ph.56.030194.000521.
5. Arata A, Tanaka I, Fujii M, Ezure K. Active inspiratory-expi-
ratory phase switching mechanism exists in the neonatal
nucleus parabrachialis. In: New Frontiers in Respiratory Con-
trol. Advances in Experimental Medicine and Biology, edited
by Homma I, Onimaru H, Fukuchi Y. New York, NY: Springer
New York, 2010, p. 135–138. doi:10.1007/978-1-4419-5692-
7_27.
6. Arata A, Hernandez YM, Lindsey BG, Morris KF, Shannon R.
Transient configurations of baroresponsive respiratory-related
brainstem neuronal assemblies in the cat. J Physiol 525: 509 –
530, 2000. doi:10.1111/j.1469-7793.2000.t01-1-00509.x.
7. Bacak BJ, Kim T, Smith JC, Rubin JE, Rybak IA. Mixed-mode
oscillations and population bursting in the pre-Bötzinger
complex. eLife 5: e13403, 2016. doi:10.7554/eLife.13403.
8. Badrov MB, Barak OF, Mijacika T, Shoemaker LN, Borrell LJ,
Lojpur M, Drvis I, Dujic Z, Shoemaker JK. Ventilation inhibits
sympathetic action potential recruitment even during severe
chemoreflex stress. J Neurophysiol 118: 2914 –2924, 2017.
doi:10.1152/jn.00381.2017.
9. Baekey DM, Molkov YI, Paton JFR, Rybak IA, Dick TE. Effect
of baroreceptor stimulation on the respiratory pattern: in-
sights into respiratory-sympathetic interactions. Respir
Physiol Neurobiol 174: 135–145, 2010. doi:10.1016/j.resp.
2010.09.006.
10. Baertsch NA, Baertsch HC, Ramirez JM. The interdepen-
dence of excitation and inhibition for the control of dynamic
breathing rhythms. Nat Commun 9: 843, 2018. doi:10.1038/
s41467-018-03223-x.
11. Balis UJ, Morris KF, Koleski J, Lindsey BG. Simulations of a
ventrolateral medullary neural network for respiratory rhyth-
mogenesis inferred from spike train cross-correlation. Biol
Cybern 70: 311–327, 1994. doi:10.1007/BF00200329.
12. Bantikyan A, Song G, Feinberg-Zadek P, Poon C-S. Intrinsic
and synaptic long-term depression of NTS relay of nocicep-
tin- and capsaicin-sensitive cardiopulmonary afferents hyper-
activity. Pflugers Arch 457: 1147–1159, 2009. doi:10.1007/
s00424-008-0571-9.
13. Barman SM, Gebber GL. Classification of caudal ventrolateral
pontine neurons with sympathetic nerve-related activity. J
Neurophysiol 80: 2433–2445, 1998. doi:10.1152/jn.1998.80.
5.2433.
14. Barman SM, Yates BJ. Deciphering the neural control of
sympathetic nerve activity: Status report and directions for
future research. Front Neurosci 11: 730, 2017. doi:10.3389/
fnins.2017.00730.
PHYSIOLOGY • Volume 33 • July 2018 • www.physiologyonline.org 291
REVIEW
15. Barman SM, Gebber GL, Kitchens H. Rostral dor-
solateral pontine neurons with sympathetic
nerve-related activity. Am J Physiol Heart Circ
Physiol 276: H401–H412, 1999.
16. Barman SM, Kitchens HL, Leckow AB, Gebber
GL. Pontine neurons are elements of the network
responsible for the 10-Hz rhythm in sympathetic
nerve discharge. Am J Physiol Heart Circ Physiol
273: H1909 –H1919, 1997.
17. Barnett WH, Abdala AP, Paton JFR, Rybak IA,
Zoccal DB, Molkov YI. Chemoreception and neu-
roplasticity in respiratory circuits. Exp Neurol
287: 153–164, 2017. doi:10.1016/j.expneurol.
2016.05.036.
18. Barnett WH, Jenkin SEM, Milsom WK, Paton JFR,
Abdala AP, Molkov YI, Zoccal DB. The Kölliker-
Fuse nucleus orchestrates the timing of expira-
tory abdominal nerve bursting. J Neurophysiol
119: 401– 412, 2018. doi:10.1152/jn.00499.2017.
19. Bartlett D Jr. Effects of hypercapnia and hypoxia on
laryngeal resistance to airflow. Respir Physiol 37: 293–
302, 1979. doi:10.1016/0034-5687(79)90076-8.
20. Basting TM, Burke PGR, Kanbar R, Viar KE, Stornetta
DS, Stornetta RL, Guyenet PG. Hypoxia silences ret-
rotrapezoid nucleus respiratory chemoreceptors
via alkalosis. J Neurosci 35: 527–543, 2015. doi:10.
1523/JNEUROSCI.2923-14.2015.
21. Behan M, Zabka AG, Mitchell GS. Age and gen-
der effects on serotonin-dependent plasticity
in respiratory motor control. Respir Physiol
Neurobiol 131: 65–77, 2002. doi:10.1016/
S1569-9048(02)00038-1.
22. Beltrán-Castillo S, Olivares MJ, Contreras RA,
Zúñiga G, Llona I, von Bernhardi R, Eugenín JL.
D-serine released by astrocytes in brainstem reg-
ulates breathing response to CO2 levels. Nat
Commun 8: 838, 2017. doi:10.1038/s41467-017-
00960-3.
23. Ben-Tal A, Shamailov SS, Paton JFR. Evaluating
the physiological significance of respiratory sinus
arrhythmia: looking beyond ventilation-perfusion
efficiency. J Physiol 590: 1989 –2008, 2012. doi:
10.1113/jphysiol.2011.222422.
24. Ben-Tal A, Shamailov SS, Paton JFR. Central reg-
ulation of heart rate and the appearance of re-
spiratory sinus arrhythmia: new insights from
mathematical modeling. Math Biosci 255: 71– 82,
2014. doi:10.1016/j.mbs.2014.06.015.
25. Boychuk CR, Hayward LF. Prenatal nicotine ex-
posure alters postnatal cardiorespiratory integra-
tion in young male but not female rats. Exp
Neurol 232: 212–221, 2011. doi:10.1016/j.
expneurol.2011.09.006.
26. Braegelmann KM, Streeter KA, Fields DP, Baker
TL. Plasticity in respiratory motor neurons in re-
sponse to reduced synaptic inputs: A form of
homeostatic plasticity in respiratory control? Exp
Neurol 287: 225–234, 2017. doi:10.1016/j.
expneurol.2016.07.012.
27. Brodin E, Linderoth B, Goiny M, Yamamoto Y,
Gazelius B, Millhorn DE, Hökfelt T, Ungerstedt U.
In vivo release of serotonin in cat dorsal vagal
complex and cervical ventral horn induced by
electrical stimulation of the medullary raphe nu-
clei. Brain Res 535: 227–236, 1990. doi:10.1016/
0006-8993(90)91605-G.
28. Brown SJ, Barnes MJ, Mündel T. Effects of
hypoxia and hypercapnia on human HRV and
respiratory sinus arrhythmia. Acta Physiol Hung
101: 263–272, 2014. doi:10.1556/APhysiol.101.
2014.3.1.
29. Buckler KJ. A novel oxygen-sensitive potassium
current in rat carotid body type I cells. J Physiol
498: 649 – 662, 1997. doi:10.1113/jphysiol.1997.
sp021890.
30. Buckler KJ. TASK channels in arterial chemore-
ceptors and their role in oxygen and acid sens-
ing. Pflugers Arch 467: 1013–1025, 2015. doi:10.
1007/s00424-015-1689-1.
292 PHYSIOLOGY • Volume 33 • July 2018 • www.physiologyonline.org
Downloaded from journals.physiology.org/journal/physiologyonline (095.252.059.005) on January 7, 2022.
31. Buckler KJ, Turner PJ. Oxygen sensitivity of mi-
tochondrial function in rat arterial chemorecep-
tor cells. J Physiol 591: 3549 –3563, 2013. doi:10.
1113/jphysiol.2013.257741.
32. Chang EY, Morris KF, Shannon R, Lindsey BG.
Repeated sequences of interspike intervals in
baroresponsive respiratory related neuronal as-
semblies of the cat brain stem. J Neurophysiol
84: 1136 –1148, 2000. doi:10.1152/jn.2000.84.3.
1136.
33. Cherniack NS, Edelman NH, Fishman AP. Pattern
of discharge of respiratory neurons during sys-
temic vasomotor waves. Am J Physiol 217: 1375–
1383, 1969.
34. Christiansen L, Urbin MA, Mitchell GS, Perez MA.
Acute intermittent hypoxia enhances corticospi-
nal synaptic plasticity in humans. eLife 7: e34304,
2018. doi:10.7554/eLife.34304.
35. Cohen MI, Feldman JL, Sommer D. Caudal med-
ullary expiratory neurone and internal intercostal
nerve discharges in the cat: effects of lung infla-
tion. J Physiol 368: 147–178, 1985. doi:10.1113/
jphysiol.1985.sp015851.
36. Cruz JC, Bonagamba LG, Stern JE, Machado BH.
Fos expression in the NTS in response to periph-
eral chemoreflex activation in awake rats. Auton
Neurosci 152: 27–34, 2010. doi:10.1016/j.autneu.
2009.08.016.
