Stress: perspectives on its impact on cognition and pharmacological treatment.

Review article 1

Stress: perspectives on its impact on cognition and pharmacological treatment Miao-Kun Sun and Daniel L. Alkon Stress in life is unavoidable, affecting everyone on a daily basis. Psychological stress in mammals triggers a rapidly organized response for survival, but it may also cause a variety of behavioral disorders and damage cognitive function. Stress is associated with biases in cognitive processing; some of the most enduring memories are formed by traumatic events. Our understanding of how cognition is shaped by stress is still relatively primitive; however, evidence is rapidly accumulating that the ‘mature’ brain has a great capacity for plasticity and that there are numerous ways through which pharmacological therapeutics could rescue cognitive function and regain cognitive balance. In this review, we discuss recent advances in our understanding of the interplay between stress and cognitive processes and potential therapeutic

Introduction ‘Stress’, derived from the Latin word stringere, meaning ‘to draw tight’, is a word that has long been used in physics. It refers to exertion of ‘force’ on a material body, resulting in ‘strain’. In biology and psychology, it describes a mental strain or a biological reaction to any challenge or threat to the well-being of an organism. The term is often loosely used to define the threats themselves, their causes, or their consequences. In addition, the types of stress appear limitless, including stress that is sensory (such as pain, bright light, noise, temperature, or environmental issues of food, air, water, housing, health, freedom, or mobility), social (relationship conflict, social defeat, deception, break-up, deaths, marriage, or divorce), or related to life experiences (war, poverty, unemployment, behavioral disorders, natural disasters, heavy drinking, insufficient sleep, and sexual abuse). Stress in everyday life is unavoidable and any ‘structure’ that does not resist environmental stress is likely to be eventually eliminated in nature. In this sense, stress is fundamental to our existence, but it can also cause damage to biological systems. Stress responses are triggered by a stressor – a cue or event that threatens the well-being of an organism – to promote coping mechanisms that will ensure survival (Koolhaas et al., 2011). Stressors experienced by mammals can be physiological or psychological. Responses to the latter type of stress require higher-order sensory processing. One good example of a psychological stressor is ‘time pressure’, the feeling that it is necessary to complete certain tasks within a set period of time. In this review, we restrict the 0955-8810 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins

approaches to stress-related behavioral and cognitive disorders. Behavioural Pharmacology 00:000–000 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. Behavioural Pharmacology 2014, 00:000–000 Keywords: anxiety, brain-derived neurotrophic factor, bryostatin-1, glucocorticoids, hippocampus, learning and memory, post-traumatic stress disorder, prefrontal cortex, protein kinase C, stress Blanchette Rockefeller Neurosciences Institute, Morgantown, West Virginia, USA Correspondence to Miao-Kun Sun, PhD, Blanchette Rockefeller Neuroscience Institute, 8 Medical Center Dr., Morgantown, WV 26505, USA E-mails: [email protected], [email protected] Received 26 February 2014 Accepted as revised 16 May 2014

use of the term ‘stress’ to conditions in which an insult exceeds the natural mental or psychological regulatory capacity of an organism, in other words, psychosocial stress. Unless otherwise defined in its context, the term refers to acute and chronic stresses in general.

Biological basis of stress The stress response in mammals mainly involves two systems: the nervous and endocrine systems (Fig. 1). The sympathetic nervous system governs the fast activation response, occurring in seconds. The endocrine response is slower and mainly involves the hypothalamic–pituitary–adrenal (HPA) axis, resulting in increased release of glucocorticoid, which reaches a peak ∼ 20–40 min after stress onset (Dickerson and Kemeny, 2004). The sympathetic nervous response involves the hypothalamus, brainstem, and hippocampus (Resstel et al., 2008; Scopinho et al., 2013). Evidence suggests that synaptic blockade in the dorsal hippocampus of rats attenuates restraint stress-evoked changes in blood pressure, heart rate, cutaneous vasoconstriction/skin temperature drop, but not the delayed anxious behavior (Scopinho et al., 2013). The endocrine response involves mainly the amygdala and the ventral hippocampus (Bertoglio et al., 2006; Felix-Ortiz and Tye, 2014). The overall response of the nervous and endocrine systems to stress is the initiation of a multiorgan and multisystem reaction to a threat through redistribution of energy to fight-or-flight organs (body muscles, the heart, and the brain), to ensure the individual’s survival. Glucocorticoids also suppress the immune system and insulin secretion DOI: 10.1097/FBP.0000000000000045

