121 Girotti2017

Accepted Manuscript
Prefrontal cortex executive processes affected by stress in health

and disease
Milena Girotti, Samantha M. Adler, Sarah E. Bulin, Elizabeth A.

Fucich, Denisse Paredes, David A. Morilak
PII: S0278-5846(17)30365-2
DOI: doi: 10.1016/j.pnpbp.2017.07.004
Reference: PNP 9164
To appear in: Progress in Neuropsychopharmacology & Biological Psychiatry
Received date: 8 May 2017
Revised date: 1 July 2017
Accepted date: 5 July 2017
Please cite this article as: Milena Girotti, Samantha M. Adler, Sarah E. Bulin, Elizabeth
A. Fucich, Denisse Paredes, David A. Morilak , Prefrontal cortex executive processes
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Prefrontal cortex executive processes affected by stress in health and disease
Milena Girotti*, Samantha M. Adler, Sarah E. Bulin, Elizabeth A. Fucich, Denisse Paredes and
David A. Morilak
Department of Pharmacology and Center for Biomedical Neuroscience
UT Health San Antonio
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7703 Floyd Curl Dr.
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San Antonio, TX 78229, USA
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* Corresponding author
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Email: Girotti@uthscsa.edu
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Highlights
 Executive functions such as working memory, attention, behavioral inhibition and cognitive
flexibility are important cognitive processes mediated in the prefrontal cortex.
 Stress impairs executive function, which can compromise adaptive behavior and lead to
psychiatric pathology.
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 Several neurotransmitter systems and molecular signaling pathways involved in mediating
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optimal executive function are altered by chronic stress.
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Understanding how chronic stress affects executive function may provide new therapeutic
targets for the treatment of executive impairments in psychiatric disorders.
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Acknowledgements
This work was funded by NIH grants MH072672, MH053851 and MH100652.
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Abstract
Prefrontal cortical executive functions comprise a number of cognitive capabilities necessary for
goal directed behavior and adaptation to a changing environment. Executive dysfunction that leads to
maladaptive behavior and is a symptom of psychiatric pathology can be instigated or exacerbated by
stress. In this review we survey research addressing the impact of stress on executive function, with
specific focus on working memory, attention, response inhibition, and cognitive flexibility. We then
consider the neurochemical pathways underlying these cognitive capabilities and, where known, how
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stress alters them. Finally, we review work exploring potential pharmacological and non-
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pharmacological approaches that can ameliorate deficits in executive function. Both preclinical and
clinical literature indicates that chronic stress negatively affects executive function. Although some of
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the circuitry and neurochemical processes underlying executive function have been characterized, a
great deal is still unknown regarding how stress affects these processes. Additional work focusing on
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this question is needed in order to make progress on developing interventions that ameliorate
executive dysfunction.
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Table of Contents
1. Introduction................................................................................................................................. 7
1.1. Overall impact of stress on executive function............................................................................................. 8
2. Methods ...................................................................................................................................... 11
3. Working Memory ...................................................................................................................... 11
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3.1. Assessments of working memory...................................................................................................................... 12
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3.2. Effects of stress on working memory .............................................................................................................. 12
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3.3. Neurochemical mechanisms and pharmacological targets................................................................ 13
3.4. Non-pharmacological treatments...................................................................................................................... 16
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4. Attention..................................................................................................................................... 18
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4.1. Assessments of attention........................................................................................................................................ 18
4.2. Effects of stress on attention ................................................................................................................................ 18

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4.3. Neurochemical mechanisms and pharmacological targets .............................................................. 19

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5. Response Inhibition ................................................................................................................. 22

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5.1. Assessments of response inhibition................................................................................................................. 23

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5.2. Effects of stress on response inhibition ........................................................................................................ 23
5.3. Neurochemical mechanisms and pharmacological targets................................................................ 24

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6. Cognitive flexibility .................................................................................................................. 28
6.1 Assessments of cognitive flexibility .................................................................................................................. 28
6.2. Reversal learning ........................................................................................................................................................ 29
6.2.1. Effects of stress on reversal learning .............................................................................................................30
6.2.2. Neurochemical mechanisms and pharmacological targets ..................................................................30

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6.2.3. Non-pharmacological treatments ....................................................................................................................34
6.3. Set-shifting ...................................................................................................................................................................... 34
6.3.1. Effects of Stress on Set-shifting.........................................................................................................................35
6.3.2. Neurochemical mechanisms and pharmacological targets ..................................................................35
6.3.3. Non-pharmacological treatments ....................................................................................................................38
7. Concluding remarks ................................................................................................................. 40
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1. Introduction
Executive function comprises several top-down cognitive processes that are necessary for
everyday adaptive behaviors, such as the need to pay attention and concentrate, plan a course of
action, adapt to unforeseen events, or control impulsive behaviors that are not appropriate to the
situation (Barnes et al 2011, Diamond 2013, Leh et al 2010, Logue & Gould 2014, Robbins & Arnsten
2009). These cognitive processes, which include working memory, attention, response inhibition and
cognitive flexibility, require effort and conscious engagement, are acquired in the course of
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development, and decline with age. Throughout life, executive function can be challenged by intense
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or prolonged stress, and the dysregulation of these processes can reduce the quality of life and daily
performance of otherwise healthy individuals. Furthermore, it has long been recognized that both
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acute stressful life events and chronic stressors are strong risk factors for the development of mental
illnesses such as mood disorders (Beck 2008, Kessler 1997), anxiety disorders and addictive
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disorders (Kessler et al 1997). Executive dysfunction is a common symptom of many of these
psychiatric conditions that include depression, generalized anxiety disorder (GAD), obsessive-
compulsive disorder (OCD), attention-deficit hyperactivity disorder (ADHD), post-traumatic stress
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disorder (PTSD), and addictive behavior (Baler & Volkow 2006, Carvalho et al 2014, Ferreri et al
2011, Polak et al 2012). Given the consistent evidence discussed below that stress compromises
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executive abilities in healthy individuals and in animal models, it seems reasonable to infer that stress
contributes to the executive dysfunction seen in these conditions. Indeed, an inverse correlation is
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found between resilience (or the capacity to respond positively to adverse situations) and indices of
anxiety and depression (Holden et al 2012, Wingo et al 2010). However, we also must acknowledge
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that in some cases, executive impairment may be a direct consequence of an underlying disease
process independent of stress. In addition, it should also be recognized that executive dysfunction in
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itself can produce a stressful experience that can then exacerbate psychiatric illness secondarily, as
has been shown with depression (Jaeger et al 2006).
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A wealth of evidence derived from lesion and inactivation studies supports the idea that
prefrontal cortical (PFC) regions (i.e., anterior cingulate, prelimbic, infralimbic, and orbitofrontal cortex
in rodents, and Brodmann areas 24b, 32 and 25, as well as the orbital cortex in humans) are essential
for optimal executive control (Baier et al 2010, Barbey et al 2013, Colvin et al 2001, Drevets et al
2008, Levens et al 2014, Muller et al 2002). However, the PFC does not work in isolation, and a
distributed network of connectivity with other regions such as the hippocampus, amygdala, striatum,
and posterior parietal cortex is essential for modulating several aspects of executive function (Holmes
& Wellman 2009). Indeed, human fMRI studies of large-scale interconnectivity networks identified the
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central executive network (CEN) as one of three core neurocognitive networks. Neurocognitive
networks are intrinsically coupled brain areas that are systematically co-activated during higher order
cognitive tasks. The CEN nodes (the dorso-lateral PFC and the lateral posterior parietal cortex) show
strong co-activation during processes requiring executive control, such as working memory and
decision-making tasks in goal-oriented behavior (Menon 2011). Thus, it is important to remember that
the behavioral outcomes of such processes stem from the coordinated activation and/or inactivation of
several brain circuits integrating PFC top-down control. In this review we will focus primarily on the
effects of stress on the prefrontal cortex, a major component of executive processes.
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We will review the effects of stress on several examples of executive function (working
memory, attention, response inhibition and cognitive flexibility), in both humans and animal models.
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We will then discuss neurotransmitter systems that have been shown to respond to stress and are
targets of current therapeutics, namely, the glutamate, GABA, dopamine, norepinephrine and
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serotonin systems. We will also discuss molecular pathways that have potential as novel therapeutic
targets and emergent non-pharmacological approaches to improve executive function in humans.
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1.1. Overall impact of stress on executive function

The stress response is a highly conserved process essential for survival under conditions of
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environmental challenge (McEwen et al 2015, McKlveen et al 2015). Thus, the response to acute
stress (i.e. to a temporary challenge to the organism homeostasis, (McEwen 2004, Selye 1973))
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rapidly mobilizes the autonomic and neuroendocrine systems, producing a nearly instantaneous
release of catecholamines and HPA axis hormones (CRF, ACTH and glucocorticoids), which alter
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several physiological functions, such as cardiovascular capacity, metabolic resource allocation, and
immune activation in order to effectively respond to a threat. Acute catecholamine effects are short-
lived, disappearing within an hour; in contrast, glucocorticoid effects can be both rapid (with onset
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within minutes after the stimulus) and long-lasting. The long-term effects develop over the course of
several hours, and comprise transcriptional effects of activated glucocorticoid receptors (Henckens et
al 2010, Henckens et al 2011). The acute stress response also has a strong impact on cognitive
function. Acute stress in humans has been shown to activate saliency networks centered around the
amygdala, cingulate cortex, hypothalamus, insula, striatum, and locus coeruleus, and is responsible
for enhancing sensory gain and environmental scanning, resulting in better performance (Cousijn et al
2010, Oei et al 2012, van Marle et al 2009, van Marle et al 2010). Conversely, processes underlying
working memory, problem solving and cognitive flexibility are negatively affected by acute stress (Oei
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et al 2006, Plessow et al 2011, Plessow et al 2012, Schoofs et al 2008, Schoofs et al 2009,
Steinhauser et al 2007). Similar immediate and detrimental effects of acute stress on cognitive
flexibility and working memory have also been shown in rodents (Butts et al 2011, George et al 2015,
Thai et al 2013). Together, these results are consistent with an adaptive strategy that, for the short
term, ensures allocation of resources to cognitive functions that increase sensory hypervigilance,
scanning attention, and rapid (but more rigid) behavioral responses, at the expense of high order
cognitive engagement. These effects require the actions of catecholamines as well as the rapid
effects of glucocorticoids.
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The adaptive value of the stress response relies on the rapid resolution of the acute effects
through negative feedback mechanisms (Herman et al 2016, Hill & Tasker 2012). Thus, about 1 hour
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after exposure to a stressful stimulus, when catecholamine levels are low but glucocorticoid levels are
still elevated, the neurocognitive processes associated with the salience network weaken (Henckens
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et al 2012, Henckens et al 2010), while working memory and the ability to perform cognitive tasks
improve, along with reduced anxiety behavior. In the aftermath of an acute stress exposure, executive
processes improve and these effects have been shown to correlate with genomic corticosteroid
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actions (Henckens et al 2011, Het & Wolf 2007, Maheu et al 2005, Oei et al 2009, Putman et al 2007).
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However, when the physiological response to stress fails to return to homeostasis after acute
activation, or with prolonged and/or intense stress exposure, (conditions that are the hallmarks of
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chronic stress) the consequences for the organism, both physiological and cognitive, can be
detrimental. This is evidenced in non-clinical human cohorts where chronic stress levels which elicited
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subjective cognitive complaint, i.e., perceived difficulties with concentration, memory and decision
making, were associated with poor performance in tests of attentional shifting and working memory
(Stenfors et al 2013). In another study of healthy individuals, chronic stress biased decision-making
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strategies towards habitual responding (Soares et al 2012). Patients with mood and anxiety disorders
also display deficits in executive function. In particular, individuals with major depressive disorder
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show impairments in working memory (Landro et al 2001, Rose & Ebmeier 2006) and cognitive
flexibility on the Wisconsin card sorting test (Merriam et al 1999). Significant deficits in cognitive
flexibility were also found in individuals that developed obsessive-compulsive symptoms after a
traumatic stress exposure (Borges et al 2011). Paralleling human studies, chronic stress impairs
working memory (Arnsten et al 2012, Barsegyan et al 2010, Mizoguchi et al 2000) as well as cognitive
flexibility (Birrell & Brown 2000, Bondi et al 2008, Cerqueira et al 2005a, Floresco et al 1997, Lapiz-
Bluhm et al 2009, Liston et al 2006) in animal models.
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Deficits in executive function following chronic stress are accompanied by morphological
changes in the prefrontal cortex. In rodents, repeated stress and chronic corticosterone administration
cause reduction in apical dendrites, debranching of pyramidal neurons, and dendritic spine loss in the
medial prefrontal cortex (mPFC) (Cerqueira et al 2005a, Cerqueira et al 2007a, Cerqueira et al 2005b,
Cerqueira et al 2007b, Cook & Wellman 2004, Dias-Ferreira et al 2009, Liston et al 2006, Michelsen
et al 2007, Radley et al 2006, Radley et al 2004, Silva-Gomez et al 2003). Interestingly, in other brain
regions, such as amygdala, orbitofrontal cortex (OFC), and putamen, chronic stress increases
dendritic elaboration and produces structural hypertrophy (Dias-Ferreira et al 2009, Liston et al 2006).
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The differential effects of stress on neurons of the mPFC and the OFC align with data suggesting
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opposing firing properties of mPFC and OFC neurons (Moghaddam & Homayoun 2008).
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Detrimental effects of chronic stress on the morphology and activation patterns in the mPFC
have also been documented in humans. In studies employing non-clinical cohorts, individuals
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exposed to chronic stress show a shift toward automated response patterns during decision-making
tasks that correlate with atrophy of the medial prefrontal cortex and the caudate (Soares et al 2012).
Conversely, the putamen presented an increase in volume and dendritic arborization following chronic
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stress (Soares et al 2012). These data complement the preclinical studies reported above (Dias-
Ferreira et al 2009), where rats exposed to chronic stress displayed atrophy of the associative
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network (dorsomedial striatum-prefrontal circuitry) and hypertrophy of the sensorimotor network

responsible for automated responses (dorsolateral striatal-prefrontal circuitry). These structural
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changes in rats were also accompanied by increased biases toward habit behaviors. Combined with
the human studies, this work demonstrates stress produces structural and functinoal changes in
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fronto-striatal circuitry that reduces the ability of an individual to shift from automated behavior to goal-
directed behavior and may be maladaptive in situations of change.
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Changes in volume, morphology and activation of the prefrontal cortex are also evident in
subjects with mood disorders. For example, several prefrontal cortex regions including the anterior
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cingulate, the orbital cortex and the ventrolateral PFC have decreased grey matter volume in
individuals with major depression and bipolar disorder (Drevets et al 2008, Lyoo et al 2004).
Anomalies in the recruitment of prefrontal circuitry and patterns of activation in major depression have
also been shown (Johnstone et al 2007), with decreases in activation of the dorsolateral PFC
(DLPFC) (Drevets 1998) and hyperactivation of the OFC (Biver et al 1994, Drevets et al 1992).
Although other factors beside stress may produce structural and functional changes in pathology, the
fact that similar alterations are reported in preclinical and non-clinical stress studies suggests that
stress contributes to these effects also in pathological states. In summary, the above literature
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documents a substantial impact of stress on the structure and function of prefrontal cortical neurons
that correlate with behavioral impairments in executive function.
2. Methods
This study is a review investigating the effects of stress on working memory, attention, response
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inhibition, reversal learning and set shifting. For the sections covering the effects of stress on each
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executive function we conducted two types of search. The first was centered on the effects of stress
on working memory, attention, etc., in animal models. The second search was focused on human
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populations. We sought articles illustrating the deficits in executive function correlating with stress
exposure in non-clinical human cohorts as well as deficits observed in disorders for which stress has
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been shown to play an etiological or exacerbating role (Depression, PTSD, OCD, ADHD). For the
“Neurochemical mechanisms and pharmacological target” sections, the combinatorial search included
the terms “stress” “working memory” etc., and “dopamine” or “glutamate”, or “transcranial magnetic
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stimulation” etc. The search engines used were Google Scholar and the electronic database Medline
(PubMed). In the latter, searches were done with MeSH (Medical Subject Headings) and were limited
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to the English language from 1960 until 2017. We excluded articles where the deficits in executive
functions were confounded by neurological conditions or physical trauma. Finally, we cross-
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referenced publications within review articles for additional citations.

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3. Working Memory
Working memory is defined as the temporary storage of information used to perform a variety
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of cognitive tasks (Baddeley 1992). The role of the PFC in working memory, particularly in tasks with
a delay component, is supported experimentally in non-human primate and rodent studies (Brito &
Brito 1990). Specifically, lesion studies indicate that the prelimbic cortex of the ventral medial PFC is
critical to working memory in rodents (Brito & Brito 1990), and similarly lesions of the homologous
lateral PFC demonstrate its importance for working memory in humans (Muller et al 2002). Similarly,
the involvement of the prefrontal cortex (PFC) in working memory in humans is evidenced by
increased PFC activity in healthy individuals performing working memory tasks (D'Esposito et al
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1995), and working memory impairments in patients with frontal lobe damage (as reviewed in (Stuss
& Benson 1984).
3.1. Assessments of working memory

In animals, T-maze alternation tasks and object recognition tasks with variable lengths of delay
are used to test spatial and non-spatial working memory, respectively (Kinnavane et al 2015, Lalonde
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2002, Warburton & Brown 2015). These tasks rely on the intrinsic propensity of the animal to explore
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novel locations or objects when given a choice between a previously experienced situation and a
novel one. Deficits in working memory will diminish preference for the novel location/object, as the
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animal does not retain information of previously encountered situations. In humans, a commonly used
test for working memory is the n-back paradigm (Jonides et al 1997, Kirchner 1958, Pelegrina et al
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2015). In this test the subject is presented with a series of stimuli and is asked to indic ate when a
current stimulus matches one from n steps earlier.
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3.2. Effects of stress on working memory

The effects of stress on working memory appear to follow an inverted “U” response in animal
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models. While acute moderate stress has been shown to have positive effects on working memory in
rats (Yuen et al 2009), more intense or prolonged stressors impair working memory in tasks such as
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spatial delayed alternation (Shansky et al 2006) and spontaneous delayed non-matching-to sample
task (Morrow et al 2000). Likewise, repeated corticosterone administration impairs temporal order
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recognition in rats (Yuen et al 2012), and in rhesus monkeys, loud noise stress impairs delayed-
response performance (Arnsten & Goldman-Rakic 1998).
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Paralleling the preclinical literature, the effects of stress on working memory in humans can be
either positive or negative, depending on intensity and duration of the stressor. For instance,
exogenous hydrocorticosteroid administration in the afternoon, near the trough of glucocorticoid
circadian rhythm, improves working memory in healthy human subjects (Lupien et al 2002). However,
working memory is impaired when the same dose is administered in the morning, at the time of
glucocorticoid peak (Lupien et al 1999). In general, prolonged or high intensity stressors worsen
performance in working memory tests. For example, social stress causes a robust deficit in working
memory as measured by a modified reading span task as well as in the n-back paradigm (Luethi et al
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2008, Schoofs et al 2008). Working memory deficits in adults, correlated with childhood poverty, could
be attributed to chronic stress experienced in early life (Evans & Schamberg 2009). Finally, working
memory deficits are present in a wide range of stress-related psychiatric illnesses, such as PTSD
(Veltmeyer et al 2006), depression (Rose & Ebmeier 2006), substance dependence (Bechara &
Martin 2004), schizophrenia (Stone et al 1998), and ADHD (Martinussen et al 2005).
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3.3. Neurochemical mechanisms and pharmacological targets
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Preclinical studies examining the mechanisms underlying stress-induced impairments in
working memory as well as current standard treatments for psychiatric illness have informed the
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testing of various therapies to ameliorate working memory deficits.
Glutamate
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The importance of excitatory glutamate signaling to optimal working memory has been
demonstrated in healthy subjects both preclinically and clinically, with antagonists of N-methyl-D-
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aspartate glutamate receptors (NMDA-Rs) resulting in working memory impairments in rodents