37. Cui Y, Kam K, Sherman D, Janczewski WA, Zheng
Y, Feldman JL. Defining preBötzinger complex
rhythm and pattern generating neural microcir-
cuits in vivo. Neuron 91: 602– 614, 2016. doi:10.
1016/j.neuron.2016.07.003.
38. Damasceno RS, Takakura AC, Moreira TS. Regu-
lation of the chemosensory control of breathing
by Kölliker-Fuse neurons. Am J Physiol Regul
Integr Comp Physiol 307: R57–R67, 2014. doi:10.
1152/ajpregu.00024.2014.
39. Damasceno RS, Takakura AC, Moreira TS. Respi-
ratory and sympathetic chemoreflex regulation
by Kölliker-Fuse neurons in rats. Pflugers Arch
467: 231–239, 2015. doi:10.1007/s00424-014-
1525-z.
40. Davenport PW, Shannon R, Mercak A, Reep RL,
Lindsey BG. Cerebral cortical evoked potentials
elicited by cat intercostal muscle mechanorecep-
tors. J Appl Physiol (1985) 74: 799 – 804, 1993.
doi:10.1152/jappl.1993.74.2.799.
41. de Britto AA, Moraes DJA. Non-chemosensitive
parafacial neurons simultaneously regulate active
expiration and airway patency under hypercapnia
in rats. J Physiol 595: 2043–2064, 2017. doi:10.
1113/JP273335.
42. De Troyer A, Estenne M, Ninane V, Van
Gansbeke D, Gorini M. Transversus abdominis
muscle function in humans. J Appl Physiol (1985)
68: 1010 –1016, 1990. doi:10.1152/jappl.1990.68.
3.1010.
43. Dean JB, Mulkey DK, Henderson RA III, Potter
SJ, Putnam RW. Hyperoxia, reactive oxygen spe-
cies, and hyperventilation: oxygen sensitivity of
brain stem neurons. J Appl Physiol (1985) 96:
784 –791, 2004. doi:10.1152/japplphysiol.00892.
2003.
44. Del Rio R, Marcus NJ, Schultz HD. Carotid
chemoreceptor ablation improves survival in
heart failure: rescuing autonomic control of
cardiorespiratory function. J Am Coll Cardiol
62: 2422–2430, 2013. doi:10.1016/j.jacc.2013.
07.079.
45. Del Rio R, Iturriaga R, Schultz HD. Editorial: Ca-
rotid body: a new target for rescuing neural con-
trol of cardiorespiratory balance in disease. Front
Physiol 6: 181, 2015. doi:10.3389/fphys.2015.
00181.
46. Dempsey JA. New perspectives concerning
feedback influences on cardiorespiratory control
during rhythmic exercise and on exercise perfor-
mance. J Physiol 590: 4129 – 4144, 2012. doi:10.
1113/jphysiol.2012.233908.
47. Devinney MJ, Nichols NL, Mitchell GS. Sustained
hypoxia elicits competing spinal mechanisms of
phrenic motor facilitation. J Neurosci 36: 7877–
7885, 2016. doi:10.1523/JNEUROSCI.4122-15.
2016.
48. Devinney MJ, Huxtable AG, Nichols NL, Mitchell
GS. Hypoxia-induced phrenic long-term facilita-
tion: emergent properties. Ann N Y Acad Sci
1279: 143–153, 2013. doi:10.1111/nyas.12085.
49. Devinney MJ, Fields DP, Huxtable AG, Peterson
TJ, Dale EA, Mitchell GS. Phrenic long-term facil-
itation requires PKC␪ activity within phrenic mo-
tor neurons. J Neurosci 35: 8107– 8117, 2015.
doi:10.1523/JNEUROSCI.5086-14.2015.
50. Dick TE, Coles SK. Ventrolateral pons mediates
short-term depression of respiratory frequency
after brief hypoxia. Respir Physiol 121: 87–100,
2000. doi:10.1016/S0034-5687(00)00121-3.
51. Dick TE, Hsieh Y-H, Wang N, Prabhakar N. Acute
intermittent hypoxia increases both phrenic and
sympathetic nerve activities in the rat. Exp
Physiol 92: 87–97, 2007. doi:10.1113/expphysiol.
2006.035758.
52. Dick TE, Hsieh YH, Morrison S, Coles SK, Prab-
hakar N. Entrainment pattern between sympa-
thetic and phrenic nerve activities in the Sprague-
Dawley rat: hypoxia-evoked sympathetic activity
during expiration. Am J Physiol Regul Integr
Comp Physiol 286: R1121–R1128, 2004. doi:10.
1152/ajpregu.00485.2003.
53. Dick TE, Baekey DM, Paton JFR, Lindsey BG,
Morris KF. Cardio-respiratory coupling depends
on the pons. Respir Physiol Neurobiol 168: 76 –
85, 2009. doi:10.1016/j.resp.2009.07.009.
54. Dick TE, Mims JR, Hsieh Y-H, Morris KF, Wehr-
wein EA. Increased cardio-respiratory coupling
evoked by slow deep breathing can persist in
normal humans. Respir Physiol Neurobiol 204:
99 –111, 2014. doi:10.1016/j.resp.2014.09.013.
55. Dick TE, Shannon R, Lindsey BG, Nuding SC,
Segers LS, Baekey DM, Morris KF. Pontine respi-
ratory-modulated activity before and after vagot-
omy in decerebrate cats. J Physiol 586: 4265–
4282, 2008. doi:10.1113/jphysiol.2008.152108.
56. Dick TE, Hsieh YH, Dhingra RR, Baekey DM, Ga-
lán RF, Wehrwein E, Morris KF. Cardiorespiratory
coupling: common rhythms in cardiac, sympa-
thetic, and respiratory activities. Prog Brain Res
209: 191–205, 2014. doi:10.1016/B978-0-444-
63274-6.00010-2.
57. Diekman CO, Thomas PJ, Wilson CG. Eupnea,
tachypnea, and autoresuscitation in a closed-
loop respiratory control model. J Neurophysiol
118: 2194 –2215, 2017. doi:10.1152/jn.00170.
2017.
58. Donnelly DF, Haddad GG. Prolonged apnea and
impaired survival in piglets after sinus and aortic
nerve section. J Appl Physiol (1985) 68: 1048 –
1052, 1990. doi:10.1152/jappl.1990.68.3.1048.
59. Dutschmann M, Dick TE. Pontine mechanisms of
respiratory control. Compr Physiol 2: 2443–2469,
2012.
60. Eckberg DL, Bastow H III, Scruby AE. Modulation
of human sinus node function by systemic hyp-
oxia. J Appl Physiol Respir Environ Exerc Physiol
52: 570 –577, 1982.
61. Eisenberg MS. Incidence and significance of
gasping or agonal respirations in cardiac arrest
patients. Curr Opin Crit Care 12: 204 –206, 2006.
doi:10.1097/01.ccx.0000224862.48087.66.
62. ElMallah MK, Stanley DA, Lee K-Z, Turner SM,
Streeter KA, Baekey DM, Fuller DD. Power spec-
tral analysis of hypoglossal nerve activity during
intermittent hypoxia-induced long-term facilita-
tion in mice. J Neurophysiol 115: 1372–1380,
2016. doi:10.1152/jn.00479.2015.

63. Erickson JT, Millhorn DE. Hypoxia and electrical
stimulation of the carotid sinus nerve induce Fos-
like immunoreactivity within catecholaminergic
and serotoninergic neurons of the rat brainstem.
J Comp Neurol 348: 161–182, 1994. doi:10.1002/
cne.903480202.
64. Erickson JT, Sposato BC. Autoresuscitation re-
sponses to hypoxia-induced apnea are delayed in
newborn 5-HT-deficient Pet-1 homozygous mice.
J Appl Physiol (1985) 106: 1785–1792, 2009. doi:
10.1152/japplphysiol.90729.2008.
65. Farmer DGS, Dutschmann M, Paton JFR, Picker-
ing AE, McAllen RM. Brainstem sources of car-
diac vagal tone and respiratory sinus arrhythmia.
J Physiol 594: 7249 –7265, 2016. doi:10.1113/
JP273164.
66. Fatemian M, Nieuwenhuijs DJF, Teppema LJ,
Meinesz S, van der Mey AG, Dahan A, Robbins
PA. The respiratory response to carbon dioxide
in humans with unilateral and bilateral resections
of the carotid bodies. J Physiol 549: 965–973,
2003. doi:10.1113/jphysiol.2003.042259.
67. Feldman JL, Loewy AD, Speck DF. Projections
from the ventral respiratory group to phrenic and
intercostal motoneurons in cat: an autoradio-
graphic study. J Neurosci 5: 1993–2000, 1985.
doi:10.1523/JNEUROSCI.05-08-01993.1985.
68. Ferretti R, Cherniack NS, Longobardo G, Levine
OR, Morkin E, Singer DH, Fishman AP. Systemic
and pulmonary vasomotor waves. Am J Physiol
209: 37–50, 1965.
69. Fiamma M-N, O’Connor ET, Roy A, Zuna I, Wil-
son RJ. The essential role of peripheral respira-
tory chemoreceptor inputs in maintaining
breathing revealed when CO2 stimulation of cen-
tral chemoreceptors is diminished. J Physiol 591:
1507–1521, 2013. doi:10.1113/jphysiol.2012.
247304.
70. Fields DP, Mitchell GS. Spinal metaplasticity in
respiratory motor control. Front Neural Circuits
9: 2, 2015. doi:10.3389/fncir.2015.00002.