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2 Behavioural Pharmacology 2014, Vol 00 No 00

Fig. 1

Potential stressors Not stressful

Reducing stressfulness, exercise, etc.

No marked impact on cognition

Stressful

Autonomic nervous system

Hypothalamic−pituitary− adrenal (HPA) axis CRF (from paraventricular nucleus of hypothalamus)

Catecholamines Adrenergic receptor blockers

ACTH (from anterior pituitary gland) Glucocorticoids (from adrenal cortex)

Oxidants Antioxidants

Memory enhancers, BDNF enhancers, synaptogenic agents

Reducing glucocorticoid release, GR/MR blockers?

1. Enhancing memories of in-context events, especially those involving simple tasks, for survival; enhancing sensitivity to potentially fearful events 2. Impairing memories of out-of-context events, especially those involving complex issues and judgments 3. Impairing memory retrieval 4. Switching from cognitive learning to habit learning and making unhealthy life choices when facing challenges (abuse, obesity, etc.)

Reducing sensitized amygdalar activity, blocking STM-LTM conversion; memory reducers+ exposure therapy, memory enhancers for memory extinction

Regaining cognitive balance and cognitive flexibility, enhancing activity and synaptogenesis in PFC

Stress responses in mammals and potential targets of pharmacological therapeutics. The figure illustrates potential targets for pharmacological treatment of stress-related cognitive abnormalities. Stress-induced behavioral changes and other stress-related responses (cardiovascular, immune, inflammatory, diabetes, accelerated cellular aging, etc.) have been omitted. ACTH, adrenocorticotropic hormone; BDNF, brain-derived neurotrophic factor; CRF, corticotropin-releasing factor; GR, glucocorticoid receptor; LTM, long-term memory; MR, mineralocorticoid receptor; PFC, prefrontal cortex; STM, short-term memory.

(Dinneen et al., 1993) and induce a transient state of insulin resistance and acute hyperglycemia (Rizza et al., 1982). Although the normal response to stressors is essential for survival, inappropriate or sustained activation of the stress response can cause a variety of behavioral and cognitive impairments. Experimental stress

In experimental animal models, a number of physiological, behavioral, and neuroendocrine responses to stress appear highly related to the clinical symptoms of psychiatric disorders. Many models of induced stress have been developed, including acute or chronic restraint (Murakami et al., 2005; Gomez and Luine, 2013; Ciccocioppo et al., 2014), the resident-intruder model of social defeat (with a nonlittermate resident intruder; Wideman et al., 2013), chronic mild stress (such as food or water deprivation, tilting cages, wet cages, overnight lighting, and changes in housing; Papp et al., 2002; Willner, 2005), acute or chronic inescapable stress (Storey et al., 2006), variable chronic and unpredictable stresses (such as a combination of varied periods of water and food deprivation, isolation, flashing light, forced swim, restraint, and cold; Herman et al., 1995; Gamaro et al.,