(Pontecorvo et al 1991), non-human primates (Baron & Wenger 2001, Frederick et al 1995, Roberts
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et al 2010), and humans (Ghoneim et al 1985, Krystal et al 1994, Oye et al 1992). In rats, the
beneficial effect of acute glucocorticoid administration on working memory is accompanied by
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increased expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA-Rs)

and NMDA-Rs as well as increased AMPA-R activity in the PFC (Yuen et al 2009). In contrast, the
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deleterious effects of repeated corticosterone exposure correlate with decreased glutamate receptor
expression and AMPA-R activity (Yuen et al 2012).
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GABA
Targeting the primary inhibitory neurotransmitter γ-aminobutyric acid (GABA) has drawn
attention from schizophrenia researchers largely due to the hypothesized role that GABAergic cortical
interneurons play in the disease. One study comparing healthy volunteers to patients with
schizophrenia and concurrent working memory impairment revealed that lorazepam, a positive
modulator at the GABAA receptor benzodiazepine site, impaired working memory in healthy controls,
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with even more impairment in the patient group. Conversely, the GABAA receptor antagonist
flumazenil significantly improved working memory in the patient group but impaired working memory
in healthy controls (Menzies et al 2007). These data suggest that GABA-related “overinhibition” may
underlie working memory impairment in schizophrenia, and that targeting this system may offer a
strategy for treating such impairments.
Dopamine and norepinephrine
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In animal models, it has been found that stress-induced working memory impairments are
accompanied by increased prefrontal dopamine turnover and release, similar to the prefrontal
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dopamine dysfunction seen in schizophrenia. These behavioral and biochemical effects of stress can
be mimicked by the anxiogenic compound FG7142, a GABAA receptor inverse agonist. The working
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memory deficits caused by this pharmacological stressor are prevented by the GABAA receptor
antagonist flumazenil (RO15-1788), as well as the dopamine receptor antagonists haloperidol,
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clozapine, and SCH23390, in both monkeys and rats (Murphy et al 1996). Despite the evidence for a
hyperdopaminergic mechanism underlying stress effects on working memory, and similarly in
psychiatric illness, Mizoguchi and colleagues argue that after a prolonged period of chronic behavioral
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stress (four weeks, as compared with one week of water immersion/restraint stress), rats actually
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show decreased prefrontal dopamine transmission that accompanied impaired working memory in a
delayed-alternation task. This group went on to show that working memory can be restored with intra-
PFC administration of low doses of the D 1 receptor agonist SKF 81297 (Mizoguchi et al 2000).
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Therefore, similar to corticosterone, an optimal range of dopamine transmission is required for optimal
working memory.
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FG7142 also mimics the increased norepinephrine release in the PFC that accompanies
stress, implicating a role for norepinephrine in the detrimental effects on PFC-mediated working
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memory. Although propranolol, a -adrenergic receptor antagonist, did not prevent the FG7142-
induced working memory deficit (Murphy et al 1996), the -1 receptor antagonist urapidil and the  2
autoreceptor agonists clonidine and guanfacine did restore working memory after pharmacological
stress in rats (Birnbaum et al 1999, Birnbaum et al 2000). Indeed, the atypical antipsychotic
risperidone, which produces dopaminergic, noradrenergic, and serotonergic antagonism, improves
working memory in schizophrenia and bipolar patients (Harvey et al 2007, Harvey et al 2005).
Additionally, adjunct administration of guanfacine to schizophrenia patients being treated with
risperidone produced mild improvements in working memory as compared to treatment with
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risperidone alone (Friedman et al 2001). Long-term administration of clonidine to patients with
schizophrenia also improved working memory (Fields et al 1988).
Given these observations, it is perhaps paradoxical then that stimulants like methylphenidate
and amphetamine, which increase prefrontal catecholamines, have commonly been used to treat
cognitive dysfunction such as working memory impairments in patients with ADHD (Arnsten 2006,
Pietrzak et al 2006). Administration of stimulants to unmedicated schizophrenic patients can enhance
positive symptoms (Angrist et al 1980, van Kammen et al 1982), which is likely due to subcortical D 2
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receptor activation. Conversely, low doses administered to stably medicated patients can improve
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cognitive performance in working memory tasks, likely via prefrontal D 1 receptor activation (Barch &
Carter 2005, Goldberg et al 1991), which would agree with the previously discussed preclinical data
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demonstrating therapeutic effects of the D 1 receptor agonist SKF81297. Furthermore, modafinil, an
atypical dopamine transporter inhibitor, reverses chronic stress-induced impairments in a
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spontaneous alternation task in mice and improves working memory in non-stressed animals (Pierard
et al 2006). Similarly, modafinil enhances working memory in healthy individuals as well as individuals
with a wide range of psychiatric illnesses, and this improvement is likely due to modafinil’s
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catecholaminergic actions (Kalechstein et al 2010, Kalechstein et al 2013, Minzenberg & Carter
2008).
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Serotonin
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With respect to the role of serotonin, while the selective serotonin reuptake inhibitor (SSRI)
fluoxetine did not appear to ameliorate the FG7142-induced working memory impairment in rats
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(Murphy et al 1996), systemic administration of fluoxetine did reverse a predator stress-induced deficit
in working memory, while the benzodiazepine diazepam was not effective (Hage et al 2004). Use of
SSRIs is not typically associated with improved cognitive functions such as working memory in
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depressed patients (see Amado-Boccara et al., 1995, but see also (Zobel et al 2004). However,
vortioxetine, a multimodal serotonin modulator used to treat depression, has gained attention recently
for its beneficial effect on cognition. These cognitive effects seem not to be mediated by its activity as
a serotonin transporter inhibitor, but rather depend on its direct actions on serotonin receptors, namely
5-HT3, 5-HT7 and 5-HT1D receptor antagonism, 5-HT1B receptor partial agonism, and 5-HT1A receptor
agonism. Indeed, vortioxetine reverses working memory impairments caused by serotonin depletion,
effects attributed to its 5HT1A agonism (du Jardin et al 2014), although a recent clinical trial of
vortioxetine in depressed patients did not reveal a significant improvement in working memory in the
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n-back task despite the many other cognitive improvements that were seen (Mahableshwarkar et al
2015).
3.4. Non-pharmacological treatments

Behavioral training
Behavioral therapies have been used clinically to counter the negative effects of stress on
working memory. Clinical evidence demonstrates that training patients with disorders, such as ADHD,
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specifically on visuospatial and verbal working memory tasks via a computerized program (i.e.,
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CogMed), can sometimes improve their working memory performance (as reviewed in (Rapport et al
2013). Preclinical lesion studies show a similar improvement after several training sessions on a T-
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maze alternation task with short inter-trial intervals. However, rats with PFC lesions never recovered
working memory with longer delays even after several training sessions (Brito & Brito 1990). It is
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possible that such training increases activity of the PFC, and thus can restore function if the brain
region is hypoactive (as is thought to be the case in ADHD and other psychiatric illnesses) rather than
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completely lesioned. Indeed, increased prefrontal activity, as measured by functional magnetic
resonance imaging, has been reported in healthy adults after working memory training (Olesen et al
2004). Furthermore, positron emission tomography (PET) data reveals increased D1 receptor density
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in the PFC after working memory training (McNab et al 2009), again highlighting a role of dopamine in
optimal working memory performance.
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Mindfulness
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Mindfulness is a type of attentional focus characterized by awareness of and attention

to the present moment, both internally and externally, allowing for negative thoughts to arise
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and be acknowledged without judgment or reaction (Bishop et al 2004). Mindfulness-Based

Cognitive Behavioral Therapy (MBCBT) is a form of cognitive behavioral therapy that utilizes
the awareness underlying the mindfulness technique (Teasdale 1999), and has been shown
to prevent relapse in depression. In combination with relaxation techniques, it produces
changes in brain and immune function (Davidson et al 2003). Military personnel with a high
practice time of mindfulness training during the high-stress pre-deployment period
demonstrated increases in working memory capacity, while those in the military control group
or those with low practice time demonstrated decreases in working memory. These increases
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or decreases were correlated with reports of positive or negative affect, respectively (Jha et al
2010). Additionally, expressive writing, in particular about a negative stressful experience,
produced higher increases in working memory capacity in college freshmen compared to
those writing about a trivial topic; these gains were associated with decreases in intrusive and
avoidant thinking (Klein & Boals 2001).
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Transcranial magnetic stimulation
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In transcranial magnetic stimulation (TMS), high intensity magnetic fields are used to
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depolarize neurons in a particular area of the brain over a course of several sessions; this can be
used to either decrease (with low frequency) or increase (with high frequency) excitability in that
region (Luber & Lisanby 2014). In support of the notion that increasing PFC activity can improve
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working memory, several clinical studies have investigated the therapeutic potential of TMS in the
dorsolateral PFC (DLPFC) (as reviewed in (Brunoni & Vanderhasselt 2014). For instance, one
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session of TMS of the DLPFC was sufficient to improve working memory on the n-back task fifteen
minutes later in antidepressant-free patients diagnosed with depression (Oliveira et al 2013).
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Repetitive TMS targeting the DLPFC in medicated schizophrenia patients has also demonstrated
improvements in working memory (e.g. (Barr et al 2013). While stimulation of other brain regions can
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also improve working memory (e.g. the parietal cortex, cerebellum, and temporal cortex), it is still
unclear how the impact on working memory may differ between healthy adults and patients with
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psychiatric illness (Brunoni & Vanderhasselt 2014).

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Vagal Nerve Stimulation

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Vagal nerve stimulation (VNS) is another paradigm used for illnesses like treatment-resistant
depression, and is thought to function via altering cortical activity and/or by changing the activity of
neurotransmitters such as norepinephrine, serotonin, glutamate, and GABA. In VNS, an electrode
surrounds the left vagus nerve and communicates with a pulse generator to send pulses of a
programmed width, frequency, current, and cycle to the vagus nerve (Schachter & Saper 1998). One
study examining the effects of VNS on cognitive function found a significant improvement in working
memory in patients with treatment-resistant depression after ten weeks of VNS (Sackeim et al 2001).
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4. Attention
Attention is defined as the readiness to detect rare or unpredictable stimuli over an extended
time period (Sarter et al 2001). Attention is another executive function of the PFC that is affected by
an individual’s emotional and motivational state (Goetz et al 2008) and is often impaired by stress in
both humans and in animal models. Lesions of the mPFC, as well as compromised connectivity of the
inferior PFC to striatal, cerebellar, and parietal regions, result in deficits in attention in rats and
humans (Maddux & Holland 2011, Muir et al 1996), (Arnsten 2009, Arnsten & Rubia 2012, Aron &
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Poldrack 2005).
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4.1. Assessments of attention
Within animal models, variants of the 5 choice serial reaction time task (5-CSRTT) can be
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used to measure both attention and response inhibition. For this task, rats are placed in a chamber
containing multiple nose-poke holes. Stimulus lights are arranged above each hole, and the rat must
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pay attention to which stimulus light is lit and respond by nose-poking the correct hole. When the rat
performs within the time that the light is on, they receive a food reward. The attention portion of the
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task measures the number of omissions that occur, in which the rat does not respond to the stimulus
light (Robbins 2002).
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Several tests are used to measure attention in humans, e.g., the Visual Attention Task,
Selective Attention Task, Test of Variables of Attention and the Sustained Attention to Response Task
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(Hanania & Smith 2010). In general, in these tests the subject responds by pressing a button when a
target object is presented. The subject may have to pay specific attention to some of the object’s
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attributes, like color or shape, (for example, in a sequence of objects only respond to red circles) or
may have to recognize one specific object among a series of distractors. Another test of attention is
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the Stroop ask. The Stroop task evaluates selective attention by determining an individual’s ability to
overcome Stroop interference (Washburn 2016) (MacLeod 1992). The classic example of the Stroop
task consists of presenting a subject with words that spell a color but are of a different color (for
example the word “green” colored in blue), thus forcing the subject direct his or her attention to the
color of the word.
4.2. Effects of stress on attention

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Several studies have shown different modalities of attention to be compromised by stress.
Selective attention, or the ability to ignore irrelevant cues, worsens in animals after they receive an
inescapable footshock (Minor et al 1984). Rats exposed to prenatal stress exhibit impaired accuracy
in the 5-CSRT (Wilson et al 2012). Stress can result in attention deficits also in humans. For example,
prenatal stress in the form of malnutrition has linked a predisposition to attention problems (Liu &
Raine 2006). Attention deficits are also linked to times of acute stress. Students tested on their ability
to pay attention to details performed more poorly during exam periods in a semester than during non-
exam periods (Vedhara et al 2000). Interestingly, short-term stress and emotional state can affect the
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redirection of attention. A study performed on college students found that students in the negative
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stressor condition (where stress was induced by engaging in a competitive computer task) were
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quicker to switch their attention from negative words to positive or neutral words, and participants who
had higher scores on the Beck Depression Inventory were slower to redirect their attention from
negative to positive words (Ellenbogen et al 2002). Another study in humans found that in high-stress
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situations, attention to irrelevant stimuli as measured by the Stroop and Garner task is decreased
when compared to low-stress situations (Chajut & Algom 2003). Further, in one study assessing
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attentional bias towards threatening information, participants who received experimentally-induced
stress paid more attention to threatening words as measured by the attention deployment task (Mogg
et al 1990). Finally, combat veterans who have experienced stressful trauma and exhibit PTSD have
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decreased attention during cognitive tasks as compared to newly recruited national guardsmen (Uddo
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et al 1993). Taken together, these studies suggest that the effects of stress on attention may depend
on the amount of time one is subjected to stress (i.e. chronic, acute, and experimentally-induced brief
stress) and the emotional valence of the stimuli presented during the task.
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Glutamate
Not much is known about the role of the glutamate system in regulating attention in conditions
of stress. In non-stressed animals both competitive NMDA-R antagonists, such as (R)-CPP (Mirjana
et al 2004) and non-competitive NMDA-R antagonists such as dizocilpine, and phencyclidine (Higgins
et al 2003, Le Pen et al 2003) injected into the mPFC produce pronounced attentional performance
deficits as measured by increase in omissions and latency for correct detection in the 5-CSRTT.
Recent work has shown that the mGluR2/3 antagonist LY341495 prevents the (R)-CPP-associated
deficits in attention (Pozzi et al 2011), suggesting a specific role of glutamate signaling at
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metabotropic glutamate receptors, potentially involving CREB signaling (Paine et al 2009, Pozzi et al
2011) in modulating attentional behaviors. In support of this, in a genome-wide study of children with
ADHD and matched controls, variations in copy number within genes interacting with metabotropic
glutamate receptors were enriched in 10% of ADHD cases (Elia et al 2011). Thus, this system may
represent a potential target for future therapeutics. Whether such mechanisms are also playing a part
in stress-induced attentional deficits is a question worthy of future testing.
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Dopamine
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Multiple studies have explored the role of D 1 and D2 receptors within the PFC in regulating
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attention in rats. Activating D1 receptors can facilitate attention but excessive D1 activation via
stimulant medication can impair mPFC function (Chen et al 2014). The effects of D1/D2 agonists vary
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between prefrontal cortical subregions. For example, direct infusion of D 1 agonists into the mPFC
increased attention and accuracy, but only in more challenging tasks (Chudasama & Robbins 2004,
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Passetti et al 2003). However, D1 agonist infusion into the OFC had no effect on attention, but D 2
agonist infusion in the same area decreased attention. In humans, dysregulation of the dopamine
system can result in attentional impairments that may be caused by a deficiency in forming reward-
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seeking connections and thus inhibit goal-directed attention (Sagvolden et al 1998). As dopamine
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functions to regulate reward-seeking behavior, impaired dopamine function in the brain can result in
deficits in reward-related memory formation (Sagvolden et al 2005). Additionally, genetic analyses in
humans have shown that individuals with attention deficits have higher expression of DAT (Krause et
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al 2000). Thus, drugs such as methylphenidate that function by increasing extracellular dopamine
through DAT inhibition are routinely used to target attention deficits, and these effects are context-
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dependent (Volkow et al 2005).

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Norepinephrine
Norepinephrine transport inhibitors increase attention in both human and animal models
(Chamberlain et al 2007, Michelson et al 2003, Navarra et al 2008). Conversely, depleting
norepinephrine in the PFC decreases attention (Carli et al 1983, Milstein et al 2007). These effects
seem to be mediated by α-adrenergic receptors, in slightly different manners. The α1-adrenoceptor
antagonist prazosin and the αβ1/β/α2 adrenergic receptor antagonist propranolol produced deficits in
attention, the α 2-adrenoceptor antagonist atipamezole improved continued attention (Bari & Robbins
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2013b). This is in contrast to studies showing deleterious effects of other α 2 receptor antagonists,
such as idazoxan and yohimbine, on attention (Arnsten & Li 2005, Rowe et al 1996). These
discrepancies have been attributed to differences in behavioral tests, as well as the lower selectivity of
the latter compounds, which may produce non-specific effects. Activation of α2 autoreceptors
improved attention in some studies (Smith & Nutt 1996), but not in others (Fernando et al 2012).
Thus, the specific role of α2 receptor in the regulation of attention still needs to be fully clarified.
A few studies have investigated the role of norepinephrine on attentional tests in chronically
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stressed animals. In adult rats exposed to variable prenatal stress, deficits in attentional responses
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were found in a variant of the 5-CSRTT, and these deficits were corrected in a dose-dependent
manner by the norepinephrine reuptake inhibitor atomoxetine (Wilson et al 2012). Other studies have
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shown that auditory attention impaired by chronic restraint stress is alleviated by reboxetine, another
norepinephrine reuptake inhibitor (Perez-Valenzuela et al 2016).
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Serotonin
The serotonergic system has long been implicated in attentional performance (Harrison et al
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1997, Hiraide et al 2013). The involvement of various serotonin receptors in regulating attention has
been extensively studied. For example, mPFC infusion of the 5-HT2A/2C receptor antagonist ketanserin
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had no effect on attention (Passetti et al 2003), while M100907, a selective 5-HT2A antagonist,
improved performance by increasing accuracy. The 5-HT2A/2C agonist DOI reduced performance by
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negatively affecting attention (Koskinen et al 2000). By contrast, a selective 5-HT1A agonist 8-OH-
DPAT had beneficial effects, increasing attention (Winstanley et al 2003). In a human study of elderly
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subjects with generalized anxiety, citalopram reduced attentional performance compared to placebo;
this effect strongly correlated with high-transcription variants of 5-HT2 A and 5-HT1B receptors (Lenze et
al 2013). Together, the above data suggest that serotonin signaling through the 5-HT1A receptor and
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concomitant inhibition of 5-HT2A receptor in the PFC would be beneficial to attention.

Non-pharmacological treatments to treat attentional deficits are often administered in adjunct
with pharmacotherapy. The molecular mechanisms underlying how these therapies work are still
being explored and may uncover new therapeutic targets.
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Cognitive behavioral therapy
CBT, alone and in combination with pharmacotherapy, has been successfully used to
ameliorate core symptoms of adult ADHD, such as attentional deficits (Safren et al 2005, Weiss et al
2012). Additionally, twelve sessions of CBT reduced abnormal functional connectivity in the fronto-
parietal network and in the superior parietal gyrus in ADHD subjects (Wang et al 2016). Another form
of behavioral therapy, mindfulness-based stress reduction (MBSR), improves subjects’ ability to direct
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attention and detect changes in stimuli through mindfulness training (Jha et al 2007).
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Transcranial magnetic stimulation
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While TMS treats multiple cognitive deficits, it specifically improves attention when targeted to
the left DLPFC. Within depressed patients, one session of TMS targeted to the left DLPFC increased
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activity within the region and increased attention in an affective go-no-go task (Bermpohl et al 2006).
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5. Response Inhibition
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Response inhibition (the lack of which results in impulsivity) is another executive function of
the PFC that is detrimentally affected by stress in both animal models and human disorders.
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Impulsivity can be viewed as the tendency to act prematurely, without foresight (Dalley et al 2011),
and has been defined as “actions which are poorly conceived, prematurely expressed, unduly risky or
inappropriate to the situation and that often result in undesirable consequences,” (Chamberlain &
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Sahakian 2007). Impulsivity spans multiple cognitive domains and comprises multiple types of
behavior: the failure to adequately collect and evaluate information before reaching decisions
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(reflection impulsivity), the tendency to opt for smaller and immediate rewards over larger delayed
rewards (impulsive choice), and the inability to suppress prepotent motor responses (response
inhibition) (Chamberlain & Sahakian 2007, Dalley et al 2011, Fineberg et al 2010). In this review we
will focus on response inhibition.
OFC and infralimbic (IL) mPFC have been shown to mediate response inhibition, as lesions of
these areas produce premature responding in the 5-CSRTT and SSRT (Chudasama et al 2003, Eagle
et al 2008a, Eagle & Robbins 2003).
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5.1. Assessments of response inhibition

Within animal models, several different behavioral tasks are used to measure response
inhibition. First, variants of the 5 choice serial reaction time task (5-CSRTT) can be used to measure
response inhibition. This portion of the task measures the number of premature responses, or when
the animal responds before a stimulus light is lit. Another behavioral task used to evaluate response
inhibition is the Stop-Signal Reaction Time Test (SSRTT). This test first developed for human subjects
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(Logan et al 1984, Votruba & Langenecker 2013) has been subsequently adapted with minor
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modifications for rats (Eagle et al 2008a, Eagle et al 2008b). In this test, subjects are trained to
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respond to a visual cue by pressing a lever or button on the left (for cue A) or on the right (for cue B).
A number of trials (generally 75%) are recorded under these conditions (Go-trials). In 25% of trials a
stop signal, generally a tone, is given concomitantly or after presentation of the visual cue and the
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subject is required to stop responding (stop or No-Go trial). The parameters measured in this test are
the accuracy of response, the proportion of successful stops, the reaction time on Go-trials, and the
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stop signal reaction time.
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5.2. Effects of stress on response inhibition

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As with other cognitive functions of the PFC, response inhibition is affected differently by acute
or chronic stressors. Local microinjections of increasing doses of corticotrophin releasing factor (CRF)
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to simulate acute stress had no effect on response inhibition in 5-CRSTT (Ohmura et al 2009).
However, chronic restraint stress reduced rats’ ability to inhibit their responses (Mika et al 2012).
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Chronic exposure to cortisol levels that simulated prolonged stress response caused reduced
response inhibition also in non-human primates (Lyons et al 2000). In human studies, acute stress
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enhanced response inhibition and this effect was blocked by the mineralocorticoid receptor antagonist
spironolactone (Schwabe et al 2013). Conversely, prolonged stress worsens response inhibition in
humans. Both adult and adolescent volunteers that were in a self-reported “high stress” state
performed worse in an impulse inhibition task than individuals in a “low stress” state (Rahdar &
Galvan 2014). Response inhibition is also compromised in psychopathology. For example, patients
with PTSD made more errors during the NoGo phase of the SSRTT than controls. Higher levels of
PTSD were correlated with even higher error rates (Swick et al 2012). Individuals with borderline
personality disorder also presented increased impulsivity following exposure to stress (Krause-Utz et
al 2013). Both human and animal studies indicate that reduced response inhibition emerge from
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compromised functionality of the inferior PFC and its connections to striatal, cerebellar, and parietal
regions (Arnsten 2009, Arnsten & Rubia 2012, Aron & Poldrack 2005).