71. Fields DP, Mitchell GS. Divergent cAMP signaling
differentially regulates serotonin-induced spinal
motor plasticity. Neuropharmacology 113: 82–
88, 2017. doi:10.1016/j.neuropharm.2016.09.
018.
72. Flor KC, Silva EF, Menezes MF, Pedrino GR, Co-
lombari E, Zoccal DB. Short-term sustained hypoxia
elevates basal and hypoxia-induced ventilation but
not the carotid body chemoreceptor activity in rats.
Front Physiol 9: 134, 2018. doi:10.3389/fphys.2018.
00134.
73. Fogarty MJ, Mantilla CB, Sieck GC. Breathing:
Motor control of diaphragm muscle. Physiology
(Bethesda) 33: 113–126, 2018.
74. Ford TW, Kirkwood PA. Cardiac modulation of
alpha motoneuron discharges. J Neurophysiol
119: 1723–1730, 2018. doi:10.1152/jn.00025.
2018.
75. Fortuna MG, West GH, Stornetta RL, Guyenet
PG. Botzinger expiratory-augmenting neurons
and the parafacial respiratory group. J Neurosci
28: 2506 –2515, 2008. doi:10.1523/JNEUROSCI.
5595-07.2008.
76. Fregosi RF, Mitchell GS. Long-term facilitation of
inspiratory intercostal nerve activity following ca-
rotid sinus nerve stimulation in cats. J Physiol
477: 469 – 479, 1994. doi:10.1113/jphysiol.1994.
sp020208.
77. Fuller DD, Mitchell GS. Respiratory neuroplastic-
ity - Overview, significance and future directions.
Exp Neurol 287: 144 –152, 2017. doi:10.1016/j.
expneurol.2016.05.022.
78. Funk GD, Rajani V, Alvares TS, Revill AL, Zhang Y,
Chu NY, Biancardi V, Linhares-Taxini C, Katzell A,
Reklow R. Neuroglia and their roles in central
respiratory control; an overview. Comp Biochem
Physiol A Mol Integr Physiol 186: 83–95, 2015.
doi:10.1016/j.cbpa.2015.01.010.
Downloaded from journals.physiology.org/journal/physiologyonline (095.252.059.005) on January 7, 2022.
79. Galán RF, Dick TE, Baekey DM. Analysis and
modeling of ensemble recordings from respira-
tory pre-motor neurons indicate changes in func-
tional network architecture after acute hypoxia.
Front Comput Neurosci 4: 131, 2010. doi:10.
3389/fncom.2010.00131.
80. Garcia AJ III, Koschnitzky JE, Dashevskiy T,
Ramirez J-M. Cardiorespiratory coupling in
health and disease. Auton Neurosci 175: 26 –37,
2013. doi:10.1016/j.autneu.2013.02.006.
81. Garcia AJ III, Dashevskiy T, Khuu MA, Ramirez
J-M. Chronic intermittent hypoxia differentially
impacts different states of inspiratory activity at
the level of the preBötzinger complex. Front
Physiol 8: 571, 2017. doi:10.3389/fphys.2017.
00571.
82. Garcia AJ III, Zanella S, Dashevskiy T, Khan SA,
Khuu MA, Prabhakar NR, Ramirez J-M. Chronic
intermittent hypoxia alters local respiratory cir-
cuit function at the level of the preBötzinger
complex. Front Neurosci 10: 4, 2016. doi:10.
3389/fnins.2016.00004.
83. Ghali MGZ. Phrenic motoneurons: output ele-
ments of a highly organized intraspinal network.
J Neurophysiol 119: 1057–1070, 2018. doi:10.
1152/jn.00705.2015.
84. Gilbert-Kawai ET, Milledge JS, Grocott MPW,
Martin DS. King of the mountains: Tibetan and
Sherpa physiological adaptations for life at high
altitude. Physiology (Bethesda) 29: 388 – 402,
2014.
85. Gilbey MP, Jordan D, Richter DW, Spyer KM.
Synaptic mechanisms involved in the inspiratory
modulation of vagal cardio-inhibitory neurones in
the cat. J Physiol 356: 65–78, 1984. doi:10.1113/
jphysiol.1984.sp015453.
86. Goldberg S, Ollila HM, Lin L, Sharifi H, Rico T,
Andlauer O, Aran A, Bloomrosen E, Faraco J,
Fang H, Mignot E. Analysis of hypoxic and hyper-
capnic ventilatory response in healthy volun-
teers. PLoS One 12: e0168930, 2017. doi:10.
1371/journal.pone.0168930.
87. Gourine AV, Funk GD. On the existence of a
central respiratory oxygen sensor. J Appl Physiol
(1985) 123: 1344 –1349, 2017. doi:10.1152/
japplphysiol.00194.2017.
88. Gourine AV, Machhada A, Trapp S, Spyer KM.
Cardiac vagal preganglionic neurones: An up-
date. Auton Neurosci 199: 24 –28, 2016. doi:10.
1016/j.autneu.2016.06.003.
89. Gourine AV, Kasymov V, Marina N, Tang F,
Figueiredo MF, Lane S, Teschemacher AG, Spyer
KM, Deisseroth K, Kasparov S. Astrocytes control
breathing through pH-dependent release of
ATP. Science 329: 571–575, 2010. doi:10.1126/
science.1190721.
90. Griffin HS, Pugh K, Kumar P, Balanos GM. Long-
term facilitation of ventilation following acute
continuous hypoxia in awake humans during sus-
tained hypercapnia. J Physiol 590: 5151–5165,
2012. doi:10.1113/jphysiol.2012.236109.
91. Guyenet PG. Regulation of breathing and auto-
nomic outflows by chemoreceptors. Compr
Physiol 4: 1511–1562, 2014. doi:10.1002/cphy.
c140004.
92. Guyenet PG, Koshiya N, Huangfu D, Verberne
AJ, Riley TA. Central respiratory control of A5
and A6 pontine noradrenergic neurons. Am J
Physiol Regul Integr Comp Physiol 264: R1035–
R1044, 1993.
93. Guyenet PG, Stornetta RL, Bochorishvili G,
Depuy SD, Burke PGR, Abbott SBG. C1 neurons:
the body’s EMTs. Am J Physiol Regul Integr
Comp Physiol 305: R187–R204, 2013. doi:10.
1152/ajpregu.00054.2013.
PHYSIOLOGY • Volume 33 • July 2018 • www.physiologyonline.org
REVIEW
94. Guyenet PG, Bayliss DA, Stornetta RL, Kanbar R,
Shi Y, Holloway BB, Souza GMPR, Basting TM,
Abbott SBG, Wenker IC. Interdependent feed-
back regulation of breathing by the carotid bod-
ies and the retrotrapezoid nucleus. J Physiol. In
press.
95. Harris DP, Balasubramaniam A, Badr MS,
Mateika JH. Long-term facilitation of ventilation
and genioglossus muscle activity is evident in the
presence of elevated levels of carbon dioxide in
awake humans. Am J Physiol Regul Integr Comp
Physiol 291: R1111–R1119, 2006. doi:10.1152/
ajpregu.00896.2005.
96. Hayashi F, Coles SK, McCrimmon DR. Respira-
tory neurons mediating the Breuer-Hering reflex
prolongation of expiration in rat. J Neurosci 16:
6526 – 6536, 1996. doi:10.1523/JNEUROSCI.16-
20-06526.1996.
97. Hayashi F, Coles SK, Bach KB, Mitchell GS, Mc-
Crimmon DR. Time-dependent phrenic nerve re-
sponses to carotid afferent activation: intact vs.
decerebellate rats. Am J Physiol Regul Integr
Comp Physiol 265: R811–R819, 1993.
98. Herbert H, Moga MM, Saper CB. Connections of
the parabrachial nucleus with the nucleus of the
solitary tract and the medullary reticular forma-
tion in the rat. J Comp Neurol 293: 540 –580,
1990. doi:10.1002/cne.902930404.
99. Herrero JL, Khuvis S, Yeagle E, Cerf M, Mehta
AD. Breathing above the brain stem: volitional
control and attentional modulation in humans. J
Neurophysiol 119: 145–159, 2018. doi:10.1152/
jn.00551.2017.
100. Hodges MR, Forster HV. Respiratory neuroplas-
ticity following carotid body denervation: central
and peripheral adaptations. Neural Regen Res 7:
1073–1079, 2012.
101. Hodson EJ, Nicholls LG, Turner PJ, Llyr R, Field-
ing JW, Douglas G, Ratnayaka I, Robbins PA,
Pugh CW, Buckler KJ, Ratcliffe PJ, Bishop T. Reg-
ulation of ventilatory sensitivity and carotid body
proliferation in hypoxia by the PHD2/HIF-2 path-
way. J Physiol 594: 1179 –1195, 2016. doi:10.
1113/JP271050.
102. Hofer MA. Role of carotid sinus and aortic nerves
in respiratory control of infant rats. Am J Physiol
Regul Integr Comp Physiol 251: R811–R817,
1986.
103. Hooper JS, Hadley SH, Morris KF, Breslin JW,
Dean JB, Taylor-Clark TE. Characterization of
cardiovascular reflexes evoked by airway stimu-
lation with allylisothiocyanate, capsaicin, and ATP
in Sprague-Dawley rats. J Appl Physiol (1985)
120: 580 –591, 2016. doi:10.1152/japplphysiol.
00944.2015.
104. Huckstepp RTR, Henderson LE, Cardoza KP,
Feldman JL. Interactions between respiratory os-
cillators in adult rats. eLife 5: e14203, 2016. doi:
10.7554/eLife.14203.
