
==== Front
Neurobiol Stress
Neurobiol Stress
Neurobiology of Stress
2352-2895
Elsevier

S2352-2895(24)00066-3
10.1016/j.ynstr.2024.100670
100670
Articles from the Special Issue on Stress and Cognition; Edited by David Morilak and Nuno Sousa
Effects of chronic stress on cognitive function – From neurobiology to intervention
Girotti Milena 1
Bulin Sarah E.
Carreno Flavia R. carrenof@uthscsa.edu
⁎
Department of Pharmacology and Center for Biomedical Neuroscience, UT Health San Antonio, 7703 Floyd Curl Dr., San Antonio, TX, 78229, USA
⁎ Corresponding author. carrenof@uthscsa.edu
1 Current address: Congressionally Directed Medical Research Programs, 1077 Patchel Street, Fort Detrick, MD 21702, USA.

02 9 2024
11 2024
02 9 2024
33 10067017 1 2024
30 8 2024
1 9 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Exposure to chronic stress contributes considerably to the development of cognitive impairments in psychiatric disorders such as depression, generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and addictive behavior. Unfortunately, unlike mood-related symptoms, cognitive impairments are not effectively treated by available therapies, a situation in part resulting from a still incomplete knowledge of the neurobiological substrates that underly cognitive domains and the difficulty in generating interventions that are both efficacious and safe.

In this review, we will present an overview of the cognitive domains affected by stress with a specific focus on cognitive flexibility, behavioral inhibition, and working memory. We will then consider the effects of stress on neuronal correlates of cognitive function and the factors which may modulate the interaction of stress and cognition. Finally, we will discuss intervention strategies for treatment of stress-related disorders and gaps in knowledge with emerging new treatments under development.

Understanding how cognitive impairment occurs during exposure to chronic stress is crucial to make progress towards the development of new and effective therapeutic approaches.

Keywords

Executive function
Stress
Therapy
Handling Editor: Rita Valentino
==== Body
pmcList of abbreviations

HPA axis hypothalamic-pituitary-adrenal axis

GCs Glucocorticoids

CORT corticosterone, cortisol

CRH/CRF corticotropin-releasing hormone/factor

ACTH adrenocorticotropic hormone

GR glucocorticoid receptor

MR mineralocorticoid receptor

E epinephrine

NE norepinephrine

CNTF ciliary neurotrophic factor

JAK Janus kinase

SSRIs elective serotonin reuptake inhibitors

PCP phencyclidine

MDMA 3,4-methylenedioxymethamphetamine

ACC anterior cingulate cortex

PVN paraventricular nucleus of the hypothalamus

LC locus coeruleus

RVLM rostral ventrolateral medulla

NTS nucleus of the solitary tract

IML dorsal intermediolateral cellular column

mPFC medial prefrontal cortex

DLPFC dorsolateral prefrontal cortex

OFC orbitofrontal cortex

NAC nucleus accumbens

BLA basolateral amygdala

PH posterior hypothalamus

STN subthalamic nucleus

MDT mediodorsal thalamus

CIC stress chronic intermittent cold stress

CMS chronic mild stress

CUS chronic unpredictable stress

PTSD post-traumatic stress disorder

AST attentional set-shifting test

ED extra-dimensional

SSRTT stop signal reaction time test

5-CSRTT 5-choice serial reaction time test

CANTAB Cambridge Neuropsychological Test Automated Battery

WCST Wisconsin Card test

CBT Cognitive Behavior Therapy

TMS Transcranial Magnetic Stimulation

rTMS repetitive TMS

tDCS Transcranial Direct Current Stimulation

TRD Treatment Resistant Depression

DREADD designer receptor exclusively activated by designer drugs

SERT serotonin transporter

LTP long-term potentiation

LTD long-term depression

NF1 neurofibromatosis 1

OCD obsessive-compulsive disorder

PTSD post-traumatic stress disorder

GAD generalized anxiety disorder

1 Introduction

Stress is a prominent part of modern life. Humans, like other species, have evolved adaptive mechanisms to limit the physiological or psychological impact of stress. However, exposure to traumatic or cumulative stressors can considerably contribute to the development of psychiatric disorders such as, depression, generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and addictive behavior (Adams et al., 2018; Maeng and Milad 2017; Patriquin and Mathew 2017; Siegrist 2008; Sinha 2008). Indeed, a recent article reported that cases of depression alone were 3-fold higher during the COVID-19 pandemic compared to pre-pandemic data (Ettman et al., 2020).

Cognitive impairment is a transdiagnostic domain shared by multiple psychiatric disorders, including stress-related disorders (Millan et al., 2012); for example, abnormalities in various cognitive functions such as cognitive flexibility, working memory and behavioral inhibition have been documented in depression, PTSD and substance use disorder (Dossi et al., 2020; Ramey and Regier 2019; Snyder 2013), and a large body of evidence suggests that stress exacerbates cognitive impairments (Lupien et al., 2009). Unfortunately, unlike mood-related symptoms, cognitive impairments are not effectively treated by currently available therapies, and large gaps still exist in both identifying the neurobiological substrates that underly cognitive domains and in developing effective interventions.

In this review, we will present an overview of the cognitive domains affected by stress with a specific focus on cognitive flexibility, behavioral inhibition, and working memory. We will then specify how these cognitive domains are affected by acute and chronic stress (see Table 1 for a summary of relevant literature). Sex differences will be discussed if reported in the original paper, however, for an in-depth analysis of the interaction of sex and stress on cognitive function we refer the reader to recent focused reviews (Bangasser and Kawasumi 2015; Orsini et al., 2022; Swaab and Bao 2020; Wellman et al., 2020). Finally, we will discuss intervention strategies for treatment of stress-related disorders and gaps in knowledge with emerging new treatments under development.Table 1 List of studies describing effects of stress on cognitive domains examined in this review.

Table 1Rodent studies	
Cognitive domain	Stress type	Stress paradigm	Sex/species	Stress effect	Sex difference	References	
Reversal learning	Acute	30 min restraint	Male rats	Facilitation		Bryce and Howland, 2015	
Acute	10 min swim, 3d	Male mice	Facilitation		Graybeal et al., 2011	
Acute	30 min restraint	Male rats	Facilitation		Thai et al., 2013	
Early life	Fragmented maternal care	Male and female rats	No effect in males, deficit in females	Y	Goodwill et al., 2018	
Chronic	6h/14d cold stress	Male rats	Deficit		Danet et al., 2010, Donegan et al., 2014, Furr et al., 2012, Lapiz-Bluhm et al., 2009, Patton et al., 2017, Wallace et al., 2014	
Chronic	14-21d unpredictable mild stress	Male rats	Deficit		Bondi et al., 2007, Bondi et al., 2010, Jett et al., 2013, Jett et al., 2015, Hill et al., 2005Quan et al., 2011, Yu et al., 2016	
Set-shifting	Acute	15 min tail pinch	Male rats	Deficit		Butts et al., 2013	
Acute	30 min restraint	Male rats	No effect		Thai et al., 2013	
Acute	Single prolonged stress	Male rats	Deficit		George et al., 2015	
Chronic	6h/14d cold stress	Male rats	No effect		Lapiz-Bluhm et al., 2009	
Chronic	21d repeated restraint	Male rats	Deficit		Liston et al., 2006	
Chronic	14d unpredictable mild stress	Male rats	Deficit		Bondi et al., 2008, Fucich et al., 2016, Jett et al., 2013, Morilak et al., 2005,	
Behavioral inhibition	Acute	Footshock on 2 consecutive days	Male rats	No effect on impulsive action		Girotti et al., 2022	
Early life	5d variable stress	Male and female rats	Increased cocaine-induced impulsive action in females	Y	Paine et al., 2021	
CORT exposure in early life	20 d corticosterone administration	Male rats	Reduced impulsive action but increased impulsive choice		Torregrossa et al., 2012	
Chronic	6h/14d cold stress	Male rats	Increase impulsive action in well trained task		Girotti et al., 2022	
Chronic	14d unpredictable mild stress	Male rats	Increase impulsive action in well trained and novel tasks		Girotti et al., 2022	
Working memory	Acute	60 min restraint	Male and female rats	Deficit in females	Y	Shansky et al., 2006	
Acute	20 min swim stress	Male rats	Enhancement		Yuen et al., 2009, Yuen et al., 2011	
Acute	40 min intermittent footshock	Male rats	Enhancement soon after stress, deficit at later times		Musazzi et al., 2019	
Early life	Maternal separation	Male rats	Deficit in adults		Banqueri et al., 2021	
Early life	Maternal separation	Male rats	Deficit in adolescence		Brenhouse and Andersen, 2011	
Early life	Maternal separation	Male rats	Deficit in adults		Sanchez et al., 2021	
Early life	Maternal separation	Male mice	Deficit in adults		Viola et al., 2019	
Early life	Maternal separation	Male and female rats	No effect in males, slight deficit in females	Y	Sun et al., 2020	
Chronic	4 weeks unpredictable mild stress	Male rats	Deficit		Cerqueira et al., 2007a	
Chronic	21d repeated restraint	Male rats	Deficit		Wright and Conrad, 2008	
Chronic	28d repeated restraint	Male rats	Deficit		Mika et al., 2012	
Chronic	7d repeated restraint	Male and female rats	Deficits in males, no effect in females	Y	Wei et al., 2014	
Human studies	
Cognitive domain	Stress type	Stress paradigm	Sex examined	Stress effect	Sex difference	References	
Reversal learning	Acute	TSST	Males	Facilitation		Wieland et al., 2023	
Acute	CPT	Males and females	Impairment	Not reported	Raio et al., 2017	
Early + Acute	Early life stress + TSST	Males and females	Increased perseveration	Not reported	Franco and Knowlton, 2023	
Early life	History of medical and mental problems	Males and females adolescents	Deficit	Not reported	Harms et al., 2018	
Chronic	Perceived chronic stress	Females	Deficit		Monni et al., 2023	
Set-shifting	Acute	TSST	Males	No effect		Hendrawan et al., 2012	
Acute	"Virtual" TSST	Males and females	Improved flexibility	Not reported	Delahaye et al., 2015	
Acute	TSST	Males and females	Deficit in males, no effect in females	Y	Shields et al., 2016	
Acute	CPT	Males and females	Deficit in males, no effect in females	Y	Kalia et al., 2018	
Acute	TSST	Males and females	Deficit	Not reported	Alexander et al., 2007	
Acute	Noise stress	Males and females	Deficit	Not reported	Hillier et al., 2006	
Chronic	Perceived chronic stress	Males and females	Deficit	Not reported	Orem et al., 2008	
Early life + Chronic	Perceived chronic stress	Males and females	Deficit	Not reported	Kalia and Knauft, 2020	
Early life + Chronic	Perceived chronic stress	Males and females	Deficit	Not reported	Kalia et al., 2021	
Behavioral inhibition	Acute	CPT	Males and females	Increase gambling as a function of trait impulsivity	Not reported	Canale et al., 2017	
Acute	CPT	Males and females	Increase decision speed	Not reported	Raio et al., 2020	
Acute	Anticipate a videotape speech	Males	Increase choice for later, larger rewards		Lempert et al., 2012	
Chronic	Lifetime stress exposure questionnaire	Males and females	Higher stress correlated with higher implsivity and food addiction	Not reported	McMullin et al., 2021	
Chronic	Lifetime stress exposure questionnaire	Males and females	Higher impulsivity and lifetime stress in metamphetamine users	Not reported	Mahoney et al., 2015	
Working memory	Acute	TSST	Males	Deficit		Luethi et al., 2008	
Acute	TSST	Males	Deficit		Schoofs et al., 2008	
Acute	CPT	Males	Deficit		Schoofs et al., 2009	
Acute	Hydrocortisone administration	Males	Deficit		Lupien et al., 1999	
Acute	CPT	Males and females	No effect	Not reported	Porcelli et al., 2008	
Acute	TSST	Males	Slight improvement		Weerda et al., 2010	
Acute	TSST	Males and females	Enhanced working memory in males	Y	Cornelisse et al., 2011b	
Acute	Video of aversive images	Females	No effect		Qin et al., 2009	
Acute	TSST	Males and females	Enhanced working memory in males, impairment in females	Y	Scoriels et al., 2013	
Abbreviations: CPT, cold pressor test; TSST, Trier Social Stress Test.

Overall, it is vital to understand the relationship between the effects of stress on the brain and how cognitive impairment occurs during exposure to chronic stress. Through better understanding of mechanisms underlying the relationship between stress and cognition, new avenues may appear towards the development of new therapeutic approaches.

2 A brief overview of stress neurobiology

The neuroendocrine stress response is a remarkably well-conserved homeostatic process from amphibians to mammals, a fact that underscores its essential role in species survival and adaptation (Sapolsky 2021). Indeed, the response to stress is fundamentally an adaptive phenomenon directed toward the reallocation of physiological resources in response to an external or internal stimulus that has threatened homeostasis. This process of active adaptation through mobilization of neuroendocrine and immune mechanisms has been called allostasis (Sterling and Eyer, 1988. Allostatic load refers to the cost of this rebalancing process for the organism. In situations of acute or sporadic stress exposure, the cost is low and transient. However, in situations where either the stressor is persistent or the organism is debilitated, the prolonged engagement or overstimulation of allostatic systems causes a physiological burden that may lead to disease (McEwen 1998).

As an example, in socially complex species such as humans and non-human primates, the stress response can be activated and sustained in the absence of an “actual” contingent stressor, in part as a reaction to negative past experiences or in anticipation of negative future events. Such chronic engagement of the stress response system has been associated with an array of health disturbances, including cardiovascular, immunological, and reproductive dysfunction and increased incidence of stress-related psychiatric disorders (Sapolsky 2021). Thus, the current view is that stress-related pathologies develop from the unnecessary, excessive, or over-lasting activation of the stress response system that takes a toll on organism physiology. Fortunately, given the conservation of the stress response across species, it is possible to investigate the mechanisms of adaptive and maladaptive stress response, including effects on cognitive function, in animal models designed for high translational validity.

2.1 Physiological response to stress

For reasons of space, we will only briefly introduce the basic concepts of autonomic and neuroendocrine responses to stress. We refer the interested reader to comprehensive reviews on the subject (Carrier et al., 2021; Godoy et al., 2018; Gray et al., 2017; Hassamal 2023; McEwen and Akil 2020).

Acute stress can be defined as a real or perceived temporary challenge to the organism ability to maintain homeostasis and can be either physiological or psychological in nature. The organism responds to acute stress by rapidly mobilizing the autonomic and neuroendocrine systems, producing physiological changes that facilitate the response to the threat and the return to homeostasis. Autonomic system activation releases epinephrine (E, secreted by the adrenal medulla) and norepinephrine (NE, from the adrenal medulla and sympathetic nerves) that act on peripheral adrenergic receptors. Additionally, catecholamines are released within the brain where they activate central nervous system receptors. Acute catecholamine effects are short-lived, disappearing within 1 h (Tank and Lee Wong 2015), and include cardiovascular actions, metabolic resource allocation and sustained alertness.

The neuroendocrine response is under the control of the hypothalamic-pituitary-adrenal axis (HPA axis). Within this system, glucocorticoids (cortisol in humans and corticosterone in rodents, CORT) are released by the adrenal cortex in response to circulating adrenocorticotropic hormone (ACTH), released by the anterior pituitary. Release of ACTH is in turn elicited by corticotropin-releasing hormone (CRH or CRF) produced by parvocellular neurons of the paraventricular nucleus of the hypothalamus (PVN). In contrast to catecholamine-driven responses, glucocorticoid effects can be both rapid (within minutes after the stimulus) and long-lasting. The long-term effects develop over several hours and include transcriptional effects of activated glucocorticoid receptors (GRs) and epigenetic effects, such as methylation changes in target genes (Gray et al., 2017; Thomassin et al., 2001). Glucocorticoids can also bind to and exert activities through the mineralocorticoid receptors (MRs) (de Kloet 2013). Glucocorticoids participate in the termination of the stress response through a negative feedback process mediated by GRs that reduces the secretion of CRH in the PVN and ACTH in the pituitary to limit the effects of these hormones (Keller-Wood and Dallman 1984). Negative feedback mechanisms include transcriptional effects that are both ligand-dependent (Lachize et al., 2009; McKay and Cidlowski 1998) and ligand-independent (Rainville et al., 2019), as well as signaling effects via membrane-bound GRs (Di et al., 2003). Finally, the HPA axis has a prominent circadian and ultradian rhythms that play an important role in the organism's health (Lightman et al., 2020; Yao and Silver 2022).

With prolonged and/or intense stress exposure (chronic stress), the physiological burden to reinstate allostasis may produce detrimental consequences for the organism. Chronic secretion of glucocorticoids decreases GR expression in the brain which results in reduced negative feedback and dysregulation of the HPA axis (for review see (Herman et al., 2016; Tsigos et al., 2000)).

Because of lowered GR levels, CRH levels increase and the balance between MR and GR expression is changed; these alterations affect the function of other brain areas, notably the prefrontal cortex and hippocampus, and may underlie the emotional and cognitive impairments produced by chronic stress.

2.2 Impact of stress hormones on cognitive function

Indeed, persistent elevation of CORT or CRF has been associated with cognitive impairment especially in hippocampal dependent memory tasks (De Alcubierre et al., 2023; Henckens et al., 2016; Spannenburg and Reed 2023). For example, exposure to elevated glucocorticoids, in healthy humans produces reversible impairments in verbal declarative memory (Newcomer et al., 1999). In patients with Cushing Syndrome, a disorder characterized by hypercortisolemia, the most frequent cognitive symptoms reported are impaired memory (83%) and shortened attention span (66%) (Starkman 2013). Possible mechanisms leading to these impairments were suggested by early animal studies showing that chronic stress or chronic glucocorticoid exposure produced hippocampal and cortical atrophy, shorter dendritic branches and alterations in neurotransmitter levels (Cerqueira et al. 2005a, 2005b; Liston and Gan 2011; Magarinos et al., 1996; Radley et al., 2006; Wellman 2001). Measures of hippocampal volume in humans receiving high doses of glucocorticoids have yielded mixed results with some studies showing decreases in volume (Bermond et al., 2005; Brown et al., 2004; Wilner et al., 2002) and others finding no change (Coluccia et al., 2008; Hajek et al., 2006). In Cushing's patients smaller hippocampal and cortical volumes were found to correlate with longer disease duration (Bauduin et al., 2020; Bourdeau et al., 2002; Starkman et al., 1992). Low glucocorticoids levels also produce impaired cognition, especially in visual memory and attention, as it has been shown in individuals with adrenal insufficiency and with Addison's disease (Klement et al., 2009; Tiemensma et al., 2016). In rodents, adrenalectomy casues dendritic retraction in the mPFC (Cerqueira et al., 2007b). Thus, glucocorticoids effects on brain function follow an inverted-U relationship (Joels 2006), where both low and high levels of glucocorticoids produce deficits, brought about by imbalanced signaling through MR and GR. Indeed, several pharmacological studies with agonists and antagonists of GR and MR have revealed the importance of each receptor in cognitive function (Otte et al., 2007; Piber et al., 2016; Vogel et al., 2016; Wingenfeld and Otte 2019; Yalin et al., 2021; Young et al., 2004). For a recent review see (de Kloet and Joels 2023).

Elevated CRH following chronic stress also has negative effects on cognition that are mainly mediated by CRFR1 receptors (Henckens et al., 2016; Maras and Baram 2012; Uribe-Marino et al., 2016). Similar to glucocorticoids, elevated CRH produces cortical and hippocampal plasticity changes, spine actin depolarization, selective loss of spines, and detrimental effects on learning and memory (Chen et al., 2013; Wang et al., 2011).

2.3 Rodent models of chronic stress

Various rodent models of chronic stress have been developed and shown to produce behavioral and neuronal changes recapitulating elements of core symptoms of mood and anxiety disorders, or other stress-dependent psychophysiological disorders (for comprehensive reviews, see (Buynitsky and Mostofsky 2009; Qiao et al., 2016). As prenatal and early life stress are addressed elsewhere in this issue, here we will focus on adult stress.

Adult life stress is a well-recognized risk factor for psychopathology, and several rodent models have been developed to study this. Here, we will focus on 3 types of adult chronic stress: repeated restraint, chronic intermittent cold stress and chronic unpredictable stress.

Repeated restraint stress has been used as a model of chronic stress since the early 1980s, initially to examine homotypic stress habituation of the adrenergic system, HPA axis, and c-Fos activation in the brain, phenomena that arise within 4–6 days of exposure (Cole et al., 2000; Girotti et al., 2006; Stone and Platt 1982; Watanabe et al., 1994). Studies investigating the duration of stress protocols as a variable revealed that distinct brain regions exhibit differential responses to varying lengths of stress exposure. Daily sessions of restraint stress as short as one week (Brown et al., 2005; Garrett and Wellman 2009) caused dendritic remodeling in the mPFC, whereas a longer duration of the same stress procedure was necessary to observe morphological changes in the hippocampus. For example, Qiao et al., (2014) demonstrated a reduction in apical spine density in hippocampal CA1 and CA3 only when employing daily restraint stress for at least 3 weeks. Similarly, Watanabe and collegues (1992) reported apical dendritic retraction in CA3 after 3 weeks, the only time point they examined. McLaughlin and collegues (2007) found that 6 h of restraint for 21 days caused dendritic retraction in CA3, whereas 2 h of restraint stress for 21 days, 2 h for 10 days, and 6 h for 10 days did not. In conclusion, morphology in the PFC appears to be more sensitive to stress than morphology in the hippocampus.

Additionally, repeated restraint has been shown to decrease sucrose preference (Mao et al., 2022), and increase aggression, allodynia, and inflammatory pain (Bardin et al., 2009; Wood et al., 2003).

Chronic intermittent cold stress (CIC stress) is a homotypic chronic metabolic stressor that reproduces behavioral and functional changes paralleling those found in psychiatric disorders. For example, CIC stress has been shown to sensitize the HPA axis response (Ma and Morilak 2005), sensitize noradrenergic reactivity (Pardon et al., 2003), alter prefrontal and hypothalamic neuronal activity (Acosta et al., 1993; Correll et al., 2005; Moore et al., 2001), change spine and dendritic morphology in the orbitofrontal cortex (Adler et al., 2020), sensitize neuroimmune activity in the prefrontal cortex and hypothalamus (Girotti et al., 2011) and increase microglia-induced neuroinflammation in the hippocampus (Lang et al., 2020).

Another widely used chronic stress paradigm is chronic unpredictable stress. First developed by Katz and colleagues (Katz et al., 1981) as a 3 week variable stress paradigm that included severe stressors such as footshock, cold swimming, and immobilization, this paradigm was subsequently modified by Willner and coworkers (Willner et al., 1987) who substituted the severe stressors with milder ones, to better reproduce the human experience of daily, light but persistent stress exposure. Other variants of the CUS/CMS paradigm have also been developed (Banasr et al., 2007; Li et al., 2011). CUS/CMS induces a spectrum of behavioral abnormalities in rodents that parallel depressive symptoms including changes in reward sensitivity, decreased motivation, reduced grooming, and sleep changes. For a comprehensive review, see (Willner 2005). Along with behavioral effects, chronic unpredictable stress also causes structural changes, such as dendritic morphology and spine changes (Dias-Ferreira et al., 2009; Li et al., 2011).

3 Effects of stress on executive function

3.1 Cognitive flexibility

Cognitive flexibility can be defined as the ability of an individual to adapt their behavior to a changing environment or the ability to suppress old information in order to learn new information. Indeed, a lack of cognitive flexibility often leads to perseverance of behaviors that are no longer beneficial, or the inability to learn a new set of “rules.” Cognitive flexibility is often dysfunctional in patients with stress-related disorders, including depression and PTSD, where biased attention to perceived threats, ruminative focus on negative outcomes and perseverative behaviors are often a main symptom of the disorder (Clancy et al., 2016; Disner et al., 2011). For example, reduced cognitive flexibility shortly after a stressful or traumatic event is predictive of PSTD symptom severity a full year later (Ben-Zion et al., 2018). Two examples of cognitive flexibility that have been studied in relation to stress will be discussed in this review: reversal learning and extradimensional set shifting.

3.1.1 Rodent models of cognitive flexibility

Several rodent models of cognitive flexibility exist, many of which were originally based on human tests, such as the Wisconsin Card Sorting Test (Merriam et al., 1999) or the Cambridge Neuropsychological Test Automated Battery (CANTAB). One example is the attentional set-shifting task (AST) developed by Birrel and Brown (Birrell and Brown 2000) as a rodent analogue of the ID/ED sub-test of the CANTAB cognitive test battery developed by Sahakian and Robbins for human and non-human primates (Robbins et al., 1998). Both reversal learning and set shifting are evaluated in this test. Briefly, in the AST, rats dig for a food reward in small pots defined by cues along two stimulus dimensions: the material with which they are filled (sawdust, beads, etc) and an odor with which they are scented. The rats must learn which of these dimensions is relevant for locating the reward, and then which cue within that dimension is associated with the reward. After mastering a given contingency, the rules are changed, and the rat must learn a new association. For instance, the odor clove signals reward at first and the odor nutmeg does not; after mastering this discrimination, the rule is switched, whereby nutmeg is now associated with the reward, and clove is not (a Reversal). Subjects are then required to learn this new rule until they meet a predefined criterion. During this phase, subjects will produce errors that can be broadly classified as “perseverative,” i.e., persistent responses according to the obsolete rule, or “regressive,” i.e., relapses back to the old contingency after a series of correct responses. After a series of such tests in which the same stimulus dimension is informative regardless of how the rules are changed, the animals form a cognitive set, or a strategy that guides them in adapting to subsequent changes. Then, in the extra-dimensional (ED) cognitive set-shift portion of the test, odor is no longer the relevant dimension, but becomes the distractor, and the digging medium becomes the cue that signals reward. Thus, the animal must abandon the strategy of using odor as a guide and pay attention to tactile information instead. Cognitive flexibility in both reversal and set-shifting is measured by how readily the animal is able to suppress the old information and learn the new rule. More recently, operant-based systems to measure reversal learning and set shifiting have been developend for rats and mice, using operant boxes with retractable levers (Brady and Floresco 2015; Floresco et al., 2008) or touchscreen pads (Turner et al., 2017).