2003), social isolation (between 72 h to a few weeks; Frisone et al., 2002; Lu et al., 2003; Kamal et al., 2013), and acute electric foot-shock (Yoshioka et al., 1995). Other techniques have also been successfully applied, such as the communication box (for hours to 7 days; Wang et al., 2008), scream sounds (for 4 or 2 h daily for 3 weeks; Hu et al., 2013), and pharmacological stressors [such as yohimbine (2.5 mg/kg intraperitoneally); Schank et al., 2014, which is anxiogenic in humans and can also be used to induce stress in rodents]. In restraint stress, an unavoidable aversive situation can be induced by placing the animals in a small plastic or metal tube; mice placed in a cylindrical tube with a diameter of 6.3 cm and a length of 21.5 cm can be stressed acutely for 60 min or chronically 6 h daily for 7 days (Ciccocioppo et al., 2014). In humans, a prevalent stressor is social stress. Social evaluative stressors, such as the Trier Social Stress Test (Kirschbaum et al., 1993), are often used. The test may consist of a simulated job interview followed by a mental arithmetic task in front of an audience (Nater et al., 2013). It should be noted that the impact of experimentally induced stress may differ greatly between individual subjects and laboratories, as the same challenges might


Pharmacology of mental stress Sun and Alkon 3

not be viewed as ‘stressful’ by certain subjects on the basis of differences in their past experiences and judgments. In contrast, any human contact or experimental procedure performed by investigators on animals is potentially ‘stressful’ for the subjects and often has unexpected consequences, such as altered biochemistry and physiology, including behavior and cognitive functions. Cognitive appraisal

It should be noted that, in the majority of cases, stress is an individual experience that does not entirely depend on a particular event or even its extent or severity. Stress may induce post-traumatic stress disorder (PTSD), anxiety, and depression, or may have no effect; each response depends on how the individual senses and interprets, or appraises, the stressor (Kleim et al., 2012). To be potentially threatening, a psychological situation must be appraised as stressful by the individual (Lazarus, 1966). Those who feel out of control in a particular situation (real or imaged) are impacted by stress exposure, whereas those who feel in control (regardless of whether their appraisal is accurate or inaccurate) are usually not impacted by the stressor. When the subject feels in control of the situation, the prefrontal cortex (PFC) and hippocampus inhibit the glucocorticoid stress response (Diorio et al., 1993). This emphasizes the essential role of subject’s sense of the situation, or cognitive appraisal, in determining their response to stress. Hypothalamic–pituitary–adrenal axis

The initial step of the stress-response cascade begins when the hypothalamus receives alarming signals (sensory inputs, emotionally charged events, or energy deficiency) from one of its many inputs (such as the cerebral cortex, limbic system, or visceral organs) about challenging conditions (Fig. 1). The hypothalamus releases corticotropin-releasing hormone (CRH), which is transported through a short blood vessel system to the pituitary gland. The pituitary gland in turn secretes adrenocorticotropic hormone into the systemic blood stream, ultimately causing the adrenal gland to release corticosteroids. The HPA axis is regulated by multiple feedbacks loops. Glucocorticoids suppress corticotropin-releasing factor (CRF) secretion and excitatory synaptic inputs to CRF neurons (Di et al., 2003), partially through a retrograde action of endocannabinoids on upstream glutamatergic neurons (Di et al., 2005). The cannabinoid CB1 receptors are abundantly expressed in the basolateral amygdala (BLA), hippocampus, and cerebral cortex (Childers and Breivogel, 1998). Pharmacological blockade or genetic disruption of the CB1 receptor leads to increased HPA axis activity (Steiner and Wotjak, 2008), whereas CB1 receptor activation stimulates GABAergic mechanisms in a distinct population of GABAergic interneurons in the