105. Iscoe S. Control of abdominal muscles. Prog
Neurobiol 56: 433–506, 1998. doi:10.1016/
S0301-0082(98)00046-X.
106. Iturriaga R. Translating carotid body function into
clinical medicine. J Physiol. In press. doi:10.1113/
JP275335.
107. Javaheri S, Dempsey JA. Central sleep apnea.
Compr Physiol 3: 141–163, 2013. doi:10.1002/
cphy.c110057.
108. Jenkin SEM, Milsom WK. Expiration: breathing’s
other face. Prog Brain Res 212: 131–147, 2014.
doi:10.1016/B978-0-444-63488-7.00008-2.
109. Jiang C, Lipski J. Extensive monosynaptic inhibi-
tion of ventral respiratory group neurons by aug-
menting neurons in the Bötzinger complex in the
cat. Exp Brain Res 81: 639 – 648, 1990. doi:10.
1007/BF02423514.
110. Jodkowski JS, Coles SK, Dick TEA. A ‘pneumo-
taxic centre’ in rats. Neurosci Lett 172: 67–72,
1994. doi:10.1016/0304-3940(94)90664-5.
293
REVIEW
111. Jodkowski JS, Coles SK, Dick TE. Prolongation in
expiration evoked from ventrolateral pons of
adult rats. J Appl Physiol (1985) 82: 377–381,
1997. doi:10.1152/jappl.1997.82.2.377.
112. Johnson BD, Joyner MJ. Carotid body denerva-
tion: too soon to get breathless about heart fail-
ure? J Am Coll Cardiol 62: 2431–2432, 2013.
doi:10.1016/j.jacc.2013.08.718.
113. Kamendi HW, Cheng Q, Dergacheva O, Frank
JG, Gorini C, Jameson HS, Pinol RA, Wang X,
Mendelowitz D. Recruitment of excitatory sero-
tonergic neurotransmission to cardiac vagal neu-
rons in the nucleus ambiguus post hypoxia and
hypercapnia. J Neurophysiol 99: 1163–1168,
2008. doi:10.1152/jn.01178.2007.
114. Kim SJ, Fong AY, Pilowsky PM, Abbott SBG.
Sympathoexcitation following intermittent hyp-
oxia in rat is mediated by circulating angiotensin
II acting at the carotid body and subfornical or-
gan. J Physiol. In press. doi:10.1113/JP275804.
115. Kinkead R, Bach KB, Johnson SM, Hodgeman BA,
Mitchell GS. Plasticity in respiratory motor con-
trol: intermittent hypoxia and hypercapnia acti-
vate opposing serotonergic and noradrenergic
modulatory systems. Comp Biochem Physiol A
Mol Integr Physiol 130: 207–218, 2001. doi:10.
1016/S1095-6433(01)00393-2.
116. Kline DD, King TL, Austgen JR, Heesch CM, Has-
ser EM. Sensory afferent and hypoxia-mediated
activation of nucleus tractus solitarius neurons
that project to the rostral ventrolateral medulla.
Neuroscience 167: 510 –527, 2010. doi:10.1016/
j.neuroscience.2010.02.012.
117. Koehle M, Sheel W, Milsom W, McKenzie D. The
effect of two different intermittent hypoxia pro-
tocols on ventilatory responses to hypoxia and
carbon dioxide at rest. In: Integration in Respira-
tory Control: From Genes to Systems, edited by
Poulin MJ, Wilson RJA. New York: Springer New
York, 2008, p. 218 –223. doi:10.1007/978-0-387-
73693-8_38.
118. Koshiya N, Guyenet PG. Role of the pons in the
carotid sympathetic chemoreflex. Am J Physiol
Regul Integr Comp Physiol 267: R508 –R518,
1994.
119. Koshiya N, Guyenet PG. A5 noradrenergic neu-
rons and the carotid sympathetic chemoreflex.
Am J Physiol Regul Integr Comp Physiol 267:
R519 –R526, 1994.
120. Koshiya N, Guyenet PG. NTS neurons with ca-
rotid chemoreceptor inputs arborize in the ros-
tral ventrolateral medulla. Am J Physiol Regul
Integr Comp Physiol 270: R1273–R1278, 1996.
121. Koshiya N, Guyenet PG. Tonic sympathetic
chemoreflex after blockade of respiratory rhyth-
mogenesis in the rat. J Physiol 491: 859 – 869,
1996. doi:10.1113/jphysiol.1996.sp021263.
122. Krause A, Nowak Z, Srbu R, Bell HJ. Respiratory
autoresuscitation following severe acute hypox-
emia in anesthetized adult rats. Respir Physiol
Neurobiol 232: 43–53, 2016. doi:10.1016/j.resp.
2016.06.006.
123. Kumar P, Prabhakar NR. Peripheral chemorecep-
tors: function and plasticity of the carotid body.
Compr Physiol 2: 141–219, 2012. doi:10.1002/
cphy.c100069.
124. Lahiri S, Hsiao C, Zhang R, Mokashi A, Nishino T.
Peripheral chemoreceptors in respiratory oscilla-
tions. J Appl Physiol (1985) 58: 1901–1908, 1985.
doi:10.1152/jappl.1985.58.6.1901.
125. Lawson EE, Richter DW, Ballantyne D, Lalley PM.
Peripheral chemoreceptor inputs to medullary in-
spiratory and postinspiratory neurons of cats.
Pflugers Arch 414: 523–533, 1989. doi:10.1007/
BF00580987.
294 PHYSIOLOGY • Volume 33 • July 2018 • www.physiologyonline.org
Downloaded from journals.physiology.org/journal/physiologyonline (095.252.059.005) on January 7, 2022.
126. Lemes EV, Aiko S, Orbem CB, Formentin C, Bassi
M, Colombari E, Zoccal DB. Long-term facilita-
tion of expiratory and sympathetic activities fol-
lowing acute intermittent hypoxia in rats. Acta
Physiol (Oxf) 217: 254 –266, 2016. doi:10.1111/
apha.12661.
127. Li Z, Morris KF, Baekey DM, Shannon R, Lindsey
BG. Multimodal medullary neurons and correla-
tional linkages of the respiratory network. J Neu-
rophysiol 82: 188 –201, 1999. doi:10.1152/jn.
1999.82.1.188.
128. Lindsey BG, Segers LS, Shannon R. Functional
associations among simultaneously monitored
lateral medullary respiratory neurons in the cat.
II. Evidence for inhibitory actions of expiratory
neurons. J Neurophysiol 57: 1101–1117, 1987.
doi:10.1152/jn.1987.57.4.1101.
129. Lindsey BG, Segers LS, Shannon R. Discharge
patterns of rostrolateral medullary expiratory
neurons in the cat: regulation by concurrent net-
work processes. J Neurophysiol 61: 1185–1196,
1989. doi:10.1152/jn.1989.61.6.1185.
130. Lindsey BG, Hernandez YM, Shannon R. Cooper-
ativity in Distributed Respiratory and Cardiovas-
cular-Related Brainstem Neural Assemblies:
Insights from Many-Neuron Recordings. Berlin:
Springer Berlin Heidelberg, 1991, p. 131–137.
131. Lindsey BG, Rybak IA, Smith JC. Computational
models and emergent properties of respiratory
neural networks. Compr Physiol 2: 1619 –1670,
2012. doi:10.1002/cphy.c110016.
132. Lindsey BG, Hernandez YM, Morris KF, Shannon
R. Functional connectivity between brain stem
midline neurons with respiratory-modulated fir-
ing rates. J Neurophysiol 67: 890 –904, 1992. doi:
10.1152/jn.1992.67.4.890.
133. Lindsey BG, Hernandez YM, Morris KF, Shannon
R, Gerstein GL. Dynamic reconfiguration of brain
stem neural assemblies: respiratory phase-de-
pendent synchrony versus modulation of firing
rates. J Neurophysiol 67: 923–930, 1992. doi:10.
1152/jn.1992.67.4.923.
134. Lindsey BG, Hernandez YM, Morris KF, Shannon
R, Gerstein GL. Respiratory-related neural as-
semblies in the brain stem midline. J Neuro-
physiol 67: 905–922, 1992. doi:10.1152/jn.1992.
67.4.905.
135. Lindsey BG, Arata A, Morris KF, Hernandez YM,
Shannon R. Medullary raphe neurones and baro-
receptor modulation of the respiratory motor
pattern in the cat. J Physiol 512: 863– 882, 1998.
doi:10.1111/j.1469-7793.1998.863bd.x.
136. Lindsey BG, Segers LS, Morris KF, Hernandez
YM, Saporta S, Shannon R. Distributed actions
and dynamic associations in respiratory-related
neuronal assemblies of the ventrolateral medulla
and brain stem midline: evidence from spike train
analysis. J Neurophysiol 72: 1830 –1851, 1994.
doi:10.1152/jn.1994.72.4.1830.
137. Ling L. Serotonin and NMDA receptors in respi-
ratory long-term facilitation. Respir Physiol Neu-
robiol 164: 233–241, 2008. doi:10.1016/j.resp.
2008.05.016.
138. Lipski J, Voss MD. “Gating” of peripheral chemo-
receptor input to medullary inspiratory neurons:
role of Bötzinger complex neurons. In: Chemore-
ceptors and Chemoreceptor Reflexes, edited by
Acker H, Trzebski A, O’Regan RC. New York:
Plenum Press, 1990, p. 323–329. doi:10.1007/
978-1-4684-8938-5_47.