Glutamate
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The role of the glutamate system in regulating response inhibition in conditions of stress is not
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very well documented. However, some studies have explored the role of NMDA receptors within the
PFC in non-stressed animals. For example, (R)-CPP produced increased premature responding,
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indicating deficits in response inhibition (Mirjana et al 2004). Further studies revealed that the IL
portion of the mPFC may be the site responsible for the effects of (R)-CPP on response inhibition
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(Murphy et al 2005); this was confirmed in other studies using the NMDA-R antagonist MK801 (Benn
& Robinson 2014).
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Glutamate is most likely being modulated by other neurotransmitters, as administration of the
serotonin 5-HT 2A receptor antagonist M100907 prevents increases in premature responding induced
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by MK-801 (Higgins et al 2003) and (R)-CPP (Ceglia et al 2004). Additionally, both NMDA-R
antagonism and 5-HT 2A receptor activation result in increased glutamate release (Aghajanian & Marek
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2000, Moghaddam et al 1997). Thus, it has been proposed that excess glutamate in the IL cortex,
acting via non-NMDA receptors, may be responsible for increases in premature responding.
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Dopamine
Although some studies have reported altered dopamine transmission in association with
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impaired pre-pulse inhibition in rats exposed to early life stress (Heidbreder et al 2000), the majority of
studies investigating the role of dopamine in response inhibition involve non-stressed cohorts. The
role of dopaminergic neurotransmission in response inhibition is complex. Multiple studies have
explored the role of D1 and D2 receptors within the PFC in regulating response inhibition in rats. Drugs
of abuse that increase dopamine in the synapse, such as amphetamine, decrease response inhibition
(Robbins 2002), however direct agonism at D1 or D2 receptors within the OFC per se does not
increase impulsivity (Winstanley et al 2010) indicating that other neurotransmitter systems or other
brain regions are involved in this behavior. Indeed, antagonism of dopamine receptors demonstrates
the complexity of the system, as blocking either D 1 or D2 in the mPFC or OFC had no effect on the 5-
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CRSTT (Granon et al 2000, Winstanley et al 2010), or the SST (Bari et al 2011, Bari & Robbins
2013b) (Bari & Robbins 2013b). However, blocking D2 receptors in the dorsal striatum negatively
affects SST performance (Eagle et al 2011). From these data it has been suggested that
dopaminergic transmission within the striatum underlies the automated motor response of the
behavior (Bari & Robbins 2013a). The role for D2 receptors in response inhibition has also been
observed in human subjects where different polymorphisms of this gene correlate with differential
response times on SSRT (Hamidovic et al 2009). Additionally, the role of striatal D2 receptors have
been linked to impulsivity and addictive behavior (Volkow et al 2007).
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Norepinephrine
Although the role of norepinephrine in impulsive behavior following stress has not been
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investigated so far, several studies have shown its importance in modulating this behavior in non-
stress conditions. For example, atomoxetine, a relatively selective norepinephrine uptake inhibitor,
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improves response inhibition in both the 5-CRSTT and the stop-signal task (Robinson et al 2008).
Conversely, guanfacine, an agonist of α2-adrenergic autoreceptors, which reduces ascending
norepinephrine release, worsens response inhibition in rats (Bari et al 2009, Bari et al 2011) while the
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antagonist atipamezole improves performance (Bari & Robbins 2013b). However, guanfacine did not
improve impulsivity in healthy volunteers (Muller et al 2005) and other α2 receptor antagonists, such
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as idazoxan and yohimbine, have been reported to decrease impulse control (Arnsten & Li 2005,
Rowe et al 1996). The α1-adrenoceptor antagonist prazosin and the αβ 1/β/α2 adrenergic receptor
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antagonist propranolol do not affect response inhibition on their own, but propranolol improves
inhibitory control impaired by yohimbine, suggesting that norepinephrine may act at multiple receptors
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to bring about its effects on impulse control (Adams et al 2017). The mechanism by which
norepinephrine improves response inhibition is not currently known, but it may reflect the role of this
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neurotransmitter in regulating signal-to-noise ratio in PFC input and reorienting attention to salient
stimuli in the environment (Woodward et al 1991) (Aston-Jones & Cohen 2005).
Serotonin
The serotonergic system has long been implicated in the regulation of behavioral inhibition
(Evenden 1999, Linnoila et al 1983). Microinjections of fluoxetine into the OFC increase response
inhibition in rats already showing impulsive tendencies, but have no effect in low impulsivity rats. This
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finding indicates direct effects of SSRIs within the PFC of animals already exhibiting a deficit, but do
not enhance response inhibition in normal animals (Darna et al 2015). However, this seems specific to
fluoxetine, as citalopram, another SSRI, does not correct deficits in response inhibition in either
human or animal studies (Chamberlain et al 2006, Clark et al 2005, Eagle et al 2008a, Eagle et al
2009). (Bari Robbins 2009) This phenomenon may be linked to the recent evidence that the serotonin
transporter genotype influences the effects of SSRIs on response inhibition in humans (Fischer et al
2015).
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The involvement of various serotonin receptors in regulating response inhibition has been
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extensively studied, and has revealed a complex picture. For example, mPFC infusion of ketanserin
increased response inhibition (Passetti et al 2003), while M100907 improved performance by
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increasing response control. DOI reduced performance by negatively affecting response inhibition
(Koskinen et al 2000). By contrast, 8-OH-DPAT had no effect on impulse inhibition (Winstanley et al
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2003). Together, the above data suggest that serotonin signaling through the 5-HT1 A receptor and
concomitant inhibition of 5-HT2A receptor in the PFC reduces impulsivity.
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Interestingly, 5-HT 2A antagonism is also able to reverse the effects of NMDA-R blockade.
Injecting M100907 subcutaneously reverses CPP-induced decreases in response inhibition (Mirjana
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et al 2004). 5-HT1A antagonism with 8-OH-DPAT within the PFC was also able to block CPP-induced
elevations in extracellular glutamate (Calcagno et al 2006). These observations suggest that
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serotonin’s effects on response inhibition may be through modulation of the glutamate system.
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Multiple Neurotransmitter Systems

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While many of the studies above have focused on each of these neurotransmitter systems
individually, it is overly simplistic to believe that a simple therapeutic approach can be discovered
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without looking at the system as a whole. Under basal conditions, the monoaminergic systems
modulate excitatory and inhibitory transmission and this convergence in signaling often underlies the
multiple and overlaying effects observed using even highly selective pharmacotherapies. In a
complementary way, the effectiveness of some pharmacological treatments depends on their multi-
systems actions. For example, methylphenidate (MPH, or Ritalin), a drug often used in the treatment
of ADHD, interacts with multiple neurotransmitter systems for its therapeutic treatment, including
dopamine, norepinephrine, and acetylcholine (Robbins 2002). MPH is also effective in increasing
response inhibition in rats (Eagle et al 2007, Navarra et al 2008) where MPH effects on response
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inhibition can be blocked with a combination of adrenoceptor antagonists and dopamine antagonists,
but are not affected if only a single antagonist is administered (Arnsten & Dudley 2005), suggesting an
interplay of the two neurotransmitter systems.
Additionally, atypical antipsychotics, such as sertindole and clozapine, that act at both
dopamine and serotonin receptors prevent CPP-induced deficits in response inhibition (Carli et al
2011). Likewise, both drugs are able to suppress the elevated glutamate release that is associated
with both NMDA-R antagonism and behavioral deficits (Carli et al 2011). These drug studies suggest
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that the serotonin and dopamine systems have a synergistic effect on the glutamate system,
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specifically in regards to NMDA receptor hypofunction.
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Cognitive behavioral therapy and mindfulness
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CBT, alone and in combination with pharmacotherapy, has been successfully used to reduce
impulsivity and disinhibition in ADD (Safren et al 2005, Weiss et al 2012). Recent studies have also
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demonstrated beneficial effects of mindfulness-based stress reduction (MBSR) training on behavioral

inhibition. Compared to non-meditators, healthy volunteers who had followed a meditation training
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course for 6-8 weeks performed better on a Stroop task (Allen et al 2012, Moore & Malinowski 2009,
Teper & Inzlicht 2013), the Hayling task (Heeren et al 2009), and response inhibition tasks (Sahdra et
al 2011).
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Vagal nerve stimulation

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Finally, another noninvasive treatment for impulse control in current use is VNS. In comparing
patients before and after 10 weeks of VNS, the treatment significantly improved response inhibition,
as well as other cognitive symptoms (Sackeim et al 2001). VNS increases firing rates of 5-HT and
norepinephrine neurons (Dorr & Debonnel 2006), which may increase levels of 5-HT and
norepinephrine leading to increased NMDA-R function within the mPFC, and subsequent beneficial
effects on response inhibition measures (Carli et al 2011, Carli & Invernizzi 2014, Darna et al 2015,
Mirjana et al 2004).
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6. Cognitive flexibility
Cognitive flexibility, or the ability to adapt one’s behavior in response to a changing
environment, is often dysregulated in patients with neuropsychiatric disorders such as depression,
post-traumatic disorder, eating disorders and schizophrenia (Anisman & Matheson 2005, Austin et al
2001, Leeson et al 2009, Tchanturia et al 2012). For example, in patients suffering from depression,
the biased attention for negative information and the maladaptive perseverative cognition and
behaviors persist despite a changing environment (Disner et al 2011, Peckham et al 2010). A large
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body of evidence indicates that stress and anxiety negatively affect several aspects of cognitive
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flexibility (McKlveen et al 2015, Park & Moghaddam 2017); in this review, we will specifically focus on
two cognitive flexibility dimensions: reversal learning and set-shifting.
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6.1 Assessments of cognitive flexibility
Since the animal tests for cognitive flexibility are modeled directly on the human tests, we will
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begin by describing the latter first. Tests used to measure cognitive flexibility in humans and non-
human primates include the Stroop Test, the Trail Making Test, the Wisconsin Card Sorting Test, and
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a computerized adaptation of the Wisconsin Card Sorting Test, the interdimensional/extradimentional

(ID/ED) set-shifting task of the Cambridge Neuropsychological Test Automated Battery (CANTAB).
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The Stroop Test measures interference in the reaction time of a task (for example, naming the color
“red” when presented with the word “green” written in red ink), and has been used not only as an
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indicator of selective attention, as mentioned above, but also of broad cognitive flexibility processes
involved in planning, decision making and managing environmental interference. The Trail Making
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Test (Sanchez-Cubillo et al 2009) measures the time employed to connect a series of dots. This test
consists of two parts: in the first segment, the subject is asked to quickly connect a set of dots
identified by numbers (1,2,3…) in ascending order; in the second segment, the subject is asked to
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connect alternating number and letters (1, A, 2, B….). The first part of the test measures visual and
scanning speed, while the second part is an index of the ability to maintain two trains of thought
simultaneously, the ability to generate and modify a plan of action, and general cognitive flexibility. In
the Wisconsin Card Sorting Test (WCST) (Berg 1948, Nyhus & Barcelo 2009, Park & Moghaddam
2017), participants have to classify cards according to different criteria (color, number, or shape of
symbols on cards). The only feedback given is “correct” or “not correct”. The classification rule
changes every 10 trials; therefore, after figuring out the rule, the subject will make a series of mistakes
when the rule changes. The test measures the ability of subjects to modify behavior in the face of a
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change in reward contingency. The ID/ED set-shifting task, used with both humans and non-human
primates, is similar but requires selection of line figures and color-filled shapes on a computer screen
(Roberts et al 1988, Tyson et al 2004, Weed et al 2008). In rodent models, the attentional set-shifting
task (AST; (Birrell & Brown 2000)), an adaptation of the ID/ED test, requires rats or mice to learn to
associate a specific cue, within one of multiple stimulus dimensions, with a reward. Once they master
a given contingency, the rules are changed, requiring them to shift attention between perceptual
dimensions, allowing tests of reversal learning and set-shifting. Detailed methodological descriptions
of this test can be found in (Birrell & Brown 2000, Bondi et al 2008, Brown & Tait 2016, Lapiz-Bluhm
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et al 2008).
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6.2. Reversal learning
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Reversal learning is a type of discrimination learning. After the acquisition of a rule associating
a specific discriminatory stimulus within one sensory dimension with a reward, the reinforcement
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contingencies are swapped (Izquierdo et al 2017). Thus, in typical paradigms, subjects are trained to
discriminate between two stimuli in one sensory dimension visual, olfactory or spatial; only one
stimulus is rewarded every time it is chosen. After successful discrimination learning, gauged by
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meeting a predefined criterion of performance, the rewarded contingency is reversed, such that the
previously negative stimulus is now associated with the reward. Subjects are then trained to learn this
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new rule until they meet the performance criterion. Reversal paradigms have high translational value
because they can be used with minor variations in different species, including humans (Fellows &
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Farah 2003, Hornak et al 2004), monkeys (Clarke et al 2008, Crofts et al 1999, Izquierdo et al 2004,
Walker et al 2009), and rodents (Bissonette & Powell 2012, Boulougouris et al 2007, Jentsch & Taylor
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2001, Schoenbaum et al 2000). In the various test paradigms, the relationship between stimuli and
outcomes can be deterministic (often used in rodent models), or probabilistic (used in monkeys and
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humans, to reduce the use of simple strategies to predict outcomes) (Costa et al 2015, Dalton et al
2016, Walton et al 2010). This form of learning is mediated by the orbitofrontal cortex (OFC), as
evidenced by impairments in reversal learning following lesions of this region in humans (Fellows &
Farah 2003, Hornak et al 2004), monkeys (Dias et al 1996), mice (Bissonette et al 2008) and rats
(McAlonan & Brown 2003). Other brain regions important for reversal learning are the striatum (Cools
et al 2002, Rogers et al 2000), amygdala (Izquierdo et al 2013, Schoenbaum et al 2003, Wassum &
Izquierdo 2015) and the hippocampus (Mala et al 2015).
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6.2.1. Effects of stress on reversal learning
Chronic stress produces deficits in reversal learning in animal models. For example, two to five
weeks of chronic intermittent cold stress results in robust deficits in the reversal learning component
of the AST in rats (Danet et al 2010, Donegan et al 2014, Furr et al 2012, Lapiz-Bluhm et al 2009,
Patton et al 2016, Wallace et al 2014). Similarly, two weeks of chronic unpredictable stress also
produces significant deficits in reversal learning, measured using the AST (Bondi et al 2007, Bondi et
al 2010, Jett et al 2015, Jett & Morilak 2013) or using a Morris water maze spatial reversal task (Hill et
al 2005, Quan et al 2011, Yu et al 2016). Reversal learning deficits have also been documented in
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several stress-related psychiatric disorders such as major depressive disorder (where it was
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accompanied by abnormalities in the OFC) obsessive-compulsive disorder, and generalized anxiety
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disorder (Drevets 2007, Szabo et al 2013). Moreover, individuals repeatedly exposed to traumatic
events, even without a diagnosis of PTSD or anxiety-related disorder, displayed impaired
performance in a cue-context reversal learning paradigm (Levy-Gigi & Richter-Levin 2014).
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6.2.2. Neurochemical mechanisms and pharmacological targets
Glutamate
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Glutamate neurotransmission is necessary for optimal reversal learning. For example, mice
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hemizygous for the vesicular glutamate transporter 1, which controls the number and size of synaptic
vesicles in excitatory synapses, show impaired reversal learning due to increased perseveration in a
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visual discrimination task (Granseth et al 2015). However, a large number of studies investigating the
contributions of NMDA-R have yielded contradictory results. In rats, acute systemic administration of
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the NMDA-R antagonist MK-801 produced deficits in reversal learning in some studies (Lobellova et
al 2013) but not in others (Svoboda et al 2015). Similarly, phencyclidine (PCP), when used at doses to
mimic schizophrenia-like symptoms in rats, impaired reversal in some cases (Abdul-Monim et al
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2007), but in other studies it was found to have no effect (Brigman et al 2010, Janhunen et al 2015),
or to even improve reversal learning (Dix et al 2010, Fellini et al 2014, McAllister et al 2015).
In stressed animals, NMDA-R antagonists appear to have beneficial effects on stress-induced

reversal deficits. Thus, amantadine, a low affinity NMDA-R antagonist, has been shown to correct
deficits in spatial reversal learning in the Morris water maze in mice that experience a combination of
chronic unpredictable stress and isolation feeding (Yu et al 2016). In addition, ketamine, another non-
competitive NMDA-R antagonist, with rapid antidepressant actions (Autry et al 2011, Duman et al
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1997, Zarate et al 2006), is able to correct a deficit in reversal learning induced by chronic cold stress
in rats (Patton et al 2016). The apparent discrepancies between studies investigating the effects of
NMDA-R antagonists in reversal learning may be due to methodological differences. However, it
should also be noted that the different compounds used in these studies vary in the other targets they
interact with in addition to the NMDA receptor. Amantadine increases dopamine release and
adrenergic activity, both of which can facilitate reversal learning (see below). In the case of ketamine,
recent evidence suggests that one of its metabolites, norketamime (HNK) is actually responsible for
the antidepressant effects of this drug, through activation of glutamate AMPA receptor (GluA-R)
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(Zanos et al 2016). Thus, it is possible that ketamine’s beneficial effects on reversal learning are due
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to regulation of AMPA-R transmission. Indeed, recent evidence suggests this may be the case. It is
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thought that synaptic depression facilitates reversal learning by preventing the interference of
previous learning with the encoding of new information necessary to respond to a task change.
Indeed, LTD is required for optimal reversal learning: administration of a ionotropic glutamate receptor
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NMDA subunit 2B (GluN2B) selective antagonist or blockade of GluA-R internalization prevents LTD
in the hippocampus, and produces a disruption of spatial reversal learning in the Morris water maze
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(Dong et al 2013, Duffy et al 2008, Mills et al 2014). In a recent study, the ability of ketamine to correct
stress-induced reversal learning deficits was accompanied by decreased field potentials in the OFC
evoked by activation of mediodorsothalamic afferents, and both effects required activation of the
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JAK2/STAT3 signaling pathway in the OFC (Patton et al 2016). JAK2 and STAT3 have been shown to
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mediate maintenance of LTD also in the hippocampus (Nicolas et al 2012). Although the precise
mechanism is not known, JAK2 has recently been shown to modulate the levels of the immediate
early gene Arc, which regulates GluA receptor internalization (Chowdhury et al 2006, Patton et al
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2016), suggesting that JAK2 facilitates LTD by modulating Arc levels. With these considerations, one
possible mechanism for the actions of ketamine on reversal learning is that by activating JAK2,
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ketamine facilitates conditions of increased GluA-R internalization and LTD within the OFC that favor
reversal learning. Supporting and extending this idea, other activators of the JAK2/STAT3 pathway,
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such as interleukin 6 (IL-6), have been shown to correct the reversal learning deficits induced by cold
stress, and blockade of IL-6 signaling or JAK2 inhibition produce deficits in reversal learning
(Donegan et al 2014).
In sum, although it is not currently clear whether NMDA-R antagonism is in itself beneficial to
reversal learning, the picture that emerges from the above studies is that modulation of glutamatergic
transmission leading to LTD in the OFC (or hippocampus) is necessary for optimal performance in
reversal learning tasks, thus suggesting potential new avenues for therapeutic development.
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Dopamine and norepinephrine
Dopamine is required for several reward-associated learning processes; therefore, the

dopamine system may represent a potential point of therapeutic intervention for reversal learning
deficits caused by stress (Adamantidis et al 2011, Rossi et al 2013, Schultz 2013). The importance of
dopaminergic transmission in reversal behavior has been well documented, especially after extensive
training on reversal learning, when the possibility of reversal is “expected” (Costa et al 2015, Klanker
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et al 2015). There seems to be regional specificity to the effects of dopamine on reversal learning. In
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particular, dopamine release, specifically in the striatum, is likely to be necessary for optimal
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performance in reversal learning tasks. Depletion of dopamine in this brain region, but not in the OFC,
caused deficits in marmosets (Clarke et al 2011, Clarke et al 2007), and optimal reversal learning in
humans was correlated with increased dopaminergic activity only in the striatum (Clatworthy et al
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2009). AN
Targeting dopamine receptors, specifically D2 receptor signaling (which is increased by
repeated social defeat stress (Montagud-Romero et al 2016) could prove effective. Impaired reversal
learning following D2/D3 antagonists was observed in rats (Boulougouris et al 2009) and monkeys
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(Lee et al 2007, Smith et al 1999). In healthy humans, the D2 receptor antagonist sulpiride enhances
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reward-based reversal learning (van der Schaaf et al 2014), whereas a D2 receptor agonist
bromocriptine impairs probabilistic reversal learning (Mehta et al 2001). Together, these results
suggest that down-regulation of D2R may facilitate reversal learning performance.
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Norepinephrine is also known to play a modulatory role in cognitive flexibility. Propanolol (a β-