BLA (Katona et al., 2001). The forebrain limbic system also plays an integral role in regulating the HPA axis (Herman et al., 2005). The amygdala activates the HPA axis in response to stressors, whereas the hippocampus and PFC inhibit the axis (Jankord and Herman, 2008). The medial PFC (mPFC) can directly modulate the activity of CRF-secreting neurons (Radley et al., 2008a). Corticosterone injection into the mPFC has been found to reduce restraint stress-induced CRF and adrenocorticotropic hormone release in rats (Diorio et al., 1993). In the hippocampus, glucocorticoids modulate membranebound mineralocorticoid receptors (MRs; Olijslagers et al., 2008), resulting in an increase in excitatory postsynaptic potentials, which activate inhibitory GABAergic input to the CRF-secreting neurons (Boudaba et al., 1996; Herman et al., 2002). The feedback system also involves inhibitory inputs from the amygdala and excitatory connections from the hippocampus to inhibitory neurons in the paraventricular nucleus of the hypothalamus. In times of chronic stress, increasing inputs from the amygdala and decreasing inputs from the hippocampus enhance the net activity of the HPA axis. Recently, ghrelin, a peptide hormone that is primarily produced by the stomach in response to stress, has been proposed as a stress mediator. Ghrelin can cross the blood–brain barrier after post-translational acylation and bind to its receptor, the growth hormone secretagogue 1a, in the BLA (Lutter et al., 2008; Alvarez-Crespo et al., 2012), thereby enhancing fear learning independent of HPA activation (Meyer et al., 2013). Ghrelin administration enhances neurogenesis but impairs spatial learning and memory in adult mice (Zhao et al., 2014). These results suggest that new neurons and spatial learning are not related, whereas other studies report that more neurons are essential and beneficial to cognition (Shors et al., 2001; Tajiri et al., 2014). The central nervous system

The brain plays a critical role in the perception of and reaction to stress and as part of the stress response, its functions are profoundly altered (Kass et al., 2013). It is well established that the amygdala is critically involved in mood regulation and actively acquires signals about safety (Genud-Gabai et al., 2013). During stress, the amygdalar projections to the brainstem and hypothalamus stimulate the release of catecholamines and glucocorticoids, resulting in consolidation of emotional information but weakening of PFC/hippocampal functioning. Loss of self-control during stress exposure, however, can increase the risk for PTSD relapse, anxiety disorder, depressive behavior, overeating, drug addiction, smoking, and alcohol-drinking. The impact of stress on cognition may be direct or indirect, as a consequence of stress-related behavioral changes. Corticosteroids can readily enter the brain. Corticosterone (in rodents; Liu et al., 2013) and cortisol



(in humans) bind to glucocorticoid receptors (GRs) with relatively low affinity and to MRs with 10-fold higher affinity. These receptors are extensively expressed in the hippocampus and amygdala. Under basal conditions, MRs are largely occupied by the ligand, and the amount of GR occupation is dependent on the increase in glucocorticoid levels that occurs in response to stress (De Kloet et al., 2005; Lupien et al., 2007). In the nucleus, both activated MRs and GRs can bind to glucocorticoid response elements in the promoters of target genes and other transcription factors to control gene expression. Ligand-bound MRs and GRs can also control rapid cellular responses independent of nuclear translocation and promoter activation; these responses include glutamate release, trafficking of postsynaptic α-amino-3-hydroxy5-methyl-4-isoxazolepropionic acid receptors, and inducing synaptic plasticity (Finsterwald and Alberini, 2013). Stress activates extracellular signal-regulated kinase (ERK)1/2 (Sweatt, 2001; Meller et al., 2003; Zheng et al., 2007), a key event in fear memory formation (Schafe et al., 2000), and reduces brain-derived neurotrophic factor (BDNF) levels in the PFC and hippocampus (Smith et al., 1995; Liu et al., 2013). BDNF activity is linked to the expression of monoamine genes in the PFC and hippocampus (Sakata and Duke, 2014) and is widely implicated in development and synaptic plasticity. BDNF is highly enriched in brain regions involved in learning and memory, including the amygdala, hippocampus, and PFC (Hofer et al., 1990). Opposite impacts of stress on neuronal activity and spines in the amygdala and hippocampus/PFC are frequently observed and appear fundamental to stressinduced behavioral and cognitive changes. Stress increases glutamatergic signaling in the BLA and hippocampus. The stress-induced increase in glutamatergic signaling in the BLA results in increased amygdalar activity (Padival et al., 2013), enhanced BDNF expression, dendritic outgrowth, and increased spine density (Mitra et al., 2005; Hill et al., 2013), most markedly of the mushroom spines (Maroun et al., 2013), the most mature, stable, ‘memory’ spines. The stress-induced increase in glutamatergic signaling in the hippocampus is accompanied by decreased activity of the pyramidal cells and decreased BDNF activity (Vyas et al., 2002; Lakshminarasimhan and Chattarji, 2012; Boyle, 2013). It has also been shown that the hippocampal pyramidal cells receiving aversive sensory information from the entorhinal cortex are actually inhibited by cholinergic input-mediated activation of CA1 dendrite-targeting interneurons in fear learning (Lovett-Barron et al., 2014). The general outcome of chronic stress is the strengthening of the amygdala (Vyas et al., 2002), by expansion of the dendrites in the structures that promote the stress response (Vyas et al., 2002), particularly its basolateral component with outputs to the mPFC and the ventral hippocampus (Vyas et al., 2002; Cerqueira et al.,