139. Lipski J, McAllen RM, Spyer KM. The carotid
chemoreceptor input to the respiratory neu-
rones of the nucleus of tractus solitarus. J
Physiol 269: 797– 810, 1977. doi:10.1113/
jphysiol.1977.sp011930.
140. Lipski J, Trzebski A, Chodobska J, Kruk P. Effects
of carotid chemoreceptor excitation on medullary
expiratory neurons in cats. Respir Physiol 57: 279 –
291, 1984. doi:10.1016/0034-5687(84)90077-X.
141. López-Barneo J, López-López JR, Ureña J,
González C. Chemotransduction in the carotid
body: K⫹ current modulated by PO2 in type I
chemoreceptor cells. Science 241: 580 –582,
1988. doi:10.1126/science.2456613.
142. López-Barneo J, González-Rodríguez P, Gao L,
Fernández-Agüera MC, Pardal R, Ortega-Sáenz
P. Oxygen sensing by the carotid body: mecha-
nisms and role in adaptation to hypoxia. Am J
Physiol Cell Physiol 310: C629 –C642, 2016. doi:
10.1152/ajpcell.00265.2015.
143. López-Barneo J, Ortega-Sáenz P, González-Ro-
dríguez P, Fernández-Agüera MC, Macías D,
Pardal R, Gao L. Oxygen-sensing by arterial
chemoreceptors: Mechanisms and medical trans-
lation. Mol Aspects Med 47-48: 90 –108, 2016.
doi:10.1016/j.mam.2015.12.002.
144. Lugliani R, Whipp BJ, Seard C, Wasserman K.
Effect of bilateral carotid-body resection on ven-
tilatory control at rest and during exercise in
man. N Engl J Med 285: 1105–1111, 1971. doi:
10.1056/NEJM197111112852002.
145. MacFarlane PM, Vinit S, Mitchell GS. Enhance-
ment of phrenic long-term facilitation following
repetitive acute intermittent hypoxia is blocked
by the glycolytic inhibitor 2-deoxyglucose. Am J
Physiol Regul Integr Comp Physiol 314: R135–
R144, 2018. doi:10.1152/ajpregu.00306.2017.
146. Macias D, Cowburn AS, Torres-Torrelo H, Or-
tega-Sáenz P, López-Barneo J, Johnson RS.
HIF-2␣ is essential for carotid body development
and function. eLife 7: e34681, 2018. doi:10.7554/
eLife.34681.
147. Magder S, Scharf SM. Venous return. In: Respi-
ratory-Circulatory Interactions in Health and Dis-
ease, edited by Scharf SM, Magder S, Pinsky MR.
New York: Marcel Dekker, Inc, 2001, p. 93–112.
148. Mantilla CB. Gene therapy and respiratory neu-
roplasticity. Exp Neurol 287: 261–267, 2017. doi:
10.1016/j.expneurol.2016.09.014.
149. Manzke T, Dutschmann M, Schlaf G, Mörschel M,
Koch UR, Ponimaskin E, Bidon O, Lalley PM, Rich-
ter DW. Serotonin targets inhibitory synapses to
induce modulation of network functions. Philos
Trans R Soc Lond B Biol Sci 364: 2589 –2602,
2009. doi:10.1098/rstb.2009.0068.
150. Marchenko V, Koizumi H, Mosher B, Koshiya N,
Tariq MF, Bezdudnaya TG, Zhang R, Molkov YI,
Rybak IA, Smith JC. Perturbations of respiratory
rhythm and pattern by disrupting synaptic inhibi-
tion within Pre-Bötzinger and Bötzinger com-
plexes. eNeuro 3: ENEURO.0011-16.2016, 2016.
doi:10.1523/ENEURO.0011-16.2016.
151. Marcus NJ, Del Rio R, Schultz EP, Xia X-H, Schultz
HD. Carotid body denervation improves auto-
nomic and cardiac function and attenuates disor-
dered breathing in congestive heart failure. J
Physiol 592: 391– 408, 2014. doi:10.1113/
jphysiol.2013.266221.
152. Marshall JM. Peripheral chemoreceptors and car-
diovascular regulation. Physiol Rev 74: 543–594,
1994. doi:10.1152/physrev.1994.74.3.543.
153. Mateika JH, Komnenov D. Intermittent hypoxia
initiated plasticity in humans: A multipronged
therapeutic approach to treat sleep apnea and
overlapping co-morbidities. Exp Neurol 287:
113–129, 2017. doi:10.1016/j.expneurol.2016.05.
011.
154. Mateika JH, El-Chami M, Shaheen D, Ivers B. Inter-
mittent hypoxia: a low-risk research tool with ther-
apeutic value in humans. J Appl Physiol (1985) 118:
520 –532, 2015. doi:10.1152/japplphysiol.00564.
2014.
155. Mateika JH, Panza G, Alex R, El-Chami M. The
impact of intermittent or sustained carbon diox-
ide on intermittent hypoxia initiated respiratory
plasticity. What is the effect of these combined
stimuli on apnea severity? Respir Physiol Neuro-
biol S1569-9048(17)30258-6. In press.

156. McAllen RM. Actions of carotid chemoreceptors
on subretrofacial bulbospinal neurons in the cat.
J Auton Nerv Syst 40: 181–188, 1992. doi:10.
1016/0165-1838(92)90199-Q.
157. McDougall SJ, Andresen MC. Independent trans-
mission of convergent visceral primary afferents
in the solitary tract nucleus. J Neurophysiol 109:
507–517, 2013. doi:10.1152/jn.00726.2012.
158. Miller JR, Neumueller S, Muere C, Olesiak S, Pan L,
Hodges MR, Forster HV. Changes in neurochemi-
cals within the ventrolateral medullary respiratory
column in awake goats after carotid body dener-
vation. J Appl Physiol (1985) 115: 1088 –1098,
2013. doi:10.1152/japplphysiol.00293.2013.
159. Millhorn DE. Stimulation of raphe (obscurus) nu-
cleus causes long-term potentiation of phrenic
nerve activity in cat. J Physiol 381: 169 –179,
1986. doi:10.1113/jphysiol.1986.sp016320.
160. Millhorn DE, Eldridge FL, Waldrop TG. Pro-
longed stimulation of respiration by endogenous
central serotonin. Respir Physiol 42: 171–188,
1980. doi:10.1016/0034-5687(80)90113-9.
161. Millhorn DE, Eldridge FL, Waldrop TG. Pro-
longed stimulation of respiration by a new cen-
tral neural mechanism. Respir Physiol 41: 87–103,
1980. doi:10.1016/0034-5687(80)90025-0.
162. Molkov YI, Rubin JE, Rybak IA, Smith JC. Com-
putational models of the neural control of
breathing. Wiley Interdiscip Rev Syst Biol Med 9:
e1371, 2017. doi:10.1002/wsbm.1371.
163. Molkov YI, Zoccal DB, Moraes DJA, Paton JFR,
Machado BH, Rybak IA. Intermittent hypoxia-in-
duced sensitization of central chemoreceptors
contributes to sympathetic nerve activity during
late expiration in rats. J Neurophysiol 105: 3080 –
3091, 2011. doi:10.1152/jn.00070.2011.
164. Molkov YI, Shevtsova NA, Park C, Ben-Tal A, Smith
JC, Rubin JE, Rybak IA. A closed-loop model of the
respiratory system: focus on hypercapnia and ac-
tive expiration. PLoS One 9: e109894, 2014. doi:
10.1371/journal.pone.0109894.
165. Molkov YI, Zoccal DB, Baekey DM, Abdala APL,
Machado BH, Dick TE, Paton JFR, Rybak IA.
Physiological and pathophysiological interactions
between the respiratory central pattern genera-
tor and the sympathetic nervous system. Prog
Brain Res 212: 1–23, 2014. doi:10.1016/B978-0-
444-63488-7.00001-X.
166. Moraes DJA, Machado BH, Paton JFR. Specific re-
spiratory neuron types have increased excitability
that drive presympathetic neurones in neurogenic
hypertension. Hypertension 63: 1309 –1318, 2014.
doi:10.1161/HYPERTENSIONAHA.113.02283.
167. Moraes DJA, Bonagamba LGH, da Silva MP, Pa-
ton JFR, Machado BH. Role of ventral medullary
catecholaminergic neurons for respiratory mod-
ulation of sympathetic outflow in rats. Sci Rep 7:
16883, 2017. doi:10.1038/s41598-017-17113-7.
168. Moraes DJA, da Silva MP, Bonagamba LGH, Me-
cawi AS, Zoccal DB, Antunes-Rodrigues J,
Varanda WA, Machado BH. Electrophysiological
properties of rostral ventrolateral medulla pre-
sympathetic neurons modulated by the respira-
tory network in rats. J Neurosci 33: 19223–
19237, 2013. doi:10.1523/JNEUROSCI.3041-13.
2013.
169. Morris KF, Gozal D. Persistent respiratory
changes following intermittent hypoxic stimula-
tion in cats and human beings. Respir Physiol
Neurobiol 140: 1– 8, 2004. doi:10.1016/j.resp.
2003.12.002.
170. Morris KF, Shannon R, and Lindsey BG. Parallel
processing of carotid chemoreceptor inputs: In
vivo experiments and network simulations, In:
IFAC Proceedings Volumes. 1994: Galveston, TX
USA. p. 573–574.