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adrenergic receptor antagonist) improved performance in the reversal learning component of the
rodent AST (Hecht et al 2014). In addition, acute and chronic administration of the norepinephrine
reuptake inhibitor desipramine (DMI) improved reversal learning in naïve rats, in both the AST (Lapiz
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et al 2007) and a four-position operant discrimination test (Seu & Jentsch 2009, Seu et al 2009).
Elevating norepinephrine transmission using either DMI or the α 2-autoreceptor inhibitor atipamezole
corrected deficits in reversal learning brought about by chronic unpredictable stress, and this effect
was dependent on α 1-receptors (Bondi et al 2010). Additionally, in human studies, by using an
anagram test as a measure of cognitive flexibility, healthy volunteers receiving propranolol had
enhanced performance in the test, while individuals receiving ephedrine (an activator of α - and β-
adrenergic receptors) had impaired performance (Beversdorf et al 1999). Taken together, this
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evidence suggests norepinephrine transmission, through α receptors but not β receptors, is required
for optimal reversal learning.
Serotonin
The role of serotonin in reversal learning has been extensively studied. Systemic
administration of agents that deplete serotonin, such as paracholorophenylalanine (PCPA) (a
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tryptophan hydroxylase inhibitor) or parachloroamphetamine (PCA) creates deficits in reward learning
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paradigms, including reversal learning, in non-stressed rats (Izquierdo et al 2012, Lapiz-Bluhm et al
2009, Masaki et al 2006). In monkeys, serotonin depletion within the prefrontal cortex using 5,7-
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dihydroxytryptamine caused reversal learning deficits, but not set-shifting deficits (Clarke et al 2004,
Clarke et al 2005). In addition, SSRIs improve reversal learning in spatial reversal tasks in naïve rats
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(Barlow et al 2015, Brown et al 2012), and correct reversal learning deficits induced by chronic cold
stress (Danet et al 2010, Lapiz-Bluhm et al 2009). Functionality of the serotonin transporter (5-HTT)
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plays an important role, as genetic inactivation of 5-HTT in mice produces deficits in reversal learning
(Brigman et al 2010), and depletion of tryptophan in healthy human volunteers homozygous for the
long allele of 5-HTT reduced the capacity of the individuals to utilize negative feedback information
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from punishment and impaired performance on reversal learning. The increased sensitivity of long
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allele homozygotes to decreased serotonin may be due in part to their accelerated serotonin reuptake
compared to short allele carriers (Finger et al 2007).
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The importance of the activation of specific serotonin receptors has also been investigated.
For example, the 5-HT2A receptor antagonist MDL 100-907, administered systemically or intra-OFC,
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produced deficits in reversal learning in naïve rats (Boulougouris et al 2008, Furr et al 2012), whereas
the 5-HT2C receptor antagonist SB 242084 improved reversal learning in naïve rats (Alsio et al 2015,
Boulougouris et al 2008, Boulougouris & Robbins 2010). Finally, the multimodal serotonin modulator,
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vortioxetine is effective in ameliorating reversal learning deficits produced by chronic cold stress
(Wallace et al 2014). The effects of vortioxetine are not due solely to its ability to inhibit serotonin
reuptake, since the drug was effective in correcting reversal learning deficits induced by serotonin
depletion with PCPA (Wallace et al 2014). Rather, it is likely that the beneficial effects of vortioxetine
are due to direct agonism at post-synaptic 5-HT1A and or 5-HT1B receptors (du Jardin et al 2014).
Together, these studies suggest that serotonergic tone in the OFC is crucial for optimal reversal
learning across species.
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6.2.3. Non-pharmacological treatments

Cognitive Behavioral Therapy
Not many studies have investigated the impact of cognitive behavioral therapy (CBT) on
reversal learning performance. However, one recent report has shown positive effects of CBT on
reversal learning in OCD patients. In this study, individuals that scored worse on a scale for OCD
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symptoms (Yale-Brown Obsessive Compulsive Scale, or YBOCS) made more spontaneous errors
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and more unnecessary strategy changes on a probabilistic reversal learning task, and showed
reduced activity in the orbitofrontal cortex and right putamen. After 8-12 weeks of CBT, these
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individuals improved both their YBOCS and reversal task scores and showed a more stable activation
of the pallidum (Freyer et al 2011). Thus, CBT may effectively improve reversal learning deficits seen
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in psychiatric disorders. AN
Repetitive Transcranial Magnetic Stimulation
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Several studies have examined the relationship between TMS and impaired cognitive
functioning (Demirtas-Tatlidede et al 2015). Repetitive TMS improved spatial reversal learning in the
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Morris water maze in non-stressed rats; these behavioral changes were associated with increased
synaptic plasticity and increased expression of BDNF, post-synaptic NMDA-R subunit NB2, and the
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presynaptic protein synaptophysin in the hippocampus (Shang et al 2016). Theta transcranial

stimulation also improved reversal learning in healthy human volunteers (Wischnewski et al 2016).
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6.3. Set-shifting
Set-shifting, unlike reversal learning, requires shifting an attentional response to
different stimulus attributes across different dimensions, when their relative reinforcement
value is changed. As mentioned earlier, the Wisconsin Card Sorting Test (WCST) is often
used to investigate set-shifting. Using positron emission tomography (PET) imaging on
human subjects, it has been shown that prefrontal cortical activity is associated with set-
shifting performance on the WCST (Miller & Cohen 2001, Rogers et al 2000). Thus,
disruption of the integrity of the prefrontal cortex, in particular the dorsolateral areas, results
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in declined performance on set-shifting in the WCST (Manes et al 2002, Miller & Cohen 2001,
Owen et al 1991, Stuss et al 2000) (Manes et al 2002, Owen et al 1991, Stuss et al 2000).
Similar outcomes are also observed in monkeys and rats (Bissonette et al 2008, Brown &
Bowman 2002). Moreover, OFC damage does not impair ED shifting, and lateral or medial
PFC damage does not impair reversal learning, suggesting a functional dissociation between
those regions.
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6.3.1. Effects of Stress on Set-shifting
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In animal models, the outcomes of experiments with acute stressors have been mixed,
possibly due to varying intensity of the stress used. Thus, 30 min restraint stress did not
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affect set-shifting acutely (Thai et al 2013), while 15 min of tail pinch produced deficits (Butts
et al 2013). Conversely, chronic stress (for example, chronic unpredictable stress (CUS) and
repeated restraint stress) has been shown to produce a deficit in ED set-shifting on the AST
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in rodents (Bondi et al 2008, Fucich et al 2016, Jett & Morilak 2013, Liston et al 2006, Morilak
et al 2005), and these behavioral changes correlate with dendritic retraction and debranching
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in the mPFC (Floresco et al 2008, Liston et al 2006). In humans, four weeks of psychosocial
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stress has been shown to alter the connectivity of DLPFC as measured by fMRI, and impair
attentional set-shifting as measured by a visual discrimination task (Liston et al 2009). In
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another study, healthy volunteers with high self-perceived chronic stress required more time
to complete the set-shifting component of the Trail Making Test (Orem et al 2008).
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6.3.2. Neurochemical mechanisms and pharmacological targets

Glutamate
Glutamate transmission is necessary for set-shifting. Intra-mPFC microinjections of

antagonists of either AMPA-R (LY293558, NBQX) or NMDA-R (MK80, AP-5) created deficits in set-
shifting (Jett et al 2017, Stefani et al 2003, Stefani & Moghaddam 2005); in particular, NMDA-R
activation is necessary for the modification of previously learned information (Stefani et al 2003).
Conversely, antagonizing the metabotropic glutamate receptor mGluR5 with MPEP did not affect ED
set-shifting (Jett et al 2017). Ketamine given systemically at a sub-anesthetic dose 24 hours before
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testing has been shown to reverse the effects of stress on ED set-shifting (Jett et al 2015).
Furthermore, an intraperitoneal injection of ketamine prior to each restraint session of a chronic
restraint stress procedure prevented the impairment of ED set-shifting performance (Nikiforuk & Popik
2014).
Norepinephrine
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Reduction of norepinephrine in the mPFC, by either noradrenergic deafferentiation or
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lesions of the dorsal noradrenergic bundle, produced marked set shifting deficits in rats
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(McGaughy et al 2008, Tait et al 2007). The serotonin and norepinephrine reuptake inhibitor
atomoxetine was able to rescue the deficits in ED caused by deafferentiation, presumably by
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preventing reuptake of norepinephrine released from the residual intact adrenergic terminals
(Newman et al 2008). Atomoxetine also improved ED set-shifting in intact adolescent rats
(Cain et al 2011). Enhancing noradrenergic neurotransmission acutely, by administration of
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the α2 -adrenergic autoreceptor antagonist atipamezole, improved performance on the ED
task through the activation of the α1 -adrenergic receptor (Bondi et al 2010, Lapiz & Morilak
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2006). Furthermore, chronic treatment with desipramine, a selective norepinephrine reuptake

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blocker, increases tonic noradrenergic transmission in the mPFC and enhances performance
on the ED task (Lapiz et al 2007). Chronic desipramine treatment also prevents the
detrimental effects of chronic stress on cognitive flexibility when administered beginning one
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week prior to the start of CUS (Bondi et al 2008). The SNRI milnacipran is prescribed as a
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treatment for fibromylagia in the United States and as an antidepressant in Europe. Although
milnacipran blocks the reuptake of both norepinephrine and serotonin, it has a high
preference for the norepinephrine transporter (Briley et al 1996, Mochizuki et al 2002, Moret
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& Briley 1997, Vaishnavi et al 2004). Chronic milnacipran treatment enhanced cognitive
flexibility compromised by chronic stress (Naegeli et al 2013). However, because
norepinephrine is released during stress (Nakane et al 1994) and is linked with the activation
of the HPA axis (Joels & Baram 2009), the repeated elicitation of acute norepinephrine and
glucocorticoid activity by chronic repeated stress may be detrimental and result in dendritic
atrophy (Woolley et al 1990). Thus, while enhancing norepinephrine tone acutely in the
mPFC can enhance cognition acutely, blocking α1-adrenergic and β2-adrenergic receptors
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prior to each stress session during a chronic unpredictable stress treatment protected against
the detrimental effects of chronic stress on set-shifting capability (Jett & Morilak 2013).
The specific association between set-shifting and norepinephrine neurotransmission in

humans is less well documented, because the most commonly used pharmaceuticals lack
selectivity for the noradrenergic system. In a study of patients diagnosed with Major
Depressive Disorder that compared the effects of the SNRI duloxetine with the SSRI
escitalopram on a battery of cognitive tests for executive function, both patient groups
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improved their scores on the Hamilton Depression Rating Scale (HSRS) and on the ID/ED
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set-shifting test (Herrera-Guzman et al 2010). Another study also reported trends to improved
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ID/ED performance in individuals with major depression that were administered duloxetine;
however, because of the small sample size, statistical significance of the effects compared to
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controls was achieved only when several measures of executive function were considered
together (Greer et al 2014).
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Serotonin
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Although serotonin depletion has been shown to impair reversal learning but not set-
shifting (Clarke et al 2005, Lapiz-Bluhm et al 2009), a role for serotonin signaling in set-
shifting is implicated by the fact that SERT knockout mice perform better than control mice on
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the set-shifting task of AST (Nonkes et al 2012). Moreover, drugs that target serotonin
reuptake can enhance cognitive function. Thus, chronic treatment with the selective 5-HT
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reuptake inhibitor escitalopram has been shown to reverse the effects of CUS on set-shifting,
and acute administration of escitalopram reversed a deficit in set-shifting caused by repeated
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restraint stress (Bondi et al 2008, Nikiforuk & Popik 2011). In depressed individuals, the SSRI
sertraline has been shown to enhance attentional and executive cognitive functions (Constant
et al 2005).
Specific serotonin receptors appear to be linked to optimal set-shifting. In rats, the

negative effects of chronic restraint stress on set-shifting were ameliorated by antagonizing
the 5-HT7 receptor, which is implicated in the cognitive and behavioral manifestation of
depression, with amisulpride (Hedlund 2009, Hedlund et al 2005, Leopoldo et al 2011,
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Nikiforuk & Popik 2013). The 5-HT6 receptor has also been implicated in the treatment of
cognitive symptoms. In PCP-treated rats, the 5-HT6 receptor antagonist, SB 271046, and
sertindole, a second generation antipsychotic that acts as an antagonist on several
neurotransmitter receptors, with high affinity for the 5-HT6 receptor, reduced the PCP-induced
deficit in set-shifting (Idris et al 2010, Rodefer et al 2008). Vortioxetine has been shown to
improve a range of cognitive impairments in depressed patients (McIntyre et al 2014,
Pehrson & Sanchez 2014, Sanchez et al 2015).
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Dopamine
Dopamine activity in the mPFC is required for optimal performance in set-shifting
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tasks. Pharmacological depletion of dopamine in the mPFC of monkeys using 6-OHDA
produced deficits in set-shifting (Crofts et al 2001, Robbins & Roberts 2007). In contrast,
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increasing dopamine activity in the mPFC improved set-shifting in humans (Apud et al 2007).
The role played by different dopamine receptors in this behavior is complex, and depends on
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differential activation of D1, D2, and D 4 dopamine receptors (Floresco 2013). For example, the
D1 receptor antagonist SCH23390 infused within the mPFC impaired set-shifting in rats
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(Haluk & Floresco 2009, Ragozzino 2002), while mPFC infusions of the D4 antagonist L-
745,870 improved set-shifting (Floresco et al 2006). Finally, administration of the D2/D3
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receptor antagonist sulpiride to human volunteers impaired extradimensional set-shifting

(Mehta et al 1999).
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6.3.3. Non-pharmacological treatments

Exposure Therapy
Cognitive behavioral therapy, such as exposure therapy, is effective in the reduction of

symptoms for some treatment-resistant patients; the combination of pharmacotherapy and
psychotherapy can improve symptoms even further (Beck 2005, Hollon et al 2002, Nemeroff et al
2003, Pampallona et al 2004). Prolonged exposure therapy shares some similarities to the process of
fear extinction training. During fear extinction training, animals that previously have associated an
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aversive stimulus to an innocuous stimulus (e.g. a shock and a tone, respectively) eventually exhibit a
decreased fear response when exposed to the innocuous stimulus in the absence of the aversive
stimulus (Myers & Davis 2007). Recent studies have shown that fear extinction rescues a deficit in
set-shifting caused by chronic stress, and that these effects are mediated by neuronal activation and
de novo protein synthesis in the IL region of the mPFC (Fucich et al 2016). These findings suggest
that behavior-driven activity of the mPFC produces plastic changes in this brain region that can
benefit other mPFC-dependent behavioral tasks, including set-shifting.
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Mindfulness
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A few studies have investigated the impact of Mindfulness-Based Stress Reduction
(MBSR) based training on cognitive flexibility. In healthy adults, MBSR did not improve set-
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shifting on the Trail Making Test (TMT) (Gallant 2016, Heeren et al 2009), or on the dual
attention to response task (DART) (Jensen et al 2012). However, MBSR improves set-shifting
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in older adults as measured by post-test performance on the TMT (Moynihan et al 2013),
suggesting that this technique may be a useful tool to improve cognitive set-shifting in
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compromised or aged individuals.

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Electroconvulsive Therapy (ECT)

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A recent meta-analysis found that patients tested before and after ECT therapy showed long-
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term improvements in various measures of executive functioning (Semkovska & McLoughlin 2010). In
particular, data from multiple studies demonstrate that ECT improved performance in the Stroop
Color-Word test and Trail Making Test Part B, two measures of cognitive flexibility. Although the
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authors still observed evidence of short-term cognitive deficits, these appeared to be fully recovered
and even improved over time. This suggests that ECT can improve deficits in cognitive flexibility
associated with psychiatric disorders.
Repetitive Transcranial Magnetic Stimulation

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Repetitive TMS has also proven to be beneficial for set-shifting. In patients with concurrent
Parkinson’s disease and major depressive disorder, rTMS over the left DLPFC significantly improved
performance on the Stroop Test and the Wisconsin Card Sorting Test (Boggio et al 2005).
7. Concluding remarks
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The impact of stress on executive function is well documented both in humans and in animal
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models. The consequences are particularly dreary for aging and clinical populations, where poor
executive skills resulting in reduced attention, impulse control, prospective memory, self-awareness,
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decision making and flexibility can cause further decline and social isolation, or can exacerbate
affective and neurological symptoms, as well as other medical illnesses. Compounding this is the fact
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that available therapies are only partially effective at ameliorating cognitive symptoms. Anatomical
lesion studies and pharmacological studies have given us a wealth of insightful knowledge about the
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brain areas and neurotransmitter systems implicated in executive function. The future challenge is to
achieve a more detailed understanding of the circuitries and molecular mechanisms involved in the
behavioral manifestations of executive processes in both healthy states and in conditions impaired by
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stress. Doing so will allow us to identify the systems most sensitive to dysregulation that may
therefore be candidate targets for new pharmacological and non-pharmacological interventions.
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References
Abdul-Monim Z, Neill JC, Reynolds GP. 2007. Sub-chronic psychotomimetic phencyclidine

induces deficits in reversal learning and alterations in parvalbumin-immunoreactive
expression in the rat. J Psychopharmacol 21: 198-205
Adamantidis AR, Tsai HC, Boutrel B, Zhang F, Stuber GD, et al. 2011. Optogenetic
interrogation of dopaminergic modulation of the multiple phases of reward-seeking
behavior. J Neurosci 31: 10829-35
Adams WK, Barrus MM, Zeeb FD, Cocker PJ, Benoit J, Winstanley CA. 2017. Dissociable
effects of systemic and orbitofrontal administration of adrenoceptor antagonists on
T
yohimbine-induced motor impulsivity. Behav Brain Res 328: 19-27
Aghajanian GK, Marek GJ. 2000. Serotonin model of schizophrenia: emerging role of
IP
glutamate mechanisms. Brain Res Brain Res Rev 31: 302-12
Allen M, Dietz M, Blair KS, van Beek M, Rees G, et al. 2012. Cognitive-affective neural
CR
plasticity following active-controlled mindfulness intervention. J Neurosci 32: 15601-10
Alsio J, Nilsson SR, Gastambide F, Wang RA, Dam SA, et al. 2015. The role of 5-HT2C
receptors in touchscreen visual reversal learning in the rat: a cross-site study.
US
Psychopharmacology (Berl) 232: 4017-31
Angrist B, Rotrosen J, Gershon S. 1980. Differential effects of amphetamine and neuroleptics
on negative vs. positive symptoms in schizophrenia. Psychopharmacology (Berl) 72:
17-9
AN
Anisman H, Matheson K. 2005. Stress, depression, and anhedonia: caveats concerning
animal models. Neurosci Biobehav Rev 29: 525-46
Apud JA, Mattay V, Chen J, Kolachana BS, Callicott JH, et al. 2007. Tolcapone improves
M
cognition and cortical information processing in normal human subjects.

Neuropsychopharmacology 32: 1011-20
ED
Arnsten AF. 2006. Stimulants: Therapeutic actions in ADHD. Neuropsychopharmacology 31:

2376-83
Arnsten AF. 2009. Toward a new understanding of attention-deficit hyperactivity disorder
PT
pathophysiology: an important role for prefrontal cortex dysfunction. CNS Drugs 23

Suppl 1: 33-41
Arnsten AF, Dudley AG. 2005. Methylphenidate improves prefrontal cortical cognitive function
CE
through alpha2 adrenoceptor and dopamine D1 receptor actions: Relevance to

therapeutic effects in Attention Deficit Hyperactivity Disorder. Behav Brain Funct 1: 2
Arnsten AF, Goldman-Rakic PS. 1998. Noise stress impairs prefrontal cortical cognitive
function in monkeys: evidence for a hyperdopaminergic mechanism. Arch Gen
AC
Psychiatry 55: 362-8

Arnsten AF, Li BM. 2005. Neurobiology of executive functions: catecholamine influences on
prefrontal cortical functions. Biol Psychiatry 57: 1377-84
Arnsten AF, Rubia K. 2012. Neurobiological circuits regulating attention, cognitive control,
motivation, and emotion: disruptions in neurodevelopmental psychiatric disorders. J
Am Acad Child Adolesc Psychiatry 51: 356-67
Arnsten AF, Wang MJ, Paspalas CD. 2012. Neuromodulation of thought: flexibilities and
vulnerabilities in prefrontal cortical network synapses. Neuron 76: 223-39
Aron AR, Poldrack RA. 2005. The cognitive neuroscience of response inhibition: relevance
for genetic research in attention-deficit/hyperactivity disorder. Biol Psychiatry 57: 1285-
92
ACCEPTED MANUSCRIPT
Aston-Jones G, Cohen JD. 2005. An integrative theory of locus coeruleus-norepinephrine
function: adaptive gain and optimal performance. Annu Rev Neurosci 28: 403-50
Austin MP, Mitchell P, Goodwin GM. 2001. Cognitive deficits in depression: possible
implications for functional neuropathology. Br J Psychiatry 178: 200-6
Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, et al. 2011. NMDA receptor blockade at
rest triggers rapid behavioural antidepressant responses. Nature 475: 91-5
Baddeley A. 1992. Working memory. Science 255: 556-9
Baier B, Karnath HO, Dieterich M, Birklein F, Heinze C, Muller NG. 2010. Keeping memory
clear and stable--the contribution of human basal ganglia and prefrontal cortex to
working memory. J Neurosci 30: 9788-92
Baler RD, Volkow ND. 2006. Drug addiction: the neurobiology of disrupted self-control.
T
Trends Mol Med 12: 559-66
IP
Barbey AK, Koenigs M, Grafman J. 2013. Dorsolateral prefrontal contributions to human
working memory. Cortex 49: 1195-205
CR
Barch DM, Carter CS. 2005. Amphetamine improves cognitive function in medicated
individuals with schizophrenia and in healthy volunteers. Schizophr Res 77: 43-58
Bari A, Eagle DM, Mar AC, Robinson ES, Robbins TW. 2009. Dissociable effects of
noradrenaline, dopamine, and serotonin uptake blockade on stop task performance in
US
rats. Psychopharmacology (Berl) 205: 273-83
Bari A, Mar AC, Theobald DE, Elands SA, Oganya KC, et al. 2011. Prefrontal and
monoaminergic contributions to stop-signal task performance in rats. J Neurosci 31:
AN
9254-63
Bari A, Robbins TW. 2013a. Inhibition and impulsivity: behavioral and neural basis of
response control. Prog Neurobiol 108: 44-79
M
Bari A, Robbins TW. 2013b. Noradrenergic versus dopaminergic modulation of impulsivity,

attention and monitoring behaviour in rats performing the stop-signal task: possible
ED
relevance to ADHD. Psychopharmacology (Berl) 230: 89-111