3.1.2 Brain areas and circuits in reversal learning

Human imaging studies show increased activity in medial prefrontal areas (Boehme et al., 2017; Cools et al., 2002), orbitofrontal areas (Ghahremani et al., 2010; Remijnse et al., 2006), parietal cortex, insula and cingulate cortex during reversal tasks (Yaple and Yu 2019). The orbitofrontal cortex is especially important for reversal learning, as evidenced in human studies (Hampshire et al., 2012), and in a large body of animal lesion studies, including monkeys (Dias et al., 1996), mice (Bissonette et al., 2008) and rats (McAlonan and Brown 2003). Other brain regions important for reversal learning are the striatum (Cools et al., 2002; Rogers et al., 2000b), amygdala (Izquierdo et al., 2013; Schoenbaum et al., 2003), and the hippocampus (Mala et al., 2015). Lesions in the ventral mid-thalamus (rhomboid and reuniens nuclei) and mediodorsal thalamus have also been shown to impair reversal learning (Chudasama et al., 2001; Linley et al., 2016). Recently, efforts have been directed at defining specific connectivity between the areas that functionally mediate reversal. Studies in humans and rodents show that major projection pathways involved in reversal include corticostriatal, thalamocortical, and cortico-amygdalar pathways. Thus, in human MRI studies, probabilistic reversal learning was associated with functional connectivity between the lateral orbitofrontal cortex and ventral striatum (Morris et al., 2016b). In rats, optogenetically inducing long-term potentiation (opto-LTP) in a MDT to orbitofrontal projection produces deficits in reversal learning (Adler et al., 2020). In an elegant study using selective viral ablation, Groman and colleagues showed that OFC-amygdala-striatal pathways mediate different aspects of value-reward encoding during a probabilistic reversal test. Rats with ablation of an OFC to nucleus accumbens projection showed deficits in reversal due to the inability to use negative outcomes to guide subsequent behaviors. By contrast, the ablation of an amygdala projection to OFC created deficits by not allowing rats to learn from positive outcomes. Interestingly, ablation of the reciprocal projection (OFC to amygdala) enhanced reversal (Groman et al., 2019). These nuanced outcomes may explain the inconsistencies in early reports of the effects of amygdala lesions on reversal learning (Izquierdo et al., 2013; Schoenbaum et al., 2003; Stalnaker et al., 2007), and indicate the necessity of circuit-level analyses to precisely dissect the anatomical correlates of reversal.

3.1.3 Neurochemical modulation of reversal learning

Glucocorticoids and CRH. Few studies have addressed the effects of elevated stress hormones on reversal learning; however, available evidence suggests that altered stress hormone signaling can negatively impact reversal learning. Thus, mice in which the MR/GR balance is altered by overexpression of MR and underexpression of GR show deficits in reversal tasks and increased perseveration (Harris et al., 2013). In rats, blockade of CRFR1 in the prefrontal cortex prevents stress-induced deficits in temporal order memory and reversal learning (Uribe-Marino et al., 2016).

Serotonin. Ample evidence points to the involvement of serotonergic signaling in the OFC in reversal. Depletion of serotonin either by removal of dietary tryptophan, 5-7-DHT lesions or use of the tryptophan hydroxylase depleting agent PCPA impairs reversal in humans, non-human primates, and rats (Clarke et al., 2007; Lapiz-Bluhm et al., 2009; Rogers et al., 1999). Receptor-specific manipulations with serotonin receptor antagonists or serotonin reuptake inhibitors suggest a complex picture of regulation. Antagonism of 5HT2A receptors impairs performance (Furr et al., 2012; Hervig et al., 2020), whereas antagonism of 5HT2C receptor facilitates reversal (Boulougouris et al., 2008; Nilsson et al., 2012), indicating a specificity in serotonergic modulation of reversal. In general, however, reduced serotonergic signaling in the OFC seems to be associated with increased perseveration (Clarke et al., 2004).

Dopamine. The importance of dopaminergic transmission in reversal behavior has been well documented, especially after extensive training on reversal learning, when the likelihood of reversal is “expected” (Costa et al., 2015; Klanker et al., 2015). There seems to be regional specificity to the effects of dopamine on reversal learning. Unlike serotonin, depleting dopamine in the OFC does not affect reversal learning (Clarke et al., 2007), whereas depletion in the striatum impairs reversal learning (Clarke et al., 2011). In human studies, increased dopaminergic activity in the striatum correlated with optimal reversal learning (Clatworthy et al., 2009). Both D1 and D2 receptor subtypes are involved in modulating reversal learning in humans, non-human primates, and rodents (Boulougouris et al., 2009; Izquierdo et al., 2006; Lee et al., 2007; Marino et al., 2022; Mehta et al., 2001; Smith et al., 1999; van der Schaaf et al., 2014). Recent evidence supports the notion that the differential role of D1 or D2 receptors in reversal may be region-specific (Sala-Bayo et al., 2020; Verharen et al., 2019).

Glutamate. Glutamate transmission in specific areas of the OFC is also implicated in visual reversal learning (Hervig et al., 2020), but little is known regarding the specific receptors involved. Subchronic administration of the NMDAR antagonist phencyclidine (PCP) produces impairments in reversal learning (Abdul-Monim et al., 2007), but subsequent analyses reported no stable effect of PCP on reversal (but reproducible negative effects on set-shifting) (Janhunen et al., 2015). Given the diversity of glutamate receptors and signaling modes, it is likely that more selective targeting of receptors or receptor subunits is required to clarify the involvement of glutamatergic transmission in reversal. In this vein, a role for the metabotropic receptor mGluR5 seems indicated by the fact that mGluR5 knockout mice display impaired visual reversal (Lim et al., 2019). Additionally, multiple studies have reported that antagonism or gene deletion of NMDA receptor subunit 2B (GluN2B) in OFC and dorsal striatum impairs reversal learning (Brigman et al., 2013; Dalton et al., 2011; Thompson et al., 2015a). Further investigation is necessary to better understand the role of glutamate signaling in reversal.

3.1.4 Stress effects on reversal learning

Human studies. Acute stress has been associated with both better performance in reversal learning (Wieland et al., 2023), as well as impairments (Raio et al., 2017) Conversely, early life stress and chronic adult stress impair reversal learning. For example, in healthy young adults, early life stress correlates with increased perseveration on a reversal task and increased propensity for increased alcohol use (Franco and Knowlton 2023). In an adolescent cohort with a history of early life stress, individuals with higher life stress scores had more difficulty in updating contingencies during reversal learning tasks (Harms et al., 2018). In a study that used a modified reversal learing task to assess sensitivity to punishement and reward, adult females with high self-reported chronic stress showed increased perseverative errors in the punishment condition and reduced punishment sensitivity in the reward condition (Monni et al., 2023). Moreover, reversal learning deficits have been documented in several stress-related psychiatric disorders such as major depressive disorder (where it was accompanied by abnormalities in the OFC) obsessive compulsive disorder, and generalized anxiety disorder (Drevets 2007; Szabo et al., 2013), and in individuals repeatedly exposed to traumatic events (Levy-Gigi and Richter-Levin 2014).

Rodent studies. In rats, acute stress is generally associated with better performance in reversal learning (Bryce and Howland 2015; Graybeal et al., 2011; Thai et al., 2013). In contrast, early life stress impaired reversal learning in female mice, and this was associated with increased expression and density of parvalbumin expressing neurons in OFC (Goodwill et al., 2018). Chronic intermittent cold stress in adult rats results in robust deficits in olfactory reversal learning task (Danet et al., 2010; Donegan et al., 2014; Furr et al., 2012; Lapiz-Bluhm et al., 2009; Patton et al., 2017; Wallace et al., 2014). Reversal impairments are also observed after two weeks of chronic unpredictable stress in both olfactory and spatial reversal tasks (Bondi et al. 2007, 2010; Hill et al., 2005; Jett et al., 2015; Jett and Morilak 2013; Quan et al., 2011; Yu et al., 2016). Mechanistically, chronic stress has been shown to decrease the levels of ciliary neurotrophic factor (CNTF) and reduce activation of its downstream effector JAK2 in the OFC. Restoration of CNTF levels within this brain region was sufficient to correct the effects of stress on reversal learning (Girotti et al., 2019). Functionally, chronic stress effects on reversal learning can be recapitulated by optogenetically inducing long term-potentiation (opto-LTP) in the OFC; conversely, chronic stress deficits are ameliorated by optogenetic long term depression (opto-LTD) in the OFC (Adler et al., 2020). Interestingly, JAK signaling is involved in hippocampal LTD (McGregor et al., 2017; Nicolas et al., 2012), and it is possible that this signaling pathway is also implicated in establishing LTD in the OFC. Taken together, these data support the notion that optimal reversal learning is associated with long-term depression in the OFC, in part mediated by CNTF/JAK signaling, that enables flexible behavior. In support of this idea, it is worth noting that depotentiation is associated with other forms of reversal; for example, temporary depotentiation in the hippocampus accompanies spatial reversal learning (Dong et al., 2013; Duffy et al., 2008; Mills et al., 2014; Morice et al., 2007). Conversely, stress may produce reversal deficits by inducing a state of increased excitability and hyperactivity in the OFC that precludes the depotentiation necessary for optimal reversal. Indeed, this possibility is supported by morphological evidence that chronic stress associated with behavioral inflexibility produces hyper-elaboration and increased dendritic length and spine numbers in the OFC (Adler et al., 2020; Liston et al., 2006).

3.1.5 Brain areas and circuits in set-shifting

Human and animal studies have long suggested that the thalamo-fronto-striatal circuit is vital in set-shifting behavior. Prefrontal activity is associated with set-shifting performance in human subjects (Manes et al., 2002; Miller and Cohen 2001; Owen et al., 1991; Rogers et al., 2000a; Stuss et al., 2000). Animal lesion studies indicate that mPFC damage results in deficits specifically in set-shifting while reversal learning remains unaffected (Birrell and Brown 2000; Bissonette et al., 2008). Lesions of mediodorsal thalamus (Ouhaz et al., 2022) or ventral hippocampus (Mala et al., 2015; Placek et al., 2013) also produce deficits in set-shifting. Optogenetically inducing long-term depression specifically within MDT terminals in the mPFC impairs set-shifting (Bulin et al., 2020).

Recent chemogenic manipulation using designer receptors exclusively activated by designer drugs (DREADDs) implicated the LC in modulating the mPFC during set-shifting. Elevated activity in LC neurons projecting specifically to mPFC was improved set-shifting and reduced regressive errors (Cope et al., 2019). Further studies suggest that the LC may be important in “rule switching”, allowing the animals to acquire the new rule easier during set shifting (McBurney-Lin et al., 2022).

3.1.6 Neurochemical modulation of set-shifting

Glucocorticoids and CRH. Few studies have addressed the role of stress hormones in set-shifting. In humans, pharmacological stimulation of GR or MR does not have any effect on flexibility tasks (Deuter et al., 2019; Wingenfeld et al., 2011). However, antagonizing MR with spironolactone diminished set shifting performance in humans, suggesting a potential role for this receptor in cognitive flexibility (Otte et al., 2007). CRH effects on set-shifting may be region-specific and dose-dependent. In one study in rodents, intracerebral administration of CRH impaired set-shifting with an inverted-U dose relationship. Conversely, microinjection into the locus coeruleus improved performance, (Snyder et al., 2012), consistent with evidence that CRH stimulates NE release from the LC (Curtis et al., 1997) and that NE in the mPFC is required for optimal set-shifting (Lapiz and Morilak 2006).

Serotonin. Evidence suggests that, besides reversal, serotonin is also involved in set-shifting. Serotonin transporter (SERT) knockout rats, which have increased extracellular serotonin, perform better than intact controls on set-shifting (Nonkes et al., 2012). However, in the opposite direction, serotonin depletion often has no effect on set-shifting (Clarke et al., 2005; Gallagher et al., 2003; Hughes et al., 2003). Serotonin receptor antagonists often ameliorate stress effects. For example, in rats, the negative effects of chronic restraint stress on set-shifting were ameliorated by the 5-HT7 receptor antagonist amisulpride (Hedlund 2009; Hedlund et al., 2005; Leopoldo et al., 2011; Nikiforuk and Popik 2013). The 5-HT6 receptor antagonists SB 271046 and sertindole were also shown to reduce deficits in set-shifting produced by PCP (Idris et al., 2010; Rodefer et al., 2008).

Dopamine and Norepinephrine. Dopamine activity in the mPFC is required for optimal performance in set-shifting tasks. Thus, in monkeys, depletion of dopamine in the mPFC using 6-OHDA produced deficits in set-shifting (Crofts et al., 2001; Robbins and Roberts 2007) and in humans increasing dopamine activity in the mPFC improved set-shifting (Apud et al., 2007). The role played by different dopamine receptors in this behavior is complex (Floresco 2013). For example, the D1 receptor antagonist SCH23390 infused within the mPFC impaired set-shifting in rats (Haluk and Floresco 2009; Ragozzino 2002), while mPFC infusions of the D4 antagonist L-745,870 improved set-shifting (McQuail et al., 2021). Norepinephrine also contributes to attentional set-shifting. Deafferentiation of noradrenergic input into the mPFC results in set-shifting deficits (McGaughy et al., 2008; Tait et al., 2007). In humans, tonic activity of noradrenergic neurons in the LC (assessed by pupillary dilation) facilitated set-shifting (Pajkossy et al., 2017). In animals, acute activation of noradrenergic signaling in the mPFC by administration of atomoxetine, a serotonin and norepinephrine uptake inhibitor (Newman et al., 2008), or atipamezole, an α2-adrenergic autoreceptor antagonist (Bondi et al., 2010; Lapiz and Morilak 2006), both improved set-shifting.

Glutamate. Glutamate transmission is also implicated in set-shifting. Direct antagonism of AMPA or NMDA receptors, but not mGluR5, in the mPFC produced set-shifting deficits (Jett et al., 2017). By contrast, systemic administration of the partial NMDA receptor agonist D-cycloserine rescued set-shifting impairments induced by scopolamine (Siddik and Fendt 2022). Expression of the GluA1 AMPA receptor subunit decreased within the mPFC of stressed animals that exhibited set-shifting deficits (Sun et al., 2022). Cortical expression of the NMDAR NR1 subunit is decreased in aged rats with set-shifting deficits (McQuail et al., 2021). Electrophysiological experiments have also revealed increased AMPA/NMDA ratios on fast-spiking interneurons in the mPFC of aged rats with set-shifting deficits (McQuail et al., 2021).

3.1.7 Stress effects on set-shifting

Human studies. In humans, not many studies have addressed the effect of stress on set-shifting using the Wisconsin Card test (WCST) or CANTAB tests and the results seem variable. For example, in one study using the WCST, acute stress did not impact cognitive flexibility (Hendrawan et al., 2012), whereas in another study using a virtual TSST and a variant of the WCST, investigators reported improved cognitive flexibility (Delahaye et al., 2015). In work comparing sexes, it was found that acute stress reduced cognitive flexibility measured with the WCST in males but not in females (Kalia et al., 2018; Shields et al., 2016). In other studies using tests of cognitive flexibility other than the WCST, some investigators have reported a negative impact of acute stress on this cognitive domain and no difference between males and females (Alexander et al., 2007; Hillier et al., 2006). In the few studies evaluating chronic stress, the data collected with tests other than the WCST suggest that high perceived stress correlates with set-shifting deficits (Orem et al., 2008). Early life stress stress also correlated with decreased cognitive flexibility in adulthood, especially in individuals with a high degree of self-reported ongoing stress (Kalia and Knauft 2020; Kalia et al., 2021).

Rodent studies. In rodent studies, the effects of acute stress on set-shifting are dependent on the type of stress the subject is exposed to prior to the set-shifting test. For example, a 15-min tail pinch is sufficient to produce deficits in set-shifting, but not reversal learning (Butts et al., 2013), while a 30-min acute restraint stress does not alter set-shifting (Thai et al., 2013). Additionally, a single prolonged stress paradigm (SPS) in which rats are acutely exposed to multiple stressors within a short time (a common model for PTSD), also resulted in set-shifting deficits (George et al., 2015). This suggests there may be a “threshold” above which acute stress produces set-shifting deficits. Subjects exposed to chronic restraint stress or CUS consistently exhibit deficits in set-shifting (Bondi et al., 2008; Fucich et al., 2016; Jett et al., 2013; Liston et al., 2006; Morilak et al., 2005). Interestingly, CIC stress that impaired reversal learning had no effect on set-shifting (Lapiz-Bluhm et al., 2009). Chronic stress can lead to decreased activity in the mPFC in both humans and animal models (Liston et al., 2009), and reduces responsivity of the mPFC to afferent stimulation as measured by local field potentials (Jett et al., 2017). Reduced response to afferent input was unique to the MDT pathway to mPFC, as the response to stimulation from the ventral hippocampus remained intact after CUS (Jett et al., 2017). Using optogenetics to induce long-term depression specifically within the MDT-mPFC pathway mimicked the effects of chronic stress on set-shifting. By contrast, long-term potentiation induced optogenetically within the MDT-mPFC pathway of stressed rats ameliorated the stress-induced deficits in set-shifting (Bulin et al., 2020). Decreased mPFC activity and responsiveness also correlate with stress-induced morphological changes, as subjects exposed to chronic stress exhibit reduced length of the apical dendrite and reduced dendritic branching in glutamatergic pyramidal neurons, and an overall loss of dendritic spines (Anderson et al., 2020; Cerqueira et al. 2005a, 2005b, 2007a, 2007b; Cook and Wellman 2004; Dias-Ferreira et al., 2009; Liston et al., 2006; Radley et al. 2004, 2006; Silva-Gomez et al., 2003).

3.2 Attention and behavioral inhibition

Broadly speaking, attention is the ability to actively process specific information in the environment while ignoring irrelevant information, whereas behavioral inhibition is characterized by the ability to restrain a response. Even within these general definitions, it is apparent that the two constructs are inter-related, in that a degree of inhibitory control is exerted during tasks of attention (when responses to extraneous stimuli need to be restrained) and vice versa, attention to environmental change is a prerequisite for inhibition of a response that has become ineffective (Bari and Robbins 2013). Indeed, as we will discuss later, behavioral tasks measuring deficits in attention also report on behavioral disinhibition.

Impulsivity is a component of normal behavior that manifests as loss of behavioral inhibition, including intolerance for delayed rewards, and actions performed hastily and without due consideration of the consequences. High levels of impulsivity are associated with psychiatric disorders such as attention-deficit disorder, bipolar disorder, substance use disorder, and other addictive disorders (Winstanley et al., 2006). Impulsivity manifests in both the innate tendency of the subject to express behavioral disinhibition (trait impulsivity) and in the response to environmental pressures that may produce disinhibited behavior (state impulsivity). Impulsivity can be conceptualized behaviorally and neurobiologically under two broad categories: motor impulsivity, or the inability to inhibit a prepotent motor response, and choice impulsivity, or the selection of a small, immediate reward in favor of a larger, delayed reward (Bari and Robbins 2013; Dalley and Robbins 2017; Evenden 1999b; Winstanley et al., 2006).

3.2.1 Rodent models for attention and behavioral inhibition

3.2.1.1 Motor impulsivity

The 5-choice serial reaction time test (5-CSRTT) is used to measure both attention and response inhibition in rodents (Bari et al., 2008; Carli et al., 1983). Modified versions of this test, e.g., the 4-choice serial reaction test and the Sussex5CSRTT, are used in humans (Sanchez-Roige et al., 2016; Voon et al., 2014). In the rodent task, subjects are trained to detect brief flashes of light presented randomly in 1 of 5 holes and make a nose-poke response in the correct location to receive a food reward. Responses made before presentation of the stimulus (premature responses) are considered an index of motor impulsivity, whereas responses in one of the unlit holes (incorrect responses) indicate deficits in attention (Eagle and Baunez 2010; Sosa et al., 2021). The Go No-Go test is another motor inhibition test in which separate signals (different tones) are associated with “go” and “no-go” trials; the subject must respond in go trials but inhibit responding in no-go trials. Motor impulsivity can also be evaluated by considering “speed” of inhibitory control, measured with the Stop-Signal-Reaction-Time Test (SSRTT). In this task, rats are presented with two levers. The animal is required to press in quick succession first the left then the right lever to receive a food pellet. On 20% of trials a stop signal (a tone, for example) is played after the left lever press signaling that the subject must withhold responding on the right lever to receive the reward (Eagle and Baunez 2010; Eagle et al., 2008). The critical measure in SSRTT is the time taken to stop the response. Thus, SSRTT specifically measures inhibition of actions that have been started and engage “stopping” processes, whereas Go No-Go and 5-CSRT tests measure the ability to inhibit the initiation of the response and engage “wait” processes during inhibitory responses. Interestingly, several studies have highlighted neuroanatomical and pharmacological differences between “waiting” and “stopping” impulsivity that provide useful frameworks for further mechanistic analysis in rodent models of impulsivity (Dalley et al., 2011; Dalley and Robbins 2017).

3.2.1.2 Choice impulsivity

Impulsive choice is exhibited by subjects who choose an immediately available small reward in preference to a larger but delayed reward. This type of decisional impulsivity is heavily shaped by reward valuation and the loss in perceived reward value when its delivery is delayed. In rodents, impulsive choice is often measured with delay-discounting tests (Evenden 1999a). Briefly, animals choose between two levers, one of which provides a reward of one pellet, the other a reward of 4 pellets. Over the period of the test the delay to the large reward increases from 0 s to 10, 20, 40, and finally 60 s and a delay-discounting curve can be obtained. Animals typically show a strong preference for the larger reward early in the session when the delay is short or absent but shift their preference to the smaller reward as delay to the larger reward increases. Individuals who generate steeper discounting curves, such that each unit of time-delay has a greater negative effect on the valuation of the reward, are described as exhibiting more decisional impulsivity.

3.2.2 Brain regions and circuits involved in attention and behavioral inhibition

3.2.2.1 Motor impulsivity

Many of the neuroanatomical substrates of behavioral inhibition have been identified from rodent brain lesion studies (for review see (Eagle and Baunez 2010)). To summarize, lesions in the OFC, dorsal medial striatum and subthalamic nucleus (STN) affect stopping processes measured on SSRT as well as premature responding on the 5-CSRTT. Additionally, lesions in the infralimbic cortex (Chudasama et al., 2003b), insular cortex (Dambacher et al., 2015), ventral hippocampus (Abela et al., 2013), and cingulate cortex (Muir et al., 1996) all increase premature responding in the 5-CSRTT. The role of the nucleus accumbens may be more nuanced with differential effects mediated by the shell and the core (Besson et al., 2010; Sesia et al., 2008). Recently, using a cued sensory association task, the secondary motor cortex was implicated in coding and controlling premature motor output (Guzulaitis et al., 2022). In humans, motor impulsivity is also associated with corticostriatal and corticosubthalamic connectivity (Aron et al., 2003; Hannah and Aron 2021). Specifically, the STN is well recognized as an inhibitory modulator of cortico-striatal motor outputs (Morris et al., 2016a). Recent evidence from human studies of Parkinson disease (Mosley et al., 2020) confirms previous work that connectivity of premotor areas to the STN signal motor stopping (Aron et al., 2016) but also show a role of STN in facilitating disinhibitory control, possibly via connectivity of STN with prefrontal and orbitofrontal cortices (Dagher 2020; Mosley et al., 2020). In rodents, several lines of evidence, including lesion studies (Baunez and Robbins 1997, 10.13039/100022632 Phillips and 10.13039/100006418 Brown 2000) and disconnect studies (Chudasama et al., 2003a) have supported the notion of the 10.13039/501100009047 STN as an “action stop” center. More recently, mapping of the underlying circuitry has confirmed the role of secondary motor cortex to STN connections (Adam et al., 2022) and mPFC to STN connections (Li et al., 2020) in motor inhibition.

3.2.2.2 Choice impulsivity

Lesion studies in rodents and functional imaging studies in humans implicate the nucleus accumbens (NAC) core, basolateral amygdala (BLA), hippocampus, insula, lateral prefrontal cortex (PFC), posterior cingulate cortex, parietal cortex, and medial and lateral orbitofrontal OFC in delay discounting impulsivity (Cardinal et al., 2001; Kable and Glimcher 2007; Tanaka et al., 2004; Winstanley et al., 2004b). With respect to corticosubthalamic circuitry, lesions of the STN actually reduce impulsive choice (Winstanley et al., 2005a). However, there is also evidence for a role of STN to mediate some aspects of cognitive or choice impulsivity, both in rodents and humans, with a putative regulation by associative and limbic cortices (mPFC and OFC) (Heston et al., 2020; Mosley et al., 2020). Indeed, a recent report showed that activity levels in the pre-supplementary motor area were shown to predict impulsive choice in a gambling test in humans (Lohse et al., 2023).