Downloaded from journals.physiology.org/journal/physiologyonline (095.252.059.005) on January 7, 2022.
171. Morris KF, Shannon R, Lindsey BG. Changes in
cat medullary neurone firing rates and synchrony
following induction of respiratory long-term facil-
itation. J Physiol 532: 483– 497, 2001. doi:10.
1111/j.1469-7793.2001.0483f.x.
172. Morris KF, Arata A, Shannon R, Lindsey BG.
Long-term facilitation of phrenic nerve activity in
cats: responses and short time scale correlations
of medullary neurones. J Physiol 490: 463– 480,
1996. doi:10.1113/jphysiol.1996.sp021158.
173. Morris KF, Arata A, Shannon R, Lindsey BG. In-
spiratory drive and phase duration during carotid
chemoreceptor stimulation in the cat: medullary
neurone correlations. J Physiol 491: 241–259,
1996. doi:10.1113/jphysiol.1996.sp021212.
174. Morris KF, Baekey DM, Shannon R, Lindsey BG.
Respiratory neural activity during long-term facil-
itation. Respir Physiol 121: 119 –133, 2000. doi:
10.1016/S0034-5687(00)00123-7.
175. Morris KF, Baekey DM, Nuding SC, Dick TE, Shan-
non R, Lindsey BG. Plasticity in respiratory motor
control. Invited review: Neural network plasticity in
respiration control. J Appl Physiol 94: 1242–1252,
2003. doi:10.1152/japplphysiol.00715.2002.
176. Morris KF, Nuding SC, Segers LS, Baekey DM,
Shannon R, Lindsey BG, Dick TE. Respiratory and
Mayer wave-related discharge patterns of raphé
and pontine neurons change with vagotomy. J
Appl Physiol (1985) 109: 189 –202, 2010. doi:10.
1152/japplphysiol.01324.2009.
177. Morris KF, Nuding SC, Segers LS, Iceman KE,
O’Connor R, Dean JB, Ott MM, Alencar PA,
Shuman D, Horton K-K, Taylor-Clark TE, Bolser
DC, Lindsey BG. Carotid chemoreceptors tune
breathing via multipath routing: reticular chain
and loop operations supported by parallel spike
train correlations. J Neurophysiol 119: 700 –722,
2018. doi:10.1152/jn.00630.2017.
178. Mörschel M, Dutschmann M. Pontine respiratory
activity involved in inspiratory/expiratory phase
transition. Philos Trans R Soc Lond B Biol Sci 364:
2517–2526, 2009. doi:10.1098/rstb.2009.0074.
179. Narkiewicz K, Ratcliffe LEK, Hart EC, Briant LJB,
Chrostowska M, Wolf J, Szyndler A, Hering D,
Abdala AP, Manghat N, Burchell AE, Durant C,
Lobo MD, Sobotka PA, Patel NK, Leiter JC, En-
gelman ZJ, Nightingale AK, Paton JFR. Unilateral
carotid body resection in resistant hypertension:
A safety and feasibility trial. JACC Basic Transl
Sci 1: 313–324, 2016. doi:10.1016/j.jacbts.2016.
06.004.
180. Nattie E, Li A. Central chemoreceptors: locations
and functions. Compr Physiol 2: 221–254, 2012.
181. Navarrete-Opazo A, Vinit S, Dougherty BJ,
Mitchell GS. Daily acute intermittent hypoxia elic-
its functional recovery of diaphragm and inspira-
tory intercostal muscle activity after acute
cervical spinal injury. Exp Neurol 266: 1–10, 2015.
doi:10.1016/j.expneurol.2015.02.007.
182. Norlander AE, Madhur MS, Harrison DG. The
immunology of hypertension. J Exp Med 215:
21–33, 2018. doi:10.1084/jem.20171773.
183. Nuding SC, Segers LS, Shannon R, O’Connor R,
Morris KF, Lindsey BG. Central and peripheral
chemoreceptors evoke distinct responses in si-
multaneously recorded neurons of the raphé-
pontomedullary respiratory network. Philos
Trans R Soc Lond B Biol Sci 364: 2501–2516,
2009. doi:10.1098/rstb.2009.0075.
184. Nuding SC, Segers LS, Baekey DM, Dick TE, Sol-
omon IC, Shannon R, Morris KF, Lindsey BG.
Pontine-ventral respiratory column interactions
through raphe circuits detected using multi-array
spike train recordings. J Neurophysiol 101:
2943–2960, 2009. doi:10.1152/jn.91305.2008.
PHYSIOLOGY • Volume 33 • July 2018 • www.physiologyonline.org
REVIEW
185. Nuding SC, Segers LS, Iceman KE, O’Connor R,
Dean JB, Bolser DC, Baekey DM, Dick TE, Shan-
non R, Morris KF, Lindsey BG. Functional connec-
tivity in raphé-pontomedullary circuits supports
active suppression of breathing during hypocap-
nic apnea. J Neurophysiol 114: 2162–2186, 2015.
doi:10.1152/jn.00608.2015.
186. O’Connor R, Segers LS, Morris KF, Nuding SC,
Pitts T, Bolser DC, Davenport PW, Lindsey BG. A
joint computational respiratory neural network-
biomechanical model for breathing and airway
defensive behaviors. Front Physiol 3: 264, 2012.
187. Oku Y, Hülsmann S. A computational model of
the respiratory network challenged and opti-
mized by data from optogenetic manipulation of
glycinergic neurons. Neuroscience 347: 111–122,
2017. doi:10.1016/j.neuroscience.2017.01.041.
188. Oshima N, Kumagai H, Onimaru H, Kawai A,
Pilowsky PM, Iigaya K, Takimoto C, Hayashi K,
Saruta T, Itoh H. Monosynaptic excitatory con-
nection from the rostral ventrolateral medulla to
sympathetic preganglionic neurons revealed by
simultaneous recordings. Hypertens Res 31:
1445–1454, 2008. doi:10.1291/hypres.31.1445.
189. Ott MM, Nuding SC, Segers LS, Lindsey BG,
Morris KF. Ventrolateral medullary functional
connectivity and the respiratory and central
chemoreceptor-evoked modulation of retrotrap-
ezoid-parafacial neurons. J Neurophysiol 105:
2960 –2975, 2011. doi:10.1152/jn.00262.2010.
190. Ott MM, Nuding SC, Segers LS, O’Connor R,
Morris KF, Lindsey BG. Central chemoreceptor
modulation of breathing via multipath tuning in
medullary ventrolateral respiratory column cir-
cuits. J Neurophysiol 107: 603– 617, 2012. doi:10.
1152/jn.00808.2011.
191. Pagliardini S, Janczewski WA, Tan W, Dickson
CT, Deisseroth K, Feldman JL. Active expiration
induced by excitation of ventral medulla in adult
anesthetized rats. J Neurosci 31: 2895–2905,
2011. doi:10.1523/JNEUROSCI.5338-10.2011.
192. Pamenter ME, Powell FL. Time domains of the
hypoxic ventilatory response and their molecular
basis. Compr Physiol 6: 1345–1385, 2016.
193. Pardal R, Ortega-Sáenz P, Durán R, López-Bar-
neo J. Glia-like stem cells sustain physiologic
neurogenesis in the adult mammalian carotid
body. Cell 131: 364 –377, 2007. doi:10.1016/j.
cell.2007.07.043.
194. Paton JFR, Deuchars J, Li YW, Kasparov S. Prop-
erties of solitary tract neurones responding to
peripheral arterial chemoreceptors. Neurosci-
ence 105: 231–248, 2001. doi:10.1016/S0306-
4522(01)00106-3.
195. Paula-Ribeiro M, Rocha A. The peripheral-central
chemoreflex interaction: where do we stand and
what is the next step? J Physiol 594: 1527–1528,
2016. doi:10.1113/JP271901.
196. Pawar A, Peng Y-J, Jacono FJ, Prabhakar NR.
Comparative analysis of neonatal and adult rat
carotid body responses to chronic intermittent
hypoxia. J Appl Physiol (1985) 104: 1287–1294,
2008. doi:10.1152/japplphysiol.00644.2007.
197. Peña F. Neuronal network properties underlying
the generation of gasping. Clin Exp Pharmacol
Physiol 36: 1218 –1228, 2009. doi:10.1111/j.
1440-1681.2009.05301.x.
198. Peng Y-J, Overholt JL, Kline D, Kumar GK, Prab-
hakar NR. Induction of sensory long-term facili-
tation in the carotid body by intermittent
hypoxia: implications for recurrent apneas. Proc
Natl Acad Sci USA 100: 10073–10078, 2003. doi:
10.1073/pnas.1734109100.
199. Peng Y-J, Yuan G, Khan S, Nanduri J, Makarenko
VV, Reddy VD, Vasavda C, Kumar GK, Semenza
GL, Prabhakar NR. Regulation of hypoxia-induc-
ible factor-␣ isoforms and redox state by carotid
body neural activity in rats. J Physiol 592: 3841–
3858, 2014. doi:10.1113/jphysiol.2014.273789.
295
REVIEW
200. Perim RR, Fields DP, Mitchell GS. Cross-talk inhi-
bition between 5-HT2B and 5-HT7 receptors in
phrenic motor facilitation via NADPH oxidase
and PKA. Am J Physiol Regul Integr Comp
Physiol 314: R709 –R715, 2018. doi:10.1152/
ajpregu.00393.2017.