2007), and weakening of the structures that provide negative feedback on the stress response, first the mPFC (Brown et al., 2005; Izquierdo et al., 2006; Cerqueira et al., 2007) and then, less sensitively, the hippocampus (McEwen, 2004). The increased neuronal activity and density of dendritic spines in the amygdala are associated and an increased functional connectivity from the amygdala to the hippocampus (Ghosh et al., 2013), thereby augmenting dominance of amygdalar activity over the hippocampus. Stress causes spine loss and debranching of dendrites on mPFC neurons (Arnsten, 2009; Hains et al., 2009). The loss of axospinous synapses could be substantial, reaching over 30% following chronic stress (Radley et al., 2008b; Bloss et al., 2011), especially of distal apical dendritic branches. Three weeks of chronic corticosterone treatment has been shown to cause retraction of dendrites in the mPFC (Wellman, 2001; Cerqueira et al., 2005). The thin spines are the most vulnerable; however, chronic stress may increase spine density in the PFC under some circumstances, especially mushroom-shaped spines (Michelsen et al., 2007). Stress also causes the release of substance P (Ebner et al., 2004), an 11 amino acid member of the tachykinin family. Substance P preferentially binds to the neurokinin-1 receptor (NK1R), producing anxiogenic effects. NK1R antagonists have been found to reverse the behavioral effects of acute stress and to produce anxiolytic effects (Ebner et al., 2008; Singewald et al., 2008; Schank et al., 2013). Interestingly, the substance P/NK1R cascade mediates the reinforcing effects of drug and alcohol use (Schank et al., 2012; Barbier et al., 2013). Oxidative stress

Chronic stress induces high levels of reactive oxygen species (ROS; Fig. 1; Gerecke et al., 2013). Corticosterone is known to trigger the release of oxidative stress markers, leading to stress-induced impairment of cognition (Sato et al., 2010). ROS are formed under normal physiological conditions and thus are unavoidable. However, when present in excess amounts, ROS are capable of oxidizing all major biomolecules, including DNA, RNA, proteins, and lipids. The brain is highly vulnerable to oxidative imbalance because of its high energy demand, high oxygen consumption, rich abundance of easily peroxidizable polyunsaturated fatty acids, high level of the potent ROS catalyst iron, and relative paucity of antioxidants and related enzymes. Stressinduced oxidants impair memories, such as olfactory memory in aged Drosophila (Haddadi et al., 2013) and spatial memory and radial maze task performance in rats (Fukui et al., 2002). The lipid peroxidation product, isoprostane 8,12-iso-iPF2alpha-VI, is increased in the urine, blood, and cerebrospinal fluid of patients with Alzheimer’s disease (AD), and the extent of the increase is correlated with the severity of the disease (Pratico et al., 2000). Oxidative stress occurs in the AD brain not only as



a prominent feature of affected brains but also early in the course of the disease (Nunomura et al., 2001; Wang et al., 2013a), suggesting a contribution toward the pathogenesis of AD.