Barlow RL, Alsio J, Jupp B, Rabinovich R, Shrestha S, et al. 2015. Markers of serotonergic
function in the orbitofrontal cortex and dorsal raphe nucleus predict individual variation
in spatial-discrimination serial reversal learning. Neuropsychopharmacology 40: 1619-
PT
30
Barnes JJ, Dean AJ, Nandam LS, O'Connell RG, Bellgrove MA. 2011. The molecular
genetics of executive function: role of monoamine system genes. Biol Psychiatry 69:
CE
e127-43
Baron SP, Wenger GR. 2001. Effects of drugs of abuse on response accuracy and bias
under a delayed matching-to-sample procedure in squirrel monkeys. Behav Pharmacol
AC
12: 247-56
Barr MS, Farzan F, Rajji TK, Voineskos AN, Blumberger DM, et al. 2013. Can repetitive
magnetic stimulation improve cognition in schizophrenia? Pilot data from a randomized
controlled trial. Biol Psychiatry 73: 510-7
Barsegyan A, Mackenzie SM, Kurose BD, McGaugh JL, Roozendaal B. 2010.
Glucocorticoids in the prefrontal cortex enhance memory consolidation and impair
working memory by a common neural mechanism. Proc Natl Acad Sci U S A 107:
16655-60
Bechara A, Martin EM. 2004. Impaired decision making related to working memory deficits in
individuals with substance addictions. Neuropsychology 18: 152-62
ACCEPTED MANUSCRIPT
Beck AT. 2005. The current state of cognitive therapy: a 40-year retrospective. Arch Gen
Beck AT. 2008. The evolution of the cognitive model of depression and its neurobiological
correlates. Am J Psychiatry 165: 969-77
Benn A, Robinson ES. 2014. Investigating glutamatergic mechanism in attention and impulse
control using rats in a modified 5-choice serial reaction time task. PLoS One 9:
e115374
Berg EA. 1948. A simple objective technique for measuring flexibility in thinking. J Gen
Psychol 39: 15-22
Bermpohl F, Fregni F, Boggio PS, Thut G, Northoff G, et al. 2006. Effect of low-frequency
transcranial magnetic stimulation on an affective go/no-go task in patients with major
T
depression: role of stimulation site and depression severity. Psychiatry Res 141: 1-13
IP
Beversdorf DQ, Hughes JD, Steinberg BA, Lewis LD, Heilman KM. 1999. Noradrenergic
modulation of cognitive flexibility in problem solving. Neuroreport 10: 2763-7
CR
Birnbaum S, Gobeske KT, Auerbach J, Taylor JR, Arnsten AF. 1999. A role for
norepinephrine in stress-induced cognitive deficits: alpha-1-adrenoceptor mediation in
the prefrontal cortex. Biol Psychiatry 46: 1266-74
Birnbaum SG, Podell DM, Arnsten AF. 2000. Noradrenergic alpha-2 receptor agonists
US
reverse working memory deficits induced by the anxiogenic drug, FG7142, in rats.
Pharmacol Biochem Behav 67: 397-403
Birrell JM, Brown VJ. 2000. Medial frontal cortex mediates perceptual attentional set shifting
AN
in the rat. J Neurosci 20: 4320-4
Bishop SR, Lau M, Shapiro S, Carlson L, Anderson ND, et al. 2004. Mindfulness: A proposed
operational definition. Clin Psychol-Sci Pr 11: 230-41
M
Bissonette GB, Martins GJ, Franz TM, Harper ES, Schoenbaum G, Powell EM. 2008. Double
dissociation of the effects of medial and orbital prefrontal cortical lesions on attentional
ED
and affective shifts in mice. J Neurosci 28: 11124-30

Bissonette GB, Powell EM. 2012. Reversal learning and attentional set-shifting in mice.
Neuropharmacology 62: 1168-74
Biver F, Goldman S, Delvenne V, Luxen A, De Maertelaer V, et al. 1994. Frontal and parietal
PT
metabolic disturbances in unipolar depression. Biol Psychiatry 36: 381-8

Boggio PS, Fregni F, Bermpohl F, Mansur CG, Rosa M, et al. 2005. Effect of repetitive TMS
and fluoxetine on cognitive function in patients with Parkinson's disease and
CE
concurrent depression. Mov Disord 20: 1178-84

Bondi CO, Barrera G, Lapiz MD, Bedard T, Mahan A, Morilak DA. 2007. Noradrenergic
facilitation of shock-probe defensive burying in lateral septum of rats, and modulation
AC
by chronic treatment with desipramine. Prog Neuropsychopharmacol Biol Psychiatry

31: 482-95
Bondi CO, Jett JD, Morilak DA. 2010. Beneficial effects of desipramine on cognitive function
of chronically stressed rats are mediated by alpha1-adrenergic receptors in medial
prefrontal cortex. Prog Neuropsychopharmacol Biol Psychiatry 34: 913-23
Bondi CO, Rodriguez G, Gould GG, Frazer A, Morilak DA. 2008. Chronic unpredictable
stress induces a cognitive deficit and anxiety-like behavior in rats that is prevented by
chronic antidepressant drug treatment. Neuropsychopharmacology 33: 320-31
Borges MC, Braga DT, Iego S, D'Alcante CC, Sidrim I, et al. 2011. Cognitive dysfunction in
post-traumatic obsessive-compulsive disorder. Aust N Z J Psychiatry 45: 76-85
ACCEPTED MANUSCRIPT
Boulougouris V, Castane A, Robbins TW. 2009. Dopamine D2/D3 receptor agonist quinpirole
impairs spatial reversal learning in rats: investigation of D3 receptor involvement in
persistent behavior. Psychopharmacology (Berl) 202: 611-20
Boulougouris V, Dalley JW, Robbins TW. 2007. Effects of orbitofrontal, infralimbic and
prelimbic cortical lesions on serial spatial reversal learning in the rat. Behav Brain Res
179: 219-28
Boulougouris V, Glennon JC, Robbins TW. 2008. Dissociable effects of selective 5-HT2A and
5-HT2C receptor antagonists on serial spatial reversal learning in rats.
Boulougouris V, Robbins TW. 2010. Enhancement of spatial reversal learning by 5-HT2C
receptor antagonism is neuroanatomically specific. J Neurosci 30: 930-8
T
Brigman JL, Mathur P, Harvey-White J, Izquierdo A, Saksida LM, et al. 2010.
IP
Pharmacological or genetic inactivation of the serotonin transporter improves reversal
learning in mice. Cereb Cortex 20: 1955-63
CR
Briley M, Prost JF, Moret C. 1996. Preclinical pharmacology of milnacipran. Int Clin
Psychopharmacol 11 Suppl 4: 9-14
Brito GN, Brito LS. 1990. Septohippocampal system and the prelimbic sector of frontal cortex:
a neuropsychological battery analysis in the rat. Behav Brain Res 36: 127-46
US
Brown HD, Amodeo DA, Sweeney JA, Ragozzino ME. 2012. The selective serotonin
reuptake inhibitor, escitalopram, enhances inhibition of prepotent responding and
spatial reversal learning. J Psychopharmacol 26: 1443-55
AN
Brown VJ, Bowman EM. 2002. Rodent models of prefrontal cortical function. Trends Neurosci
25: 340-3
Brown VJ, Tait DS. 2016. Attentional Set-Shifting Across Species. Curr Top Behav Neurosci
M
28: 363-95
Brunoni AR, Vanderhasselt MA. 2014. Working memory improvement with non-invasive brain
ED
stimulation of the dorsolateral prefrontal cortex: a systematic review and meta-

analysis. Brain Cogn 86: 1-9
Butts KA, Floresco SB, Phillips AG. 2013. Acute stress impairs set-shifting but not reversal
learning. Behav Brain Res 252: 222-9
PT
Butts KA, Weinberg J, Young AH, Phillips AG. 2011. Glucocorticoid receptors in the
prefrontal cortex regulate stress-evoked dopamine efflux and aspects of executive
function. Proc Natl Acad Sci U S A 108: 18459-64
CE
Cain RE, Wasserman MC, Waterhouse BD, McGaughy JA. 2011. Atomoxetine facilitates
attentional set shifting in adolescent rats. Dev Cogn Neurosci 1: 552-9
Calcagno E, Carli M, Invernizzi R. 2006. The 5‐ HT1A receptor agonist 8‐ OH‐ DPAT
AC
prevents prefrontocortical glutamate and serotonin release in response to blockade of

cortical NMDA receptors. Journal of neurochemistry 96: 853-60
Carli M, Calcagno E, Mainini E, Arnt J, Invernizzi RW. 2011. Sertindole restores attentional
performance and suppresses glutamate release induced by the NMDA receptor
antagonist CPP. Psychopharmacology (Berl) 214: 625-37
Carli M, Invernizzi RW. 2014. Serotoninergic and dopaminergic modulation of cortico-striatal
circuit in executive and attention deficits induced by NMDA receptor hypofunction in
the 5-choice serial reaction time task. Front Neural Circuits 8: 58
Carli M, Robbins TW, Evenden JL, Everitt BJ. 1983. Effects of lesions to ascending
noradrenergic neurones on performance of a 5-choice serial reaction task in rats;
ACCEPTED MANUSCRIPT
implications for theories of dorsal noradrenergic bundle function based on selective
attention and arousal. Behav Brain Res 9: 361-80
Carvalho AF, Miskowiak KK, Hyphantis TN, Kohler CA, Alves GS, et al. 2014. Cognitive
dysfunction in depression - pathophysiology and novel targets. CNS Neurol Disord
Drug Targets 13: 1819-35
Ceglia I, Carli M, Baviera M, Renoldi G, Calcagno E, Invernizzi RW. 2004. The 5-HT receptor
antagonist M100,907 prevents extracellular glutamate rising in response to NMDA
receptor blockade in the mPFC. J Neurochem 91: 189-99
Cerqueira JJ, Catania C, Sotiropoulos I, Schubert M, Kalisch R, et al. 2005a. Corticosteroid
status influences the volume of the rat cingulate cortex - a magnetic resonance
imaging study. J Psychiatr Res 39: 451-60
T
Cerqueira JJ, Mailliet F, Almeida OF, Jay TM, Sousa N. 2007a. The prefrontal cortex as a
IP
key target of the maladaptive response to stress. J Neurosci 27: 2781-7
Cerqueira JJ, Pego JM, Taipa R, Bessa JM, Almeida OF, Sousa N. 2005b. Morphological
CR
correlates of corticosteroid-induced changes in prefrontal cortex-dependent behaviors.
J Neurosci 25: 7792-800
Cerqueira JJ, Taipa R, Uylings HB, Almeida OF, Sousa N. 2007b. Specific configuration of
dendritic degeneration in pyramidal neurons of the medial prefrontal cortex induced by
US
differing corticosteroid regimens. Cereb Cortex 17: 1998-2006
Chajut E, Algom D. 2003. Selective attention improves under stress: implications for theories
of social cognition. J Pers Soc Psychol 85: 231-48
AN
Chamberlain SR, Muller U, Blackwell AD, Clark L, Robbins TW, Sahakian BJ. 2006.
Neurochemical modulation of response inhibition and probabilistic learning in humans.
Science 311: 861-3
M
Chamberlain SR, Robbins TW, Sahakian BJ. 2007. The neurobiology of attention-
deficit/hyperactivity disorder. Biol Psychiatry 61: 1317-9
ED
Chamberlain SR, Sahakian BJ. 2007. The neuropsychiatry of impulsivity. Curr Opin
Chen JX, Yao LH, Xu BB, Qian K, Wang HL, et al. 2014. Glutamate transporter 1-mediated
antidepressant-like effect in a rat model of chronic unpredictable stress. J Huazhong
PT
Univ Sci Technolog Med Sci 34: 838-44

Chowdhury S, Shepherd JD, Okuno H, Lyford G, Petralia RS, et al. 2006. Arc/Arg3.1
interacts with the endocytic machinery to regulate AMPA receptor trafficking. Neuron
CE
52: 445-59
Chudasama Y, Passetti F, Rhodes SE, Lopian D, Desai A, Robbins TW. 2003. Dissociable
aspects of performance on the 5-choice serial reaction time task following lesions of
AC
the dorsal anterior cingulate, infralimbic and orbitofrontal cortex in the rat: differential
effects on selectivity, impulsivity and compulsivity. Behav Brain Res 146: 105-19
Chudasama Y, Robbins TW. 2004. Dopaminergic modulation of visual attention and working
memory in the rodent prefrontal cortex. Neuropsychopharmacology 29: 1628-36
Clark L, Roiser JP, Cools R, Rubinsztein DC, Sahakian BJ, Robbins TW. 2005. Stop signal
response inhibition is not modulated by tryptophan depletion or the serotonin
transporter polymorphism in healthy volunteers: implications for the 5-HT theory of
impulsivity. Psychopharmacology (Berl) 182: 570-8
Clarke HF, Dalley JW, Crofts HS, Robbins TW, Roberts AC. 2004. Cognitive inflexibility after
prefrontal serotonin depletion. Science 304: 878-80
ACCEPTED MANUSCRIPT
Clarke HF, Hill GJ, Robbins TW, Roberts AC. 2011. Dopamine, but not serotonin, regulates
reversal learning in the marmoset caudate nucleus. J Neurosci 31: 4290-7
Clarke HF, Robbins TW, Roberts AC. 2008. Lesions of the medial striatum in monkeys
produce perseverative impairments during reversal learning similar to those produced
by lesions of the orbitofrontal cortex. J Neurosci 28: 10972-82
Clarke HF, Walker SC, Crofts HS, Dalley JW, Robbins TW, Roberts AC. 2005. Prefrontal
serotonin depletion affects reversal learning but not attentional set shifting. J Neurosci
25: 532-8
Clarke HF, Walker SC, Dalley JW, Robbins TW, Roberts AC. 2007. Cognitive inflexibility after
prefrontal serotonin depletion is behaviorally and neurochemically specific. Cereb
Cortex 17: 18-27
T
Clatworthy PL, Lewis SJ, Brichard L, Hong YT, Izquierdo D, et al. 2009. Dopamine release in
IP
dissociable striatal subregions predicts the different effects of oral methylphenidate on
reversal learning and spatial working memory. J Neurosci 29: 4690-6
CR
Colvin MK, Dunbar K, Grafman J. 2001. The effects of frontal lobe lesions on goal
achievement in the water jug task. J Cogn Neurosci 13: 1129-47
Constant EL, Adam S, Gillain B, Seron X, Bruyer R, Seghers A. 2005. Effects of sertraline on
depressive symptoms and attentional and executive functions in major depression.
US
Depress Anxiety 21: 78-89
Cook SC, Wellman CL. 2004. Chronic stress alters dendritic morphology in rat medial
prefrontal cortex. J Neurobiol 60: 236-48
AN
Cools R, Clark L, Owen AM, Robbins TW. 2002. Defining the neural mechanisms of
probabilistic reversal learning using event-related functional magnetic resonance
imaging. J Neurosci 22: 4563-7
M
Costa VD, Tran VL, Turchi J, Averbeck BB. 2015. Reversal learning and dopamine: a
bayesian perspective. J Neurosci 35: 2407-16
ED
Cousijn H, Rijpkema M, Qin S, van Marle HJ, Franke B, et al. 2010. Acute stress modulates
genotype effects on amygdala processing in humans. Proc Natl Acad Sci U S A 107:
9867-72
Crofts HS, Dalley JW, Collins P, Van Denderen JC, Everitt BJ, et al. 2001. Differential effects
PT
of 6-OHDA lesions of the frontal cortex and caudate nucleus on the ability to acquire
an attentional set. Cereb Cortex 11: 1015-26
Crofts HS, Muggleton NG, Bowditch AP, Pearce PC, Nutt DJ, Scott EA. 1999. Home cage
CE
presentation of complex discrimination tasks to marmosets and rhesus monkeys. Lab

Anim 33: 207-14
D'Esposito M, Detre JA, Alsop DC, Shin RK, Atlas S, Grossman M. 1995. The neural basis of
AC
the central executive system of working memory. Nature 378: 279-81

Dalley JW, Everitt BJ, Robbins TW. 2011. Impulsivity, compulsivity, and top-down cognitive
control. Neuron 69: 680-94
Dalton GL, Wang NY, Phillips AG, Floresco SB. 2016. Multifaceted Contributions by Different
Regions of the Orbitofrontal and Medial Prefrontal Cortex to Probabilistic Reversal
Learning. J Neurosci 36: 1996-2006
Danet M, Lapiz-Bluhm S, Morilak DA. 2010. A cognitive deficit induced in rats by chronic
intermittent cold stress is reversed by chronic antidepressant treatment. Int J
Neuropsychopharmacol 13: 997-1009
ACCEPTED MANUSCRIPT
Darna M, Chow JJ, Yates JR, Charnigo RJ, Beckmann JS, et al. 2015. Role of serotonin
transporter function in rat orbitofrontal cortex in impulsive choice. Behav Brain Res
293: 134-42
Davidson RJ, Kabat-Zinn J, Schumacher J, Rosenkranz M, Muller D, et al. 2003. Alterations
in brain and immune function produced by mindfulness meditation. Psychosom Med
65: 564-70
Demirtas-Tatlidede A, Alonso-Alonso M, Shetty RP, Ronen I, Pascual-Leone A, Fregni F.
2015. Long-term effects of contralesional rTMS in severe stroke: safety, cortical
excitability, and relationship with transcallosal motor fibers. NeuroRehabilitation 36:
51-9
Diamond A. 2013. Executive functions. Annu Rev Psychol 64: 135-68
T
Dias R, Robbins TW, Roberts AC. 1996. Primate analogue of the Wisconsin Card Sorting
IP
Test: effects of excitotoxic lesions of the prefrontal cortex in the marmoset. Behav
Neurosci 110: 872-86
CR
Dias-Ferreira E, Sousa JC, Melo I, Morgado P, Mesquita AR, et al. 2009. Chronic stress
causes frontostriatal reorganization and affects decision-making. Science 325: 621-5
Disner SG, Beevers CG, Haigh EA, Beck AT. 2011. Neural mechanisms of the cognitive
model of depression. Nat Rev Neurosci 12: 467-77
US
Dix S, Gilmour G, Potts S, Smith JW, Tricklebank M. 2010. A within-subject cognitive battery
in the rat: differential effects of NMDA receptor antagonists. Psychopharmacology
(Berl) 212: 227-42
AN
Donegan JJ, Girotti M, Weinberg MS, Morilak DA. 2014. A novel role for brain interleukin-6:
facilitation of cognitive flexibility in rat orbitofrontal cortex. J Neurosci 34: 953-62
Dong Z, Bai Y, Wu X, Li H, Gong B, et al. 2013. Hippocampal long-term depression mediates
M
spatial reversal learning in the Morris water maze. Neuropharmacology 64: 65-73
Dorr AE, Debonnel G. 2006. Effect of vagus nerve stimulation on serotonergic and
ED
noradrenergic transmission. J Pharmacol Exp Ther 318: 890-8

Drevets WC. 1998. Functional neuroimaging studies of depression: the anatomy of
melancholia. Annu Rev Med 49: 341-61
Drevets WC. 2007. Orbitofrontal cortex function and structure in depression. Ann N Y Acad
PT
Sci 1121: 499-527

Drevets WC, Price JL, Furey ML. 2008. Brain structural and functional abnormalities in mood
disorders: implications for neurocircuitry models of depression. Brain Struct Funct 213:
CE
93-118
Drevets WC, Videen TO, Price JL, Preskorn SH, Carmichael ST, Raichle ME. 1992. A
functional anatomical study of unipolar depression. J Neurosci 12: 3628-41
AC
du Jardin KG, Jensen JB, Sanchez C, Pehrson AL. 2014. Vortioxetine dose-dependently
reverses 5-HT depletion-induced deficits in spatial working and object recognition
memory: a potential role for 5-HT1A receptor agonism and 5-HT3 receptor
antagonism. Eur Neuropsychopharmacol 24: 160-71
Duffy S, Labrie V, Roder JC. 2008. D-serine augments NMDA-NR2B receptor-dependent
hippocampal long-term depression and spatial reversal learning.
Duman RS, Heninger GR, Nestler EJ. 1997. A molecular and cellular theory of depression.
Arch Gen Psychiatry 54: 597-606
ACCEPTED MANUSCRIPT
Eagle DM, Bari A, Robbins TW. 2008a. The neuropsychopharmacology of action inhibition:
cross-species translation of the stop-signal and go/no-go tasks. Psychopharmacology
(Berl) 199: 439-56
Eagle DM, Baunez C, Hutcheson DM, Lehmann O, Shah AP, Robbins TW. 2008b. Stop-
signal reaction-time task performance: role of prefrontal cortex and subthalamic
nucleus. Cereb Cortex 18: 178-88
Eagle DM, Lehmann O, Theobald DE, Pena Y, Zakaria R, et al. 2009. Serotonin depletion
impairs waiting but not stop-signal reaction time in rats: implications for theories of the
role of 5-HT in behavioral inhibition. Neuropsychopharmacology 34: 1311-21
Eagle DM, Robbins TW. 2003. Inhibitory control in rats performing a stop-signal reaction-time
task: effects of lesions of the medial striatum and d-amphetamine. Behav Neurosci
T
117: 1302-17
IP
Eagle DM, Tufft MR, Goodchild HL, Robbins TW. 2007. Differential effects of modafinil and
methylphenidate on stop-signal reaction time task performance in the rat, and
CR
interactions with the dopamine receptor antagonist cis-flupenthixol.
Eagle DM, Wong JC, Allan ME, Mar AC, Theobald DE, Robbins TW. 2011. Contrasting roles
for dopamine D1 and D2 receptor subtypes in the dorsomedial striatum but not the
US
nucleus accumbens core during behavioral inhibition in the stop-signal task in rats. J
Elia J, Glessner JT, Wang K, Takahashi N, Shtir CJ, et al. 2011. Genome-wide copy number
AN
variation study associates metabotropic glutamate receptor gene networks with
attention deficit hyperactivity disorder. Nat Genet 44: 78-84
Ellenbogen MA, Schwartzman AE, Stewart J, Walker CD. 2002. Stress and selective
M
attention: the interplay of mood, cortisol levels, and emotional information processing.
Psychophysiology 39: 723-32
ED
Evans GW, Schamberg MA. 2009. Childhood poverty, chronic stress, and adult working
memory. Proc Natl Acad Sci U S A 106: 6545-9
Evenden JL. 1999. Varieties of impulsivity. Psychopharmacology (Berl) 146: 348-61
Fellini L, Kumar G, Gibbs S, Steckler T, Talpos J. 2014. Re-evaluating the PCP challenge as
PT
a pre-clinical model of impaired cognitive flexibility in schizophrenia. Eur