201. Phillips DB, Steinback CD, Collins SÉ, Fuhr DP,
Bryan TL, Wong EY, Tedjasaputra V, Bhutani M,
Stickland MK. The carotid chemoreceptor con-
tributes to the elevated arterial stiffness and va-
soconstrictor outflow in COPD. J Physiol. In
press. doi:10.1113/JP275762.
202. Poliaek I, Morris KF, Lindsey BG, Segers LS,
Rose MJ, Corrie LW-C, Wang C, Pitts TE, Daven-
port PW, Bolser DC. Blood pressure changes al-
ter tracheobronchial cough: computational
model of the respiratory-cough network and in
vivo experiments in anesthetized cats. J Appl
Physiol (1985) 111: 861– 873, 2011. doi:10.1152/
japplphysiol.00458.2011.
203. Poon C-S, Song G. Bidirectional plasticity of pon-
tine pneumotaxic postinspiratory drive: implica-
tion for a pontomedullary respiratory central
pattern generator. Prog Brain Res 209: 235–254,
2014. doi:10.1016/B978-0-444-63274-6.00012-6.
204. Song G, Tin C, Poon CS. Bilateral lesions of pon-
tine Kölliker-Fuse nuclei provoke apnea instead
of apneusis in anesthetized adult rats. Adv Exp
Med Biol 669: 185–188, 2010. doi:10.1007/978-
1-4419-5692-7_37.
205. Powell FL, Fu Z. HIF-1 and ventilatory acclimati-
zation to chronic hypoxia. Respir Physiol Neuro-
biol 164: 282–287, 2008. doi:10.1016/j.resp.
2008.07.017.
206. Powell FL, Milsom WK, Mitchell GS. Time do-
mains of the hypoxic ventilatory response. Respir
Physiol 112: 123–134, 1998. doi:10.1016/S0034-
5687(98)00026-7.
207. Prabhakar NR. Carotid body chemoreflex: a
driver of autonomic abnormalities in sleep ap-
noea. Exp Physiol 101: 975–985, 2016. doi:10.
1113/EP085624.
208. Prabhakar NR, Semenza GL. Oxygen sensing and
homeostasis. Physiology (Bethesda) 30: 340 –
348, 2015. doi:10.1152/physiol.00022.2015.
209. Prabhakar NR, Peng Y-J, Kumar GK, Nanduri J.
Peripheral chemoreception and arterial pressure
responses to intermittent hypoxia. Compr
Physiol 5: 561–577, 2015. doi:10.1002/cphy.
c140039.
210. Ptak K, Yamanishi T, Aungst J, Milescu LS, Zhang
R, Richerson GB, Smith JC. Raphé neurons stim-
ulate respiratory circuit activity by multiple mech-
anisms via endogenously released serotonin and
substance P. J Neurosci 29: 3720 –3737, 2009.
doi:10.1523/JNEUROSCI.5271-08.2009.
211. Rajani V, Zhang Y, Jalubula V, Rancic V, Sheikh-
Bahaei S, Zwicker JD, Pagliardini S, Dickson CT,
Ballanyi K, Kasparov S, Gourine AV, Funk GD.
Release of ATP by pre-Bötzinger complex astro-
cytes contributes to the hypoxic ventilatory re-
sponse via a Ca2⫹-dependent P2Y1 receptor
mechanism. J Physiol. In press. doi:10.1113/
jp274727.
212. Rakoczy RJ, Wyatt CN. Acute oxygen sensing by
the carotid body: a rattlebag of molecular mech-
anisms. J Physiol. In press. doi:10.1113/
JP274351.
213. Ramanantsoa N, Hirsch M-R, Thoby-Brisson M,
Dubreuil V, Bouvier J, Ruffault P-L, Matrot B,
Fortin G, Brunet J-F, Gallego J, Goridis C.
Breathing without CO(2) chemosensitivity in con-
ditional Phox2b mutants. J Neurosci 31: 12880 –
12888, 2011. doi:10.1523/JNEUROSCI.1721-11.
2011.
214. Ramirez J-M, Garcia AJ III, Anderson TM, Ko-
schnitzky JE, Peng Y-J, Kumar GK, Prabhakar NR.
Central and peripheral factors contributing to
obstructive sleep apneas. Respir Physiol Neuro-
biol 189: 344 –353, 2013. doi:10.1016/j.resp.
2013.06.004.
296 PHYSIOLOGY • Volume 33 • July 2018 • www.physiologyonline.org
Downloaded from journals.physiology.org/journal/physiologyonline (095.252.059.005) on January 7, 2022.
215. Rice CD, Lois JH, Kerman IA, Yates BJ. Localiza-
tion of serotoninergic neurons that participate in
regulating diaphragm activity in the cat. Brain
Res 1279: 71– 81, 2009. doi:10.1016/j.brainres.
2009.05.003.
216. Richter DW, Smith JC. Respiratory rhythm gen-
eration in vivo. Physiology (Bethesda) 29: 58 –71,
2014. doi:10.1152/physiol.00035.2013.
217. Richter DW, Bischoff A, Anders K, Bellingham M,
Windhorst U. Response of the medullary respiratory
network of the cat to hypoxia. J Physiol 443: 231–256,
1991. doi:10.1113/jphysiol.1991.sp018832.
218. Richter DW, Schmidt-Garcon P, Pierrefiche O,
Bischoff AM, Lalley PM. Neurotransmitters and
neuromodulators controlling the hypoxic respira-
tory response in anaesthetized cats. J Physiol
514: 567–578, 1999. doi:10.1111/j.1469-7793.
1999.567ae.x.
219. Road JD, Ford TW, Kirkwood PA. Connections
between expiratory bulbospinal neurons and ex-
piratory motoneurons in thoracic and upper lum-
bar segments of the spinal cord. J Neurophysiol
109: 1837–1851, 2013. doi:10.1152/jn.01008.
2012.
220. Robbins PA. Role of the peripheral chemoreflex
in the early stages of ventilatory acclimatization
to altitude. Respir Physiol Neurobiol 158: 237–
242, 2007. doi:10.1016/j.resp.2007.03.008.
221. Robotham JL, Lixfeld W, Holland L, MacGregor
D, Bryan AC, Rabson J. Effects of respiration on
cardiac performance. J Appl Physiol Respir Envi-
ron Exerc Physiol 44: 703–709, 1978.
222. Ronen R, Zhou D, Bafna V, Haddad GG. The
genetic basis of chronic mountain sickness. Phys-
iology (Bethesda) 29: 403– 412, 2014. doi:10.
1152/physiol.00008.2014.
223. Rosin DL, Chang DA, Guyenet PG. Afferent and
efferent connections of the rat retrotrapezoid
nucleus. J Comp Neurol 499: 64 – 89, 2006. doi:
10.1002/cne.21105.
224. Roy A, Farnham MMJ, Derakhshan F, Pilowsky
PM, Wilson RJA. Acute intermittent hypoxia with
concurrent hypercapnia evokes P2X and TRPV1
receptor-dependent sensory long-term facilita-
tion in naïve carotid bodies. J Physiol. In press.
doi:10.1113/JP275001.
225. Rybak IA, Molkov YI, Jasinski PE, Shevtsova NA,
Smith JC. Rhythmic bursting in the pre-Bötzinger
complex: mechanisms and models. Prog Brain
Res 209: 1–23, 2014. doi:10.1016/B978-0-444-
63274-6.00001-1.
226. Rybak IA, O’Connor R, Ross A, Shevtsova NA,
Nuding SC, Segers LS, Shannon R, Dick TE,
Dunin-Barkowski WL, Orem JM, Solomon IC,
Morris KF, Lindsey BG. Reconfiguration of the
pontomedullary respiratory network: a computa-
tional modeling study with coordinated in vivo
experiments. J Neurophysiol 100: 1770 –1799,
2008. doi:10.1152/jn.90416.2008.
227. Safic IS, Pecotic R, Dodig IP, Dogas Z, Valic Z,
Valic M. Phrenic long term depression evoked by
intermittent hypercapnia is modulated by sero-
tonergic and adrenergic receptors in raphe nu-
clei. J Neurophysiol. In press. doi:10.1152/jn.
00776.2017.
228. Sarton E, Teppema L, Dahan A. Sex differences in
morphine-induced ventilatory depression reside
within the peripheral chemoreflex loop. Anesthe-
siology 90: 1329 –1338, 1999. doi:10.1097/
00000542-199905000-00017.
229. Schwarzacher SW, Smith JC, Richter DW. Pre-Bötz-
inger complex in the cat. J Neurophysiol 73: 1452–
1461, 1995. doi:10.1152/jn.1995.73.4.1452.
230. Segers LS, Shannon R, Lindsey BG. Interactions
between rostral pontine and ventral medullary
respiratory neurons. J Neurophysiol 54: 318 –
334, 1985. doi:10.1152/jn.1985.54.2.318.
231. Segers LS, Shannon R, Saporta S, Lindsey BG.
Functional associations among simultaneously
monitored lateral medullary respiratory neurons
in the cat. I. Evidence for excitatory and inhibi-
tory actions of inspiratory neurons. J Neuro-
physiol 57: 1078 –1100, 1987. doi:10.1152/jn.
1987.57.4.1078.
232. Segers LS, Nuding SC, Dick TE, Shannon R, Bae-
key DM, Solomon IC, Morris KF, Lindsey BG.
Functional connectivity in the pontomedullary re-
spiratory network. J Neurophysiol 100: 1749 –
1769, 2008. doi:10.1152/jn.90414.2008.