3.2.3 Neurochemical modulation of attention and behavioral inhibition

3.2.3.1 Motor impulsivity

Glucocorticoids and CRH. Studies that have investigated the role of stress hormones in impulsive responding did not report significant effects (Kentrop et al., 2016). Instead, stress hormones seem to affect attention. In particular, MR blockade impairs selective attention in healthy humans (Cornelisse et al., 2011a; Otte et al., 2007) and polymorphisms within the MR gene are associated with increased hyperactivity and decreased attention in ADHD cohorts (Kortmann et al., 2013).

Serotonin. Serotonin neurotransmission plays an important role in both reward evaluation and inhibitory responses (Desrochers et al., 2022). Several lines of evidence, not all in concordance, have shown the importance of serotonin in motor inhibition. Thus, in some studies, increased tonic extracellular serotonin levels in mPFC correlated with impulsive action in the 5-CSRTT (Dalley et al., 2002; Puumala and Sirvio 1998). However, there is also evidence that depleting serotonin in the frontal cortex increases motor impulsivity in rodents (Harrison et al., 1997; Winstanley et al., 2004a) and humans (Worbe et al., 2014) and that increasing serotonin in the cortex improves wait impulsivity. (Fonseca et al., 2015; Miyazaki et al. 2014, 2020). Thus, to fully characterize serotonergic involvement in impulsivity a more nuanced approach that considers receptor-, region- or circuit-specific effects may be necessary. With respect to receptor subtypes, 5-HT2A and 5-HT2C receptors seem to have opposite effects on motor impulsivity; 5-HT2C receptor antagonism (in prefrontal cortex and accumbens) is associated with greater premature responding, and activation of these receptors lowers premature responding in 5-CSRTT. Conversely, 5-HT2A receptor antagonism is associated with decreased premature responding and activation is associated with increased premature responding in 5-CSRTT (Fletcher et al., 2007; Koskinen et al., 2000; Robinson et al., 2008a; Silveira et al., 2020; Winstanley et al., 2004c).

Dopamine and norepinephrine. The dopaminergic and noradrenergic systems are also implicated in the modulation of impulsive responding in the 5-CSRTT, perhaps through cross-signaling. In particular, D2 receptor availability has been associated with high trait impulsivity in humans (Volkow et al. 1993, 2001) and in rodents performing tests of motor impulsivity (Caprioli et al., 2013; Dalley et al., 2007; Pattij et al., 2007). Increasing norepinephrine (and dopamine) levels with NE reuptake inhibitors such as atomoxetine and desipramine decreases impulsive responding in the 5-CSRTT (Navarra et al., 2008; Paine et al., 2007; Paterson et al., 2011; Robinson et al., 2008b). Finally, interactions between the noradrenergic and dopaminergic systems were reported in a study where the beneficial effects of atomoxetine and duloxetine (a serotonin and norepinephrine reuptake inhibitor) on decreasing motor impulsivity were blocked by a D1-like receptor antagonist (Sasamori et al., 2019).

Glutamate and GABA. Other neurotransmitter systems that have a role in impulsive action include the ionotropic and metabotropic glutamate receptors (Higgins et al., 2016; Isherwood et al., 2017). In particular, metabotropic glutamate receptor 5 (mGluR5) is differentially involved in impulsive action and impulsive choice, as positive allosteric modulation of this receptor reduces impulsive action but does not affect impulsive choice (Isherwood et al., 2015). GABAergic transmission also plays a role in motor impulsivity. Thus, high trait impulsivity in rats is associated with reduced GABA levels in the ventral striatum and decreasing glutamate decarboxylase (GAD65/67) expression in the nucleus accumbens increased impulsivity in low impulsivity rats (Caprioli et al., 2014; Sawiak et al., 2016).

3.2.3.2 Choice impulsivity

Serotonin. Serotonin's role in behavioral inhibition is not restricted to motor impulsivity but extends to choice impulsivity, although in this instance again, pharmacological effects are complex and outcomes have varied across studies. Some studies indicated that depleting central serotonin in rodents does not produce effects on a delay discounting task (Winstanley et al., 2004a), in concordance with human studies. (Crean et al., 2002; Dougherty et al., 2015; Worbe et al., 2014). In other work, however, central 5-HT depletion did increase impulsive choice in rodents (Mobini et al., 2000) and serotonin efflux in the dorsal raphe nucleus is higher while waiting for delayed rewards (Miyazaki et al., 2011). Moreover, in rodents, selective serotonin reuptake inhibitors (SSRIs) increase selection of larger, delayed rewards (Bizot et al., 1999). Thus, serotonin effects appear to be complex and may depend on interplay with other neurotransmitter systems (Winstanley et al., 2005b).

Dopamine and norepinephrine. Depletion of dopamine in the striatum increases discounting rates in delay discounting tests (Tedford et al., 2015), and rats with higher discounting rates have a blunted cue dopamine response (Moschak and Carelli 2017). Accordingly, optogenetic stimulation that induces dopamine release within the nucleus accumbens produces a shift toward waiting for delayed larger rewards in rats (Saddoris et al., 2015). Expression of D2 receptors is important for choice impulsivity as knock-down of these receptors in the ventral tegmental area shifted preference for the smaller, immediate reward in rats (Bernosky-Smith et al., 2018). As with other neurotransmitters, however, the effects of dopamine on delay discounting seems to be region-dependent. Thus, discounting rates are increased by infusions of D2, but not D1, receptor antagonists in nucleus accumbens (Yates and Bardo 2017). Conversely, discounting rates are increased when D1, but not D2, antagonists are infused in the prefrontal cortex (Loos et al., 2010). These functional differences may be linked to the heterogeneity of dopamine receptor expression in cortical compared to subcortical regions.

A large volume of work with norepinephrine reuptake inhibitors suggests an important role for norepinephrine not only in impulsive action but also in impulsive choice. Pharmacological increases in extracellular norepinephrine levels by norepinephrine transporter (NET) blockers, such as atomoxetine, consistently increase preference for larger delayed rewards in delay discounting tasks (Robinson et al., 2008b; Sun et al., 2012). These effects appear to be mediated by the α2 adrenergic receptor, as administration of α2 agonists decrease impulsive choice (Nishitomi et al., 2018) and α2 antagonists increase impulsive choice (Schippers et al., 2016). Despite the clear role of norepinephrine in impulsivity it is important to note the possibility that some of the behavioral effects described above may be in part due to changes in dopaminergic tone, as atomoxetine also increases cortical dopamine levels (Bymaster et al., 2002) and α2 agonists have been found to decrease dopamine release (Ihalainen and Tanila 2002).

Glutamate and GABA. Like motor impulsivity, choice impulsivity is also regulated by excitatory and inhibitory neurotransmitters. Thus, levels of cortical glutamate-glutamine and GABA predict impulsive decision making and gambling severity in humans (Weidacker et al., 2020). In rodents, ionotropic glutamate receptors have been shown to be implicated in delay discounting (Yates and Bardo 2017; Yates et al., 2015).

3.2.4 Stress effects on behavioral inhibition

Human studies. In humans there is evidence that both acute and chronic stress affect behavioral inhibition. A meta-analysis of interactions of acute stress and risky behaviors revealed that overall, stress exposure led to more disadvantageous and risky decisions than nonstress conditions (Starcke and Brand 2016). Interestingly, stress does not uniformly increase impulsive responding, rather it interacts with trait impulsivity as a factor to reveal preexisting biases in goal-directed behavior. Thus, in healthy adults acute stress impaired decision making and speed of choice in both non-gambling and gambling settings, and these effects were more pronounced in individuals with higher impulsivity (Canale et al., 2017; Raio et al., 2020). However, in humans other complicating factors, such as Individual perception of stress, may also affect choice behavior. In one study, researchers found that in the presence of an acute stressor individuals who are more likely to perceive stressful situations as such show a preference for larger, delayed rewards, while those with low perceived stress prefer short, immediate rewards (Lempert et al., 2012). The authors suggest that individuals with high perceived stress may interpret the acute stress as more threatening and this reduces their reward response in the short term. Indeed, a correlation between acute stress, decreased reward sensitivity and increased choice for later reward have been documented in previous work (Bogdan and Pizzagalli 2006). More prolonged stress has been linked to increased impulsivity and increased risk of developing specific addictive behaviors. In one study, greater lifetime stress exposure was significantly correlated with a greater tendency to make impulsive decisions under negative emotionality and was predictive of developing food addiction but not alcohol addiction (McMullin et al., 2021). In another study, stress significantly correlated with higher impulsivity in methamphetamine users but not in cocaine users (Mahoney et al., 2015).

Rodent studies. Fewer studies have addressed the role of stress on impulsivity in rodents. Perinatal stress has been shown to increase impulsive action but reduce impulsive choice in adulthood (reviewed in (Sanchez and Bangasser 2022)). Moreover, sex difference may be at play, as the type of perinatal stress applied elicits different effects on impulsivity (especially impulsive choice) in males versus females (Paine et al., 2021; Sanchez and Bangasser 2022). Conversely, administration of corticosterone to adolescent rats decreased premature responding at longer intertrial intervals on the 5-CSRTT but increased delay discounting (Torregrossa et al., 2012). Thus, with the caveat that corticosterone administration does not fully recapitulate the effects of natural stress, it appears that stress experienced before adulthood may have differential effects on impulsive action and impulsive choice. Stress applied in adulthood is also capable of altering impulse control in rodents. Accordingly, the response of rats in a motor impulsivity test analogous to the 5-CSRTT varies in a manner that is dependent on the type of stress used: while an acute stressor did not change performance, CIC stress lowered premature responses while CUS increased premature responses at longer intertrial interval times (Girotti et al., 2022). CUS also increased impulsive choice in a genetic mouse model of schizophrenia (Buhusi et al., 2017). Taken together, a large body of evidence suggests that stress has a nuanced effect on impulsive responding that depends on individual baseline setpoints of goal-directed behavior.

3.3 Working memory

Working memory is defined as the temporary storage and manipulation of content used to perform cognitive tasks such as language comprehension, learning, and reasoning (Baddeley 1992). This also requires attentional processes, in particular focused or selective attention (Diamond 2013). In humans working memory can directly be assessed with simple ordering tasks (presenting subjects with random numbers and asking them to reorder them in ascending or descending order). The N-back task, in which the subject is presented with a series of stimuli and is asked to indicate when a current stimulus matches one from n steps earlier, is also a widely used task to assess working memory, although selective and sustained attention are also heavily employed in this task (Owen et al., 2005; Pelegrina et al., 2015).

3.3.1 Rodent models for working memory

In rodents, T-maze alternation tasks, the 8-arm radial maze, and object recognition tasks with variable lengths of delay are some of the most used tests of spatial and non-spatial working memory (Kinnavane et al., 2015; Lalonde 2002; Olton 1987; Warburton and Brown 2015). These tasks rely on the intrinsic propensity of the animal to explore 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 animal does not retain information about previously encountered situations.

3.3.2 Brains areas and circuits of working memory

Human and non-human primate studies have revealed a central role of the frontal cortex in the regulation of working memory. Early studies in monkeys identified neurons in the PFC that maintain robust activity during cue presentation and during the delay period while the subjects keep stimulus information in working memory. This sustained activity is correlated with the ability to remember the information and is susceptible to distractions (Fuster & Alexander 1971, 1973). Human neuroimaging studies also found sustained activation in the lateral PFC while the subjects kept visual items in working memory (Courtney et al., 1998; Sakai et al., 2002). Moreover, specific involvement of parietal, sensory and premotor cortices has been shown in both human and primate studies of working memory (Khan and Muly 2011; Klingberg et al., 1997).

Rodent lesion studies have shown the importance of perirhinal, entorhinal cortex, hippocampus, prefrontal cortex and insular cortex for recognition memory (Albasser et al., 2012; Barker and Warburton 2011; Bermudez-Rattoni 2014; Ennaceur and Aggleton 1997; Tuscher et al., 2018; Warburton and Brown 2015). Subcortical areas involved in recognition memory include thalamus, hypothalamus, striatum, septum, amygdala and cerebellum (for a comprehensive review see (Chao et al., 2022)). At the circuit level, electrophysiology studies implicated connectivity between PFC-thalamus (reuniens nucleus) and hippocampus as mediating behavior in a T-maze test (Hallock et al., 2016; Ito et al., 2015). Moreover, chemogenic inhibition showed that reciprocal PFC-mediodorsal thalamus (MDT) projections mediate different phases of working memory processing, and that MDT input is necessary in sustaining prefrontal activity during working memory maintenance (Bolkan et al., 2017).

3.3.3 Neurochemical modulation of working memory

Glucocorticoids and CRH. Several reports indicate that alteration of stress hormone signaling negatively impacts working memory. MR seems to be particularly important for working memory. For example, individuals with Addison's disease performed better in working memory tasks when both receptors were activated compared to when only GRs were activated (Tytherleigh et al., 2004). In another study, mifepristone, a GR antagonist that shifts the MR/GR balance towards MR, improved spatial working memory and recognition memory in individuals with bipolar disorder (Young et al., 2004). CRHR1 signaling is also implicated in working memory. In humans CRHR1 polymorphisms interact with early life stress to produce deficits in working memory (Fuge et al., 2014). Administration of a selective CRFR1 antagonist prevented cognitive impairments in recognition memory in stressed mice (Philbert et al., 2013).

Dopamine and Norepinephrine. The importance of dopamine in working memory was established from observations that monkeys with dopamine depletion in the PFC showed profound deficits in working memory (Brozoski et al., 1979). Early studies aimed at defining receptor subtypes unveiled a critical role for D1 receptors in the effect of dopamine on working memory. Interestingly, optimal outcomes follow an inverted-U-shaped dose-response curve where both insufficient and excessive D1 activation result in impairments (Williams and Castner 2006; Williams and Goldman-Rakic 1995). Since D1 receptors are more abundant than D2 receptors in the prefrontal cortex they have been the focus of much early research; however, more recent studies have also highlighted a potential role for D2 receptor signaling in working memory. For example, bromocriptine, a D2 receptor agonist, improved working memory in a variety of rodent maze tests (Onaolapo and Onaolapo 2013; Phelps et al., 2015; Tarantino et al., 2011), and treatment with a D2 receptor antagonist (haloperidol) produced deficits in spatial working memory and object recognition (Terry et al. 2007a, 2007b).

Noradrenergic receptor signaling is also important for working memory, in particular α2 adrenoreceptors. Prefrontal cortex infusion of yohimbine, a noradrenergic α2 receptor antagonist, impairs performance on working memory tasks (Li et al., 1999), whereas, administration of the α2-adrenoceptors agonist guanfacine improves working memory functions in humans (Jakala et al., 1999; Swartz et al., 2008), monkeys (Arnsten et al., 1988) and rats (Hains et al., 2015).

Other neurotransmitter systems. In addition to catecholamines, there is evidence for an involvement of cholinergic receptors, with differential roles of nicotinic and muscarinic receptors in different aspects of the working memory processing (Granon et al., 1995). The glutamate system is also important for working memory function. For example, in rodents, infusion of NMDA within the septum improves consolidation in a working memory task (Puma et al., 1998). Administration of NMDA receptor antagonists either systemically or locally within the dorsomedial PFC impairs spatial working memory in rats (Aura and Riekkinen 1999; Gutnikov and Rawlins 1996). Interestingly, the NMDA antagonist AP5 infused within the septum, showed dose-dependent effects, with improved performance in a recognition task at low doses (Puma and Bizot 1998) and impairment at high doses (Puma et al., 1998), underscoring the potential subtleties of pharmacological manipulation on this behavioral measure. Beside excitatory transmission, evidence shows that inhibitory transmission also modulates working memory. For example, levels of GABA in the prefrontal cortex change during working memory tasks in humans (Michels et al., 2012; Yoon et al., 2016) and blockade of GABAA receptors in the prefrontal cortex of monkeys and rats reduces working memory capacity (Auger and Floresco 2014; Rao et al., 2000).

Finally, the role of serotonin in working memory is not well defined. Work in non-human primates suggests that 5-HT2A receptor stimulation facilitates spatial working memory (Williams et al., 2002), and studies in rodents indicate that prefrontal serotonin depletion may exert negative effects on select aspects of working memory (Gonzalez-Burgos et al., 2012). However, many outstanding questions remain, in part because serotonergic influence on working memory may, in fact, not be direct but derive from interplay with other neurotransmitter systems (such as the cholinergic system) (Ohno and Watanabe 1997).

3.3.4 Stress effects on working memory

Human studies. Stress has been reported to have mixed effects on working memory in healthy humans. Thus, some studies reported impairments in working memory after acute stress (Luethi et al., 2008; Schoofs et al. 2008, 2009) or after acute administration of corticosteroids (Lupien et al., 1999). But other studies found no effect of stress (Porcelli et al., 2008) or even enhancement of working memory (Cornelisse et al., 2011b; Weerda et al., 2010). Some studies showed enhancement of working memory in males but no effect or impairments in females (Cornelisse et al., 2011b; Qin et al., 2009; Schoofs et al., 2013). One issue may be the use of widely different tasks to measure working memory, some relying on visual imagery, others on letter recognition or digit-based n-back tasks that may differentially recruit other executive functions such as sustained attention.

Another important factor influencing stress outcomes on working memory may be related to the timing of behavioral testing with respect to stress exposure. In a recent metanalysis of existing literature by (Geissler et al., 2023) the authors found that negative effects of stress on working memory are clustered within two timeframes of 0–9 min and 25–50 min post-stressor. The authors suggest these timeframes represent effects mediated by sympathetic nervous system activation (early phase) and cortisol effects (late phase).

Rodent studies. In rodents, stress has also been shown to produce different effects depending on the timing and stressor type (for a metanalysis see (Moreira et al., 2016) Acute stress was shown to improve working memory with a mechanism attributed to glucocorticoid receptor-dependent regulation of glutamate receptors in the prefrontal cortex in male rats (Yuen et al. 2009, 2011). Another group reported improved performance in male rats in the T-maze soon after application of acute footshock, but worse performance at later times of testing (Musazzi et al., 2019). In a study comparing male and female rats it was shown that 60 min restraint produced impairments in proestrus female rats but not male rats, whereas 2h restraint produced deficits in both sexes, leading the authors to conclude that high estrogen levels may render females more sensitive to the effects of stress on working memory (Shansky et al., 2006). With respect to chronic stress, some models have been shown to improve working memory, particularly in spatial working memory tests (see (Conrad 2010). However, chronic stress is also reported to impair working memory in male rats (Cerqueira et al., 2007a; Mika et al., 2012; Wright and Conrad 2008). In one study, one week of repeated restraint impaired working memory in male rats but not female rats (Wei et al., 2014). Early life stress has generally produced deficits in working memory in the male offspring (Banqueri et al., 2021; Brenhouse and Andersen 2011), and can exacerbate outcomes after additional insults (Sanchez et al., 2021; Viola et al., 2019). Some studies, however, did not observe the negative impacts of early stress on working memory in males but did observe slight deficits in females, again highlighting that stress outcomes are greatly nuanced and variable depending on protocols, sex, and age of testing (Sun et al., 2020).

4 Treatment strategies for cognitive impairment in stress-related psychiatric illness

This section will delve into current clinical interventions and novel therapeutic targets identified either preclinically or clinically for treatment to mitigate stress-induced cognitive dysfunctions. When appropriate, we discuss key preclinical mechanistic studies with translational potential. In other instances, such as the case concerning device-based neuromodulation approaches (section 4.2), we focus primarily on clinical studies.

4.1 Pharmacological treatments

4.1.1 Monoamine neurotransmission targeting drugs

As discussed in the previous sections, monoaminergic neurotransmission involving serotonin, norepinephrine and dopamine exert a critical role in brain circuits associated with cognitive functions.

Pehrson and colleagues (Pehrson et al., 2015) conducted an in-depth review of preclinical studies in rodents on monoamine neurotransmission-targeting drugs and their impact on cognition. Monoamine-targeting drugs, often referred to as conventional antidepressants, are the leading prescribed drugs to treat stress-related psychiatric disorders. While conventional antidepressants have shown varying degrees of clinical efficacy regarding mood improvement, their impact on cognitive symptoms remains negligible (Rosenblat et al., 2015; Shilyansky et al., 2016), except for vortioxetine (Bennabi et al., 2019), a multi-modal drug that is the only FDA-approved antidepressant for which the prescribing information mentions enhancements in cognitive domains.

4.1.1.1 Serotonergic system targeting drugs

As previously noted, the serotonergic system has crucial regulatory effects on different domains of cognitive function. Not surprisingly then, several preclinical studies have supported the use of serotonergic modulators to improve cognitive deficits. For example, CIC-induced deficits in reversal learning in male rats were rescued by acute and chronic treatment with the selective serotonin reuptake inhibitor (SSRI), citalopram (Danet et al., 2010). This effect was specific to the serotonin system because desipramine treatment (a norepinephrine reuptake blocker) did not rescue the CIC stress-induced reversal learning deficit (Danet et al., 2010). SSRIs such as citalopram, escitalopram and fluoxetine have also shown to be effective in ameliorating CUS-induced set-shifting deficits in male rats (Bondi et al., 2008; Minchew et al., 2021; Nikiforuk and Popik 2011).

Vortioxetine, an N-arylpiperazine derivative, is a potent selective inhibitor of the SERT, similar in this respect to other SSRIs. However, it also has potent actions at multiple 5-HT receptors (partial 5-HT1B agonism, 5-HT1A agonism, and 5-HT1D, 5-HT3, 5-HT7 antagonism), a property not shared by other SSRIs. In addition, vortioxetine can modulate the dopaminergic, noradrenergic, histaminergic, cholinergic, GABAergic, and glutamatergic systems (Pehrson et al., 2016). An in-depth review of preclinical and clinical findings implicating the antidepressant effects of vortioxetine was published by Sanchez and colleagues (Sanchez et al., 2015). Preclinical studies carried out in male rats have also shown that vortioxetine efficacy in rescuing 5-HT depletion-induced deficits in reversal learning is likely due to its action at postsynaptic 5-HT receptors, as PCPA-induced blockade of serotonin reuptake did not prevent the beneficial effects of vortioxetine (Wallace et al., 2014). In the same study, the authors also showed that chronic vortioxetine treatment rescued CIC-induced deficits in reversal learning. Vortioxetine has recently been shown to recover set-shifting deficits in male rats. (Vaiana et al., 2023). In a preclinical study relevant to the study of depression and anxiety-related disorders, vortioxetine mitigated the excessive display of conditioned fear and rescued adaptive coping behaviors compromised by chronic stress in male rats (Hatherall et al., 2017).

It is worth noting that, more recently, a promising target that has garnered attention in the realm of therapeutics for stress-related psychiatric disorders is the 5-HT4 receptors. As such, an extensive review of the role of 5-HT4 receptor pharmacology, its role in cognition, and its potential as therapeutics for stress-related psychiatric disorders has been published (Murphy et al., 2021).

4.1.1.2 Noradrenergic system targeting drugs

Lapiz and colleagues demonstrated that naïve male rats treated subchronically with the NE-reuptake blocker desipramine showed improvement in set-shifting correlated with upregulation of mPFC NE (Lapiz et al., 2007). Chronic treatment with milnacipran, a serotonin-norepinephrine uptake inhibitor, can also restore set-shifting compromised by stress (Craine et al., 2023; Naegeli et al., 2013). In male rats subject to CUS, chronic treatments with either the norepinephrine reuptake blocker desipramine or the SSRI escitalopram prevented the deficit in set-shifting induced by stress (Bondi et al. 2008, 2010). In male rats. acute postsynaptic α1 adrenergic receptor antagonism with benoxathian administration into the mPFC before testing prevented the beneficial effects of desipramine (Bondi et al., 2010), whereas infusions of β1 or β2 adrenergic receptor antagonists into the mPFC do not have a similar blocking effect (Lapiz and Morilak 2006). Furthermore, the same authors demonstrated that the systemic administration of atipamezole, an α2A-adrenergic receptor antagonist, enhances set-shifting in male rats. However, while the faciliatory effects of norepinephrine persisted during chronic stress, they became detrimental to reversal learning in male rats (Jett et al., 2013).

These data show that while antagonism of α2A-adrenergic receptor is associated with cognitive improvement (Bondi et al., 2007), it is essential to recognize that treatments targeting the modulatory role of α2A-adrenergic receptors in rescuing stress-induced cognitive deficits will vary as a function of the inverted-U shaped noradrenergic-mediated response to stress (Arnsten 2011, 2015; Berridge and Arnsten 2013).

4.1.1.2.1 The α2A-adrenergic receptor agonist guanfacine

Guanfacine is a selective and potent agonist of postsynaptic α2A-adrenergic receptors, capable of strengthening PFC network connections (Arnsten and Jin 2012; Arnsten 2020). Moreover, guanfacine treatment exhibits pro-cognitive effects across species (Arnsten 2020). In 2009, the FDA approved a long-acting formulation of the drug (Intuniv™) for the treatment of ADHD in children.

Mice with a single copy deletion of the neurofibromatosis 1 (NF1) gene, namely, NF1 (±) mice, are useful for the study of ADHD and associated deficits in inhibitory control, as NF1 mutations in humans are associated with ADHD in clinical populations (Hyman et al., 2005; Hyman et al., 2005) Using the delay discounting test as a proxy for choice impulsivity, NF1 (±) male mice displayed greater impulsivity when compared to the wild-type male mice. Treatment with guanfacine (0.3 mg/kg, i.p.) was effective in rescuing NF1 (±) mice deficits in choice impulsivity (Lukkes et al., 2020).

The repurposing of guanfacine for various indications linked to neurological and psychiatric disorders has increased significantly (Woolley 2023), bearing profound implications for the amelioration of cognitive deficits associated with cognitive dysfunction in a clinical population characterized as biotype 6 described in section 4.4.