Fellows LK, Farah MJ. 2003. Ventromedial frontal cortex mediates affective shifting in
CE
humans: evidence from a reversal learning paradigm. Brain 126: 1830-7

Fernando AB, Economidou D, Theobald DE, Zou MF, Newman AH, et al. 2012. Modulation of
high impulsivity and attentional performance in rats by selective direct and indirect
AC
dopaminergic and noradrenergic receptor agonists. Psychopharmacology (Berl) 219:

341-52
Ferreri F, Lapp LK, Peretti CS. 2011. Current research on cognitive aspects of anxiety
disorders. Curr Opin Psychiatry 24: 49-54
Fields RB, Van Kammen DP, Peters JL, Rosen J, Van Kammen WB, et al. 1988. Clonidine
improves memory function in schizophrenia independently from change in psychosis.
Preliminary findings. Schizophr Res 1: 417-23
Fineberg NA, Potenza MN, Chamberlain SR, Berlin HA, Menzies L, et al. 2010. Probing
compulsive and impulsive behaviors, from animal models to endophenotypes: a
narrative review. Neuropsychopharmacology 35: 591-604
ACCEPTED MANUSCRIPT
Finger EC, Marsh AA, Buzas B, Kamel N, Rhodes R, et al. 2007. The impact of tryptophan
depletion and 5-HTTLPR genotype on passive avoidance and response reversal
instrumental learning tasks. Neuropsychopharmacology 32: 206-15
Fischer AG, Endrass T, Reuter M, Kubisch C, Ullsperger M. 2015. Serotonin reuptake
inhibitors and serotonin transporter genotype modulate performance monitoring
functions but not their electrophysiological correlates. J Neurosci 35: 8181-90
Floresco SB. 2013. Prefrontal dopamine and behavioral flexibility: shifting from an "inverted-
U" toward a family of functions. Front Neurosci 7: 62
Floresco SB, Block AE, Tse MT. 2008. Inactivation of the medial prefrontal cortex of the rat
impairs strategy set-shifting, but not reversal learning, using a novel, automated
procedure. Behav Brain Res 190: 85-96
T
Floresco SB, Magyar O, Ghods-Sharifi S, Vexelman C, Tse MT. 2006. Multiple dopamine
IP
receptor subtypes in the medial prefrontal cortex of the rat regulate set-shifting.
CR
Floresco SB, Seamans JK, Phillips AG. 1997. Selective roles for hippocampal, prefrontal
cortical, and ventral striatal circuits in radial-arm maze tasks with or without a delay. J
Frederick DL, Gillam MP, Allen RR, Paule MG. 1995. Acute behavioral effects of
US
phencyclidine on rhesus monkey performance in an operant test battery. Pharmacol
Biochem Behav 52: 789-97
Freyer T, Kloppel S, Tuscher O, Kordon A, Zurowski B, et al. 2011. Frontostriatal activation in
AN
patients with obsessive-compulsive disorder before and after cognitive behavioral
therapy. Psychol Med 41: 207-16
Friedman JI, Adler DN, Temporini HD, Kemether E, Harvey PD, et al. 2001. Guanfacine
M
treatment of cognitive impairment in schizophrenia. Neuropsychopharmacology 25:

402-9
ED
Fucich EA, Paredes D, Morilak DA. 2016. Therapeutic Effects of Extinction Learning as a
Model of Exposure Therapy in Rats. Neuropsychopharmacology 41: 3092-102
Furr A, Lapiz-Bluhm MD, Morilak DA. 2012. 5-HT2A receptors in the orbitofrontal cortex
facilitate reversal learning and contribute to the beneficial cognitive effects of chronic
PT
citalopram treatment in rats. Int J Neuropsychopharmacol 15: 1295-305

Gallant SN. 2016. Mindfulness meditation practice and executive functioning: Breaking down
the benefit. Conscious Cogn 40: 116-30
CE
George SA, Rodriguez-Santiago M, Riley J, Rodriguez E, Liberzon I. 2015. The effect of

chronic phenytoin administration on single prolonged stress induced extinction
retention deficits and glucocorticoid upregulation in the rat medial prefrontal cortex.
AC

Ghoneim MM, Hinrichs JV, Mewaldt SP, Petersen RC. 1985. Ketamine: behavioral effects of
subanesthetic doses. J Clin Psychopharmacol 5: 70-7
Goetz PW, Robinson MD, Meier BP. 2008. Attentional training of the appetitive motivation
system: Effects on sensation seeking preferences and reward-based behavior.
Motivation and Emotion 32: 120-26
Goldberg TE, Bigelow LB, Weinberger DR, Daniel DG, Kleinman JE. 1991. Cognitive and
behavioral effects of the coadministration of dextroamphetamine and haloperidol in
schizophrenia. Am J Psychiatry 148: 78-84
ACCEPTED MANUSCRIPT
Granon S, Passetti F, Thomas KL, Dalley JW, Everitt BJ, Robbins TW. 2000. Enhanced and
impaired attentional performance after infusion of D1 dopaminergic receptor agents
into rat prefrontal cortex. J Neurosci 20: 1208-15
Granseth B, Andersson FK, Lindstrom SH. 2015. The initial stage of reversal learning is
impaired in mice hemizygous for the vesicular glutamate transporter (VGluT1). Genes
Brain Behav 14: 477-85
Greer TL, Sunderajan P, Grannemann BD, Kurian BT, Trivedi MH. 2014. Does duloxetine
improve cognitive function independently of its antidepressant effect in patients with
major depressive disorder and subjective reports of cognitive dysfunction? Depress
Res Treat 2014: 627863
Hage WE, Peronny S, Griebel G, Belzung C. 2004. Impaired memory following predatory
T
stress in mice is improved by fluoxetine. Prog Neuro-Psychoph 28: 123-28
IP
Haluk DM, Floresco SB. 2009. Ventral striatal dopamine modulation of different forms of
behavioral flexibility. Neuropsychopharmacology 34: 2041-52
CR
Hamidovic A, Dlugos A, Skol A, Palmer AA, de Wit H. 2009. Evaluation of genetic variability
in the dopamine receptor D2 in relation to behavioral inhibition and
impulsivity/sensation seeking: an exploratory study with d-amphetamine in healthy
participants. Exp Clin Psychopharmacol 17: 374-83
US
Hanania R, Smith LB. 2010. Selective attention and attention switching: towards a unified
developmental approach. Dev Sci 13: 622-35
Harrison AA, Everitt BJ, Robbins TW. 1997. Central 5-HT depletion enhances impulsive
AN
responding without affecting the accuracy of attentional performance: interactions with
dopaminergic mechanisms. Psychopharmacology (Berl) 133: 329-42
Harvey PD, Hassman H, Mao L, Gharabawi GM, Mahmoud RA, Engelhart LM. 2007.
M
Cognitive functioning and acute sedative effects of risperidone and quetiapine in

patients with stable bipolar I disorder: a randomized, double-blind, crossover study. J
ED
Clin Psychiatry 68: 1186-94

Harvey PD, Rabinowitz J, Eerdekens M, Davidson M. 2005. Treatment of cognitive
impairment in early psychosis: a comparison of risperidone and haloperidol in a large
long-term trial. Am J Psychiatry 162: 1888-95
PT
Hecht PM, Will MJ, Schachtman TR, Welby LM, Beversdorf DQ. 2014. Beta-adrenergic
antagonist effects on a novel cognitive flexibility task in rodents. Behav Brain Res 260:
148-54
CE
Hedlund PB. 2009. The 5-HT7 receptor and disorders of the nervous system: an overview.
Hedlund PB, Huitron-Resendiz S, Henriksen SJ, Sutcliffe JG. 2005. 5-HT7 receptor inhibition
AC
and inactivation induce antidepressantlike behavior and sleep pattern. Biol Psychiatry
58: 831-7
Heeren A, Van Broeck N, Philippot P. 2009. The effects of mindfulness on executive
processes and autobiographical memory specificity. Behav Res Ther 47: 403-9
Heidbreder CA, Weiss IC, Domeney AM, Pryce C, Homberg J, et al. 2000. Behavioral,
neurochemical and endocrinological characterization of the early social isolation
syndrome. Neuroscience 100: 749-68
Henckens MJ, Pu Z, Hermans EJ, van Wingen GA, Joels M, Fernandez G. 2012.
Dynamically changing effects of corticosteroids on human hippocampal and prefrontal
processing. Hum Brain Mapp 33: 2885-97
ACCEPTED MANUSCRIPT
Henckens MJ, van Wingen GA, Joels M, Fernandez G. 2010. Time-dependent effects of
corticosteroids on human amygdala processing. J Neurosci 30: 12725-32
Henckens MJ, van Wingen GA, Joels M, Fernandez G. 2011. Time-dependent corticosteroid
modulation of prefrontal working memory processing. Proc Natl Acad Sci U S A 108:
5801-6
Herman JP, McKlveen JM, Ghosal S, Kopp B, Wulsin A, et al. 2016. Regulation of the
Hypothalamic-Pituitary-Adrenocortical Stress Response. Compr Physiol 6: 603-21
Herrera-Guzman I, Herrera-Abarca JE, Gudayol-Ferre E, Herrera-Guzman D, Gomez-
Carbajal L, et al. 2010. Effects of selective serotonin reuptake and dual serotonergic-
noradrenergic reuptake treatments on attention and executive functions in patients
with major depressive disorder. Psychiatry Res 177: 323-9
T
Het S, Wolf OT. 2007. Mood changes in response to psychosocial stress in healthy young
IP
women: effects of pretreatment with cortisol. Behav Neurosci 121: 11-20
Higgins GA, Enderlin M, Haman M, Fletcher PJ. 2003. The 5-HT2A receptor antagonist
CR
M100,907 attenuates motor and 'impulsive-type' behaviours produced by NMDA
receptor antagonism. Psychopharmacology (Berl) 170: 309-19
Hill MN, Patel S, Carrier EJ, Rademacher DJ, Ormerod BK, et al. 2005. Downregulation of
endocannabinoid signaling in the hippocampus following chronic unpredictable stress.
US
Hill MN, Tasker JG. 2012. Endocannabinoid signaling, glucocorticoid-mediated negative
feedback, and regulation of the hypothalamic-pituitary-adrenal axis. Neuroscience 204:
AN
5-16
Hiraide S, Ueno K, Yamaguchi T, Matsumoto M, Yanagawa Y, et al. 2013. Behavioural
effects of monoamine reuptake inhibitors on symptomatic domains in an animal model
M
of attention-deficit/hyperactivity disorder. Pharmacol Biochem Behav 105: 89-97

Holden KB, Hall SP, Robinson M, Triplett S, Babalola D, et al. 2012. Psychosocial and
ED
sociocultural correlates of depressive symptoms among diverse African American

women. J Natl Med Assoc 104: 493-504
Hollon SD, Thase ME, Markowitz JC. 2002. Treatment and Prevention of Depression.
Psychol Sci Public Interest 3: 39-77
PT
Holmes A, Wellman CL. 2009. Stress-induced prefrontal reorganization and executive

dysfunction in rodents. Neurosci Biobehav Rev 33: 773-83
Hornak J, O'Doherty J, Bramham J, Rolls ET, Morris RG, et al. 2004. Reward-related reversal
CE
learning after surgical excisions in orbito-frontal or dorsolateral prefrontal cortex in

humans. J Cogn Neurosci 16: 463-78
Idris N, Neill J, Grayson B, Bang-Andersen B, Witten LM, et al. 2010. Sertindole improves
AC
sub-chronic PCP-induced reversal learning and episodic memory deficits in rodents:

involvement of 5-HT(6) and 5-HT (2A) receptor mechanisms. Psychopharmacology
(Berl) 208: 23-36
Izquierdo A, Brigman JL, Radke AK, Rudebeck PH, Holmes A. 2017. The neural basis of
reversal learning: An updated perspective. Neuroscience 345: 12-26
Izquierdo A, Carlos K, Ostrander S, Rodriguez D, McCall-Craddolph A, et al. 2012. Impaired
reward learning and intact motivation after serotonin depletion in rats. Behav Brain
Res 233: 494-9
Izquierdo A, Darling C, Manos N, Pozos H, Kim C, et al. 2013. Basolateral amygdala lesions
facilitate reward choices after negative feedback in rats. J Neurosci 33: 4105-9
ACCEPTED MANUSCRIPT
Izquierdo A, Suda RK, Murray EA. 2004. Bilateral orbital prefrontal cortex lesions in rhesus
monkeys disrupt choices guided by both reward value and reward contingency. J
Neurosci 24: 7540-8
Jaeger J, Berns S, Uzelac S, Davis-Conway S. 2006. Neurocognitive deficits and disability in
major depressive disorder. Psychiatry Res 145: 39-48
Janhunen SK, Svard H, Talpos J, Kumar G, Steckler T, et al. 2015. The subchronic
phencyclidine rat model: relevance for the assessment of novel therapeutics for
cognitive impairment associated with schizophrenia. Psychopharmacology (Berl) 232:
4059-83
Jensen CG, Vangkilde S, Frokjaer V, Hasselbalch SG. 2012. Mindfulness training affects
attention--or is it attentional effort? J Exp Psychol Gen 141: 106-23
T
Jentsch JD, Taylor JR. 2001. Impaired inhibition of conditioned responses produced by
IP
subchronic administration of phencyclidine to rats. Neuropsychopharmacology 24: 66-
74
CR
Jett JD, Boley AM, Girotti M, Shah A, Lodge DJ, Morilak DA. 2015. Antidepressant-like
cognitive and behavioral effects of acute ketamine administration associated with
plasticity in the ventral hippocampus to medial prefrontal cortex pathway.
US
Jett JD, Bulin SE, Hatherall LC, McCartney CM, Morilak DA. 2017. Deficits in cognitive
flexibility induced by chronic unpredictable stress are associated with impaired
glutamate neurotransmission in the rat medial prefrontal cortex. Neuroscience 346:
AN
284-97
Jett JD, Morilak DA. 2013. Too much of a good thing: blocking noradrenergic facilitation in
medial prefrontal cortex prevents the detrimental effects of chronic stress on cognition.
M

Jha AP, Krompinger J, Baime MJ. 2007. Mindfulness training modifies subsystems of
ED
attention. Cogn Affect Behav Neurosci 7: 109-19

Jha AP, Stanley EA, Kiyonaga A, Wong L, Gelfand L. 2010. Examining the protective effects
of mindfulness training on working memory capacity and affective experience. Emotion
10: 54-64
PT
Joels M, Baram TZ. 2009. The neuro-symphony of stress. Nat Rev Neurosci 10: 459-66
Johnstone T, van Reekum CM, Urry HL, Kalin NH, Davidson RJ. 2007. Failure to regulate:
counterproductive recruitment of top-down prefrontal-subcortical circuitry in major
CE
depression. J Neurosci 27: 8877-84

Jonides J, Schumacher EH, Smith EE, Lauber EJ, Awh E, et al. 1997. Verbal Working
Memory Load Affects Regional Brain Activation as Measured by PET. J Cogn
AC
Neurosci 9: 462-75
Kalechstein AD, De La Garza R, 2nd, Newton TF. 2010. Modafinil administration improves
working memory in methamphetamine-dependent individuals who demonstrate
baseline impairment. Am J Addict 19: 340-4
Kalechstein AD, Mahoney JJ, 3rd, Yoon JH, Bennett R, De la Garza R, 2nd. 2013. Modafinil,
but not escitalopram, improves working memory and sustained attention in long-term,
high-dose cocaine users. Neuropharmacology 64: 472-8
Kessler RC. 1997. The effects of stressful life events on depression. Annu Rev Psychol 48:
191-214
Kessler RC, Davis CG, Kendler KS. 1997. Childhood adversity and adult psychiatric disorder
in the US National Comorbidity Survey. Psychol Med 27: 1101-19
ACCEPTED MANUSCRIPT
Kinnavane L, Albasser MM, Aggleton JP. 2015. Advances in the behavioural testing and
network imaging of rodent recognition memory. Behav Brain Res 285: 67-78
Kirchner WK. 1958. Age differences in short-term retention of rapidly changing information. J
Exp Psychol 55: 352-8
Klanker M, Sandberg T, Joosten R, Willuhn I, Feenstra M, Denys D. 2015. Phasic dopamine
release induced by positive feedback predicts individual differences in reversal
learning. Neurobiol Learn Mem 125: 135-45
Klein K, Boals A. 2001. Expressive writing can increase working memory capacity. J Exp
Psychol Gen 130: 520-33
Koskinen T, Ruotsalainen S, Puumala T, Lappalainen R, Koivisto E, et al. 2000. Activation of
5-HT2A receptors impairs response control of rats in a five-choice serial reaction time
T
task. Neuropharmacology 39: 471-81
IP
Krause KH, Dresel SH, Krause J, Kung HF, Tatsch K. 2000. Increased striatal dopamine
transporter in adult patients with attention deficit hyperactivity disorder: effects of
CR
methylphenidate as measured by single photon emission computed tomography.
Neurosci Lett 285: 107-10
Krause-Utz A, Sobanski E, Alm B, Valerius G, Kleindienst N, et al. 2013. Impulsivity in
relation to stress in patients with borderline personality disorder with and without co-
US
occurring attention-deficit/hyperactivity disorder: an exploratory study. J Nerv Ment Dis
201: 116-23
Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, et al. 1994. Subanesthetic effects
AN
of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic,
perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 51: 199-
214
M
Lalonde R. 2002. The neurobiological basis of spontaneous alternation. Neurosci Biobehav

Rev 26: 91-104
ED
Landro NI, Rund BR, Lund A, Sundet K, Mjellem N, et al. 2001. Honig's model of working
memory and brain activation: an fMRI study. Neuroreport 12: 4047-54
Lapiz MD, Bondi CO, Morilak DA. 2007. Chronic treatment with desipramine improves
cognitive performance of rats in an attentional set-shifting test.
PT

Lapiz MD, Morilak DA. 2006. Noradrenergic modulation of cognitive function in rat medial
prefrontal cortex as measured by attentional set shifting capability. Neuroscience 137:
CE
1039-49
Lapiz-Bluhm MD, Bondi CO, Doyen J, Rodriguez GA, Bedard-Arana T, Morilak DA. 2008.
Behavioural assays to model cognitive and affective dimensions of depression and
AC
anxiety in rats. J Neuroendocrinol 20: 1115-37

Lapiz-Bluhm MD, Soto-Pina AE, Hensler JG, Morilak DA. 2009. Chronic intermittent cold
stress and serotonin depletion induce deficits of reversal learning in an attentional set-
shifting test in rats. Psychopharmacology (Berl) 202: 329-41
Le Pen G, Grottick AJ, Higgins GA, Moreau JL. 2003. Phencyclidine exacerbates attentional
deficits in a neurodevelopmental rat model of schizophrenia.
Lee B, Groman S, London ED, Jentsch JD. 2007. Dopamine D2/D3 receptors play a specific
role in the reversal of a learned visual discrimination in monkeys.
ACCEPTED MANUSCRIPT
Leeson VC, Robbins TW, Matheson E, Hutton SB, Ron MA, et al. 2009. Discrimination
learning, reversal, and set-shifting in first-episode schizophrenia: stability over six
years and specific associations with medication type and disorganization syndrome.
Biol Psychiatry 66: 586-93
Leh SE, Petrides M, Strafella AP. 2010. The neural circuitry of executive functions in healthy
subjects and Parkinson's disease. Neuropsychopharmacology 35: 70-85
Lenze EJ, Dixon D, Nowotny P, Lotrich FE, Dore PM, et al. 2013. Escitalopram reduces
attentional performance in anxious older adults with high-expression genetic variants
at serotonin 2A and 1B receptors. Int J Neuropsychopharmacol 16: 279-88
Leopoldo M, Lacivita E, Berardi F, Perrone R, Hedlund PB. 2011. Serotonin 5-HT7 receptor
agents: Structure-activity relationships and potential therapeutic applications in central
T
nervous system disorders. Pharmacol Ther 129: 120-48
IP
Levens SM, Larsen JT, Bruss J, Tranel D, Bechara A, Mellers BA. 2014. What might have
been? The role of the ventromedial prefrontal cortex and lateral orbitofrontal cortex in
CR
counterfactual emotions and choice. Neuropsychologia 54: 77-86
Levy-Gigi E, Richter-Levin G. 2014. The hidden price of repeated traumatic exposure. Stress
17: 343-51
Linnoila M, Virkkunen M, Scheinin M, Nuutila A, Rimon R, Goodwin FK. 1983. Low
US
cerebrospinal fluid 5-hydroxyindoleacetic acid concentration differentiates impulsive
from nonimpulsive violent behavior. Life Sci 33: 2609-14
Liston C, McEwen BS, Casey BJ. 2009. Psychosocial stress reversibly disrupts prefrontal
AN
processing and attentional control. Proc Natl Acad Sci U S A 106: 912-7
Liston C, Miller MM, Goldwater DS, Radley JJ, Rocher AB, et al. 2006. Stress-induced
alterations in prefrontal cortical dendritic morphology predict selective impairments in
M
perceptual attentional set-shifting. J Neurosci 26: 7870-4