Behavioral and cognitive changes The impact of stress on memories is complicated and depends on the extent of the stress and the relevance of the stressful event to the formed memories. The general rule is that the formation of memories of the events that are related to the ongoing stressor (Cahill et al., 2003; Smeets et al., 2007; Zoladz et al., 2011; Schonfeld et al., 2013) and procedural knowledge that does not involve working memory (Schwabe and Wolf, 2012) are enhanced by acute stress, whereas the majority of other memories that are unrelated to the stressor, including memory retrieval, are impaired (De Quervain et al., 1998; Kuhlmann et al., 2005; Schwabe and Wolf, 2009; Guez et al., 2013) by acute stress. Memory of stressful experiences

Acute stress promotes selective attention processes. Stress can initiate molecular and hormonal responses, prompting the formation of long-term memories that help the individual survive similarly stressful events in the future. Stress and its induced release of glucocorticoid are essential to contextual fear conditioning and spatial and inhibitory avoidance memories (Roozendaal et al., 1996; Cordero et al., 2002). Noradrenalin may also act on the amygdala to enhance fear memory (Debiec and LeDoux, 2006). Acute stress and the stress level of glucocorticoid at the time of encoding of the emotional event improve the memory of the event (Roozendaal et al., 2006; Payne et al., 2007; Weiss, 2007; Wirkner et al., 2013), especially with regard to simple memory tasks. In this scenario, the stress itself is part of the trigger, related to the events. The performance of well-practiced simple tasks involving basal ganglia circuits, but not the mPFC, may appear improved under this circumstance. This does not rule out the fact that moderate stress may enhance spatial learning and memory (Akirav et al., 2004; Galliot et al., 2010). The difficulty here is whether ‘stress’ at moderate levels should be viewed differently. Contextual fear memory involves several brain structures, including the hippocampus and amygdala. The former is mainly involved in context encoding, and forming and storing the contextual representatives, rather than forming the context-aversive stimuli association, in which the amygdala plays a critical role (encoding, storing, and retrieving the direct association; LeDoux, 2000; Fanselow and Poulos, 2005; Maren et al., 2013). The dorsal hippocampus in rodents (corresponding to the posterior hippocampus in primates) is critically involved in memory storage of spatial information. The ventral hippocampus (anterior in primates) connects with the amygdala, the nucleus of the stria terminalis, the

striatum, and the prelimbic and infralimbic areas of the mPFC and is involved in endogenous anxiety. It has been shown that genome-independent mechanisms of GRs activate the endocannabonoid system in the BLA and hippocampus, resulting in an enhancement of emotional memories (Atsak et al., 2012). Fear expression is also causally related to phasic inhibition of prefrontal parvalbumin interneurons, whose inhibition disinhibits prefrontal projection neurons (to the BLA) to drive fear expression (Courtin et al., 2014). Stress events trigger the release of cortisol and norepinephrine and, if the stress events are sufficiently intense, they result in the release of histone deacetylases (HDACs, the molecular ‘brake pads’) from the promoter to allow histone acetylation and formation and maintenance of stress-related long-term memory (White and Wood, 2013). Histone deacetylases remove acetyl groups from histone tails, which returns chromatin structure to a state that generally silences gene expression (Kouzarides, 2007). The amygdala is a critical brain region in stress-induced hormonal influences on memory consolidation (McGaugh, 2013). Bilateral damage to the amygdala impairs memory of emotional events (Barros-Loscertales et al., 2006). BDNF deletion or tyrosine kinase receptor B impairment in the amygdala has been shown to inhibit both appetitive and aversive learning in mice (Heldt et al., 2014). The effect of stress, and glucocorticoids at large, on memory consolidation depends on the timing, extent, and context of the stress. It has been well recognized that effects of glucocorticoids on memory consolidation are dose-dependent (Roozendaal, 2000; Abercrombie et al., 2003). Stress may enhance the consolidation of extinction memory (Hamacher-Dang et al., 2013), probably through two mechanisms: glucocorticoidmediated impairment of aversive memory retrieval in the exposure session and enhancement of extinction memory consolidation (Bentz et al., 2010; but see Akirav et al., 2009). Memory impairment