4.1.2 Multiple neurotransmitter system targeting drug: modafinil success in the clinic

Modafinil is a prescription medication used to promote wakefulness and enhance cognitive function with a complex pharmacological profile, including the blockade of monoamines (noradrenaline, dopamine, and serotonin) as well as modulation of the glutamatergic and GABAergic system (Mereu et al., 2013). Modafinil is FDA-approved for use in individuals with multiple sleep-associated disorders, effectively aiding them in maintaining alertness during waking hours. In preclinical studies, acute but not chronic modafinil treatment promotes neurogenesis by increasing precursor cell proliferation and survival (Brandt et al., 2014). Modafinil treatment reversed stress-induced spatial memory deficits in rats (Alam and Choudhary 2023).In healthy individuals, short-term modafinil treatment improves cognition and attentional set-shifting (Turner et al., 2004). Schizophrenia-related cognitive impairments were also improved with acute modafinil treatment (Scoriels et al., 2013; Turner et al., 2004) but not with chronic administration (Sinkeviciute et al., 2018).

In remitted depressed patients with persistent cognitive symptoms, modafinil treatment significantly improved episodic and working memory, but no beneficial effects were detected on attention and planning strategies (Kaser et al., 2017). Furthermore, although systematic reviews and meta-analyses of the clinical use of augmentation drugs for depression show favorable results for modafinil (Goss et al., 2013; Nunez et al., 2022), clinical trials evaluating its effects on various cognitive domains are lacking.

4.1.3 Ketamine as a breakthrough leading to novel therapeutic modalities: glutamatergic and GABAergic system-targeting drugs

Ketamine, an NMDA receptor channel blocker, is a rapidly acting antidepressant with its (S)-isomer, (S)-ketamine (intranasal Spravato), approved by the FDA in 2019 for Treatment Resistant Depression (TRD). The fact that ketamine is mechanistically distinct from conventional monoamine-based antidepressants has stimulated research for drugs that would reproduce its rapid therapeutic effects associated with the improvement of depressive symptomatology without the confounds of its psychotomimetic and abuse-related properties.

The disinhibition hypothesis posits that ketamine initially blocks NMDA receptors on fast-spiking GABAergic neurons, thus promoting local inhibition of interneuron (Zanos and Gould 2018). Consequently, transient disinhibition of glutamatergic pyramidal cells occurs and rapidly induces AMPA receptor-mediated synaptic plasticity in relevant corticolimbic circuits. Furthermore, the disinhibition-induced plasticity of excitatory synapses weakened by chronic stress has become a therapeutic principle for achieving rapid (24 h after treatment) restoration of stress-induced deficits in reward sensitivity related to mood disorders (Thompson et al., 2015b).

In preclinical studies, ketamine has shown promising effects in correcting the effects of stress on executive functions. Ketamine administered 24 h before testing rescued deficits in set-shifting and reversal learning in stressed male rats (Jett et al., 2015). When ketamine was administered daily before stress, it prevented stress-induced deficits in set-shifting (Nikiforuk and Popik 2014). The prophylactic effects of ketamine have been reviewed recently (Evers et al., 2022). Moreover, a subanesthetic dose of ketamine in combination with an AMPAkine reduces premature responses in a motor impulsivity test in non-stressed rats (Davis-Reyes et al., 2021). Ketamine administration to TRD patients has been linked to improvements in executive function, visual memory, and working memory (Gill et al., 2021; Shiroma et al. 2014, 2022; Stippl et al., 2021). In addition, ketamine is associated with a reduction in suicidal ideation, with indications associating this effect to enhanced inhibitory control (Lee et al., 2016; Zhang and Ho 2016). It is worth noting that acute ketamine has been reported to also induce cognitive impairments (likely due to its psychotomimetic-inducing properties) in healthy but not in TRD patients. Specifically, in healthy volunteers, but not in TRD patients, ketamine administration was correlated with transient decreases in working memory, attention, and long-term memory measured up to 1 h post treatment (Harborne et al., 1996; Hetem et al., 2000; Morgan et al., 2004). Measures of functional connectivity in these cohorts revealed increases and decreases in frontostriatal functional connectivity in TRD and healthy individuals, respectively (Mkrtchian et al., 2021), reflecting the contrasting impacts of ketamine on executive function.

Given the side effects associated with the use of ketamine (Short et al., 2018), an alternative approach to promoting disinhibition of pyramidal neurons is to use subtype-selective modulation of benzodiazepine (BZ) site–containing GABAA receptors (GABAARs). Although α5-containing GABAARs (α5-GABAARs) comprise only 10% of total brain GABAARs, the expression of α5-GABAARs is enriched in the hippocampus and the prefrontal cortex. Selective a5-GABAAR negative allosteric modulators (a5-GABAAR-NAMs) such as L-655,708, aIA, and MRK-016 are being developed as potential cognitive enhancers with the idea of selectively targeting hippocampus and cortex (Atack 2011). Although selective a5-GABAAR-NAMs have been shown preclinically to improve memory in naïve rodents (Chambers et al., 2002; Street et al., 2004), they have not been extensively tested preclinically in stress-induced cognitive dysfunctions. Moreover, poor pharmacokinetics, toxicity issues, and low tolerance in older adults prevented further testing in humans (Atack 2010, 2011; Atack et al., 2009).

A more recently screened selective α5-GABAAR-NAM, Basmisanil, mitigated diazepam-induced hippocampal-dependent spatial learning impairment in male rats (assessed using the Morris water maze), and improved prefrontal cortex-mediated executive function in male non-human primates (evaluated using the object retrieval task in cynomolgus macaques) (Hipp et al., 2021). In addition, Basmisanil did not demonstrate anxiogenic or proconvulsant effects in male rats and Phase I clinical studies (Hipp et al., 2021). Therefore, Basmisanil possesses a favorable profile for exploring the potential therapeutic advantages of α5-GABAAR modulation.

In contrast to selective NAMs acting through the a5-GABAAR benzodiazepine binding site, S44819 is a recently identified GABA competitive antagonist at a5-GABAAR. It shares pro-cognitive effects with NAMs in preclinical studies, including inhibiting a5-GABAAR tonic current, enhancing LTP, reversing scopolamine-induced spatial working memory impairment, and improving object recognition memory (Etherington et al., 2017; Ling et al., 2015). Additional research is needed to explore its potential impact on stress-induced executive function deficits.

In addition to the beneficial effects of a5-GABAAR-NAMs discussed thus far, there is a body of work showing that selective positive allosteric modulators of the a5-GABAAR (a5-GABAAR-PAMs) have potential for the treatment of mood disorders as well as cognitive dysfunctions (Luscher et al., 2023; Prevot et al., 2019). Chronic treatment with the selective a5-GABAAR-PAM GL-II-73 rescued stress-induced and age-related working memory deficits in mice (Prevot et al., 2019). A putative reconciliation and working hypothesis explaining how a5-GABAAR-NAMs and a5-GABAAR-PAMs might exert similar outcomes has been proposed by Prevot and Sibille (Prevot and Sibille 2021) and is that both treatments increase signal-to-noise ratio of hippocampal and cortical transmission, although via distinct mechanism.

Many other compounds targeting the GABAergic system, collectively known as GABAkines, are currently being tested for the treatment of neurological and stress-induced psychiatric disorders (Cerne et al., 2022; Witkin et al., 2022; Zou et al., 2023).

4.2 Non-pharmacological treatments

4.2.1 Device-based neuromodulation

In contrast to pharmacological interventions, which predominantly target neurochemical communication between cells, device-based neuromodulation offers a distinct approach by selectively targeting specific components of neural cell activity, namely the membrane potentials in axons and dendrites. Device-based neuromodulation holds the potential to serve a dual role: first, as a valuable research tool, enabling the selective and non-invasive alteration of neural excitability to explore its effects on brain circuits and behavior; second, as an effective non-invasive therapeutic approach for stress-induced cognitive dysfunctions (Begemann et al., 2020). In this section, we describe clinical studies.

4.2.1.1 Transcranial magnetic stimulation (TMS)

During TMS, an alternating magnetic field produces weak electrical currents in the brain. The precise control of the magnetic field allows for non-invasive targeted stimulation, making it a valuable tool in neuroscience research and clinical practice. In 2008, TMS became FDA-approved for TRD. In 2017, deep TMS was approved as an adjunct treatment for OCD, and in 2020, for smoking cessation. The disadvantage of TMS is that it must be applied in a specialized clinical facility, as the equipment is large and expensive.

To test the hypothesis that impulsivity could be associated with poor weight management in obese patients, one group received deep TMS with active stimulation in the PFC and insula for 5 weeks, while the other received sham stimulation. The results showed a reduction of impulsivity in patients receiving deep TMS accompanied by significant improvement in body mass index, illustrating the effectiveness of deep TMS therapy in restoring the top-down inhibitory control of the PFC (Luzi et al., 2021).

A recent review evaluating the effectiveness of repetitive TMS (rTMS) to the PFC for TRD concludes that rTMS is reliable, well-tolerated, and efficacious (Adu et al., 2022). Nonetheless, although emerging evidence substantiates its short-term effectiveness in improving depressive symptomatology, there is a scarcity of literature supporting its long-term effects in cognitive symptom domains in TRD patients. Furthermore, to establish a standardized approach to rTMS implementation, further research is essential to explore variables such as frequency, intensity, pulse quantities, site of application, and inclusion of cognitive tests.

Regarding treatment for trauma-related disorders, a meta-analysis performed by Cirillo and colleagues (Cirillo et al., 2019) evaluating the effects of rTMS (ranging from 1 to 20 Hz) with traditional figure-of-eight coils to DLPFC indicates that rTMS is effective for PTSD and generalized anxiety disorders.

4.2.1.2 Transcranial direct current stimulation (tDCS)

tDCS is a safe way to non-invasively manipulate brain activity using weak electrical currents between two electrodes, one acting as a positive pole (anode) and the other as a negative pole (cathode) over the targeted cortical regions. The effects of tDCS will vary based on the polarity configuration, such that anodal stimulation promotes cell membrane depolarization, consequently increasing brain excitability. Cathodal stimulation has the opposite effect. The advantages of tDCS are portability and relatively low cost.

Evidence-based reviews of tDCS effectiveness in neurological and psychiatric disorders have been published (Fregni et al., 2021). Additionally, although the tDCS-induced current density is restricted primarily to the brain region surrounding the electrodes, the effects can be extended to distant neural networks, promoting broader connectivity-related effects (Ardolino et al., 2005; Cambiaghi et al., 2020). Researchers have increasingly used tDCS to investigate how cognitive and behavioral functions are linked to specific brain circuits. For example, applying anodal tDCS to the dorsolateral prefrontal cortex (DLPFC) in healthy individuals has been shown to improve planning (Dockery et al., 2009), working memory (Zaehle et al., 2011), attention (Stone and Tesche 2009), and reduced risk-taking behavior (Fecteau et al., 2007; Pripfl et al., 2013). Moreover, in patients with gambling disorder, anodal tDCS over the DLPFC improved decision-making and impulse control (Salatino et al., 2022). Another critical brain region with an established role in decision-making and impulse control is the OFC, and a small study in healthy individuals whereby anodal tDCS targeted the OFC showed improvement in decision-making and impulse control (Ouellet et al., 2015). A recent pilot study has established the feasibility of the use of tDCS over the OFC as a neuromodulatory non-invasive treatment of OCD (Fineberg et al., 2023).

In summary, non-invasive brain neuromodulation holds great promise regarding treatment options for cognitive dysfunctions. Recent research, with its emphasis on customizing brain stimulation to individual requirements, is pivotal in enhancing the effectiveness and safety of these techniques for all individuals. This personalized approach seeks to extend the advantages of brain stimulation to a broader spectrum of patients. A limited preliminary study suggested that anodal tDCS may improve extinction consolidation in patients with PTSD (Van't Wout et al., 2017).

4.2.2 Cognitive behavior therapy (CBT)

CBT encompasses a variety of techniques and strategies, including exposure therapy, aimed at identifying and modifying negative thought patterns and behaviors. Negatively biased cognitive inflexibility is present in both PTSD and depression, and it manifests as the automatic generation of thoughts, reactions, and interpretations consistently reinforced by avoidance behaviors.

Evidence-based exposure therapy treatments for PTSD revolve around reducing avoidance behaviors and actively engaging with traumatic memories. The cognitive element in the case of exposure therapy, where extinction plays a crucial role, is new learning-induced circuit-level plasticity, enabling cognitive flexibility and transitioning towards more adaptive and suitable behavioral responses. In a preclinical model of prolonged exposure therapy, one session of cue-conditioned fear extinction learning 24 h before testing rescued CUS-induced set-shifting impairments. Inhibition of protein synthesis within the IL mPFC during extinction prevented these behavioral effects, and the activity of IL mPFC glutamatergic neurons was necessary and sufficient for the therapeutic effects of extinction (Fucich et al. 2016, 2018; Paredes and Morilak 2019). At the circuit level, extinction reversed the CUS-induced attenuation of medial dorsal thalamus glutamatergic afferent-evoked electrical responses in IL mPFC (Fucich et al., 2018). While the ventral hippocampal afferent-evoked electrical responses in the IL mPFC were not affected by CUS, BDNF signaling within this pathway was necessary for the therapeutic effects of extinction (Paredes and Morilak 2023).

Although exposure therapy successfully improves PTSD-related cognitive dysfunctions (Nijdam and Vermetten 2018), a significant shortcoming is the high drop-out rate. Therefore, novel therapeutic approaches to enhance the effectiveness of exposure therapy are needed, as discussed in 4.2.3.

4.2.3 Therapy enhancement by adjunct treatment

Research evaluating novel therapeutic agents given in combination with well-established standard treatments, especially when patients have only partially responded, has gained attention in clinical and preclinical settings. The goal is to identify synergistic pairings that can enhance treatment effectiveness while minimizing the time it takes to achieve a response, and to minimize potential adverse effects or issues related to tolerability, to improve treatment results.

Krystal and Neumeister (Krystal and Neumeister 2009) proposed that combined exposure therapy and pharmacotherapy for PTSD act to enhance neuroplasticity, likely by activating neurotrophic factor signaling. In preclinical studies carried out in both male and female rats, combining a sub-therapeutic dose of ketamine with an abbreviated, sub-threshold extinction learning protocol completely reversed CUS-induced set-shifting deficits (Paredes et al., 2022). These outcomes may arise from molecular mechanisms shared by extinction and ketamine, such as enhanced neuronal plasticity in relevant circuitry (e.g., hippocampus-mPFC) or increased BDNF signaling (Paredes and Morilak 2023). Other recent research combining the entactogen phenethylamine 3,4-methylenedioxymethamphetamine (MDMA) with psychotherapy has shown improvement in PTSD symptoms Such studies suggest novel drugs that may be useful in combination with behavioral interventions to shorten treatment duration and potentially enhance efficacy (Bahji et al., 2020; Mitchell et al., 2023; Sessa et al., 2019).

4.3 Future directions and conclusions

One promising approach to achieve better treatment outcomes is associated with the characterization of biotypes of stress-related psychiatric disorders, made possible by recent advances in brain imaging and computation. Six biotypes of depression have been characterized, and each one of those biotypes are clustered based on distinct dysfunctions in large-scale brain connectivity amongst patients with varying degrees of symptomatology (Drysdale et al., 2017; Williams 2016). These clusters can provide valuable insights into clinical outcomes following treatment interventions. Of relevance to this review, biotype 6 of depression, also known as the cognitive dysfunction biotype, is characterized by disruption of cognitive control circuitry connectivity (heavily linked to the DLPFC/ACC/Precentral Gyrus/Dorsal Parietal Cortex) (Hack et al., 2023; Williams 2016), and no response to SSRIs (Tozzi et al., 2020). A clinical trial-guided study is currently in Phase 4, testing the drug guanfacine, which mechanism of action was discussed in 4.1.1.2, as a novel therapy for cognitive impairment in biotype 6 of depression, targeting the DLPFC (NCT04181736).

Therefore, assessment of individual brain connectivity maps may inform predictions regarding treatment response, facilitating selection of more tailored and effective treatments for patients with varying degrees of executive function impairment.

In summary, the field is confronted with several crucial challenges.1. Mechanistic Insights into Subtypes: There is a need to develop a deeper mechanistic understanding of various subtypes of stress-related psychiatric disorders to pave the way to develop precise individualized therapeutic strategies. Preclinically, such insights will serve as a testing ground for tailored interventions.

2. Emphasis on Prediction and Prevention: Shifting the focus toward then predicting and preventing stress-related cognitive dysfunction is a crucial challenge. Identifying subtypes and risk factors, and strategies to mitigate them, the field can lead to significant strides in reducing the overall burden of these conditions.

These challenges underscore the need for multidisciplinary complementary research combining reductionist science, personalized medicine, and validated animal models to address stress-related cognitive dysfunctions and develop strategies to manage them before they progress to clinical disorder.

Funding

This work was supported by the 10.13039/100000025 National Institute of Mental Health (research grant R01MH053851), by the 10.13039/100000738 US Department of Veterans Affairs 10.13039/100007496 Biomedical Laboratory Research and Development Program (merit award I01BX000559, and grant I01BX003512) and by a UTH Center for Biomedical Neuroscience Pilot Project Grant. The contents of this paper do not represent the views of the Department of Veterans Affairs or the US Government.

CRediT authorship contribution statement

Milena Girotti: Writing – review & editing, Writing – original draft, Conceptualization. Sarah E. Bulin: Writing – review & editing, Writing – original draft, Conceptualization. Flavia R. Carreno: Writing – review & editing, Writing – original draft, Conceptualization.