Liu J, Raine A. 2006. The effect of childhood malnutrition on externalizing behavior. Curr
ED
Opin Pediatr 18: 565-70

Lobellova V, Entlerova M, Svojanovska B, Hatalova H, Prokopova I, et al. 2013. Two learning
tasks provide evidence for disrupted behavioural flexibility in an animal model of
schizophrenia-like behaviour induced by acute MK-801: a dose-response study. Behav
PT
Brain Res 246: 55-62

Logan GD, Cowan WB, Davis KA. 1984. On the ability to inhibit simple and choice reaction
time responses: a model and a method. J Exp Psychol Hum Percept Perform 10: 276-
CE
91
Logue SF, Gould TJ. 2014. The neural and genetic basis of executive function: attention,
cognitive flexibility, and response inhibition. Pharmacol Biochem Behav 123: 45-54
AC
Luber B, Lisanby SH. 2014. Enhancement of human cognitive performance using transcranial
magnetic stimulation (TMS). Neuroimage 85 Pt 3: 961-70
Luethi M, Meier B, Sandi C. 2008. Stress effects on working memory, explicit memory, and
implicit memory for neutral and emotional stimuli in healthy men. Front Behav
Neurosci 2: 5
Lupien SJ, Gillin CJ, Hauger RL. 1999. Working memory is more sensitive than declarative
memory to the acute effects of corticosteroids: a dose-response study in humans.
Behav Neurosci 113: 420-30
Lupien SJ, Wilkinson CW, Briere S, Menard C, Ng Ying Kin NM, Nair NP. 2002. The
modulatory effects of corticosteroids on cognition: studies in young human
populations. Psychoneuroendocrinology 27: 401-16
ACCEPTED MANUSCRIPT
Lyons DM, Lopez JM, Yang C, Schatzberg AF. 2000. Stress-level cortisol treatment impairs
inhibitory control of behavior in monkeys. J Neurosci 20: 7816-21
Lyoo IK, Kim MJ, Stoll AL, Demopulos CM, Parow AM, et al. 2004. Frontal lobe gray matter
density decreases in bipolar I disorder. Biol Psychiatry 55: 648-51
MacLeod CM. 1992. The Stroop Task: The "Gold Standard" of Attentional Measures. Journal
of Experimental Psychology General 121: 12-14
Maddux JM, Holland PC. 2011. Effects of dorsal or ventral medial prefrontal cortical lesions
on five-choice serial reaction time performance in rats. Behav Brain Res 221: 63-74
Mahableshwarkar AR, Zajecka J, Jacobson W, Chen Y, Keefe RS. 2015. A Randomized,
Placebo-Controlled, Active-Reference, Double-Blind, Flexible-Dose Study of the
Efficacy of Vortioxetine on Cognitive Function in Major Depressive Disorder.
T
IP
Maheu FS, Joober R, Lupien SJ. 2005. Declarative memory after stress in humans:
differential involvement of the beta-adrenergic and corticosteroid systems. J Clin
CR
Endocrinol Metab 90: 1697-704
Mala H, Andersen LG, Christensen RF, Felbinger A, Hagstrom J, et al. 2015. Prefrontal
cortex and hippocampus in behavioural flexibility and posttraumatic functional
recovery: reversal learning and set-shifting in rats. Brain Res Bull 116: 34-44
US
Manes F, Sahakian B, Clark L, Rogers R, Antoun N, et al. 2002. Decision-making processes
following damage to the prefrontal cortex. Brain 125: 624-39
Martinussen R, Hayden J, Hogg-Johnson S, Tannock R. 2005. A meta-analysis of working
AN
memory impairments in children with attention-deficit/hyperactivity disorder. J Am
Acad Child Adolesc Psychiatry 44: 377-84
Masaki D, Yokoyama C, Kinoshita S, Tsuchida H, Nakatomi Y, et al. 2006. Relationship
M
between limbic and cortical 5-HT neurotransmission and acquisition and reversal
learning in a go/no-go task in rats. Psychopharmacology (Berl) 189: 249-58
ED
McAllister KA, Mar AC, Theobald DE, Saksida LM, Bussey TJ. 2015. Comparing the effects
of subchronic phencyclidine and medial prefrontal cortex dysfunction on cognitive tests
relevant to schizophrenia. Psychopharmacology (Berl) 232: 3883-97
McAlonan K, Brown VJ. 2003. Orbital prefrontal cortex mediates reversal learning and not
PT
attentional set shifting in the rat. Behav Brain Res 146: 97-103
McEwen BS. 2004. Protection and damage from acute and chronic stress: allostasis and
allostatic overload and relevance to the pathophysiology of psychiatric disorders. Ann
CE
N Y Acad Sci 1032: 1-7

McEwen BS, Bowles NP, Gray JD, Hill MN, Hunter RG, et al. 2015. Mechanisms of stress in
the brain. Nat Neurosci 18: 1353-63
AC
McGaughy J, Ross RS, Eichenbaum H. 2008. Noradrenergic, but not cholinergic,

deafferentation of prefrontal cortex impairs attentional set-shifting. Neuroscience 153:
63-71
McIntyre RS, Lophaven S, Olsen CK. 2014. A randomized, double-blind, placebo-controlled
study of vortioxetine on cognitive function in depressed adults. Int J
McKlveen JM, Myers B, Herman JP. 2015. The medial prefrontal cortex: coordinator of
autonomic, neuroendocrine and behavioural responses to stress. J Neuroendocrinol
27: 446-56
McNab F, Varrone A, Farde L, Jucaite A, Bystritsky P, et al. 2009. Changes in cortical
dopamine D1 receptor binding associated with cognitive training. Science 323: 800-2
ACCEPTED MANUSCRIPT
Mehta MA, Sahakian BJ, McKenna PJ, Robbins TW. 1999. Systemic sulpiride in young adult
volunteers simulates the profile of cognitive deficits in Parkinson's disease.
Mehta MA, Swainson R, Ogilvie AD, Sahakian J, Robbins TW. 2001. Improved short-term
spatial memory but impaired reversal learning following the dopamine D(2) agonist
bromocriptine in human volunteers. Psychopharmacology (Berl) 159: 10-20
Menon V. 2011. Large-scale brain networks and psychopathology: a unifying triple network
model. Trends Cogn Sci 15: 483-506
Menzies L, Ooi C, Kamath S, Suckling J, McKenna P, et al. 2007. Effects of gamma-
aminobutyric acid-modulating drugs on working memory and brain function in patients
with schizophrenia. Arch Gen Psychiatry 64: 156-67
T
Merriam EP, Thase ME, Haas GL, Keshavan MS, Sweeney JA. 1999. Prefrontal cortical
IP
dysfunction in depression determined by Wisconsin Card Sorting Test performance.
Am J Psychiatry 156: 780-2
CR
Michelsen KA, van den Hove DL, Schmitz C, Segers O, Prickaerts J, Steinbusch HW. 2007.
Prenatal stress and subsequent exposure to chronic mild stress influence dendritic
spine density and morphology in the rat medial prefrontal cortex. BMC Neurosci 8: 107
Michelson D, Adler L, Spencer T, Reimherr FW, West SA, et al. 2003. Atomoxetine in adults
US
with ADHD: two randomized, placebo-controlled studies. Biol Psychiatry 53: 112-20
Mika A, Mazur GJ, Hoffman AN, Talboom JS, Bimonte-Nelson HA, et al. 2012. Chronic stress
impairs prefrontal cortex-dependent response inhibition and spatial working memory.
AN
Behav Neurosci 126: 605-19
Miller EK, Cohen JD. 2001. An integrative theory of prefrontal cortex function. Annu Rev
M
Mills F, Bartlett TE, Dissing-Olesen L, Wisniewska MB, Kuznicki J, et al. 2014. Cognitive
flexibility and long-term depression (LTD) are impaired following beta-catenin
ED
stabilization in vivo. Proc Natl Acad Sci U S A 111: 8631-6

Milstein JA, Lehmann O, Theobald DE, Dalley JW, Robbins TW. 2007. Selective depletion of
cortical noradrenaline by anti-dopamine beta-hydroxylase-saporin impairs attentional
function and enhances the effects of guanfacine in the rat. Psychopharmacology (Berl)
PT
190: 51-63
Minor TR, Jackson RL, Maier SF. 1984. Effects of task-irrelevant cues and reinforcement
delay on choice-escape learning following inescapable shock: evidence for a deficit in
CE
selective attention. J Exp Psychol Anim Behav Process 10: 543-56

Minzenberg MJ, Carter CS. 2008. Modafinil: a review of neurochemical actions and effects on
cognition. Neuropsychopharmacology 33: 1477-502
AC
Mirjana C, Baviera M, Invernizzi RW, Balducci C. 2004. The serotonin 5-HT2A receptors
antagonist M100907 prevents impairment in attentional performance by NMDA
receptor blockade in the rat prefrontal cortex. Neuropsychopharmacology 29: 1637-47
Mizoguchi K, Yuzurihara M, Ishige A, Sasaki H, Chui DH, Tabira T. 2000. Chronic stress
induces impairment of spatial working memory because of prefrontal dopaminergic
dysfunction. J Neurosci 20: 1568-74
Mochizuki D, Hokonohara T, Kawasaki K, Miki N. 2002. Repeated administration of
milnacipran induces rapid desensitization of somatodendritic 5-HT1A autoreceptors
but not postsynaptic 5-HT1A receptors. J Psychopharmacol 16: 253-60
Mogg K, Mathews A, Bird C, Macgregor-Morris R. 1990. Effects of stress and anxiety on the
processing of threat stimuli. J Pers Soc Psychol 59: 1230-7
ACCEPTED MANUSCRIPT
Moghaddam B, Adams B, Verma A, Daly D. 1997. Activation of glutamatergic
neurotransmission by ketamine: a novel step in the pathway from NMDA receptor
blockade to dopaminergic and cognitive disruptions associated with the prefrontal
cortex. J Neurosci 17: 2921-7
Moghaddam B, Homayoun H. 2008. Divergent plasticity of prefrontal cortex networks.
Montagud-Romero S, Reguilon MD, Roger-Sanchez C, Pascual M, Aguilar MA, et al. 2016.
Role of dopamine neurotransmission in the long-term effects of repeated social defeat
on the conditioned rewarding effects of cocaine. Prog Neuropsychopharmacol Biol
Moore A, Malinowski P. 2009. Meditation, mindfulness and cognitive flexibility. Conscious
T
Cogn 18: 176-86
IP
Moret C, Briley M. 1997. Effects of milnacipran and pindolol on extracellular noradrenaline
and serotonin levels in guinea pig hypothalamus. J Neurochem 69: 815-22
CR
Morilak DA, Barrera G, Echevarria DJ, Garcia AS, Hernandez A, et al. 2005. Role of brain
norepinephrine in the behavioral response to stress. Prog Neuropsychopharmacol Biol
Morrow BA, Roth RH, Elsworth JD. 2000. TMT, a predator odor, elevates mesoprefrontal
US
dopamine metabolic activity and disrupts short-term working memory in the rat. Brain
Res Bull 52: 519-23
Moynihan JA, Chapman BP, Klorman R, Krasner MS, Duberstein PR, et al. 2013.
AN
Mindfulness-based stress reduction for older adults: effects on executive function,
frontal alpha asymmetry and immune function. Neuropsychobiology 68: 34-43
Muir JL, Everitt BJ, Robbins TW. 1996. The cerebral cortex of the rat and visual attentional
M
function: dissociable effects of mediofrontal, cingulate, anterior dorsolateral, and

parietal cortex lesions on a five-choice serial reaction time task. Cereb Cortex 6: 470-
ED
81
Muller NG, Machado L, Knight RT. 2002. Contributions of subregions of the prefrontal cortex
to working memory: evidence from brain lesions in humans. J Cogn Neurosci 14: 673-
86
PT
Muller U, Clark L, Lam ML, Moore RM, Murphy CL, et al. 2005. Lack of effects of guanfacine
on executive and memory functions in healthy male volunteers. Psychopharmacology
(Berl) 182: 205-13
CE
Murphy BL, Arnsten AF, Goldman-Rakic PS, Roth RH. 1996. Increased dopamine turnover in
the prefrontal cortex impairs spatial working memory performance in rats and
monkeys. Proc Natl Acad Sci U S A 93: 1325-9
AC
Murphy ER, Dalley JW, Robbins TW. 2005. Local glutamate receptor antagonism in the rat
prefrontal cortex disrupts response inhibition in a visuospatial attentional task.
Myers KM, Davis M. 2007. Mechanisms of fear extinction. Mol Psychiatry 12: 120-50
Naegeli KJ, O'Connor JA, Banerjee P, Morilak DA. 2013. Effects of milnacipran on cognitive
flexibility following chronic stress in rats. Eur J Pharmacol 703: 62-6
Nakane H, Shimizu N, Hori T. 1994. Stress-induced norepinephrine release in the rat
prefrontal cortex measured by microdialysis. Am J Physiol 267: R1559-66
Navarra R, Graf R, Huang Y, Logue S, Comery T, et al. 2008. Effects of atomoxetine and
methylphenidate on attention and impulsivity in the 5-choice serial reaction time test.
Prog Neuropsychopharmacol Biol Psychiatry 32: 34-41
ACCEPTED MANUSCRIPT
Nemeroff CB, Heim CM, Thase ME, Klein DN, Rush AJ, et al. 2003. Differential responses to
psychotherapy versus pharmacotherapy in patients with chronic forms of major
depression and childhood trauma. Proc Natl Acad Sci U S A 100: 14293-6
Newman LA, Darling J, McGaughy J. 2008. Atomoxetine reverses attentional deficits
produced by noradrenergic deafferentation of medial prefrontal cortex.
Nicolas CS, Peineau S, Amici M, Csaba Z, Fafouri A, et al. 2012. The Jak/STAT pathway is
involved in synaptic plasticity. Neuron 73: 374-90
Nikiforuk A, Popik P. 2011. Long-lasting cognitive deficit induced by stress is alleviated by
acute administration of antidepressants. Psychoneuroendocrinology 36: 28-39
Nikiforuk A, Popik P. 2013. Amisulpride promotes cognitive flexibility in rats: the role of 5-HT7
T
receptors. Behav Brain Res 248: 136-40
IP
Nikiforuk A, Popik P. 2014. Ketamine prevents stress-induced cognitive inflexibility in rats.
Psychoneuroendocrinology 40: 119-22
CR
Nonkes LJ, van de V, II, de Leeuw MJ, Wijlaars LP, Maes JH, Homberg JR. 2012. Serotonin
transporter knockout rats show improved strategy set-shifting and reduced latent
inhibition. Learn Mem 19: 190-3
Nyhus E, Barcelo F. 2009. The Wisconsin Card Sorting Test and the cognitive assessment of
US
prefrontal executive functions: a critical update. Brain Cogn 71: 437-51
Oei NY, Everaerd WT, Elzinga BM, van Well S, Bermond B. 2006. Psychosocial stress
impairs working memory at high loads: an association with cortisol levels and memory
AN
retrieval. Stress 9: 133-41
Oei NY, Tollenaar MS, Spinhoven P, Elzinga BM. 2009. Hydrocortisone reduces emotional
distracter interference in working memory. Psychoneuroendocrinology 34: 1284-93
M
Oei NY, Veer IM, Wolf OT, Spinhoven P, Rombouts SA, Elzinga BM. 2012. Stress shifts brain
activation towards ventral 'affective' areas during emotional distraction. Soc Cogn
ED
Affect Neurosci 7: 403-12

Ohmura Y, Yamaguchi T, Futami Y, Togashi H, Izumi T, et al. 2009. Corticotropin releasing
factor enhances attentional function as assessed by the five-choice serial reaction time
task in rats. Behav Brain Res 198: 429-33
PT
Olesen PJ, Westerberg H, Klingberg T. 2004. Increased prefrontal and parietal activity after
training of working memory. Nat Neurosci 7: 75-9
Oliveira JF, Zanao TA, Valiengo L, Lotufo PA, Bensenor IM, et al. 2013. Acute working
CE
memory improvement after tDCS in antidepressant-free patients with major depressive

disorder. Neurosci Lett 537: 60-4
Orem DM, Petrac DC, Bedwell JS. 2008. Chronic self-perceived stress and set-shifting
AC
performance in undergraduate students. Stress 11: 73-8

Owen AM, Roberts AC, Polkey CE, Sahakian BJ, Robbins TW. 1991. Extra-dimensional
versus intra-dimensional set shifting performance following frontal lobe excisions,
temporal lobe excisions or amygdalo-hippocampectomy in man. Neuropsychologia 29:
993-1006
Oye I, Paulsen O, Maurset A. 1992. Effects of ketamine on sensory perception: evidence for
a role of N-methyl-D-aspartate receptors. J Pharmacol Exp Ther 260: 1209-13
Paine TA, Neve RL, Carlezon WA, Jr. 2009. Attention deficits and hyperactivity following
inhibition of cAMP-dependent protein kinase within the medial prefrontal cortex of rats.
ACCEPTED MANUSCRIPT
Pampallona S, Bollini P, Tibaldi G, Kupelnick B, Munizza C. 2004. Combined
pharmacotherapy and psychological treatment for depression: a systematic review.
Arch Gen Psychiatry 61: 714-9
Park J, Moghaddam B. 2017. Impact of anxiety on prefrontal cortex encoding of cognitive
flexibility. Neuroscience 345: 193-202
Passetti F, Dalley JW, Robbins TW. 2003. Double dissociation of serotonergic and
dopaminergic mechanisms on attentional performance using a rodent five-choice
reaction time task. Psychopharmacology (Berl) 165: 136-45
Patton MS, Lodge DJ, Morilak DA, Girotti M. 2016. Ketamine Corrects Stress-Induced
Cognitive Dysfunction through JAK2/STAT3 Signaling in the Orbitofrontal Cortex.
Neuropsychopharmacology
T
Peckham AD, McHugh RK, Otto MW. 2010. A meta-analysis of the magnitude of biased
IP
attention in depression. Depress Anxiety 27: 1135-42
Pehrson AL, Sanchez C. 2014. Serotonergic modulation of glutamate neurotransmission as a
CR
strategy for treating depression and cognitive dysfunction. CNS Spectr 19: 121-33
Pelegrina S, Lechuga MT, Garcia-Madruga JA, Elosua MR, Macizo P, et al. 2015. Normative
data on the n-back task for children and young adolescents. Front Psychol 6: 1544
Perez-Valenzuela C, Garate-Perez MF, Sotomayor-Zarate R, Delano PH, Dagnino-Subiabre
US
A. 2016. Reboxetine Improves Auditory Attention and Increases Norepinephrine
Levels in the Auditory Cortex of Chronically Stressed Rats. Front Neural Circuits 10:
108
AN
Pierard C, Liscia P, Valleau M, Drouet I, Chauveau F, et al. 2006. Modafinil-induced
modulation of working memory and plasma corticosterone in chronically-stressed
mice. Pharmacol Biochem Behav 83: 1-8
M
Pietrzak RH, Mollica CM, Maruff P, Snyder PJ. 2006. Cognitive effects of immediate-release
methylphenidate in children with attention-deficit/hyperactivity disorder. Neurosci
ED
Biobehav Rev 30: 1225-45

Plessow F, Fischer R, Kirschbaum C, Goschke T. 2011. Inflexibly focused under stress:
acute psychosocial stress increases shielding of action goals at the expense of
reduced cognitive flexibility with increasing time lag to the stressor. J Cogn Neurosci
PT
23: 3218-27
Plessow F, Kiesel A, Kirschbaum C. 2012. The stressed prefrontal cortex and goal-directed
behaviour: acute psychosocial stress impairs the flexible implementation of task goals.
CE
Exp Brain Res 216: 397-408

Polak AR, Witteveen AB, Reitsma JB, Olff M. 2012. The role of executive function in
posttraumatic stress disorder: a systematic review. J Affect Disord 141: 11-21
AC
Pontecorvo MJ, Clissold DB, White MF, Ferkany JW. 1991. N-methyl-D-aspartate
antagonists and working memory performance: comparison with the effects of
scopolamine, propranolol, diazepam, and phenylisopropyladenosine. Behav Neurosci
105: 521-35
Pozzi L, Baviera M, Sacchetti G, Calcagno E, Balducci C, et al. 2011. Attention deficit
induced by blockade of N-methyl D-aspartate receptors in the prefrontal cortex is
associated with enhanced glutamate release and cAMP response element binding
protein phosphorylation: role of metabotropic glutamate receptors 2/3. Neuroscience
176: 336-48
ACCEPTED MANUSCRIPT
Putman P, Hermans EJ, Koppeschaar H, van Schijndel A, van Honk J. 2007. A single
administration of cortisol acutely reduces preconscious attention for fear in anxious
young men. Psychoneuroendocrinology 32: 793-802
Quan M, Zheng C, Zhang N, Han D, Tian Y, et al. 2011. Impairments of behavior, information
flow between thalamus and cortex, and prefrontal cortical synaptic plasticity in an
animal model of depression. Brain Res Bull 85: 109-16
Radley JJ, Rocher AB, Miller M, Janssen WG, Liston C, et al. 2006. Repeated stress induces
dendritic spine loss in the rat medial prefrontal cortex. Cereb Cortex 16: 313-20
Radley JJ, Sisti HM, Hao J, Rocher AB, McCall T, et al. 2004. Chronic behavioral stress
induces apical dendritic reorganization in pyramidal neurons of the medial prefrontal
cortex. Neuroscience 125: 1-6
T
Ragozzino ME. 2002. The effects of dopamine D(1) receptor blockade in the prelimbic-
IP
infralimbic areas on behavioral flexibility. Learn Mem 9: 18-28
Rahdar A, Galvan A. 2014. The cognitive and neurobiological effects of daily stress in
CR
adolescents. Neuroimage 92: 267-73
Rapport MD, Orban SA, Kofler MJ, Friedman LM. 2013. Do programs designed to train
working memory, other executive functions, and attention benefit children with ADHD?
A meta-analytic review of cognitive, academic, and behavioral outcomes. Clin Psychol
US
Rev 33: 1237-52
Robbins TW. 2002. The 5-choice serial reaction time task: behavioural pharmacology and
functional neurochemistry. Psychopharmacology (Berl) 163: 362-80
AN
Robbins TW, Arnsten AF. 2009. The neuropsychopharmacology of fronto-executive function:
monoaminergic modulation. Annu Rev Neurosci 32: 267-87
Robbins TW, Roberts AC. 2007. Differential regulation of fronto-executive function by the
M
monoamines and acetylcholine. Cereb Cortex 17 Suppl 1: i151-60