Enhancing the memory of stress-related information through stress comes at the cost of impairing other memories, especially those involving complex issues and judgments. The central action of stress on cognition is mostly damaging and disrupts both memory formation and updating (De Kloet et al., 1999), especially of contextually unrelated memories and those that require complex decision-making. Cognitive function of the PFC and hippocampus is particularly vulnerable. The dorsolateral PFC in humans and nonhuman primates is responsible for timing and establishing the appropriate sequence of actions for goal-directed behavior (McEwen and Morrison, 2013) and for guiding the top–down emotional and attentional process and regulating the amygdala (Kalisch, 2009; Ochsner et al., 2012). The timing and establishment of the appropriate sequence of



actions for goal-directed behavior depend on attention, attention shifting, and top–down control (Gazzaley and Nobre, 2012), a process that effectively holds the relevant information in mind as in working memory (De Fockert et al., 2001). It possesses an internal construct of reality independent of sensory perception of the outside world (Funahashi et al., 1989). Stress impairs many of these higher cognitive processes (Roozendaal et al., 2009; Arnsten et al., 2012), including cognitive flexibility (Alexander et al., 2007; Plessow et al., 2011), goal-directed behavior (Plessow et al., 2012), working memory (Elzinga and Roelofs, 2005), and self-control (Heatherton and Wagner, 2011). Overall, decreased PFC activity reflects deficits in cognitive control of subcortical structures, including the amygdala and hippocampus. Working memory in female individuals has been shown to be particularly vulnerable to social stress (Schoofs et al., 2013). Sex differences may, however, be related to appraisal of the same challenge, such as performing a mental arithmetic task in front of a committee, as more stressful by female individuals as compared with male individuals. In rodents, the mPFC (anterior cingulate, prelimbic, and infralimbic cortices) is believed to be the key region mediating attention and attention shifting in goal-directed behavior (Birrell and Brown, 2000; Barense et al., 2002; Kesner and Churchwell, 2011). In addition to hippocampal deficits, stress exposure, including acute stress, impairs cognition and task performance that requires the PFC-mediated complex and flexible thinking, and switches the control of behavior and emotion to more primitive brain circuits (Arnsten, 2009; Hains et al., 2009). Stress impairs mPFC-dependent cognition (Arnsten, 2009; Hains et al., 2009), with the degree of the impairment being correlated to the extent of dendritic shrinkage (Liston et al., 2006; Hains et al., 2009). Impaired functions include working memory performance (Honzel et al., 2013), spatial learning and memory (Bian et al., 2012; Liu et al., 2013), theta activity (Jacinto et al., 2013), category-learning task performance (McCoy et al., 2013), novel object recognition task performance (Chen et al., 2010; Eagle et al., 2013; Guez et al., 2013; Jacinto et al., 2013; Kim et al., 2013; Liu et al., 2013; Nava-Mesa et al., 2013), and fear extinction (Izquierdo et al., 2006; Maroun et al., 2013). Chronic stress may also cause degenerative-like changes (Drevets et al., 1997; Mika et al., 2012). Stress is viewed as one of most potent inhibitors of adult neurogenesis and BDNF activity in the hippocampus (Gould and Tanapat, 1999; Mirescu and Gould, 2006; Zhao et al., 2008; Kim et al., 2013), disrupting the integrity of hippocampal dendritic spines (Chen et al., 2010). Reduction in BDNF is critically involved in the pathogenesis of stressassociated cognitive deficits (McEwen, 2005). The involvement of BDNF in cognitive impairment by chronic stress is supported by the evidence that BDNF

infusion ameliorates chronic stress-induced spatial learning and memory deficits (Radecki et al., 2005). Dendritic retraction has been coupled with impaired extinction of fear (Izquierdo et al., 2006). A single episode of social defeat stress has been shown to induce cognitive impairments in mice 8 h later without affecting locomotion and anxiety levels, an impact probably mediated by mGluR5/Homer1b/c interaction in the dorsal hippocampus (Wagner et al., 2013). Blockade of mGluR5 during the social stress or overexpression of Homer1b/c in the dorsal hippocampus rescues the cognitive impairment (Wagner et al., 2013). Long-term impacts