Declaration of competing interest

The authors have nothing to declare.
==== Refs
References

Abdul-Monim Z. Neill J.C. Reynolds G.P. Sub-chronic psychotomimetic phencyclidine induces deficits in reversal learning and alterations in parvalbumin-immunoreactive expression in the rat J. Psychopharmacol. 21 2007 198 205 17329300
Abela A.R. Dougherty S.D. Fagen E.D. Hill C.J. Chudasama Y. Inhibitory control deficits in rats with ventral hippocampal lesions Cereb Cortex 23 2013 1396 1409 22615141
Acosta G.B. Otero Losada M.E. Rubio M.C. Area-dependent changes in GABAergic function after acute and chronic cold stress Neurosci. Lett. 154 1993 175 178 8361637
Adam E.M. Johns T. Sur M. Dynamic control of visually guided locomotion through corticosubthalamic projections Cell Rep. 40 2022 111139
Adams T.G. Kelmendi B. Brake C.A. Gruner P. Badour C.L. Pittenger C. The role of stress in the pathogenesis and maintenance of obsessive-compulsive disorder Chronic Stress (Thousand Oaks) 2 2018
Adler S.M. Girotti M. Morilak D.A. Optogenetically-induced long term depression in the rat orbitofrontal cortex ameliorates stress-induced reversal learning impairment Neurobiol Stress 13 2020 100258
Adu M.K. Shalaby R. Chue P. Agyapong V.I.O. Repetitive transcranial magnetic stimulation for the treatment of resistant depression: a scoping review Behav. Sci. 12 2022
Alam N. Choudhary K. Neurochemical effects of methylphenidate and modafinil in ameliorating stress-induced cognitive deficits ACS Pharmacol. Transl. Sci. 6 2023 1357 1372 37854618
Albasser M.M. Amin E. Lin T.C. Iordanova M.D. Aggleton J.P. Evidence that the rat hippocampus has contrasting roles in object recognition memory and object recency memory Behav. Neurosci. 126 2012 659 669 23025831
Alexander J.K. Hillier A. Smith R.M. Tivarus M.E. Beversdorf D.Q. Beta-adrenergic modulation of cognitive flexibility during stress J Cogn Neurosci 19 2007 468 478 17335395
Anderson R.M. Johnson S.B. Lingg R.T. Hinz D.C. Romig-Martin S.A. Radley J.J. Evidence for similar prefrontal structural and functional alterations in male and female rats following chronic stress or glucocorticoid exposure Cereb Cortex 30 2020 353 370 31184364
Apud J.A. Mattay V. Chen J. Kolachana B.S. Callicott J.H. Tolcapone improves cognition and cortical information processing in normal human subjects Neuropsychopharmacology 32 2007 1011 1020 17063156
Ardolino G. Bossi B. Barbieri S. Priori A. Non-synaptic mechanisms underlie the after-effects of cathodal transcutaneous direct current stimulation of the human brain J Physiol 568 2005 653 663 16037080
Arnsten A.F. Stress weakens prefrontal networks: molecular insults to higher cognition Nat. Neurosci. 18 2015 1376 1385 26404712
Arnsten A.F. Cai J.X. Goldman-Rakic P.S. The alpha-2 adrenergic agonist guanfacine improves memory in aged monkeys without sedative or hypotensive side effects: evidence for alpha-2 receptor subtypes J. Neurosci. 8 1988 4287 4298 2903226
Arnsten A.F. Jin L.E. Guanfacine for the treatment of cognitive disorders: a century of discoveries at Yale Yale J. Biol. Med. 85 2012 45 58 22461743
Arnsten A.F.T. Catecholamine influences on dorsolateral prefrontal cortical networks Biol Psychiatry 69 2011 e89 e99 21489408
Arnsten A.F.T. Guanfacine's mechanism of action in treating prefrontal cortical disorders: Successful translation across species Neurobiol. Learn. Mem. 176 2020 107327
Aron A.R. Fletcher P.C. Bullmore E.T. Sahakian B.J. Robbins T.W. Stop-signal inhibition disrupted by damage to right inferior frontal gyrus in humans Nat. Neurosci. 6 2003 115 116 12536210
Aron A.R. Herz D.M. Brown P. Forstmann B.U. Zaghloul K. Frontosubthalamic circuits for control of action and cognition J. Neurosci. 36 2016 11489 11495 27911752
Atack J.R. Preclinical and clinical pharmacology of the GABAA receptor alpha5 subtype-selective inverse agonist alpha5IA Pharmacol. Ther. 125 2010 11 26 19770002
Atack J.R. GABAA receptor subtype-selective modulators. II. alpha5-selective inverse agonists for cognition enhancement Curr. Top. Med. Chem. 11 2011 1203 1214 21050171
Atack J.R. Maubach K.A. Wafford K.A. O'Connor D. Rodrigues A.D. In vitro and in vivo properties of 3-tert-butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylmethoxy)-pyrazolo[1,5-d]-[1,2,4]triazine (MRK-016), a GABAA receptor alpha5 subtype-selective inverse agonist J Pharmacol Exp Ther 331 2009 470 484 19704033
Auger M.L. Floresco S.B. Prefrontal cortical GABA modulation of spatial reference and working memory Int. J. Neuropsychopharmacol. 18 2014
Aura J. Riekkinen P. Jr. Blockade of NMDA receptors located at the dorsomedial prefrontal cortex impairs spatial working memory in rats Neuroreport 10 1999 243 248 10203316
Baddeley A. Working memory Science 255 1992 556 559 1736359
Bahji A. Forsyth A. Groll D. Hawken E.R. Efficacy of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for posttraumatic stress disorder: a systematic review and meta-analysis Prog. Neuro-Psychopharmacol. Biol. Psychiatry 96 2020 109735
Banasr M. Valentine G.W. Li X.-Y. Gourley S.L. Taylor J.R. Duman R.S. Chronic unpredictable stress decreases cell proliferation in the cerebral cortex of the adult rat Biol Psychiatry 62 2007 496 504 17585885
Bangasser D.A. Kawasumi Y. Cognitive disruptions in stress-related psychiatric disorders: a role for corticotropin releasing factor (CRF) Horm. Behav. 76 2015 125 135 25888454
Banqueri M. Gutierrez-Menendez A. Mendez M. Conejo N.M. Arias J.L. Early life stress due to repeated maternal separation alters the working memory acquisition brain functional network Stress 24 2021 87 95 32510270
Bardin L. Malfetes N. Newman-Tancredi A. Depoortere R. Chronic restraint stress induces mechanical and cold allodynia, and enhances inflammatory pain in rat: relevance to human stress-associated painful pathologies Behav. Brain Res. 205 2009 360 366 19616033
Bari A. Dalley J.W. Robbins T.W. The application of the 5-choice serial reaction time task for the assessment of visual attentional processes and impulse control in rats Nat. Protoc. 3 2008 759 767 18451784
Bari A. Robbins T.W. Inhibition and impulsivity: behavioral and neural basis of response control Prog Neurobiol 108 2013 44 79 23856628
Barker G.R. Warburton E.C. When is the hippocampus involved in recognition memory? J. Neurosci. 31 2011 10721 10731 21775615
Bauduin S. van der Pal Z. Pereira A.M. Meijer O.C. Giltay E.J. Cortical thickness abnormalities in long-term remitted Cushing's disease Transl. Psychiatry 10 2020 293 32826851
Baunez C. Robbins T.W. Bilateral lesions of the subthalamic nucleus induce multiple deficits in an attentional task in rats Eur. J. Neurosci. 9 1997 2086 2099 9421169
Begemann M.J. Brand B.A. Curcic-Blake B. Aleman A. Sommer I.E. Efficacy of non-invasive brain stimulation on cognitive functioning in brain disorders: a meta-analysis Psychol. Med. 50 2020 2465 2486 33070785
Ben-Zion Z. Fine N.B. Keynan N.J. Admon R. Green N. Cognitive flexibility predicts PTSD symptoms: observational and interventional studies Front Psychiatry 9 2018 477 30337890
Bennabi D. Haffen E. Van Waes V. Vortioxetine for cognitive enhancement in major depression: from animal models to clinical research Front Psychiatry 10 2019 771 31780961
Bermond B. Surachno S. Lok A. ten Berge I.J. Plasmans B. Memory functions in prednisone-treated kidney transplant patients Clin. Transplant. 19 2005 512 517 16008597
Bermudez-Rattoni F. The forgotten insular cortex: its role on recognition memory formation Neurobiol. Learn. Mem. 109 2014 207 216 24406466
Bernosky-Smith K.A. Qiu Y.Y. Feja M. Lee Y.B. Loughlin B. Ventral tegmental area D2 receptor knockdown enhances choice impulsivity in a delay-discounting task in rats Behav. Brain Res. 341 2018 129 134 29287910
Berridge C.W. Arnsten A.F. Psychostimulants and motivated behavior: arousal and cognition Neurosci. Biobehav. Rev. 37 2013 1976 1984 23164814
Besson M. Belin D. McNamara R. Theobald D.E. Castel A. Dissociable control of impulsivity in rats by dopamine d2/3 receptors in the core and shell subregions of the nucleus accumbens Neuropsychopharmacology 35 2010 560 569 19847161
Birrell J.M. Brown V.J. Medial frontal cortex mediates perceptual attentional set shifting in the rat J. Neurosci. 20 2000 4320 4324 10818167
Bissonette G.B. Martins G.J. Franz T.M. Harper E.S. Schoenbaum G. Powell E.M. Double dissociation of the effects of medial and orbital prefrontal cortical lesions on attentional and affective shifts in mice J. Neurosci. 28 2008 11124 11130 18971455
Bizot J. Le Bihan C. Puech A.J. Hamon M. Thiebot M. Serotonin and tolerance to delay of reward in rats Psychopharmacology (Berl) 146 1999 400 412 10550490
Boehme R. Lorenz R.C. Gleich T. Romund L. Pelz P. Reversal learning strategy in adolescence is associated with prefrontal cortex activation Eur. J. Neurosci. 45 2017 129 137 27628616
Bogdan R. Pizzagalli D.A. Acute stress reduces reward responsiveness: implications for depression Biol Psychiatry 60 2006 1147 1154 16806107
Bolkan S.S. Stujenske J.M. Parnaudeau S. Spellman T.J. Rauffenbart C. Thalamic projections sustain prefrontal activity during working memory maintenance Nat. Neurosci. 20 2017 987 996 28481349
Bondi C.O. Barrera G. Lapiz M.D.S. Bédard T. Mahan A. Morilak D.A. Noradrenergic facilitation of shock-probe defensive burying in lateral septum of rats, and modulation by chronic treatment with desipramine Prog. Neuro-Psychopharmacol. Biol. Psychiatry 31 2007 482 495
Bondi C.O. Jett J.D. Morilak D.A. Beneficial effects of desipramine on cognitive function of chronically stressed rats are mediated by alpha1-adrenergic receptors in medial prefrontal cortex Prog. Neuro-Psychopharmacol. Biol. Psychiatry 34 2010 913 923
Bondi C.O. Rodriguez G. Gould G.G. Frazer A. Morilak D.A. Chronic unpredictable stress induces a cognitive deficit and anxiety-like behavior in rats that is prevented by chronic antidepressant drug treatment Neuropsychopharmacology 33 2008 320 331 17406647
Boulougouris V. Castane A. Robbins T.W. Dopamine D2/D3 receptor agonist quinpirole impairs spatial reversal learning in rats: investigation of D3 receptor involvement in persistent behavior Psychopharmacology (Berl) 202 2009 611 620 18836703
Boulougouris V. Glennon J.C. Robbins T.W. Dissociable effects of selective 5-HT2A and 5-HT2C receptor antagonists on serial spatial reversal learning in rats Neuropsychopharmacology 33 2008 2007 2019 17957219
Bourdeau I. Bard C. Noel B. Leclerc I. Cordeau M.P. Loss of brain volume in endogenous Cushing's syndrome and its reversibility after correction of hypercortisolism J. Clin. Endocrinol. Metab. 87 2002 1949 1954 11994323
Brady A.M. Floresco S.B. Operant procedures for assessing behavioral flexibility in rats J. Vis. Exp. 2015 e52387
Brandt M.D. Ellwardt E. Storch A. Short- and long-term treatment with modafinil differentially affects adult hippocampal neurogenesis Neuroscience 278 2014 267 275 25158676
Brenhouse H.C. Andersen S.L. Nonsteroidal anti-inflammatory treatment prevents delayed effects of early life stress in rats Biol Psychiatry 70 2011 434 440 21679927
Brigman J.L. Daut R.A. Wright T. Gunduz-Cinar O. Graybeal C. GluN2B in corticostriatal circuits governs choice learning and choice shifting Nat. Neurosci. 16 2013 1101 1110 23831965
Brown E.S. Jw D. Frol A. Bobadilla L. Khan D.A. Hippocampal volume, spectroscopy, cognition, and mood in patients receiving corticosteroid therapy Biol Psychiatry 55 2004 538 545 15023583
Brown S.M. Henning S. Wellman C.L. Mild, short-term stress alters dendritic morphology in rat medial prefrontal cortex Cereb Cortex 15 2005 1714 1722 15703248
Brozoski T.J. Brown R.M. Rosvold H.E. Goldman P.S. Cognitive deficit caused by regional depletion of dopamine in prefrontal cortex of rhesus monkey Science 205 1979 929 932 112679
Bryce C.A. Howland J.G. Stress facilitates late reversal learning using a touchscreen-based visual discrimination procedure in male Long Evans rats Behav. Brain Res. 278 2015 21 28 25251839
Buhusi M. Olsen K. Buhusi C.V. Increased temporal discounting after chronic stress in CHL1-deficient mice is reversed by 5-HT2C agonist Ro 60-0175 Neuroscience 357 2017 110 118 28583411
Bulin S.E. Hohl K.M. Paredes D. Silva J.D. Morilak D.A. Bidirectional optogenetically-induced plasticity of evoked responses in the rat medial prefrontal cortex can impair or enhance cognitive set-shifting eNeuro 7 2020
Butts K.A. Floresco S.B. Phillips A.G. Acute stress impairs set-shifting but not reversal learning Behav. Brain Res. 252 2013 222 229 23764458
Buynitsky T. Mostofsky D.I. Restraint stress in biobehavioral research: recent developments Neurosci. Biobehav. Rev. 33 2009 1089 1098 19463853
Bymaster F.P. Katner J.S. Nelson D.L. Hemrick-Luecke S.K. Threlkeld P.G. Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder Neuropsychopharmacology 27 2002 699 711 12431845
Cambiaghi M. Buffelli M. Masin L. Valtorta F. Comai S. Transcranial direct current stimulation of the mouse prefrontal cortex modulates serotonergic neural activity of the dorsal raphe nucleus Brain Stimul. 13 2020 548 550 32289674
Canale N. Rubaltelli E. Vieno A. Pittarello A. Billieux J. Impulsivity influences betting under stress in laboratory gambling Sci. Rep. 7 2017 10668
Caprioli D. Hong Y.T. Sawiak S.J. Ferrari V. Williamson D.J. Baseline-dependent effects of cocaine pre-exposure on impulsivity and D2/3 receptor availability in the rat striatum: possible relevance to the attention-deficit hyperactivity syndrome Neuropsychopharmacology 38 2013 1460 1471 23399948
Caprioli D. Sawiak S.J. Merlo E. Theobald D.E. Spoelder M. Gamma aminobutyric acidergic and neuronal structural markers in the nucleus accumbens core underlie trait-like impulsive behavior Biol Psychiatry 75 2014 115 123 23973096
Cardinal R.N. Pennicott D.R. Sugathapala C.L. Robbins T.W. Everitt B.J. Impulsive choice induced in rats by lesions of the nucleus accumbens core Science 292 2001 2499 2501 11375482
Carli M. Robbins T.W. Evenden J.L. Everitt B.J. Effects of lesions to ascending noradrenergic neurones on performance of a 5-choice serial reaction task in rats; implications for theories of dorsal noradrenergic bundle function based on selective attention and arousal Behav. Brain Res. 9 1983 361 380 6639741
Carrier M. Simoncicova E. St-Pierre M.K. McKee C. Tremblay M.E. Psychological stress as a risk factor for accelerated cellular aging and cognitive decline: the involvement of microglia-neuron crosstalk Front. Mol. Neurosci. 14 2021 749737
Cerne R. Lippa A. Poe M.M. Smith J.L. Jin X. GABAkines - advances in the discovery, development, and commercialization of positive allosteric modulators of GABA(A) receptors Pharmacol. Ther. 234 2022 108035
Cerqueira J.J. Catania C. Sotiropoulos I. Schubert M. Kalisch R. Corticosteroid status influences the volume of the rat cingulate cortex - a magnetic resonance imaging study J. Psychiatr. Res. 39 2005 451 460 15992553
Cerqueira J.J. Mailliet F. Almeida O.F. Jay T.M. Sousa N. The prefrontal cortex as a key target of the maladaptive response to stress J. Neurosci. 27 2007 2781 2787 17360899
Cerqueira J.J. Pego J.M. Taipa R. Bessa J.M. Almeida O.F. Sousa N. Morphological correlates of corticosteroid-induced changes in prefrontal cortex-dependent behaviors J. Neurosci. 25 2005 7792 7800 16120780
Cerqueira J.J. Taipa R. Uylings H.B. Almeida O.F. Sousa N. Specific configuration of dendritic degeneration in pyramidal neurons of the medial prefrontal cortex induced by differing corticosteroid regimens Cereb Cortex 17 2007 1998 2006 17082516
Chambers M.S. Atack J.R. Bromidge F.A. Broughton H.B. Cook S. 6,7-Dihydro-2-benzothiophen-4(5H)-ones: a novel class of GABA-A alpha5 receptor inverse agonists J. Med. Chem. 45 2002 1176 1179 11881985
Chao O.Y. Nikolaus S. Yang Y.M. Huston J.P. Neuronal circuitry for recognition memory of object and place in rodent models Neurosci. Biobehav. Rev. 141 2022 104855
Chen Y. Kramar E.A. Chen L.Y. Babayan A.H. Andres A.L. Impairment of synaptic plasticity by the stress mediator CRH involves selective destruction of thin dendritic spines via RhoA signaling Mol Psychiatry 18 2013 485 496 22411227
Chudasama Y. Baunez C. Robbins T.W. Functional disconnection of the medial prefrontal cortex and subthalamic nucleus in attentional performance: evidence for corticosubthalamic interaction J. Neurosci. 23 2003 5477 5485 12843247
Chudasama Y. Bussey T.J. Muir J.L. Effects of selective thalamic and prelimbic cortex lesions on two types of visual discrimination and reversal learning Eur. J. Neurosci. 14 2001 1009 1020 11595039
Chudasama Y. Passetti F. Rhodes S.E. Lopian D. Desai A. Robbins T.W. Dissociable aspects of performance on the 5-choice serial reaction time task following lesions of the dorsal anterior cingulate, infralimbic and orbitofrontal cortex in the rat: differential effects on selectivity, impulsivity and compulsivity Behav. Brain Res. 146 2003 105 119 14643464
Cirillo P. Gold A.K. Nardi A.E. Ornelas A.C. Nierenberg A.A. Transcranial magnetic stimulation in anxiety and trauma-related disorders: a systematic review and meta-analysis Brain Behav 9 2019 e01284
Clancy F. Prestwich A. Caperon L. O'Connor D.B. Perseverative cognition and health behaviors: a systematic review and meta-analysis Front. Hum. Neurosci. 10 2016 534 27877119
Clarke H.F. Dalley J.W. Crofts H.S. Robbins T.W. Roberts A.C. Cognitive inflexibility after prefrontal serotonin depletion Science 304 2004 878 880 15131308
Clarke H.F. Hill G.J. Robbins T.W. Roberts A.C. Dopamine, but not serotonin, regulates reversal learning in the marmoset caudate nucleus J. Neurosci. 31 2011 4290 4297 21411670
Clarke H.F. Walker S.C. Crofts H.S. Dalley J.W. Robbins T.W. Roberts A.C. Prefrontal serotonin depletion affects reversal learning but not attentional set shifting J. Neurosci. 25 2005 532 538 15647499
Clarke H.F. Walker S.C. Dalley J.W. Robbins T.W. Roberts A.C. Cognitive inflexibility after prefrontal serotonin depletion is behaviorally and neurochemically specific Cerebr. Cortex 17 2007 18 27
Clatworthy P.L. Lewis S.J. Brichard L. Hong Y.T. Izquierdo D. Dopamine release in dissociable striatal subregions predicts the different effects of oral methylphenidate on reversal learning and spatial working memory J. Neurosci. 29 2009 4690 4696 19369539
Cole M.A. Kalman B.A. Pace T.W.W. Topczewski F. Lowrey M.J. Spencer R.L. Selective blockade of the mineralocorticoid receptor impairs hypothalamic-pituitary-adrenal axis expression of habituation J. Neuroendocrinol. 12 2000 1034 1042 11012846
Coluccia D. Wolf O.T. Kollias S. Roozendaal B. Forster A. de Quervain D.J. Glucocorticoid therapy-induced memory deficits: acute versus chronic effects J. Neurosci. 28 2008 3474 3478 18367613
Conrad C.D. A critical review of chronic stress effects on spatial learning and memory Prog. Neuro-Psychopharmacol. Biol. Psychiatry 34 2010 742 755
Cook S.C. Wellman C.L. Chronic stress alters dendritic morphology in rat medial prefrontal cortex J. Neurobiol. 60 2004 236 248 15266654
Cools R. Clark L. Owen A.M. Robbins T.W. Defining the neural mechanisms of probabilistic reversal learning using event-related functional magnetic resonance imaging J. Neurosci. 22 2002 4563 4567 12040063
Cope Z.A. Vazey E.M. Floresco S.B. Aston Jones G.S. DREADD-mediated modulation of locus coeruleus inputs to mPFC improves strategy set-shifting Neurobiol. Learn. Mem. 161 2019 1 11 30802603
Cornelisse S. Joels M. Smeets T. A randomized trial on mineralocorticoid receptor blockade in men: effects on stress responses, selective attention, and memory Neuropsychopharmacology 36 2011 2720 2728 21881569
Cornelisse S. van Stegeren A.H. Joels M. Implications of psychosocial stress on memory formation in a typical male versus female student sample Psychoneuroendocrinology 36 2011 569 578 20933337
Correll C.M. Rosenkranz J.A. Grace A.A. Chronic cold stress alters prefrontal cortical modulation of amygdala neuronal activity in rats Biol Psychiatry 58 2005 382 391 16023619
Costa V.D. Tran V.L. Turchi J. Averbeck B.B. Reversal learning and dopamine: a bayesian perspective J. Neurosci. 35 2015 2407 2416 25673835
Courtney S.M. Petit L. Maisog J.M. Ungerleider L.G. Haxby J.V. An area specialized for spatial working memory in human frontal cortex Science 279 1998 1347 1351 9478894
Craine T.J. Race N.S. Kutash L.A. Iouchmanov A.L. Moschonas E.H. Milnacipran ameliorates executive function impairments following frontal lobe traumatic brain injury in male rats: a multimodal behavioral assessment J. Neurotrauma 40 2023 112 124 35979888
Crean J. Richards J.B. de Wit H. Effect of tryptophan depletion on impulsive behavior in men with or without a family history of alcoholism Behav. Brain Res. 136 2002 349 357 12429396
Crofts H.S. Dalley J.W. Collins P. Van Denderen J.C. Everitt B.J. Differential effects of 6-OHDA lesions of the frontal cortex and caudate nucleus on the ability to acquire an attentional set Cerebr. Cortex 11 2001 1015 1026
Curtis A.L. Lechner S.M. Pavcovich L.A. Valentino R.J. Activation of the locus coeruleus noradrenergic system by intracoerulear microinfusion of corticotropin-releasing factor: effects on discharge rate, cortical norepinephrine levels and cortical electroencephalographic activity J Pharmacol Exp Ther 281 1997 163 172 9103494
Dagher A. Mapping the hyper-direct circuitry of impulsivity Brain 143 2020 1973 1974 32671403
Dalley J.W. Everitt B.J. Robbins T.W. Impulsivity, compulsivity, and top-down cognitive control Neuron 69 2011 680 694 21338879
Dalley J.W. Fryer T.D. Brichard L. Robinson E.S. Theobald D.E. Nucleus accumbens D2/3 receptors predict trait impulsivity and cocaine reinforcement Science 315 2007 1267 1270 17332411
Dalley J.W. Robbins T.W. Fractionating impulsivity: neuropsychiatric implications Nat. Rev. Neurosci. 18 2017 158 171
Dalley J.W. Theobald D.E. Eagle D.M. Passetti F. Robbins T.W. Deficits in impulse control associated with tonically-elevated serotonergic function in rat prefrontal cortex Neuropsychopharmacology 26 2002 716 728 12007742
Dalton G.L. Ma L.M. Phillips A.G. Floresco S.B. Blockade of NMDA GluN2B receptors selectively impairs behavioral flexibility but not initial discrimination learning Psychopharmacology 216 2011 525 535 21384103
Dambacher F. Sack A.T. Lobbestael J. Arntz A. Brugman S. Schuhmann T. Out of control: evidence for anterior insula involvement in motor impulsivity and reactive aggression Soc Cogn Affect Neurosci 10 2015 508 516 24837479
Danet M. Lapiz-Bluhm S. Morilak D.A. A cognitive deficit induced in rats by chronic intermittent cold stress is reversed by chronic antidepressant treatment Int. J. Neuropsychopharmacol. 13 2010 997 1009 20149267
Davis-Reyes B.D. Smith A.E. Xu J. Cunningham K.A. Zhou J. Anastasio N.C. Subanesthetic ketamine with an AMPAkine attenuates motor impulsivity in rats Behav. Pharmacol. 32 2021 335 344 33595955
De Alcubierre D. Ferrari D. Mauro G. Isidori A.M. Tomlinson J.W. Pofi R. Glucocorticoids and cognitive function: a walkthrough in endogenous and exogenous alterations J. Endocrinol. Invest. 46 2023 1961 1982 37058223
de Kloet E.R. Functional profile of the binary brain corticosteroid receptor system: mediating, multitasking, coordinating, integrating Eur. J. Pharmacol. 719 2013 53 62 23876452
de Kloet E.R. Joels M. The cortisol switch between vulnerability and resilience Mol Psychiatry 2023
Delahaye M. Lemoine P. Cartwright S. Deuring G. Beck J. Learning aptitude, spatial orientation and cognitive flexibility tested in a virtual labyrinth after virtual stress induction BMC Psychol 3 2015 22 26146558
Desrochers S.S. Spring M.G. Nautiyal K.M. A role for serotonin in modulating opposing drive and brake circuits of impulsivity Front. Behav. Neurosci. 16 2022 791749
Deuter C.E. Wingenfeld K. Schultebraucks K. Otte C. Kuehl L.K. Influence of glucocorticoid and mineralocorticoid receptor stimulation on task switching Horm. Behav. 109 2019 18 24 30684522
Di S. Malcher-Lopes R. Halmos K.C. Tasker J.G. Nongenomic glucocorticoid inhibition via endocannabinoid release in the hypothalamus: a fast feedback mechanism J. Neurosci. 23 2003 4850 4857 12832507
Diamond A. Executive functions Annu. Rev. Psychol. 64 2013 135 168 23020641
Dias R. Robbins T.W. Roberts A.C. Primate analogue of the Wisconsin Card Sorting Test: effects of excitotoxic lesions of the prefrontal cortex of the marmoset Behav. Neurosci. 110 1996 872 886 8918991
Dias-Ferreira E. Sousa J.C. Melo I. Morgado P. Mesquita A.R. Chronic stress causes frontostriatal reorganization and affects decision-making Science 325 2009 621 625 19644122
Disner S.G. Beevers C.G. Haigh E.A.P. Beck A.T. Neural mechanisms of the cognitive model of depression Nat. Rev. Neurosci. 12 2011 467 477 21731066