Roberts AC, Robbins TW, Everitt BJ. 1988. The effects of intradimensional and
ED
extradimensional shifts on visual discrimination learning in humans and non-human

primates. Q J Exp Psychol B 40: 321-41
Roberts BM, Shaffer CL, Seymour PA, Schmidt CJ, Williams GV, Castner SA. 2010. Glycine
transporter inhibition reverses ketamine-induced working memory deficits. Neuroreport
PT
21: 390-4
Robinson ES, Eagle DM, Mar AC, Bari A, Banerjee G, et al. 2008. Similar effects of the
selective noradrenaline reuptake inhibitor atomoxetine on three distinct forms of
CE
impulsivity in the rat. Neuropsychopharmacology 33: 1028-37

Rodefer JS, Nguyen TN, Karlsson JJ, Arnt J. 2008. Reversal of subchronic PCP-induced
deficits in attentional set shifting in rats by sertindole and a 5-HT6 receptor antagonist:
AC
comparison among antipsychotics. Neuropsychopharmacology 33: 2657-66

Rogers RD, Andrews TC, Grasby PM, Brooks DJ, Robbins TW. 2000. Contrasting cortical
and subcortical activations produced by attentional-set shifting and reversal learning in
humans. J Cogn Neurosci 12: 142-62
Rose EJ, Ebmeier KP. 2006. Pattern of impaired working memory during major depression. J
Affect Disord 90: 149-61
Rossi MA, Sukharnikova T, Hayrapetyan VY, Yang L, Yin HH. 2013. Operant self-stimulation
of dopamine neurons in the substantia nigra. PLoS One 8: e65799
Rowe JB, Saunders JR, Durantou F, Robbins TW. 1996. Systemic idazoxan impairs
performance in a non-reversal shift test: implications for the role of the central
noradrenergic systems in selective attention. J Psychopharmacol 10: 188-94
ACCEPTED MANUSCRIPT
Sackeim HA, Keilp JG, Rush AJ, George MS, Marangell LB, et al. 2001. The effects of vagus
nerve stimulation on cognitive performance in patients with treatment-resistant
depression. Neuropsychiatry Neuropsychol Behav Neurol 14: 53-62
Safren SA, Otto MW, Sprich S, Winett CL, Wilens TE, Biederman J. 2005. Cognitive-
behavioral therapy for ADHD in medication-treated adults with continued symptoms.
Behav Res Ther 43: 831-42
Sagvolden T, Aase H, Zeiner P, Berger D. 1998. Altered reinforcement mechanisms in
attention-deficit/hyperactivity disorder. Behav Brain Res 94: 61-71
Sagvolden T, Johansen EB, Aase H, Russell VA. 2005. A dynamic developmental theory of
attention-deficit/hyperactivity disorder (ADHD) predominantly hyperactive/impulsive
and combined subtypes. Behav Brain Sci 28: 397-419; discussion 19-68
T
Sahdra BK, MacLean KA, Ferrer E, Shaver PR, Rosenberg EL, et al. 2011. Enhanced
IP
response inhibition during intensive meditation training predicts improvements in self-
reported adaptive socioemotional functioning. Emotion 11: 299-312
CR
Sanchez C, Asin KE, Artigas F. 2015. Vortioxetine, a novel antidepressant with multimodal
activity: review of preclinical and clinical data. Pharmacol Ther 145: 43-57
Sanchez-Cubillo I, Perianez JA, Adrover-Roig D, Rodriguez-Sanchez JM, Rios-Lago M, et al.
2009. Construct validity of the Trail Making Test: role of task-switching, working
US
memory, inhibition/interference control, and visuomotor abilities. J Int Neuropsychol
Soc 15: 438-50
Sarter M, Givens B, Bruno JP. 2001. The cognitive neuroscience of sustained attention:
AN
where top-down meets bottom-up. Brain Res Brain Res Rev 35: 146-60
Schachter SC, Saper CB. 1998. Vagus nerve stimulation. Epilepsia 39: 677-86
Schoenbaum G, Chiba AA, Gallagher M. 2000. Changes in functional connectivity in
M
orbitofrontal cortex and basolateral amygdala during learning and reversal training. J
ED
Schoenbaum G, Setlow B, Nugent SL, Saddoris MP, Gallagher M. 2003. Lesions of

orbitofrontal cortex and basolateral amygdala complex disrupt acquisition of odor-
guided discriminations and reversals. Learn Mem 10: 129-40
Schoofs D, Preuss D, Wolf OT. 2008. Psychosocial stress induces working memory
PT
impairments in an n-back paradigm. Psychoneuroendocrinology 33: 643-53

Schoofs D, Wolf OT, Smeets T. 2009. Cold pressor stress impairs performance on working
memory tasks requiring executive functions in healthy young men. Behav Neurosci
CE
123: 1066-75
Schultz W. 2013. Updating dopamine reward signals. Curr Opin Neurobiol 23: 229-38
Schwabe L, Hoffken O, Tegenthoff M, Wolf OT. 2013. Stress-induced enhancement of
AC
response inhibition depends on mineralocorticoid receptor activation.

Psychoneuroendocrinology 38: 2319-26
Selye H. 1973. The evolution of the stress concept. Am Sci 61: 692-9
Semkovska M, McLoughlin DM. 2010. Objective cognitive performance associated with
electroconvulsive therapy for depression: a systematic review and meta-analysis. Biol
Seu E, Jentsch JD. 2009. Effect of acute and repeated treatment with desipramine or
methylphenidate on serial reversal learning in rats. Neuropharmacology 57: 665-72
Seu E, Lang A, Rivera RJ, Jentsch JD. 2009. Inhibition of the norepinephrine transporter
improves behavioral flexibility in rats and monkeys. Psychopharmacology (Berl) 202:
505-19
ACCEPTED MANUSCRIPT
Shang Y, Wang X, Shang X, Zhang H, Liu Z, et al. 2016. Repetitive transcranial magnetic
stimulation effectively facilitates spatial cognition and synaptic plasticity associated
with increasing the levels of BDNF and synaptic proteins in Wistar rats. Neurobiol
Learn Mem 134 Pt B: 369-78
Shansky RM, Rubinow K, Brennan A, Arnsten AF. 2006. The effects of sex and hormonal
status on restraint-stress-induced working memory impairment. Behav Brain Funct 2: 8
Silva-Gomez AB, Rojas D, Juarez I, Flores G. 2003. Decreased dendritic spine density on
prefrontal cortical and hippocampal pyramidal neurons in postweaning social isolation
rats. Brain Res 983: 128-36
Smith A, Nutt D. 1996. Noradrenaline and attention lapses. Nature 380: 291
Smith AG, Neill JC, Costall B. 1999. The dopamine D3/D2 receptor agonist 7-OH-DPAT
T
induces cognitive impairment in the marmoset. Pharmacol Biochem Behav 63: 201-11
IP
Soares JM, Sampaio A, Ferreira LM, Santos NC, Marques F, et al. 2012. Stress-induced
changes in human decision-making are reversible. Transl Psychiatry 2: e131
CR
Stefani MR, Groth K, Moghaddam B. 2003. Glutamate receptors in the rat medial prefrontal
cortex regulate set-shifting ability. Behav Neurosci 117: 728-37
Stefani MR, Moghaddam B. 2005. Systemic and prefrontal cortical NMDA receptor blockade
differentially affect discrimination learning and set-shift ability in rats. Behav Neurosci
US
119: 420-8
Steinhauser M, Maier M, Hubner R. 2007. Cognitive control under stress: how stress affects
strategies of task-set reconfiguration. Psychol Sci 18: 540-5
AN
Stenfors CU, Marklund P, Magnusson Hanson LL, Theorell T, Nilsson LG. 2013. Subjective
cognitive complaints and the role of executive cognitive functioning in the working
population: a case-control study. PLoS One 8: e83351
M
Stone M, Gabrieli JD, Stebbins GT, Sullivan EV. 1998. Working and strategic memory deficits
in schizophrenia. Neuropsychology 12: 278-88
ED
Stuss DT, Benson DF. 1984. Neuropsychological studies of the frontal lobes. Psychol Bull 95:
3-28
Stuss DT, Levine B, Alexander MP, Hong J, Palumbo C, et al. 2000. Wisconsin Card Sorting
Test performance in patients with focal frontal and posterior brain damage: effects of
PT
lesion location and test structure on separable cognitive processes. Neuropsychologia

38: 388-402
Svoboda J, Stankova A, Entlerova M, Stuchlik A. 2015. Acute administration of MK-801 in an
CE
animal model of psychosis in rats interferes with cognitively demanding forms of

behavioral flexibility on a rotating arena. Front Behav Neurosci 9: 75
Swick D, Honzel N, Larsen J, Ashley V, Justus T. 2012. Impaired response inhibition in
AC
veterans with post-traumatic stress disorder and mild traumatic brain injury. J Int
Neuropsychol Soc 18: 917-26
Szabo C, Nemeth A, Keri S. 2013. Ethical sensitivity in obsessive-compulsive disorder and
generalized anxiety disorder: the role of reversal learning. J Behav Ther Exp
Tait DS, Brown VJ, Farovik A, Theobald DE, Dalley JW, Robbins TW. 2007. Lesions of the
dorsal noradrenergic bundle impair attentional set-shifting in the rat. Eur J Neurosci
25: 3719-24
Tchanturia K, Davies H, Roberts M, Harrison A, Nakazato M, et al. 2012. Poor cognitive
flexibility in eating disorders: examining the evidence using the Wisconsin Card Sorting
Task. PLoS One 7: e28331
ACCEPTED MANUSCRIPT
Teasdale JD. 1999. Metacognition, mindfulness and the modification of mood disorders. Clin
Psychol Psychot 6: 146-55
Teper R, Inzlicht M. 2013. Meditation, mindfulness and executive control: the importance of
emotional acceptance and brain-based performance monitoring. Soc Cogn Affect
Neurosci 8: 85-92
Thai CA, Zhang Y, Howland JG. 2013. Effects of acute restraint stress on set-shifting and
reversal learning in male rats. Cogn Affect Behav Neurosci 13: 164-73
Tyson PJ, Laws KR, Roberts KH, Mortimer AM. 2004. Stability of set-shifting and planning
abilities in patients with schizophrenia. Psychiatry Res 129: 229-39
Uddo M, Vasterling JJ, Brailey K, Sutker PB. 1993. Memory and attention in combat-related
post-traumatic stress disorder (PTSD). Journal of Psychopathology and Behavioral
T
Assessment 15: 43-52
IP
Vaishnavi SN, Nemeroff CB, Plott SJ, Rao SG, Kranzler J, Owens MJ. 2004. Milnacipran: a
comparative analysis of human monoamine uptake and transporter binding affinity.
CR
Biol Psychiatry 55: 320-2
van der Schaaf ME, van Schouwenburg MR, Geurts DE, Schellekens AF, Buitelaar JK, et al.
2014. Establishing the dopamine dependency of human striatal signals during reward
and punishment reversal learning. Cereb Cortex 24: 633-42
US
van Kammen DP, Bunney WE, Jr., Docherty JP, Marder SR, Ebert MH, et al. 1982. d-
Amphetamine-induced heterogeneous changes in psychotic behavior in
schizophrenia. Am J Psychiatry 139: 991-7
AN
van Marle HJ, Hermans EJ, Qin S, Fernandez G. 2009. From specificity to sensitivity: how
acute stress affects amygdala processing of biologically salient stimuli. Biol Psychiatry
66: 649-55
M
van Marle HJ, Hermans EJ, Qin S, Fernandez G. 2010. Enhanced resting-state connectivity
of amygdala in the immediate aftermath of acute psychological stress. Neuroimage 53:
ED
348-54
Vedhara K, Hyde J, Gilchrist ID, Tytherleigh M, Plummer S. 2000. Acute stress, memory,
attention and cortisol. Psychoneuroendocrinology 25: 535-49
Veltmeyer MD, McFarlane AC, Bryant RA, Mayo T, Gordon E, Clark CR. 2006. Integrative
PT
assessment of brain function in PTSD: brain stability and working memory. J Integr
Neurosci 5: 123-38
Volkow ND, Fowler JS, Wang GJ, Swanson JM, Telang F. 2007. Dopamine in drug abuse
CE
and addiction: results of imaging studies and treatment implications. Arch Neurol 64:
1575-9
Volkow ND, Wang GJ, Fowler JS, Ding YS. 2005. Imaging the effects of methylphenidate on
AC
brain dopamine: new model on its therapeutic actions for attention-deficit/hyperactivity

disorder. Biol Psychiatry 57: 1410-5
Votruba KL, Langenecker SA. 2013. Factor structure, construct validity, and age- and
education-based normative data for the Parametric Go/No-Go Test. J Clin Exp
Neuropsychol 35: 132-46
Walker SC, Robbins TW, Roberts AC. 2009. Differential contributions of dopamine and
serotonin to orbitofrontal cortex function in the marmoset. Cereb Cortex 19: 889-98
Wallace A, Pehrson AL, Sanchez C, Morilak DA. 2014. Vortioxetine restores reversal learning
impaired by 5-HT depletion or chronic intermittent cold stress in rats. Int J
ACCEPTED MANUSCRIPT
Walton ME, Behrens TE, Buckley MJ, Rudebeck PH, Rushworth MF. 2010. Separable
learning systems in the macaque brain and the role of orbitofrontal cortex in contingent
learning. Neuron 65: 927-39
Wang X, Cao Q, Wang J, Wu Z, Wang P, et al. 2016. The effects of cognitive-behavioral
therapy on intrinsic functional brain networks in adults with attention-
deficit/hyperactivity disorder. Behav Res Ther 76: 32-9
Warburton EC, Brown MW. 2015. Neural circuitry for rat recognition memory. Behav Brain
Res 285: 131-9
Washburn DA. 2016. The Stroop effect at 80: The competition between stimulus control and
cognitive control. J Exp Anal Behav 105: 3-13
Wassum KM, Izquierdo A. 2015. The basolateral amygdala in reward learning and addiction.
T
Neurosci Biobehav Rev 57: 271-83
IP
Weed MR, Bryant R, Perry S. 2008. Cognitive development in macaques: attentional set-
shifting in juvenile and adult rhesus monkeys. Neuroscience 157: 22-8
CR
Weiss M, Murray C, Wasdell M, Greenfield B, Giles L, Hechtman L. 2012. A randomized
controlled trial of CBT therapy for adults with ADHD with and without medication. BMC
Psychiatry 12: 30
Wilson CA, Schade R, Terry AV, Jr. 2012. Variable prenatal stress results in impairments of
US
sustained attention and inhibitory response control in a 5-choice serial reaction time
task in rats. Neuroscience 218: 126-37
Wingo AP, Wrenn G, Pelletier T, Gutman AR, Bradley B, Ressler KJ. 2010. Moderating
AN
effects of resilience on depression in individuals with a history of childhood abuse or
trauma exposure. J Affect Disord 126: 411-4
Winstanley CA, Chudasama Y, Dalley JW, Theobald DE, Glennon JC, Robbins TW. 2003.
M
Intra-prefrontal 8-OH-DPAT and M100907 improve visuospatial attention and

decrease impulsivity on the five-choice serial reaction time task in rats.
ED

Winstanley CA, Zeeb FD, Bedard A, Fu K, Lai B, et al. 2010. Dopaminergic modulation of the
orbitofrontal cortex affects attention, motivation and impulsive responding in rats
performing the five-choice serial reaction time task. Behav Brain Res 210: 263-72
PT
Wischnewski M, Zerr P, Schutter DJ. 2016. Effects of Theta Transcranial Alternating Current
Stimulation Over the Frontal Cortex on Reversal Learning. Brain Stimul 9: 705-11
Woodward DJ, Moises HC, Waterhouse BD, Yeh HH, Cheun JE. 1991. Modulatory actions of
CE
norepinephrine on neural circuits. Adv Exp Med Biol 287: 193-208

Woolley CS, Gould E, McEwen BS. 1990. Exposure to excess glucocorticoids alters dendritic
morphology of adult hippocampal pyramidal neurons. Brain Res 531: 225-31
AC
Yu M, Zhang Y, Chen X, Zhang T. 2016. Antidepressant-like effects and possible

mechanisms of amantadine on cognitive and synaptic deficits in a rat model of chronic
stress. Stress 19: 104-13
Yuen EY, Liu W, Karatsoreos IN, Feng J, McEwen BS, Yan Z. 2009. Acute stress enhances
glutamatergic transmission in prefrontal cortex and facilitates working memory. Proc
Natl Acad Sci U S A 106: 14075-9
Yuen EY, Wei J, Liu W, Zhong P, Li X, Yan Z. 2012. Repeated stress causes cognitive
impairment by suppressing glutamate receptor expression and function in prefrontal
cortex. Neuron 73: 962-77
Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, et al. 2016. NMDAR inhibition-
independent antidepressant actions of ketamine metabolites. Nature 533: 481-6
ACCEPTED MANUSCRIPT
Zarate CA, Jr., Singh JB, Carlson PJ, Brutsche NE, Ameli R, et al. 2006. A randomized trial
of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch
Gen Psychiatry 63: 856-64
Zobel AW, Schulze-Rauschenbach S, von Widdern OC, Metten M, Freymann N, et al. 2004.
Improvement of working but not declarative memory is correlated with HPA
normalization during antidepressant treatment. J Psychiatr Res 38: 377-83
T
IP
CR
US
AN
M
ED
PT
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Prefrontal cortex executive processes affected by stress in health

Milena Girotti, Samantha M. Adler, Sarah E. Bulin, Elizabeth A.

Department of Pharmacology and Center for Biomedical Neuroscience

UT Health San Antonio

1.1. Overall impact of stress on executive function............................................................................................. 8

3. Working Memory ...................................................................................................................... 11

3.4. Non-pharmacological treatments...................................................................................................................... 16

4.2. Effects of stress on attention ................................................................................................................................ 18

4.3. Neurochemical mechanisms and pharmacological targets .............................................................. 19

4.4. Non-pharmacological treatments...................................................................................................................... 21

5. Response Inhibition ................................................................................................................. 22

5.1. Assessments of response inhibition................................................................................................................. 23

5.2. Effects of stress on response inhibition ........................................................................................................ 23

5.3. Neurochemical mechanisms and pharmacological targets................................................................ 24

5.4. Non-pharmacological treatments...................................................................................................................... 27

6. Cognitive flexibility .................................................................................................................. 28

6.1 Assessments of cognitive flexibility .................................................................................................................. 28

6.2. Reversal learning ........................................................................................................................................................ 29

6.2.1. Effects of stress on reversal learning .............................................................................................................30

6.2.2. Neurochemical mechanisms and pharmacological targets ..................................................................30

6.3. Set-shifting ...................................................................................................................................................................... 34

6.3.1. Effects of Stress on Set-shifting.........................................................................................................................35

6.3.2. Neurochemical mechanisms and pharmacological targets ..................................................................35

6.3.3. Non-pharmacological treatments ....................................................................................................................38

7. Concluding remarks ................................................................................................................. 40

1.1. Overall impact of stress on executive function

network (dorsomedial striatum-prefrontal circuitry) and hypertrophy of the sensorimotor network

referenced publications within review articles for additional citations.

3.1. Assessments of working memory

3.2. Effects of stress on working memory

aspartate glutamate receptors (NMDA-Rs) resulting in working memory impairments in rodents

increased expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA-Rs)

Dopamine and norepinephrine

3.4. Non-pharmacological treatments

Mindfulness is a type of attentional focus characterized by awareness of and attention

and be acknowledged without judgment or reaction (Bishop et al 2004). Mindfulness-Based

psychiatric illness (Brunoni & Vanderhasselt 2014).

Vagal Nerve Stimulation

4.2. Effects of stress on attention

4.3. Neurochemical mechanisms and pharmacological targets

dependent (Volkow et al 2005).

concomitant inhibition of 5-HT2A receptor in the PFC would be beneficial to attention.

4.4. Non-pharmacological treatments

Cognitive behavioral therapy

5.1. Assessments of response inhibition

5.2. Effects of stress on response inhibition

5.3. Neurochemical mechanisms and pharmacological targets

Multiple Neurotransmitter Systems

demonstrated beneficial effects of mindfulness-based stress reduction (MBSR) training on behavioral

Vagal nerve stimulation

a computerized adaptation of the Wisconsin Card Sorting Test, the interdimensional/extradimentional

In stressed animals, NMDA-R antagonists appear to have beneficial effects on stress-induced

Dopamine and norepinephrine

Dopamine is required for several reward-associated learning processes; therefore, the

Norepinephrine is also known to play a modulatory role in cognitive flexibility. Propanolol (a β-

6.2.3. Non-pharmacological treatments

presynaptic protein synaptophysin in the hippocampus (Shang et al 2016). Theta transcranial

6.3.2. Neurochemical mechanisms and pharmacological targets

Glutamate transmission is necessary for set-shifting. Intra-mPFC microinjections of

2006). Furthermore, chronic treatment with desipramine, a selective norepinephrine reuptake

The specific association between set-shifting and norepinephrine neurotransmission in