233. Segers LS, Nuding SC, Ott MM, Dean JB, Bolser
DC, O’Connor R, Morris KF, Lindsey BG. Periph-
eral chemoreceptors tune inspiratory drive via
tonic expiratory neuron hubs in the medullary
ventral respiratory column network. J Neuro-
physiol 113: 352–368, 2015. doi:10.1152/jn.
00542.2014.
234. Segers LS, Nuding SC, Vovk A, Pitts T, Baekey
DM, O’Connor R, Morris KF, Lindsey BG, Shan-
non R, Bolser DC. Discharge identity of medullary
inspiratory neurons is altered during repetitive
fictive cough. Front Physiol 3: 223, 2012. doi:10.
3389/fphys.2012.00223.
235. Semenza GL. Hypoxia-inducible factors in physi-
ology and medicine. Cell 148: 399 – 408, 2012.
doi:10.1016/j.cell.2012.01.021.
236. Semenza GL, Prabhakar NR. The role of hypoxia-
inducible factors in carotid body (patho) physiol-
ogy. J Physiol. In press. doi:10.1113/JP275696.
237. Sheikhbahaei S, Gourine AV, Smith JC. Respira-
tory rhythm irregularity after carotid body den-
ervation in rats. Respir Physiol Neurobiol 246:
92–97, 2017. doi:10.1016/j.resp.2017.08.001.
238. Sherman D, Worrell JW, Cui Y, Feldman JL. Op-
togenetic perturbation of preBötzinger complex
inhibitory neurons modulates respiratory pat-
tern. Nat Neurosci 18: 408 – 414, 2015. doi:10.
1038/nn.3938.
239. Silva JN, Lucena EV, Silva TM, Damasceno RS,
Takakura AC, Moreira TS. Inhibition of the pon-
tine Kölliker-Fuse nucleus reduces genioglossal
activity elicited by stimulation of the retrotrap-
ezoid chemoreceptor neurons. Neuroscience
328: 9 –21, 2016. doi:10.1016/j.neuroscience.
2016.04.028.
240. Smith JC, Ellenberger HH, Ballanyi K, Richter
DW, Feldman JL. Pre-Bötzinger complex: a brain-
stem region that may generate respiratory
rhythm in mammals. Science 254: 726 –729, 1991.
doi:10.1126/science.1683005.
241. Smith PG, Mills E. Restoration of reflex ventila-
tory response to hypoxia after removal of carotid
bodies in the cat. Neuroscience 5: 573–580,
1980. doi:10.1016/0306-4522(80)90054-8.
242. Song G, Poon C-S. Lateral parabrachial nucleus
mediates shortening of expiration and increase
of inspiratory drive during hypercapnia. Respir
Physiol Neurobiol 165: 9 –12, 2009. doi:10.1016/
j.resp.2008.10.009.
243. Song G, Poon C-S. ␣2-Adrenergic blockade res-
cues hypoglossal motor defense against obstruc-
tive sleep apnea. JCI Insight 2: e91456, 2017.
doi:10.1172/jci.insight.91456.
244. Song G, Xu H, Wang H, Macdonald SM, Poon CS.
Hypoxia-excited neurons in NTS send axonal
projections to Kölliker-Fuse/parabrachial com-
plex in dorsolateral pons. Neuroscience 175:
145–153, 2011. doi:10.1016/j.neuroscience.2010.
11.065.
245. St-John WM, Li A, Leiter JC. Genesis of gasping
is independent of levels of serotonin in the Pet-1
knockout mouse. J Appl Physiol (1985) 107: 679 –
685, 2009. doi:10.1152/japplphysiol.91461.2008.
246. St John WM, Bianchi AL. Responses of bulbospi-
nal and laryngeal respiratory neurons to hyper-
capnia and hypoxia. J Appl Physiol (1985) 59:
1201–1207, 1985. doi:10.1152/jappl.1985.59.4.
1201.

247. Streeter KA, Sunshine MD, Patel S, Gonzalez-
Rothi EJ, Reier PJ, Baekey DM, Fuller DD.
Intermittent hypoxia enhances functional con-
nectivity of midcervical spinal interneurons. J
Neurosci 37: 8349 – 8362, 2017. doi:10.1523/
JNEUROSCI.0992-17.2017.
248. Tadjalli A, Duffin J, Peever J. Identification of a
novel form of noradrenergic-dependent respira-
tory motor plasticity triggered by vagal feed-
back. J Neurosci 30: 16886 –16895, 2010. doi:10.
1523/JNEUROSCI.3394-10.2010.
249. Teppema LJ, Dahan A. The ventilatory response
to hypoxia in mammals: mechanisms, measure-
ment, and analysis. Physiol Rev 90: 675–754,
2010. doi:10.1152/physrev.00012.2009.
250. Tort ABL, Brankak J, Draguhn A. Respiration-
entrained brain rhythms are global but often
overlooked. Trends Neurosci 41: 186 –197, 2018.
doi:10.1016/j.tins.2018.01.007.
251. Tryba AK, Peña F, Ramirez J-M. Gasping activity
in vitro: a rhythm dependent on 5-HT2A recep-
tors. J Neurosci 26: 2623–2634, 2006. doi:10.
1523/JNEUROSCI.4186-05.2006.
252. Turner S, Streeter KA, Greer J, Mitchell GS, Fuller
DD. Pharmacological modulation of hypoxia-in-
duced respiratory neuroplasticity. Respir Physiol
Neurobiol S1569-9048(17)30279-3. In press. doi:
10.1016/j.resp.2017.11.008.
253. Turovsky E, Theparambil SM, Kasymov V, Deit-
mer JW, Del Arroyo AG, Ackland GL, Cor-
neveaux JJ, Allen AN, Huentelman MJ, Kasparov
S, Marina N, Gourine AV. Mechanisms of
CO2/H⫹ sensitivity of astrocytes. J Neurosci 36:
10750 –10758, 2016. doi:10.1523/JNEUROSCI.
1281-16.2016.
Downloaded from journals.physiology.org/journal/physiologyonline (095.252.059.005) on January 7, 2022.
254. Tzeng YC, Larsen PD, Galletly DC. Effects of
hypercapnia and hypoxemia on respiratory sinus
arrhythmia in conscious humans during sponta-
neous respiration. Am J Physiol Heart Circ
Physiol 292: H2397–H2407, 2007. doi:10.1152/
ajpheart.00817.2006.
255. West JB. Causes of and compensations for hy-
poxemia and hypercapnia. Compr Physiol 1:
1541–1553, 2011.
256. White DP. Long-term facilitation (LTF) and ob-
structive sleep apnea. Respir Physiol Neurobiol
158: 112–113, 2007. doi:10.1016/j.resp.2007.03.
001.
257. Wilkerson JER, Devinney M, Mitchell GS. Inter-
mittent but not sustained moderate hypoxia
elicits long-term facilitation of hypoglossal mo-
tor output. Respir Physiol Neurobiol S1569-
9048(17)30221-5. In press. doi:10.1016/j.resp.
2017.10.005.
258. Willeput R, Rondeux C, De Troyer A. Breathing
affects venous return from legs in humans. J Appl
Physiol Respir Environ Exerc Physiol 57: 971–976,
1984.
259. Wilson RJA, Teppema LJ. Integration of central
and peripheral respiratory chemoreflexes.
Compr Physiol 6: 1005–1041, 2016. doi:10.1002/
cphy.c140040.
260. Xing T, Pilowsky PM, Fong AY. Mechanism of
sympathetic activation and blood pressure eleva-
tion in humans and animals following acute inter-
mittent hypoxia. Prog Brain Res 209: 131–146,
2014. doi:10.1016/B978-0-444-63274-6.00007-2.
PHYSIOLOGY • Volume 33 • July 2018 • www.physiologyonline.org
REVIEW
261. Yamamoto K, Lalley P, Mifflin S. Acute intermit-
tent optogenetic stimulation of nucleus tractus
solitarius neurons induces sympathetic long-term
facilitation. Am J Physiol Regul Integr Comp
Physiol 308: R266 –R275, 2015. doi:10.1152/
ajpregu.00381.2014.
262. Yasuma F, Hayano JI. Impact of acute hypoxia on
heart rate and blood pressure variability in con-
scious dogs. Am J Physiol Heart Circ Physiol 279:
H2344 –H2349, 2000. doi:10.1152/ajpheart.2000.
279.5.H2344.
263. Yasuma F, Hirai M, Hayano JI. Differential effects
of hypoxia and hypercapnia on respiratory sinus
arrhythmia in conscious dogs. Jpn Circ J 65: 738 –
742, 2001. doi:10.1253/jcj.65.738.
264. Zoccal DB, Machado BH. Sympathetic overactiv-
ity coupled with active expiration in rats submit-
ted to chronic intermittent hypoxia. Respir
Physiol Neurobiol 174: 98 –101, 2010. doi:10.
1016/j.resp.2010.08.011.
265. Zoccal DB, Furuya WI, Bassi M, Colombari DSA,
Colombari E. The nucleus of the solitary tract and
the coordination of respiratory and sympathetic
activities. Front Physiol 5: 238, 2014. doi:10.
3389/fphys.2014.00238.
266. Zuperku EJ, Stucke AG, Hopp FA, Stuth EAE.
Characteristics of breathing rate control medi-
ated by a subregion within the pontine parabra-
chial complex. J Neurophysiol 117: 1030 –1042,
2017. doi:10.1152/jn.00591.2016.
297