Dockery C.A. Hueckel-Weng R. Birbaumer N. Plewnia C. Enhancement of planning ability by transcranial direct current stimulation J. Neurosci. 29 2009 7271 7277 19494149
Donegan J.J. Girotti M. Weinberg M.S. Morilak D.A. A novel role for brain interleukin-6: facilitation of cognitive flexibility in rat orbitofrontal cortex J. Neurosci. 34 2014 953 962 24431453
Dong Z. Bai Y. Wu X. Li H. Gong B. Hippocampal long-term depression mediates spatial reversal learning in the Morris water maze Neuropharmacology 64 2013 65 73 22732443
Dossi G. Delvecchio G. Prunas C. Soares J.C. Brambilla P. Neural bases of cognitive impairments in post-traumatic stress disorders: a mini-review of functional magnetic resonance imaging findings Front Psychiatry 11 2020 176 32256405
Dougherty D.M. Mullen J. Hill-Kapturczak N. Liang Y. Karns T.E. Effects of tryptophan depletion and a simulated alcohol binge on impulsivity Exp. Clin. Psychopharmacol 23 2015 109 121 25730415
Drevets W.C. Orbitofrontal cortex function and structure in depression Ann. N. Y. Acad. Sci. 1121 2007 499 527 17872395
Drysdale A.T. Grosenick L. Downar J. Dunlop K. Mansouri F. Resting-state connectivity biomarkers define neurophysiological subtypes of depression Nat Med 23 2017 28 38 27918562
Duffy S. Labrie V. Roder J.C. D-serine augments NMDA-NR2B receptor-dependent hippocampal long-term depression and spatial reversal learning Neuropsychopharmacology 33 2008 1004 1018 17625504
Eagle D.M. Baunez C. Is there an inhibitory-response-control system in the rat? Evidence from anatomical and pharmacological studies of behavioral inhibition Neurosci. Biobehav. Rev. 34 2010 50 72 19615404
Eagle D.M. Baunez C. Hutcheson D.M. Lehmann O. Shah A.P. Robbins T.W. Stop-signal reaction-time task performance: role of prefrontal cortex and subthalamic nucleus Cereb Cortex 18 2008 178 188 17517682
Ennaceur A. Aggleton J.P. The effects of neurotoxic lesions of the perirhinal cortex combined to fornix transection on object recognition memory in the rat Behav. Brain Res. 88 1997 181 193 9404627
Etherington L.A. Mihalik B. Palvolgyi A. Ling I. Pallagi K. Selective inhibition of extra-synaptic alpha5-GABA(A) receptors by S44819, a new therapeutic agent Neuropharmacology 125 2017 353 364 28807671
Ettman C.K. Abdalla S.M. Cohen G.H. Sampson L. Vivier P.M. Galea S. Prevalence of depression symptoms in US adults before and during the COVID-19 pandemic JAMA Netw. Open 3 2020 e2019686
Evenden J. The pharmacology of impulsive behaviour in rats V: the effects of drugs on responding under a discrimination task using unreliable visual stimuli Psychopharmacology (Berl) 143 1999 111 122 10326773
Evenden J.L. Varieties of impulsivity Psychopharmacology (Berl) 146 1999 348 361 10550486
Evers A.G. Murrough J.W. Charney D.S. Costi S. Ketamine as a prophylactic resilience-enhancing agent Front Psychiatry 13 2022 833259
Fecteau S. Pascual-Leone A. Zald D.H. Liguori P. Theoret H. Activation of prefrontal cortex by transcranial direct current stimulation reduces appetite for risk during ambiguous decision making J. Neurosci. 27 2007 6212 6218 17553993
Fineberg N.A. Cinosi E. Smith M.V.A. Busby A.D. Wellsted D. Feasibility, acceptability and practicality of transcranial stimulation in obsessive compulsive symptoms (FEATSOCS): a randomised controlled crossover trial Compr Psychiatry 122 2023 152371
Fletcher P.J. Tampakeras M. Sinyard J. Higgins G.A. Opposing effects of 5-HT(2A) and 5-HT(2C) receptor antagonists in the rat and mouse on premature responding in the five-choice serial reaction time test Psychopharmacology (Berl) 195 2007 223 234 17673981
Floresco S.B. Prefrontal dopamine and behavioral flexibility: shifting from an "inverted-U" toward a family of functions Front. Neurosci. 7 2013 62 23626521
Floresco S.B. Block A.E. Tse M.T. 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 2008 85 96 18359099
Fonseca M.S. Murakami M. Mainen Z.F. Activation of dorsal raphe serotonergic neurons promotes waiting but is not reinforcing Curr. Biol. 25 2015 306 315 25601545
Franco C.Y. Knowlton B.J. Effects of early-life stress on probabilistic reversal learning and response perseverance in young adults Neurobiol. Learn. Mem. 205 2023 107839
Fregni F. El-Hagrassy M.M. Pacheco-Barrios K. Carvalho S. Leite J. Evidence-based guidelines and secondary meta-analysis for the use of transcranial direct current stimulation in neurological and psychiatric disorders Int. J. Neuropsychopharmacol. 24 2021 256 313 32710772
Fucich E.A. Paredes D. Morilak D.A. Therapeutic effects of extinction learning as a model of exposure therapy in rats Neuropsychopharmacology 41 2016 3092 3102 27417516
Fucich E.A. Paredes D. Saunders M. Morilak D.A. Activity in the ventral medial prefrontal cortex is necessary for the therapeutic effects of extinction in rats J. Neurosci. 2018 (in press)
Fuge P. Aust S. Fan Y. Weigand A. Gartner M. Interaction of early life stress and corticotropin-releasing hormone receptor gene: effects on working memory Biol Psychiatry 76 2014 888 894 24931706
Furr A. Lapiz-Bluhm D.S. Morilak D.A. 5-HT2A-receptors in the orbitofrontal cortex facilitate reversal learning and contribute to the beneficial cognitive effects of chronic citalopram treatment in rats Int. J. Neuropsychopharmacol. 15 2012 1295 1305 22008191
Fuster J.M. Alexander G.E. Neuron activity related to short-term memory Science 173 1971 652 654 4998337
Fuster J.M. Alexander G.E. Firing changes in cells of the nucleus medialis dorsalis associated with delayed response behavior Brain Res. 61 1973 79 91 4204130
Gallagher P. Massey A.E. Young A.H. McAllister-Williams R.H. Effects of acute tryptophan depletion on executive function in healthy male volunteers BMC Psychiatr. 3 2003 10
Garrett J.E. Wellman C.L. Chronic stress effects on dendritic morphology in medial prefrontal cortex: sex differences and estrogen dependence Neuroscience 162 2009 195 207 19401219
Geissler C.F. Friehs M.A. Frings C. Domes G. Time-dependent effects of acute stress on working memory performance: a systematic review and hypothesis Psychoneuroendocrinology 148 2023 105998
George S.A. Rodriguez-Santiago M. Riley J. Abelson J.L. Floresco S.B. Liberzon I. Alterations in cognitive flexibility in a rat model of post-traumatic stress disorder Behav. Brain Res. 286 2015 256 264 25746511
Ghahremani D.G. Monterosso J. Jentsch J.D. Bilder R.M. Poldrack R.A. Neural components underlying behavioral flexibility in human reversal learning Cereb Cortex 20 2010 1843 1852 19915091
Gill H. Gill B. Rodrigues N.B. Lipsitz O. Rosenblat J.D. The effects of ketamine on cognition in treatment-resistant depression: a systematic review and priority avenues for future research Neurosci. Biobehav. Rev. 120 2021 78 85 33242561
Girotti M. Carreno F.R. Morilak D.A. Role of orbitofrontal cortex and differential effects of acute and chronic stress on motor impulsivity measured with 1-choice serial reaction time test in male rats Int. J. Neuropsychopharmacol. 25 2022 1026 1036 36087292
Girotti M. Donegan J.J. Morilak D.A. Chronic intermittent cold stress sensitizes neuro-immune reactivity in the rat brain Psychoneuroendocrinology 36 2011 1164 1174 21411230
Girotti M. Pace T.W. Gaylord R.I. Rubin B.A. Herman J.P. Spencer R.L. Habituation to repeated restraint stress is associated with lack of stress-induced c-fos expression in primary sensory processing areas of the rat brain Neuroscience 138 2006 1067 1081 16431027
Girotti M. Silva J.D. George C.M. Morilak D.A. Ciliary neurotrophic factor signaling in the rat orbitofrontal cortex ameliorates stress-induced deficits in reversal learning Neuropharmacology 160 2019 107791
Godoy L.D. Rossignoli M.T. Delfino-Pereira P. Garcia-Cairasco N. de Lima Umeoka E.H. A comprehensive overview on stress neurobiology: basic concepts and clinical implications Front. Behav. Neurosci. 12 2018 127 30034327
Gonzalez-Burgos I. Fletes-Vargas G. Gonzalez-Tapia D. Gonzalez-Ramirez M.M. Rivera-Cervantes M.C. Martinez-Degollado M. Prefrontal serotonin depletion impairs egocentric, but not allocentric working memory in rats Neurosci. Res. 73 2012 321 327 22609361
Goodwill H.L. Manzano-Nieves G. LaChance P. Teramoto S. Lin S. Early life stress drives sex-selective impairment in reversal learning by affecting parvalbumin interneurons in orbitofrontal cortex of mice Cell Rep. 25 2018 2299 22307 e4 30485800
Goss A.J. Kaser M. Costafreda S.G. Sahakian B.J. Fu C.H. Modafinil augmentation therapy in unipolar and bipolar depression: a systematic review and meta-analysis of randomized controlled trials J. Clin. Psychiatry 74 2013 1101 1107 24330897
Granon S. Poucet B. Thinus-Blanc C. Changeux J.P. Vidal C. Nicotinic and muscarinic receptors in the rat prefrontal cortex: differential roles in working memory, response selection and effortful processing Psychopharmacology (Berl) 119 1995 139 144 7659760
Gray J.D. Kogan J.F. Marrocco J. McEwen B.S. Genomic and epigenomic mechanisms of glucocorticoids in the brain Nat. Rev. Endocrinol. 13 2017 661 673 28862266
Graybeal C. Feyder M. Schulman E. Saksida L.M. Bussey T.J. Paradoxical reversal learning enhancement by stress or prefrontal cortical damage: rescue with BDNF Nat. Neurosci. 14 2011 1507 1509 22057192
Groman S.M. Keistler C. Keip A.J. Hammarlund E. DiLeone R.J. Orbitofrontal circuits control multiple reinforcement-learning processes Neuron 103 2019 734 746 e3 31253468
Gutnikov S.A. Rawlins J.N. Systemic NMDA antagonist CGP-37849 produces non-specific impairment in a working memory task: the effect does not resemble those of AP5 and of lesions of the hippocampus or fornix Neuropsychologia 34 1996 311 314 8657361
Guzulaitis R. Godenzini L. Palmer L.M. Neural basis of anticipation and premature impulsive action in the frontal cortex Nat. Neurosci. 25 2022 1683 1692 36376483
Hack L.M. Tozzi L. Zenteno S. Olmsted A.M. Hilton R. A cognitive biotype of depression and symptoms, behavior measures, neural circuits, and differential treatment outcomes: a prespecified secondary analysis of a randomized clinical trial JAMA Netw. Open 6 2023 e2318411
Hains A.B. Yabe Y. Arnsten A.F. Chronic stimulation of alpha-2A-adrenoceptors with guanfacine protects rodent prefrontal cortex dendritic spines and cognition from the effects of chronic stress Neurobiol Stress 2 2015 1 9 25664335
Hajek T. Kopecek M. Preiss M. Alda M. Hoschl C. Prospective study of hippocampal volume and function in human subjects treated with corticosteroids Eur Psychiatry 21 2006 123 128 16516109
Hallock H.L. Wang A. Griffin A.L. Ventral midline thalamus is critical for hippocampal-prefrontal synchrony and spatial working memory J. Neurosci. 36 2016 8372 8389 27511010
Haluk D.M. Floresco S.B. Ventral striatal dopamine modulation of different forms of behavioral flexibility Neuropsychopharmacology 34 2009 2041 2052 19262467
Hampshire A. Chaudhry A.M. Owen A.M. Roberts A.C. Dissociable roles for lateral orbitofrontal cortex and lateral prefrontal cortex during preference driven reversal learning Neuroimage 59 2012 4102 4112 22075266
Hannah R. Aron A.R. Towards real-world generalizability of a circuit for action-stopping Nat. Rev. Neurosci. 22 2021 538 552 34326532
Harborne G.C. Watson F.L. Healy D.T. Groves L. The effects of sub-anaesthetic doses of ketamine on memory, cognitive performance and subjective experience in healthy volunteers J. Psychopharmacol. 10 1996 134 140 22302890
Harms M.B. Shannon Bowen K.E. Hanson J.L. Pollak S.D. Instrumental learning and cognitive flexibility processes are impaired in children exposed to early life stress Dev. Sci. 21 2018 e12596
Harris A.P. Holmes M.C. de Kloet E.R. Chapman K.E. Seckl J.R. Mineralocorticoid and glucocorticoid receptor balance in control of HPA axis and behaviour Psychoneuroendocrinology 38 2013 648 658 22980941
Harrison A.A. Everitt B.J. Robbins T.W. Central 5-HT depletion enhances impulsive responding without affecting the accuracy of attentional performance: interactions with dopaminergic mechanisms Psychopharmacology (Berl) 133 1997 329 342 9372531
Hassamal S. Chronic stress, neuroinflammation, and depression: an overview of pathophysiological mechanisms and emerging anti-inflammatories Front Psychiatry 14 2023 1130989
Hatherall L. Sanchez C. Morilak D.A. Chronic vortioxetine treatment reduces exaggerated expression of conditioned fear memory and restores active coping behavior in chronically stressed rats Int. J. Neuropsychopharmacol. 20 2017 316 323 27927740
Hedlund P.B. The 5-HT7 receptor and disorders of the nervous system: an overview Psychopharmacology (Berl) 206 2009 345 354 19649616
Hedlund P.B. Huitron-Resendiz S. Henriksen S.J. Sutcliffe J.G. 5-HT7 receptor inhibition and inactivation induce antidepressantlike behavior and sleep pattern Biol Psychiatry 58 2005 831 837 16018977
Henckens M.J. Deussing J.M. Chen A. Region-specific roles of the corticotropin-releasing factor-urocortin system in stress Nat. Rev. Neurosci. 17 2016 636 651 27586075
Hendrawan D. Yamakawa K. Kimura M. Murakami H. Ohira H. Executive functioning performance predicts subjective and physiological acute stress reactivity: preliminary results Int. J. Psychophysiol. 84 2012 277 283 22497897
Herman J.P. McKlveen J.M. Ghosal S. Kopp B. Wulsin A. Regulation of the hypothalamic-pituitary-adrenocortical stress response Compr. Physiol. 6 2016 603 621 27065163
Hervig M.E. Piilgaard L. Bozic T. Alsio J. Robbins T.W. Glutamatergic and serotonergic modulation of rat medial and lateral orbitofrontal cortex in visual serial reversal learning Psychol Neurosci 13 2020 438 458 33613854
Heston J. Friedman A. Baqai M. Bavafa N. Aron A.R. Hnasko T.S. Activation of subthalamic nucleus stop circuit disrupts cognitive performance eNeuro 7 2020
Hetem L.A. Danion J.M. Diemunsch P. Brandt C. Effect of a subanesthetic dose of ketamine on memory and conscious awareness in healthy volunteers Psychopharmacology (Berl) 152 2000 283 288 11105938
Higgins G.A. Silenieks L.B. MacMillan C. Sevo J. Zeeb F.D. Thevarkunnel S. Enhanced attention and impulsive action following NMDA receptor GluN2B-selective antagonist pretreatment Behav. Brain Res. 311 2016 1 14 27180168
Hill M.N. Patel S. Carrier E.J. Rademacher D.J. Ormerod B.K. Downregulation of endocannabinoid signaling in the hippocampus following chronic unpredictable stress Neuropsychopharmacology 30 2005 508 515 15525997
Hillier A. Alexander J.K. Beversdorf D.Q. The effect of auditory stressors on cognitive flexibility Neurocase 12 2006 228 231 17000592
Hipp J.F. Knoflach F. Comley R. Ballard T.M. Honer M. Basmisanil, a highly selective GABA(A)-alpha5 negative allosteric modulator: preclinical pharmacology and demonstration of functional target engagement in man Sci. Rep. 11 2021 7700 33833333
Hughes J.H. Gallagher P. Stewart M.E. Matthews D. Kelly T.P. Young A.H. The effects of acute tryptophan depletion on neuropsychological function J. Psychopharmacol. 17 2003 300 309 14513922
Hyman S.L. Shores A. North K.N. The nature and frequency of cognitive deficits in children with neurofibromatosis type 1 Neurology 65 2005 1037 1044 16217056
Idris N. Neill J. Grayson B. Bang-Andersen B. Witten L.M. Sertindole improves 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 2010 23 36 19851757
Ihalainen J.A. Tanila H. In vivo regulation of dopamine and noradrenaline release by alpha2A-adrenoceptors in the mouse prefrontal cortex Eur. J. Neurosci. 15 2002 1789 1794 12081658
Isherwood S.N. Pekcec A. Nicholson J.R. Robbins T.W. Dalley J.W. Dissociable effects of mGluR5 allosteric modulation on distinct forms of impulsivity in rats: interaction with NMDA receptor antagonism Psychopharmacology (Berl) 232 2015 3327 3344 26063678
Isherwood S.N. Robbins T.W. Nicholson J.R. Dalley J.W. Pekcec A. Selective and interactive effects of D(2) receptor antagonism and positive allosteric mGluR4 modulation on waiting impulsivity Neuropharmacology 123 2017 249 260 28487067
Ito H.T. Zhang S.J. Witter M.P. Moser E.I. Moser M.B. A prefrontal-thalamo-hippocampal circuit for goal-directed spatial navigation Nature 522 2015 50 55 26017312
Izquierdo A. Darling C. Manos N. Pozos H. Kim C. Basolateral amygdala lesions facilitate reward choices after negative feedback in rats J. Neurosci. 33 2013 4105 4109 23447618
Izquierdo A. Wiedholz L.M. Millstein R.A. Yang R.J. Bussey T.J. Genetic and dopaminergic modulation of reversal learning in a touchscreen-based operant procedure for mice Behav. Brain Res. 171 2006 181 188 16713639
Jakala P. Riekkinen M. Sirvio J. Koivisto E. Kejonen K. Guanfacine, but not clonidine, improves planning and working memory performance in humans Neuropsychopharmacology 20 1999 460 470 10192826
Janhunen S.K. Svard H. Talpos J. Kumar G. Steckler T. The subchronic phencyclidine rat model: relevance for the assessment of novel therapeutics for cognitive impairment associated with schizophrenia Psychopharmacology (Berl) 232 2015 4059 4083 26070547
Jett J.D. Boley A.M. Girotti M. Shah A. Lodge D.J. Morilak D.A. Antidepressant-like cognitive and behavioral effects of acute ketamine administration associated with plasticity in the ventral hippocampus to medial prefrontal cortex pathway Psychopharmacology 232 2015 3123 3133 25986748
Jett J.D. Bulin S.E. Hatherall L.C. McCartney C.M. Morilak D.A. Deficits in cognitive flexibility induced by chronic unpredictable stress are associated with impaired glutamate neurotransmission in the rat medial prefrontal cortex Neuroscience 346 2017 284 297 28131625
Jett J.D. Evans L. Girotti M. Lodge D. Morilak D.A. Effects of acute ketamine administration on chronic stress-induced cognitive deficits in rats Soc. Neurosci. Abstr. 39 2013 Online Program no.: 730.15
Jett J.D. Morilak D.A. Too much of a good thing: blocking noradrenergic facilitation in medial prefrontal cortex prevents the detrimental effects of chronic stress on cognition Neuropsychopharmacology 38 2013 585 595 23132268
Joels M. Corticosteroid effects in the brain: U-shape it Trends Pharmacol. Sci. 27 2006 244 250 16584791
Kable J.W. Glimcher P.W. The neural correlates of subjective value during intertemporal choice Nat. Neurosci. 10 2007 1625 1633 17982449
Kalia V. Knauft K. Emotion regulation strategies modulate the effect of adverse childhood experiences on perceived chronic stress with implications for cognitive flexibility PLoS One 15 2020 e0235412
Kalia V. Knauft K. Hayatbini N. Adverse childhood experiences (ACEs) associated with reduced cognitive flexibility in both college and community samples PLoS One 16 2021 e0260822
Kalia V. Vishwanath K. Knauft K. Vellen B.V. Luebbe A. Williams A. Acute stress attenuates cognitive flexibility in males only: an fNIRS examination Front. Psychol. 9 2018 2084 30443232
Kaser M. Deakin J.B. Michael A. Zapata C. Bansal R. Modafinil improves episodic memory and working memory cognition in patients with remitted depression: a double-blind, randomized, placebo-controlled study Biol Psychiatry Cogn Neurosci Neuroimaging 2 2017 115 122 28299368
Katz R.J. Roth K.A. Carroll B.J. Acute and chronic stress effects on open field activity in the rat: implications for a model of depression Neurosci Biobehav Revs 5 1981 247 251 7196554
Keller-Wood M.E. Dallman M.F. Corticosteroid inhibition of ACTH secretion Endocr. Rev. 5 1984 1 24 6323158
Kentrop J. van der Tas L. Loi M. van I.M.H. Bakermans-Kranenburg M.J. Mifepristone treatment during early adolescence fails to restore maternal deprivation-induced deficits in behavioral inhibition of adult male rats Front. Behav. Neurosci. 10 2016 122 27378873
Khan Z.U. Muly E.C. Molecular mechanisms of working memory Behav. Brain Res. 219 2011 329 341 21232555
Kinnavane L. Albasser M.M. Aggleton J.P. Advances in the behavioural testing and network imaging of rodent recognition memory Behav. Brain Res. 285 2015 67 78 25106740
Klanker M. Sandberg T. Joosten R. Willuhn I. Feenstra M. Denys D. Phasic dopamine release induced by positive feedback predicts individual differences in reversal learning Neurobiol. Learn. Mem. 125 2015 135 145 26343836
Klement J. Hubold C. Hallschmid M. Loeck C. Oltmanns K.M. Effects of glucose infusion on neuroendocrine and cognitive parameters in Addison disease Metabolism 58 2009 1825 1831 19709691
Klingberg T. O'Sullivan B.T. Roland P.E. Bilateral activation of fronto-parietal networks by incrementing demand in a working memory task Cereb Cortex 7 1997 465 471 9261575
Kortmann G.L. Contini V. Bertuzzi G.P. Mota N.R. Rovaris D.L. The role of a mineralocorticoid receptor gene functional polymorphism in the symptom dimensions of persistent ADHD Eur. Arch. Psychiatr. Clin. Neurosci. 263 2013 181 188
Koskinen T. Ruotsalainen S. Sirvio J. The 5-HT(2) receptor activation enhances impulsive responding without increasing motor activity in rats Pharmacol. Biochem. Behav. 66 2000 729 738 10973510
Krystal J.H. Neumeister A. Noradrenergic and serotonergic mechanisms in the neurobiology of posttraumatic stress disorder and resilience Brain Res. 1293 2009 13 23 19332037
Lachize S. Apostolakis E.M. van der Laan S. Tijssen A.M. Xu J. Steroid receptor coactivator-1 is necessary for regulation of corticotropin-releasing hormone by chronic stress and glucocorticoids Proc Natl Acad Sci U S A 106 2009 8038 8042 19416907
Lalonde R. The neurobiological basis of spontaneous alternation Neurosci. Biobehav. Rev. 26 2002 91 104 11835987
Lang L. Xu B. Yuan J. Li S. Lian S. GABA-mediated activated microglia induce neuroinflammation in the hippocampus of mice following cold exposure through the NLRP3 inflammasome and NF-kappaB signaling pathways Int Immunopharmacol 89 2020 106908
Lapiz M.D. Morilak D.A. Noradrenergic modulation of cognitive function in rat medial prefrontal cortex as measured by attentional set shifting capability Neuroscience 137 2006 1039 1049 16298081
Lapiz M.D.S. Bondi C.O. Morilak D.A. Chronic treatment with desipramine improves cognitive performance of rats in an attentional set shifting test Neuropsychopharmacology 32 2007 1000 1010 17077810
Lapiz-Bluhm M.D. Soto-Pina A.E. Hensler J.G. Morilak D.A. Chronic intermittent cold stress and serotonin depletion induce deficits of reversal learning in an attentional set-shifting test in rats Psychopharmacology (Berl) 202 2009 329 341 18587666
Lee B. Groman S. London E.D. Jentsch J.D. Dopamine D2/D3 receptors play a specific role in the reversal of a learned visual discrimination in monkeys Neuropsychopharmacology 32 2007 2125 2134 17299511
Lee Y. Syeda K. Maruschak N.A. Cha D.S. Mansur R.B. A new perspective on the anti-suicide effects with ketamine treatment: a procognitive effect J. Clin. Psychopharmacol. 36 2016 50 56 26658082
Lempert K.M. Porcelli A.J. Delgado M.R. Tricomi E. Individual differences in delay discounting under acute stress: the role of trait perceived stress Front. Psychol. 3 2012 251 22833731
Leopoldo M. Lacivita E. Berardi F. Perrone R. Hedlund P.B. Serotonin 5-HT7 receptor agents: structure-activity relationships and potential therapeutic applications in central nervous system disorders Pharmacol. Ther. 129 2011 120 148 20923682
Levy-Gigi E. Richter-Levin G. The hidden price of repeated traumatic exposure Stress 17 2014 343 351 24810272
Li B. Nguyen T.P. Ma C. Dan Y. Inhibition of impulsive action by projection-defined prefrontal pyramidal neurons Proc Natl Acad Sci U S A 117 2020 17278 17287 32631999
Li B.M. Mao Z.M. Wang M. Mei Z.T. Alpha-2 adrenergic modulation of prefrontal cortical neuronal activity related to spatial working memory in monkeys Neuropsychopharmacology 21 1999 601 610 10516956
Li N. Liu R.-J. Dwyer J.M. Banasr M. Lee B. Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure Biol Psychiatry 69 2011 754 761 21292242
Lightman S.L. Birnie M.T. Conway-Campbell B.L. Dynamics of ACTH and cortisol secretion and implications for disease Endocr. Rev. 41 2020
Lim J. Kim E. Noh H.J. Kang S. Phillips B.U. Assessment of mGluR5 KO mice under conditions of low stress using a rodent touchscreen apparatus reveals impaired behavioural flexibility driven by perseverative responses Mol. Brain 12 2019 37 30971312
Ling I. Mihalik B. Etherington L.A. Kapus G. Palvolgyi A. A novel GABA(A) alpha 5 receptor inhibitor with therapeutic potential Eur. J. Pharmacol. 764 2015 497 507 26169564
Linley S.B. Gallo M.M. Vertes R.P. Lesions of the ventral midline thalamus produce deficits in reversal learning and attention on an odor texture set shifting task Brain Res. 1649 2016 110 122 27544424
Liston C. Gan W.B. Glucocorticoids are critical regulators of dendritic spine development and plasticity in vivo Proc Natl Acad Sci U S A 108 2011 16074 16079 21911374
Liston C. McEwen B.S. Casey B.J. Psychosocial stress reversibly disrupts prefrontal processing and attentional control Proc Natl Acad Sci U S A 106 2009 912 917 19139412
Liston C. Miller M.M. Goldwater D.S. Radley J.J. Rocher A.B. Stress-induced alterations in prefrontal cortical dendritic morphology predict selective impairments in perceptual attentional set-shifting J. Neurosci. 26 2006 7870 7874 16870732
Lohse A. Lokkegaard A. Siebner H.R. Meder D. Linking impulsivity to activity levels in pre-supplementary motor area during sequential gambling J. Neurosci. 43 2023 1414 1421 36650059
Loos M. Pattij T. Janssen M.C. Counotte D.S. Schoffelmeer A.N. Dopamine receptor D1/D5 gene expression in the medial prefrontal cortex predicts impulsive choice in rats Cereb Cortex 20 2010 1064 1070 19690230
Luethi M. Meier B. Sandi C. Stress effects on working memory, explicit memory, and implicit memory for neutral and emotional stimuli in healthy men Front. Behav. Neurosci. 2 2008 5 19169362
Lukkes J.L. Drozd H.P. Fitz S.D. Molosh A.I. Clapp D.W. Shekhar A. Guanfacine treatment improves ADHD phenotypes of impulsivity and hyperactivity in a neurofibromatosis type 1 mouse model J. Neurodev. Disord. 12 2 2020
Lupien S.J. Gillin C.J. Hauger R.L. Working memory is more sensitive than declarative memory to the acute effects of corticosteroids: a dose-response study in humans Behav. Neurosci. 113 1999 420 430 10443770
Lupien S.J. McEwen B.S. Gunnar M.R. Heim C. Effects of stress throughout the lifespan on the brain, behaviour and cognition Nat. Rev. Neurosci. 10 2009 434 445 19401723
Luscher B. Maguire J.L. Rudolph U. Sibille E. GABA(A) receptors as targets for treating affective and cognitive symptoms of depression Trends Pharmacol. Sci. 44 2023 586 600 37543478
Luzi L. Gandini S. Massarini S. Bellerba F. Terruzzi I. Reduction of impulsivity in patients receiving deep transcranial magnetic stimulation treatment for obesity Endocrine 74 2021 559 570 34173157
Ma S. Morilak D.A. Chronic intermittent cold stress sensitizes the HPA response to a novel acute stress by enhancing noradrenergic influence in the rat paraventricular nucleus J. Neuroendocrinol. 17 2005 761 769 16219005
Maeng L.Y. Milad M.R. Post-traumatic stress disorder: the relationship between the fear response and chronic stress Chronic Stress 1 2017 2470547017713297 Thousand Oaks
Magarinos A.M. McEwen B.S. Flugge G. Fuchs E. Chronic psychosocial stress causes apical dendritic atrophy of hippocampal CA3 pyramidal neurons in subordinate tree shrews J. Neurosci. 16 1996 3534 3540 8627386
Mahoney J.J. 3rd Thompson-Lake D.G. Cooper K. Verrico C.D. Newton T.F. De La Garza R. 2nd A comparison of impulsivity, depressive symptoms, lifetime stress and sensation seeking in healthy controls versus participants with cocaine or methamphetamine use disorders J. Psychopharmacol. 29 2015 50 56 25424624
Mala H. Andersen L.G. Christensen R.F. Felbinger A. Hagstrom J. Prefrontal cortex and hippocampus in behavioural flexibility and posttraumatic functional recovery: reversal learning and set-shifting in rats Brain Res. Bull. 116 2015 34 44 26033702
Manes F. Sahakian B. Clark L. Rogers R. Antoun N. Decision-making processes following damage to the prefrontal cortex Brain 125 2002 624 639 11872618
Mao Y. Xu Y. Yuan X. Validity of chronic restraint stress for modeling anhedonic-like behavior in rodents: a systematic review and meta-analysis J. Int. Med. Res. 50 2022 3000605221075816
Maras P.M. Baram T.Z. Sculpting the hippocampus from within: stress, spines, and CRH Trends in Neuroscience 35 2012 315 324
Marino R.A. Gaprielian P. Levy R. Systemic D1-R and D2-R antagonists in non-human primates differentially impact learning and memory while impairing motivation and motor performance Eur. J. Neurosci. 56 2022 4121 4140 35746869
McAlonan K. Brown V.J. Orbital prefrontal cortex mediates reversal learning and not attentional set shifting in the rat Behav. Brain Res. 146 2003 97 103 14643463
McBurney-Lin J. Vargova G. Garad M. Zagha E. Yang H. The locus coeruleus mediates behavioral flexibility Cell Rep. 41 2022 111534
McEwen B.S. Stress, adaptation, and disease. Allostasis and allostatic load Ann. N. Y. Acad. Sci. 840 1998 33 44 9629234
McEwen B.S. Akil H. Revisiting the stress concept: implications for affective disorders J. Neurosci. 40 2020 12 21 31896560
McGaughy J. Ross R.S. Eichenbaum H. Noradrenergic, but not cholinergic, deafferentation of prefrontal cortex impairs attentional set-shifting Neuroscience 153 2008 63 71 18355972
McGregor G. Irving A.J. Harvey J. Canonical JAK-STAT signaling is pivotal for long-term depression at adult hippocampal temporoammonic-CA1 synapses FASEB (Fed. Am. Soc. Exp. Biol.) J. 31 2017 3449 3466
McKay L.I. Cidlowski J.A. Cross-talk between nuclear factor-kappa B and the steroid hormone receptors: mechanisms of mutual antagonism Mol. Endocrinol. 12 1998 45 56 9440809
McMullin S.D. Shields G.S. Slavich G.M. Buchanan T.W. Cumulative lifetime stress exposure predicts greater impulsivity and addictive behaviors J. Health Psychol. 26 2021 2921 2936 32643970
McQuail J.A. Beas B.S. Kelly K.B. Hernandez C.M. 3rd Bizon J.L. Frazier C.J. Attenuated NMDAR signaling on fast-spiking interneurons in prefrontal cortex contributes to age-related decline of cognitive flexibility Neuropharmacology 197 2021 108720
Mehta M.A. Swainson R. Ogilvie A.D. Sahakian J. Robbins T.W. Improved short-term spatial memory but impaired reversal learning following the dopamine D(2) agonist bromocriptine in human volunteers Psychopharmacology (Berl) 159 2001 10 20 11797064
Mereu M. Bonci A. Newman A.H. Tanda G. The neurobiology of modafinil as an enhancer of cognitive performance and a potential treatment for substance use disorders Psychopharmacology (Berl) 229 2013 415 434 23934211
Merriam E.P. Thase M.E. Haas G.L. Keshavan M.S. Sweeney J.A. Prefrontal cortical dysfunction in depression determined by Wisconsin Card Sorting Test performance Am J Psychiatry 156 1999 780 782 10327916
Michels L. Martin E. Klaver P. Edden R. Zelaya F. Frontal GABA levels change during working memory PLoS One 7 2012 e31933
Mika A. Mazur G.J. Hoffman A.N. Talboom J.S. Bimonte-Nelson H.A. Chronic stress impairs prefrontal cortex-dependent response inhibition and spatial working memory Behav. Neurosci. 126 2012 605 619 22905921
Millan M.J. Agid Y. Brune M. Bullmore E.T. Carter C.S. Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy Nat. Rev. Drug Discov. 11 2012 141 168 22293568
Miller E.K. Cohen J.D. An integrative theory of prefrontal cortex function Annu. Rev. Neurosci. 24 2001 167 202 11283309
Mills F. Bartlett T.E. Dissing-Olesen L. Wisniewska M.B. Kuznicki J. Cognitive flexibility and long-term depression (LTD) are impaired following beta-catenin stabilization in vivo Proc Natl Acad Sci U S A 111 2014 8631 8636 24912177
Minchew H.M. Radabaugh H.L. LaPorte M.L. Free K.E. Cheng J.P. Bondi C.O. A combined therapeutic regimen of citalopram and environmental enrichment ameliorates attentional set-shifting performance after brain trauma Eur. J. Pharmacol. 904 2021 174174
Mitchell J.M. Ot'alora G.M. van der Kolk B. Shannon S. Bogenschutz M. MDMA-assisted therapy for moderate to severe PTSD: a randomized, placebo-controlled phase 3 trial Nat Med 29 2023 2473 2480 37709999
Miyazaki K. Miyazaki K.W. Sivori G. Yamanaka A. Tanaka K.F. Doya K. Serotonergic projections to the orbitofrontal and medial prefrontal cortices differentially modulate waiting for future rewards Sci. Adv. 6 2020
Miyazaki K.W. Miyazaki K. Doya K. Activation of the central serotonergic system in response to delayed but not omitted rewards Eur. J. Neurosci. 33 2011 153 160 21070390
Miyazaki K.W. Miyazaki K. Tanaka K.F. Yamanaka A. Takahashi A. Optogenetic activation of dorsal raphe serotonin neurons enhances patience for future rewards Curr. Biol. 24 2014 2033 2040 25155504
Mkrtchian A. Evans J.W. Kraus C. Yuan P. Kadriu B. Ketamine modulates fronto-striatal circuitry in depressed and healthy individuals Mol Psychiatry 26 2021 3292 3301 32929215
Mobini S. Chiang T.J. Ho M.Y. Bradshaw C.M. Szabadi E. Effects of central 5-hydroxytryptamine depletion on sensitivity to delayed and probabilistic reinforcement Psychopharmacology (Berl) 152 2000 390 397 11140331
Monni A. Scandola M. Helie S. Scalas L.F. Cognitive flexibility assessment with a new Reversal learning task paradigm compared with the Wisconsin card sorting test exploring the moderating effect of gender and stress Psychol. Res. 87 2023 1439 1453 36369387
Moore H. Rose H.J. Grace A.A. Chronic cold stress reduces the spontaneous activity of ventral tegmental dopamine neurons Neuropsychopharmacology 24 2001 410 419 11182536
Moreira P.S. Almeida P.R. Leite-Almeida H. Sousa N. Costa P. Impact of chronic stress protocols in learning and memory in rodents: systematic review and meta-analysis PLoS One 11 2016 e0163245
Morgan C.J. Mofeez A. Brandner B. Bromley L. Curran H.V. Acute effects of ketamine on memory systems and psychotic symptoms in healthy volunteers Neuropsychopharmacology 29 2004 208 218 14603267
Morice E. Billard J.M. Denis C. Mathieu F. Betancur C. Parallel loss of hippocampal LTD and cognitive flexibility in a genetic model of hyperdopaminergia Neuropsychopharmacology 32 2007 2108 2116 17342172
Morilak D.A. Ma S. Fleming T. Ji L.L. Mifflin S.W. Cunningham J.T. Chronic cold stress and chronic intermittent hypoxia sensitize acute stress-induced ACTH secretion and Fos staining in LC and forebrain of rats Soc. Neurosci. Abstr. 31 2005 Online: Program no. 526.7
Morris L.S. Kundu P. Baek K. Irvine M.A. Mechelmans D.J. Jumping the gun: mapping neural correlates of waiting impulsivity and relevance across alcohol misuse Biol Psychiatry 79 2016 499 507 26185010
Morris L.S. Kundu P. Dowell N. Mechelmans D.J. Favre P. Fronto-striatal organization: defining functional and microstructural substrates of behavioural flexibility Cortex 74 2016 118 133 26673945
Moschak T.M. Carelli R.M. Impulsive rats exhibit blunted dopamine release dynamics during a delay discounting task independent of cocaine history eNeuro 4 2017
Mosley P.E. Paliwal S. Robinson K. Coyne T. Silburn P. The structural connectivity of subthalamic deep brain stimulation correlates with impulsivity in Parkinson's disease Brain 143 2020 2235 2254 32568370
Muir J.L. Everitt B.J. Robbins T.W. The cerebral cortex of the rat and visual attentional function: dissociable effects of mediofrontal, cingulate, anterior dorsolateral, and parietal cortex lesions on a five-choice serial reaction time task Cereb Cortex 6 1996 470 481 8670672
Murphy S.E. de Cates A.N. Gillespie A.L. Godlewska B.R. Scaife J.C. Translating the promise of 5HT(4) receptor agonists for the treatment of depression Psychol. Med. 51 2021 1111 1120 32241310
Musazzi L. Sala N. Tornese P. Gallivanone F. Belloli S. Acute inescapable stress rapidly increases synaptic energy metabolism in prefrontal cortex and alters working memory performance Cereb Cortex 29 2019 4948 4957 30877789
Naegeli K.J. O'Connor J.A. Banerjee P. Morilak D.A. Effects of milnacipran on cognitive flexibility following chronic stress in rats Eur. J. Pharmacol. 703 2013 62 66 23422875
Navarra R. Graf R. Huang Y. Logue S. Comery T. Effects of atomoxetine and methylphenidate on attention and impulsivity in the 5-choice serial reaction time test Prog. Neuro-Psychopharmacol. Biol. Psychiatry 32 2008 34 41
Newcomer J.W. Selke G. Melson A.K. Hershey T. Craft S. Decreased memory performance in healthy humans induced by stress-level cortisol treatment Arch Gen Psychiatry 56 1999 527 533 10359467
Newman L.A. Darling J. McGaughy J. Atomoxetine reverses attentional deficits produced by noradrenergic deafferentation of medial prefrontal cortex Psychopharmacology (Berl) 200 2008 39 50 18568443
Nicolas C.S. Peineau S. Amici M. Csaba Z. Fafouri A. The JAK/STAT pathway is involved in synaptic plasticity Neuron 73 2012 374 390 22284190
Nijdam M.J. Vermetten E. Moving forward in treatment of posttraumatic stress disorder: innovations to exposure-based therapy Eur. J. Psychotraumatol. 9 2018 1458568
Nikiforuk A. Popik P. Long-lasting cognitive deficit induced by stress is alleviated by acute administration of antidepressants Psychoneuroendocrinology 36 2011 28 39 20580164
Nikiforuk A. Popik P. Amisulpride promotes cognitive flexibility in rats: the role of 5-HT7 receptors Behav. Brain Res. 248 2013 136 140 23603557
Nikiforuk A. Popik P. Ketamine prevents stress-induced cognitive inflexibility in rats Psychoneuroendocrinology 40 2014 119 122 24485483
Nilsson S.R. Ripley T.L. Somerville E.M. Clifton P.G. Reduced activity at the 5-HT(2C) receptor enhances reversal learning by decreasing the influence of previously non-rewarded associations Psychopharmacology (Berl) 224 2012 241 254 22644128
Nishitomi K. Yano K. Kobayashi M. Jino K. Kano T. Systemic administration of guanfacine improves food-motivated impulsive choice behavior primarily via direct stimulation of postsynaptic alpha(2A)-adrenergic receptors in rats Behav. Brain Res. 345 2018 21 29 29476896
Nonkes L.J. vande V. II de Leeuw M.J. Wijlaars L.P. Maes J.H. Homberg J.R. Serotonin transporter knockout rats show improved strategy set-shifting and reduced latent inhibition Learn. Mem. 19 2012 190 193 22505721
Nunez N.A. Joseph B. Pahwa M. Kumar R. Resendez M.G. Augmentation strategies for treatment resistant major depression: a systematic review and network meta-analysis J. Affect. Disord. 302 2022 385 400 34986373
Ohno M. Watanabe S. Differential effects of 5-HT3 receptor antagonism on working memory failure due to deficiency of hippocampal cholinergic and glutamatergic transmission in rats Brain Res. 762 1997 211 215 9262175
Olton D.S. The radial arm maze as a tool in behavioral pharmacology Physiol. Behav. 40 1987 793 797 3313453
Onaolapo O.J. Onaolapo A.Y. Subchronic oral bromocriptine methanesulfonate enhances open field novelty-induced behavior and spatial memory in male Swiss albino mice Neurosci J 2013 2013 948241
Orem D.M. Petrac D.C. Bedwell J.S. Chronic self-perceived stress and set-shifting performance in undergraduate students Stress 11 2008 73 78 17853073
Orsini C.A. Truckenbrod L.M. Wheeler A.R. Regulation of sex differences in risk-based decision making by gonadal hormones: insights from rodent models Behav Processes 200 2022 104663
Otte C. Moritz S. Yassouridis A. Koop M. Madrischewski A.M. Blockade of the mineralocorticoid receptor in healthy men: effects on experimentally induced panic symptoms, stress hormones, and cognition Neuropsychopharmacology 32 2007 232 238 17035932
Ouellet J. McGirr A. Van den Eynde F. Jollant F. Lepage M. Berlim M.T. Enhancing decision-making and cognitive impulse control with transcranial direct current stimulation (tDCS) applied over the orbitofrontal cortex (OFC): a randomized and sham-controlled exploratory study J. Psychiatr. Res. 69 2015 27 34 26343591
Ouhaz Z. Perry B.A.L. Nakamura K. Mitchell A.S. Mediodorsal thalamus is critical for updating during extradimensional shifts but not reversals in the attentional set-shifting task eNeuro 9 2022
Owen A.M. McMillan K.M. Laird A.R. Bullmore E. N-back working memory paradigm: a meta-analysis of normative functional neuroimaging studies Hum. Brain Mapp. 25 2005 46 59 15846822
Owen A.M. Roberts A.C. Polkey C.E. Sahakian B.J. Robbins T.W. Extra-dimensional versus intra-dimensional set shifting performance following frontal lobe excisions, temporal lobe excisions or amygdalo-hippocampectomy in man Neuropsychologia 29 1991 993 1006 1762678
Paine T.A. Brainard S. Keppler E. Poyle R. Sai-Hardebeck E. Juvenile stress increases cocaine-induced impulsivity in female rats Behav. Brain Res. 414 2021 113488
Paine T.A. Tomasiewicz H.C. Zhang K. Carlezon W.A. Jr. Sensitivity of the five-choice serial reaction time task to the effects of various psychotropic drugs in Sprague-Dawley rats Biol Psychiatry 62 2007 687 693 17343834
Pajkossy P. Szollosi A. Demeter G. Racsmany M. Tonic noradrenergic activity modulates explorative behavior and attentional set shifting: evidence from pupillometry and gaze pattern analysis Psychophysiology 54 2017 1839 1854 28755458
Pardon M.-C. Ma S. Morilak D.A. Chronic cold stress sensitizes brain noradrenergic reactivity and noradrenergic facilitation of the HPA stress response in Wistar Kyoto rats Brain Res. 971 2003 55 65 12691837
Paredes D. Knippenberg A.R. Bulin S.E. Keppler L.J. Morilak D.A. Adjunct treatment with ketamine enhances the therapeutic effects of extinction learning after chronic unpredictable stress Neurobiol Stress 19 2022 100468
Paredes D. Morilak D.A. A rodent model of exposure therapy: the use of fear extinction as a therapeutic intervention for PTSD Front. Behav. Neurosci. 13 2019 46 30914932
Paredes D. Morilak D.A. Ventral hippocampal input to infralimbic cortex is necessary for the therapeutic-like effects of extinction in stressed rats Int. J. Neuropsychopharmacol. 26 2023 529 536 37480574
Paterson N.E. Ricciardi J. Wetzler C. Hanania T. Sub-optimal performance in the 5-choice serial reaction time task in rats was sensitive to methylphenidate, atomoxetine and d-amphetamine, but unaffected by the COMT inhibitor tolcapone Neurosci. Res. 69 2011 41 50 20934466
Patriquin M.A. Mathew S.J. The neurobiological mechanisms of generalized anxiety disorder and chronic stress Chronic Stress 2017 1 Thousand Oaks
Pattij T. Janssen M.C. Vanderschuren L.J. Schoffelmeer A.N. van Gaalen M.M. Involvement of dopamine D1 and D2 receptors in the nucleus accumbens core and shell in inhibitory response control Psychopharmacology (Berl) 191 2007 587 598 16972104
Patton M.S. Lodge D.J. Morilak D.A. Girotti M. Ketamine corrects stress-induced cognitive dysfunction through JAK2/STAT3 signaling in the orbitofrontal cortex Neuropsychopharmacology 42 2017 1220 1230 27748739
Pehrson A.L. Jeyarajah T. Sanchez C. Regional distribution of serotonergic receptors: a systems neuroscience perspective on the downstream effects of the multimodal-acting antidepressant vortioxetine on excitatory and inhibitory neurotransmission CNS Spectr. 21 2016 162 183 26250622
Pehrson A.L. Leiser S.C. Gulinello M. Dale E. Li Y. Treatment of cognitive dysfunction in major depressive disorder--a review of the preclinical evidence for efficacy of selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors and the multimodal-acting antidepressant vortioxetine Eur. J. Pharmacol. 753 2015 19 31 25107284
Pelegrina S. Lechuga M.T. Garcia-Madruga J.A. Elosua M.R. Macizo P. Normative data on the n-back task for children and young adolescents Front. Psychol. 6 2015 1544 26500594
Phelps T.I. Bondi C.O. Ahmed R.H. Olugbade Y.T. Kline A.E. Divergent long-term consequences of chronic treatment with haloperidol, risperidone, and bromocriptine on traumatic brain injury-induced cognitive deficits J. Neurotrauma 32 2015 590 597 25275833
Philbert J. Belzung C. Griebel G. The CRF(1) receptor antagonist SSR125543 prevents stress-induced cognitive deficit associated with hippocampal dysfunction: comparison with paroxetine and D-cycloserine Psychopharmacology (Berl) 228 2013 97 107 23407783
Piber D. Schultebraucks K. Mueller S.C. Deuter C.E. Wingenfeld K. Otte C. Mineralocorticoid receptor stimulation effects on spatial memory in healthy young adults: a study using the virtual Morris Water Maze task Neurobiol. Learn. Mem. 136 2016 139 146 27725248
Placek K. Dippel W.C. Jones S. Brady A.M. Impairments in set-shifting but not reversal learning in the neonatal ventral hippocampal lesion model of schizophrenia: further evidence for medial prefrontal deficits Behav. Brain Res. 256 2013 405 413 23994544
Porcelli A.J. Cruz D. Wenberg K. Patterson M.D. Biswal B.B. Rypma B. The effects of acute stress on human prefrontal working memory systems Physiol. Behav. 95 2008 282 289 18692209
Prevot T. Sibille E. Altered GABA-mediated information processing and cognitive dysfunctions in depression and other brain disorders Mol Psychiatry 26 2021 151 167 32346158
Prevot T.D. Li G. Vidojevic A. Misquitta K.A. Fee C. Novel benzodiazepine-like ligands with various anxiolytic, antidepressant, or pro-cognitive profiles Mol. Neuropsychiatry 5 2019 84 97 31192221
Pripfl J. Neumann R. Kohler U. Lamm C. Effects of transcranial direct current stimulation on risky decision making are mediated by 'hot' and 'cold' decisions, personality, and hemisphere Eur. J. Neurosci. 38 2013 3778 3785 24124667
Puma C. Baudoin C. Bizot J.C. Effects of intraseptal infusions of N-methyl-D-aspartate receptor ligands on memory in an object recognition task in rats Neurosci. Lett. 244 1998 97 100 9572594
Puma C. Bizot J.C. Intraseptal infusions of a low dose of AP5, a NMDA receptor antagonist, improves memory in an object recognition task in rats Neurosci. Lett. 248 1998 183 186 9654339
Puumala T. Sirvio J. Changes in activities of dopamine and serotonin systems in the frontal cortex underlie poor choice accuracy and impulsivity of rats in an attention task Neuroscience 83 1998 489 499 9460757
Qiao H. An S.C. Ren W. Ma X.M. Progressive alterations of hippocampal CA3-CA1 synapses in an animal model of depression Behav. Brain Res. 275 2014 191 200 25192638
Qiao H. Li M.X. Xu C. Chen H.B. An S.C. Ma X.M. Dendritic spines in depression: what we learned from animal models Neural Plast. 2016 2016 8056370
Qin S. Hermans E.J. van Marle H.J. Luo J. Fernandez G. Acute psychological stress reduces working memory-related activity in the dorsolateral prefrontal cortex Biol Psychiatry 66 2009 25 32 19403118
Quan M. Zheng C. Zhang N. Han D. Tian Y. Impairments of behavior, information flow between thalamus and cortex, and prefrontal cortical synaptic plasticity in an animal model of depression Brain Res. Bull. 85 2011 109 116 21396989
Radley J.J. Rocher A.B. Miller M. Janssen W.G. Liston C. Repeated stress induces dendritic spine loss in the rat medial prefrontal cortex Cereb Cortex 16 2006 313 320 15901656
Radley J.J. Sisti H.M. Hao J. Rocher A.B. McCall T. Chronic behavioral stress induces apical dendritic reorganization in pyramidal neurons of the medial prefrontal cortex Neuroscience 125 2004 1 6 15051139
Ragozzino M.E. The effects of dopamine D(1) receptor blockade in the prelimbic-infralimbic areas on behavioral flexibility Learn. Mem. 9 2002 18 28 11917003
Rainville J.R. Weiss G.L. Evanson N. Herman J.P. Vasudevan N. Tasker J.G. Membrane-initiated nuclear trafficking of the glucocorticoid receptor in hypothalamic neurons Steroids 142 2019 55 64 29242167
Raio C.M. Hartley C.A. Orederu T.A. Li J. Phelps E.A. Stress attenuates the flexible updating of aversive value Proc Natl Acad Sci U S A 114 2017 11241 11246 28973957
Raio C.M. Konova A.B. Otto A.R. Trait impulsivity and acute stress interact to influence choice and decision speed during multi-stage decision-making Sci. Rep. 10 2020 7754 32385327
Ramey T. Regier P.S. Cognitive impairment in substance use disorders CNS Spectr. 24 2019 102 113 30591083
Rao S.G. Williams G.V. Goldman-Rakic P.S. Destruction and creation of spatial tuning by disinhibition: GABA(A) blockade of prefrontal cortical neurons engaged by working memory J. Neurosci. 20 2000 485 494 10627624
Remijnse P.L. Nielen M.M. van Balkom A.J. Cath D.C. van Oppen P. Reduced orbitofrontal-striatal activity on a reversal learning task in obsessive-compulsive disorder Arch Gen Psychiatry 63 2006 1225 1236 17088503
Robbins T.W. James M. Owen A.M. Sahakian B.J. Lawrence A.D. A study of performance on tests from the CANTAB battery sensitive to frontal lobe dysfunction in a large sample of normal volunteers: implications for theories of executive functioning and cognitive aging. Cambridge Neuropsychological Test Automated Battery J. Int. Neuropsychol. Soc. 4 1998 474 490 9745237
Robbins T.W. Roberts A.C. Differential regulation of fronto-executive function by the monoamines and acetylcholine Cereb Cortex 17 Suppl. 1 2007 i151 i160 17725997
Robinson E.S. Dalley J.W. Theobald D.E. Glennon J.C. Pezze M.A. Opposing roles for 5-HT2A and 5-HT2C receptors in the nucleus accumbens on inhibitory response control in the 5-choice serial reaction time task Neuropsychopharmacology 33 2008 2398 2406 18046307
Robinson E.S. Eagle D.M. Mar A.C. Bari A. Banerjee G. Similar effects of the selective noradrenaline reuptake inhibitor atomoxetine on three distinct forms of impulsivity in the rat Neuropsychopharmacology 33 2008 1028 1037 17637611
Rodefer J.S. Nguyen T.N. Karlsson J.J. Arnt J. Reversal of subchronic PCP-induced deficits in attentional set shifting in rats by sertindole and a 5-HT6 receptor antagonist: comparison among antipsychotics Neuropsychopharmacology 33 2008 2657 2666 18094666
Rogers R.D. Andrews T.C. Grasby P.M. Brooks D.J. Robbins T.W. Contrasting cortical and subcortical activations produced by attentional set shifting and reversal learning in humans J Cognitive Neurosci 12 2000 142 162
Rogers R.D. Andrews T.C. Grasby P.M. Brooks D.J. Robbins T.W. Contrasting cortical and subcortical activations produced by attentional-set shifting and reversal learning in humans J Cogn Neurosci 12 2000 142 162 10769312
Rogers R.D. Blackshaw A.J. Middleton H.C. Matthews K. Hawtin K. Tryptophan depletion impairs stimulus-reward learning while methylphenidate disrupts attentional control in healthy young adults: implications for the monoaminergic basis of impulsive behaviour Psychopharmacology (Berl) 146 1999 482 491 10550499
Rosenblat J.D. Kakar R. McIntyre R.S. The cognitive effects of antidepressants in major depressive disorder: a systematic review and meta-analysis of randomized clinical trials Int. J. Neuropsychopharmacol. 19 2015 pyv082
Saddoris M.P. Sugam J.A. Stuber G.D. Witten I.B. Deisseroth K. Carelli R.M. Mesolimbic dopamine dynamically tracks, and is causally linked to, discrete aspects of value-based decision making Biol Psychiatry 77 2015 903 911 25541492
Sakai K. Rowe J.B. Passingham R.E. Active maintenance in prefrontal area 46 creates distractor-resistant memory Nat. Neurosci. 5 2002 479 484 11953754
Sala-Bayo J. Fiddian L. Nilsson S.R.O. Hervig M.E. McKenzie C. Dorsal and ventral striatal dopamine D1 and D2 receptors differentially modulate distinct phases of serial visual reversal learning Neuropsychopharmacology 45 2020 736 744 31940660
Salatino A. Miccolis R. Gammeri R. Ninghetto M. Belli F. Improvement of impulsivity and decision making by transcranial direct current stimulation of the dorsolateral prefrontal cortex in a patient with gambling disorder J. Gambl. Stud. 38 2022 627 634 34213750
Sanchez C. Asin K.E. Artigas F. Vortioxetine, a novel antidepressant with multimodal activity: review of preclinical and clinical data Pharmacol. Ther. 145 2015 43 57 25016186
Sanchez C.M. Titus D.J. Wilson N.M. Freund J.E. Atkins C.M. Early life stress exacerbates outcome after traumatic brain injury J. Neurotrauma 38 2021 555 565 32862765
Sanchez E.O. Bangasser D.A. The effects of early life stress on impulsivity Neurosci. Biobehav. Rev. 137 2022 104638
Sanchez-Roige S. Stephens D.N. Duka T. Heightened impulsivity: associated with family history of alcohol misuse, and a consequence of alcohol intake Alcohol Clin. Exp. Res. 40 2016 2208 2217 27565012
Sapolsky R.M. Glucocorticoids, the evolution of the stress-response, and the primate predicament Neurobiol Stress 14 2021 100320
Sasamori H. Ohmura Y. Yoshida T. Yoshioka M. Noradrenaline reuptake inhibition increases control of impulsive action by activating D(1)-like receptors in the infralimbic cortex Eur. J. Pharmacol. 844 2019 17 25 30503361
Sawiak S.J. Jupp B. Taylor T. Caprioli D. Carpenter T.A. Dalley J.W. In vivo gamma-aminobutyric acid measurement in rats with spectral editing at 4.7T J Magn Reson Imaging 43 2016 1308 1312 26633759
Schippers M.C. Schetters D. De Vries T.J. Pattij T. Differential effects of the pharmacological stressor yohimbine on impulsive decision making and response inhibition Psychopharmacology (Berl) 233 2016 2775 2785 27251129
Schoenbaum G. Setlow B. Nugent S.L. Saddoris M.P. Gallagher M. Lesions of orbitofrontal cortex and basolateral amygdala complex disrupt acquisition of odor-guided discriminations and reversals Learn. Mem. 10 2003 129 140 12663751
Schoofs D. Pabst S. Brand M. Wolf O.T. Working memory is differentially affected by stress in men and women Behav. Brain Res. 241 2013 144 153 23238042
Schoofs D. Preuss D. Wolf O.T. Psychosocial stress induces working memory impairments in an n-back paradigm Psychoneuroendocrinology 33 2008 643 653 18359168
Schoofs D. Wolf O.T. Smeets T. Cold pressor stress impairs performance on working memory tasks requiring executive functions in healthy young men Behav. Neurosci. 123 2009 1066 1075 19824773
Scoriels L. Jones P.B. Sahakian B.J. Modafinil effects on cognition and emotion in schizophrenia and its neurochemical modulation in the brain Neuropharmacology 64 2013 168 184 22820555
Sesia T. Temel Y. Lim L.W. Blokland A. Steinbusch H.W. Visser-Vandewalle V. Deep brain stimulation of the nucleus accumbens core and shell: opposite effects on impulsive action Exp. Neurol. 214 2008 135 139 18762185
Sessa B. Higbed L. Nutt D. A review of 3,4-methylenedioxymethamphetamine (MDMA)-Assisted psychotherapy Front Psychiatry 10 2019 138 30949077
Shansky R.M. Rubinow K. Brennan A. Arnsten A.F. The effects of sex and hormonal status on restraint-stress-induced working memory impairment Behav. Brain Funct. 2 2006 8 16522198
Shields G.S. Trainor B.C. Lam J.C. Yonelinas A.P. Acute stress impairs cognitive flexibility in men, not women Stress 19 2016 542 546 27230831
Shilyansky C. Williams L.M. Gyurak A. Harris A. Usherwood T. Etkin A. Effect of antidepressant treatment on cognitive impairments associated with depression: a randomised longitudinal study Lancet Psychiatr. 3 2016 425 435
Shiroma P.R. Albott C.S. Johns B. Thuras P. Wels J. Lim K.O. Neurocognitive performance and serial intravenous subanesthetic ketamine in treatment-resistant depression Int. J. Neuropsychopharmacol. 17 2014 1805 1813 24963561
Shiroma P.R. Velit-Salazar M.R. Vorobyov Y. A systematic review of neurocognitive effects of subanesthetic doses of intravenous ketamine in major depressive disorder, post-traumatic stress disorder, and healthy population Clin Drug Investig 42 2022 549 566
Short B. Fong J. Galvez V. Shelker W. Loo C.K. Side-effects associated with ketamine use in depression: a systematic review Lancet Psychiatr. 5 2018 65 78
Siddik M.A.B. Fendt M. D-cycloserine rescues scopolamine-induced deficits in cognitive flexibility in rats measured by the attentional set-shifting task Behav. Brain Res. 431 2022 113961
Siegrist J. Chronic psychosocial stress at work and risk of depression: evidence from prospective studies Eur. Arch. Psychiatr. Clin. Neurosci. 258 Suppl. 5 2008 115 119
Silva-Gomez A.B. Rojas D. Juarez I. Flores G. Decreased dendritic spine density on prefrontal cortical and hippocampal pyramidal neurons in postweaning social isolation rats Brain Res. 983 2003 128 136 12914973
Silveira M.M. Wittekindt S.N. Mortazavi L. Hathaway B.A. Winstanley C.A. Investigating serotonergic contributions to cognitive effort allocation, attention, and impulsive action in female rats J. Psychopharmacol. 34 2020 452 466 31913079
Sinha R. Chronic stress, drug use, and vulnerability to addiction Ann. N. Y. Acad. Sci. 1141 2008 105 130 18991954
Sinkeviciute I. Begemann M. Prikken M. Oranje B. Johnsen E. Efficacy of different types of cognitive enhancers for patients with schizophrenia: a meta-analysis NPJ Schizophr 4 2018 22 30361502
Smith A.G. Neill J.C. Costall B. The dopamine D3/D2 receptor agonist 7-OH-DPAT induces cognitive impairment in the marmoset Pharmacol. Biochem. Behav. 63 1999 201 211 10371648
Snyder H.R. Major depressive disorder is associated with broad impairments on neuropsychological measures of executive function: a meta-analysis and review Psychol. Bull. 139 2013 81 132 22642228
Snyder K. Wang W.W. Han R. McFadden K. Valentino R.J. Corticotropin-releasing factor in the norepinephrine nucleus, locus coeruleus, facilitates behavioral flexibility Neuropsychopharmacology 37 2012 520 530 21993205
Sosa J.L.R. Buonomano D. Izquierdo A. The orbitofrontal cortex in temporal cognition Behav. Neurosci. 135 2021 154 164 34060872
Spannenburg L. Reed H. Adverse cognitive effects of glucocorticoids: a systematic review of the literature Steroids 200 2023 109314
Stalnaker T.A. Franz T.M. Singh T. Schoenbaum G. Basolateral amygdala lesions abolish orbitofrontal-dependent reversal impairments Neuron 54 2007 51 58 17408577
Starcke K. Brand M. Effects of stress on decisions under uncertainty: a meta-analysis Psychol. Bull. 142 2016 909 933 27213236
Starkman M.N. Neuropsychiatric findings in Cushing syndrome and exogenous glucocorticoid administration Endocrinol Metab Clin North Am 42 2013 477 488 24011881
Starkman M.N. Gebarski S.S. Berent S. Schteingart D.E. Hippocampal formation volume, memory dysfunction, and cortisol levels in patients with Cushing's syndrome Biol Psychiatry 32 1992 756 765 1450290
Sterling P. Eyer J. Allostasis: a new paradigm to explain arousal pathology Fisher S. Reason J. Handbook of Life Stress, Cognition and Health 1988 John Wiley &Sons New York 629 649
Stippl A. Scheidegger M. Aust S. Herrera A. Bajbouj M. Ketamine specifically reduces cognitive symptoms in depressed patients: an investigation of associated neural activation patterns J. Psychiatr. Res. 136 2021 402 408 33647855
Stone D.B. Tesche C.D. Transcranial direct current stimulation modulates shifts in global/local attention Neuroreport 20 2009 1115 1119 19590395
Stone E.A. Platt J.E. Brain adrenergic receptors and resistance to stress Brain Res. 237 1982 405 414 6282389
Street L.J. Sternfeld F. Jelley R.A. Reeve A.J. Carling R.W. Synthesis and biological evaluation of 3-heterocyclyl-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazines and analogues as subtype-selective inverse agonists for the GABA(A)alpha5 benzodiazepine binding site J. Med. Chem. 47 2004 3642 3657 15214791
Stuss D.T. Levine B. Alexander M.P. Hong J. Palumbo C. Wisconsin Card Sorting Test performance in patients with focal frontal and posterior brain damage: effects of lesion location and test structure on separable cognitive processes Neuropsychologia 38 2000 388 402 10683390
Sun H. Cocker P.J. Zeeb F.D. Winstanley C.A. Chronic atomoxetine treatment during adolescence decreases impulsive choice, but not impulsive action, in adult rats and alters markers of synaptic plasticity in the orbitofrontal cortex Psychopharmacology (Berl) 219 2012 285 301 21809008
Sun J. Jia K. Sun M. Zhang X. Chen J. The GluA1-related BDNF pathway is involved in PTSD-induced cognitive flexibility deficit in attentional set-shifting tasks of rats J. Clin. Med. 11 2022
Sun X. Zhang Y. Li X. Liu X. Qin C. Early-life neglect alters emotional and cognitive behavior in a sex-dependent manner and reduces glutamatergic neuronal excitability in the prefrontal cortex Front Psychiatry 11 2020 572224
Swaab D.F. Bao A.M. Sex differences in stress-related disorders: major depressive disorder, bipolar disorder, and posttraumatic stress disorder Handb. Clin. Neurol. 175 2020 335 358 33008536
Swartz B.E. McDonald C.R. Patel A. Torgersen D. The effects of guanfacine on working memory performance in patients with localization-related epilepsy and healthy controls Clin. Neuropharmacol. 31 2008 251 260 18836342
Szabo C. Nemeth A. Keri S. Ethical sensitivity in obsessive-compulsive disorder and generalized anxiety disorder: the role of reversal learning J Behav Ther Exp Psychiatry 44 2013 404 410 23693154
Tait D.S. Brown V.J. Farovik A. Theobald D.E. Dalley J.W. Robbins T.W. Lesions of the dorsal noradrenergic bundle impair attentional set-shifting in the rat Eur. J. Neurosci. 25 2007 3719 3724 17610591
Tanaka S.C. Doya K. Okada G. Ueda K. Okamoto Y. Yamawaki S. Prediction of immediate and future rewards differentially recruits cortico-basal ganglia loops Nat. Neurosci. 7 2004 887 893 15235607
Tank A.W. Lee Wong D. Peripheral and central effects of circulating catecholamines Compr. Physiol. 5 2015 1 15 25589262
Tarantino I.S. Sharp R.F. Geyer M.A. Meves J.M. Young J.W. Working memory span capacity improved by a D2 but not D1 receptor family agonist Behav. Brain Res. 219 2011 181 188 21232557
Tedford S.E. Persons A.L. Napier T.C. Dopaminergic lesions of the dorsolateral striatum in rats increase delay discounting in an impulsive choice task PLoS One 10 2015 e0122063
Terry A.V. Jr. Gearhart D.A. Warner S. Hohnadel E.J. Middlemore M.L. Protracted effects of chronic oral haloperidol and risperidone on nerve growth factor, cholinergic neurons, and spatial reference learning in rats Neuroscience 150 2007 413 424 17942237
Terry A.V. Jr. Gearhart D.A. Warner S.E. Zhang G. Bartlett M.G. Oral haloperidol or risperidone treatment in rats: temporal effects on nerve growth factor receptors, cholinergic neurons, and memory performance Neuroscience 146 2007 1316 1332 17434684
Thai C.A. Zhang Y. Howland J.G. Effects of acute restraint stress on set-shifting and reversal learning in male rats Cogn Affect Behav Neurosci 13 2013 164 173 23055093
Thomassin H. Flavin M. Espinas M.L. Grange T. Glucocorticoid-induced DNA demethylation and gene memory during development EMBO J. 20 2001 1974 1983 11296230
Thompson S.M. Josey M. Holmes A. Brigman J.L. Conditional loss of GluN2B in cortex and hippocampus impairs attentional set formation Behav. Neurosci. 129 2015 105 112 25798630
Thompson S.M. Kallarackal A.J. Kvarta M.D. Van Dyke A.M. LeGates T.A. Cai X. An excitatory synapse hypothesis of depression Trends in Neuroscience 38 2015 279 294
Tiemensma J. Andela C.D. Biermasz N.R. Romijn J.A. Pereira A.M. Mild cognitive deficits in patients with primary adrenal insufficiency Psychoneuroendocrinology 63 2016 170 177 26454105
Torregrossa M.M. Xie M. Taylor J.R. Chronic corticosterone exposure during adolescence reduces impulsive action but increases impulsive choice and sensitivity to yohimbine in male Sprague-Dawley rats Neuropsychopharmacology 37 2012 1656 1670 22334120
Tozzi L. Goldstein-Piekarski A.N. Korgaonkar M.S. Williams L.M. Connectivity of the cognitive control network during response inhibition as a predictive and response biomarker in major depression: evidence from a randomized clinical trial Biol Psychiatry 87 2020 462 472 31601424
Tsigos C. Kyrou I. Kassi E. Chrousos G.P. Feingold K.R. Anawalt B. Blackman M.R. Boyce A. Chrousos G. Stress: Endocrine Physiology and Pathophysiology in Endotext 2000 South Dartmouth (MA)
Turner D.C. Clark L. Dowson J. Robbins T.W. Sahakian B.J. Modafinil improves cognition and response inhibition in adult attention-deficit/hyperactivity disorder Biol Psychiatry 55 2004 1031 1040 15121488
Turner K.M. Simpson C.G. Burne T.H.J. Touchscreen-based visual discrimination and reversal tasks for mice to test cognitive flexibility Bio Protoc 7 2017 e2583
Tuscher J.J. Taxier L.R. Fortress A.M. Frick K.M. Chemogenetic inactivation of the dorsal hippocampus and medial prefrontal cortex, individually and concurrently, impairs object recognition and spatial memory consolidation in female mice Neurobiol. Learn. Mem. 156 2018 103 116 30408525
Tytherleigh M.Y. Vedhara K. Lightman S.L. Mineralocorticoid and glucocorticoid receptors and their differential effects on memory performance in people with Addison's disease Psychoneuroendocrinology 29 2004 712 723 15110920
Uribe-Marino A. Gassen N.C. Wiesbeck M.F. Balsevich G. Santarelli S. Prefrontal cortex corticotropin-releasing factor receptor 1 conveys acute stress-induced executive dysfunction Biol Psychiatry 80 2016 743 753 27318500
Vaiana A.M. Asher A.M. Tapia K. Morilak D.A. Vortioxetine reverses impairment of visuospatial memory and cognitive flexibility induced by degarelix as a model of androgen deprivation therapy in rats Neuroendocrinology 2023
van der Schaaf M.E. van Schouwenburg M.R. Geurts D.E. Schellekens A.F. Buitelaar J.K. Establishing the dopamine dependency of human striatal signals during reward and punishment reversal learning Cereb Cortex 24 2014 633 642 23183711
Verharen J.P.H. Adan R.A.H. Vanderschuren L. Differential contributions of striatal dopamine D1 and D2 receptors to component processes of value-based decision making Neuropsychopharmacology 44 2019 2195 2204 31254972
Viola T.W. Creutzberg K.C. Zaparte A. Kestering-Ferreira E. Tractenberg S.G. Acute neuroinflammation elicited by TLR-3 systemic activation combined with early life stress induces working memory impairments in male adolescent mice Behav. Brain Res. 376 2019 112221
Vogel S. Fernandez G. Joels M. Schwabe L. Cognitive adaptation under stress: a case for the mineralocorticoid receptor Trends Cogn Sci 20 2016 192 203 26803208
Volkow N.D. Chang L. Wang G.J. Fowler J.S. Ding Y.S. Low level of brain dopamine D2 receptors in methamphetamine abusers: association with metabolism in the orbitofrontal cortex Am J Psychiatry 158 2001 2015 2021 11729018
Volkow N.D. Fowler J.S. Wang G.J. Hitzemann R. Logan J. Decreased dopamine D2 receptor availability is associated with reduced frontal metabolism in cocaine abusers Synapse 14 1993 169 177 8101394
Voon V. Irvine M.A. Derbyshire K. Worbe Y. Lange I. Measuring "waiting" impulsivity in substance addictions and binge eating disorder in a novel analogue of rodent serial reaction time task Biol Psychiatry 75 2014 148 155 23790224
Wallace A. Pehrson A.L. Sanchez C. Morilak D.A. Vortioxetine restores reversal learning impaired by 5-HT depletion or chronic intermittent cold stress in rats Int. J. Neuropsychopharmacol. 17 2014 1695 1706 24852131
Wang X.D. Chen Y. Wolf M. Wagner K.V. Liebl C. Forebrain CRHR1 deficiency attenuates chronic stress-induced cognitive deficits and dendritic remodeling Neurobiol. Dis. 42 2011 300 310 21296667
Warburton E.C. Brown M.W. Neural circuitry for rat recognition memory Behav. Brain Res. 285 2015 131 139 25315129
Watanabe Y. Gould E. McEwen B.S. Stress induces atrophy of apical dendrites of hippocampal CA3 pyramidal neurons Brain Res. 588 1992 341 345 1393587
Watanabe Y. Stone E. McEwen B.S. Induction and habituation of c-fos and zif/268 by acute and repeated stressors Neuroreport 5 1994 1321 1324 7919189
Weerda R. Muehlhan M. Wolf O.T. Thiel C.M. Effects of acute psychosocial stress on working memory related brain activity in men Hum. Brain Mapp. 31 2010 1418 1429 20127868
Wei J. Yuen E.Y. Liu W. Li X. Zhong P. Estrogen protects against the detrimental effects of repeated stress on glutamatergic transmission and cognition Mol Psychiatry 19 2014 588 598 23835908
Weidacker K. Johnston S.J. Mullins P.G. Boy F. Dymond S. Impulsive decision-making and gambling severity: the influence of gamma-amino-butyric acid (GABA) and glutamate-glutamine (Glx) Eur. Neuropsychopharmacol 32 2020 36 46 31901336
Wellman C.L. Dendritic reorganization in pyramidal neurons in medial prefrontal cortex after chronic corticosterone administration J. Neurobiol. 49 2001 245 253 11745662
Wellman C.L. Bollinger J.L. Moench K.M. Effects of stress on the structure and function of the medial prefrontal cortex: insights from animal models Int. Rev. Neurobiol. 150 2020 129 153 32204829
Wieland L. Ebrahimi C. Katthagen T. Panitz M. Luettgau L. Acute stress alters probabilistic reversal learning in healthy male adults Eur. J. Neurosci. 57 2023 824 839 36656136
Williams G.V. Castner S.A. Under the curve: critical issues for elucidating D1 receptor function in working memory Neuroscience 139 2006 263 276 16310964
Williams G.V. Goldman-Rakic P.S. Modulation of memory fields by dopamine D1 receptors in prefrontal cortex Nature 376 1995 572 575 7637804
Williams G.V. Rao S.G. Goldman-Rakic P.S. The physiological role of 5-HT2A receptors in working memory J. Neurosci. 22 2002 2843 2854 11923449
Williams L.M. Precision psychiatry: a neural circuit taxonomy for depression and anxiety Lancet Psychiatr. 3 2016 472 480
Willner P. Chronic mild stress (CMS) revisited: consistency and behavioural-neurobiological concordance in the effects of CMS Neuropsychobiology 52 2005 90 110 16037678
Willner P. Towell A. Sampson D. Sophokleous S. Muscat R. Reduction of sucrose preference by chronic unpredictable mild stress, and its restoration by a tricyclic antidepressant Psychopharmacology 93 1987 358 364 3124165
Wilner A.P. de Varennes B. Gregoire P.A. Lupien S. Pruessner J.C. Glucocorticoids and hippocampal atrophy after heart transplantation Ann. Thorac. Surg. 73 2002 1965 1967 12078806
Wingenfeld K. Otte C. Mineralocorticoid receptor function and cognition in health and disease Psychoneuroendocrinology 105 2019 25 35 30243757
Wingenfeld K. Wolf S. Krieg J.C. Lautenbacher S. Working memory performance and cognitive flexibility after dexamethasone or hydrocortisone administration in healthy volunteers Psychopharmacology (Berl) 217 2011 323 329 21484237
Winstanley C.A. Baunez C. Theobald D.E. Robbins T.W. Lesions to the subthalamic nucleus decrease impulsive choice but impair autoshaping in rats: the importance of the basal ganglia in Pavlovian conditioning and impulse control Eur. J. Neurosci. 21 2005 3107 3116 15978020
Winstanley C.A. Dalley J.W. Theobald D.E. Robbins T.W. Fractionating impulsivity: contrasting effects of central 5-HT depletion on different measures of impulsive behavior Neuropsychopharmacology 29 2004 1331 1343 15054475
Winstanley C.A. Eagle D.M. Robbins T.W. Behavioral models of impulsivity in relation to ADHD: translation between clinical and preclinical studies Clin. Psychol. Rev. 26 2006 379 395 16504359
Winstanley C.A. Theobald D.E. Cardinal R.N. Robbins T.W. Contrasting roles of basolateral amygdala and orbitofrontal cortex in impulsive choice J. Neurosci. 24 2004 4718 4722 15152031
Winstanley C.A. Theobald D.E. Dalley J.W. Robbins T.W. Interactions between serotonin and dopamine in the control of impulsive choice in rats: therapeutic implications for impulse control disorders Neuropsychopharmacology 30 2005 669 682 15688093
Winstanley C.A. Theobald D.E.H. Dalley J.W. Glennon J.C. Robbins T.W. 5-HT2A and 5-HT2C receptor antagonists have opposing effects on a measure of impulsivity: interactions with global 5-HT depletion Psychopharmacology 176 2004 376 385 15232674
Witkin J.M. Lippa A. Smith J.L. Jin X. Ping X. The imidazodiazepine, KRM-II-81: an example of a newly emerging generation of GABAkines for neurological and psychiatric disorders Pharmacol. Biochem. Behav. 213 2022 173321
Wood G.E. Young L.T. Reagan L.P. McEwen B.S. Acute and chronic restraint stress alter the incidence of social conflict in male rats Horm. Behav. 43 2003 205 213 12614651
Woolley B. Growing off-label neuro-cognitive uses for guanfacine? An informal review of publications from 2022 with discussion about two clinical trials scheduled to conclude in 2023-2024 Issues Ment. Health Nurs. 44 2023 923 925 37713724
Worbe Y. Savulich G. Voon V. Fernandez-Egea E. Robbins T.W. Serotonin depletion induces 'waiting impulsivity' on the human four-choice serial reaction time task: cross-species translational significance Neuropsychopharmacology 39 2014 1519 1526 24385133
Wright R.L. Conrad C.D. Enriched environment prevents chronic stress-induced spatial learning and memory deficits Behav. Brain Res. 187 2008 41 47 17904657
Yalin N. Kempton M.J. Mazibuko N. Mehta M.A. Young A.H. Stokes P.R. Mifepristone enhances the neural efficiency of human visuospatial memory encoding and recall Psychoneuroendocrinology 125 2021 105116
Yao Y. Silver R. Mutual shaping of circadian body-wide synchronization by the suprachiasmatic nucleus and circulating steroids Front. Behav. Neurosci. 16 2022 877256
Yaple Z.A. Yu R. Fractionating adaptive learning: a meta-analysis of the reversal learning paradigm Neurosci. Biobehav. Rev. 102 2019 85 94 31004627
Yates J.R. Bardo M.T. Effects of intra-accumbal administration of dopamine and ionotropic glutamate receptor drugs on delay discounting performance in rats Behav. Neurosci. 131 2017 392 405 28956947
Yates J.R. Batten S.R. Bardo M.T. Beckmann J.S. Role of ionotropic glutamate receptors in delay and probability discounting in the rat Psychopharmacology (Berl) 232 2015 1187 1196 25270726
Yoon J.H. Grandelis A. Maddock R.J. Dorsolateral prefrontal cortex GABA concentration in humans predicts working memory load processing capacity J. Neurosci. 36 2016 11788 11794 27852785
Young A.H. Gallagher P. Watson S. Del-Estal D. Owen B.M. Ferrier I.N. Improvements in neurocognitive function and mood following adjunctive treatment with mifepristone (RU-486) in bipolar disorder Neuropsychopharmacology 29 2004 1538 1545 15127079
Yu M. Zhang Y. Chen X. Zhang T. Antidepressant-like effects and possible mechanisms of amantadine on cognitive and synaptic deficits in a rat model of chronic stress Stress 19 2016 104 113 26466744
Yuen E.Y. Liu W. Karatsoreos I.N. Feng J. McEwen B.S. Yan Z. Acute stress enhances glutamatergic transmission in prefrontal cortex and facilitates working memory Proc Natl Acad Sci U S A 106 2009 14075 14079 19666502
Yuen E.Y. Liu W. Karatsoreos I.N. Ren Y. Feng J. Mechanisms for acute stress-induced enhancement of glutamatergic transmission and working memory Mol Psychiatry 16 2011 156 170 20458323
Zaehle T. Sandmann P. Thorne J.D. Jancke L. Herrmann C.S. Transcranial direct current stimulation of the prefrontal cortex modulates working memory performance: combined behavioural and electrophysiological evidence BMC Neurosci. 12 2011 2 21211016
Zanos P. Gould T.D. Mechanisms of ketamine action as an antidepressant Mol Psychiatry 23 2018 801 811 29532791
Zhang M.W. Ho R.C. Controversies of the effect of ketamine on cognition Front Psychiatry 7 2016 47 27065891
Zou J. Yang L. Yang G. Gao J. The efficacy and safety of some new GABAkines for treatment of depression: a systematic review and meta-analysis from randomized controlled trials Psychiatry Res 328 2023 115450