Early-life stress, occurring during early neurodevelopment in utero and in the postnatal phase, may produce amygdala-mediated (Cohen et al., 2013; Olsavsky et al., 2013; Rifkin-Graboi et al., 2013; Sarro et al., 2014), longlasting changes, including habit-related health problems like addiction and obesity, at the expense of hippocampus-dependent cognitive memory (Patterson et al., 2013). Early-life stress may also increase the risk for mental health problems in adulthood (Baram et al., 2012; Kim et al., 2013). Beyond this window of emotional development, the underlying circuitry is less plastic or more resistant to change. One change involves decreased expression of the cell adhesion molecule nectin-3 in the hippocampus of postnatally stressed adult mice (Wang et al., 2013b). The stress-induced effects on nectin-3, however, could not be reproduced by systemic administration of dexamethasone or intracerebroventricular infusion of corticosterone (Wang et al., 2013b), indicating that the mechanism involves CRH but is GR independent. Excessively released CRH binds to CRHR1 and evokes structural changes (Chen et al., 2012; Maras and Baram, 2012), including elimination of thin dendritic spines (Chen et al., 2008, 2013). Enhancing hippocampal nectin-3 expression has been found to rescue the effects of early-life stress on spine density and memory (Wang et al., 2013b). Stress-related drug addiction

Stress, especially chronic stress, increases sensitivity to drug-associated cues (Lipton, 1997; Enoch, 2011; Mantsch et al., 2014) and relapse to ethanol use and drugs even after years of abstinence (Kosten et al., 1986; Chaplin et al., 2010; Fig. 1), although sensitivity to reward appears to be reduced (Berghorst et al., 2013). Stressinduced increased vulnerability to addiction and instatement of drug-seeking behavior is believed to involve the extended amygdala, including the bed of nucleus of the stria terminalis, the central nucleus of the amygdala, and the shell of the nucleus accumbens (Flavin and Winder, 2013). The ventral tegmental area is believed to be the key integration site where stresscontext and drug-context/cue-related inputs converge;



this area contains dopaminergic neurons projecting into the mPFC (Ilango et al., 2014). Stress-related drug addiction may involve a cognitive switch in behavior control (Fig. 1). Learning and memory are coordinated by multiple memory systems to optimize the behavior for a particular type of memory. Stress increases catecholaminergic and glucocorticoid activity in the PFC and triggers a bias from a goal-related system to a habit–memory system (Dias-Ferreira et al., 2009). Noradrenergic and dopaminergic neurons in the brainstem change their firing in relation to the arousal state and relevance of events and increase their release in the PFC during stress (Roth et al., 1988; Deutch and Roth, 1990; Finlay et al., 1995). Concurrent glucocorticoid and noradrenergic activity, evoked by stressors, is sufficient to trigger a bias from cognitive learning (or goal-directed system) to a habit–memory system (Schwabe et al., 2010, 2011; Schwabe and Wolf, 2013). Distinct neural networks underlie cognitive learning and habit learning; cognitive learning involves an undertaking of motivational evaluation of the outcome in decision-making. Post-traumatic stress disorder

PTSD is a severe anxiety disorder that can develop after exposure to an event (experienced or witnessed) that results in psychological trauma. PTSD, which affects about 11 million US adults (Kessler et al., 2005), is diagnosed when the traumatic event is followed by at least 1 month of three distinct symptoms: intrusive recollection or re-experiencing (daytime thoughts, night-time dreams, and nightmares), avoidance or emotional numbing, and hyperarousal. For its induction and maintenance, self-relevant appraisals are critically involved. Most people are exposed to traumatic events in their life, often to multiple traumatic events, but only a minority develops PTSD. The lifetime prevalence of exposure to a severe traumatic event is estimated at up to 90% (Kessler et al., 1995; Breslau et al., 1998). Individuals facing such stressful events might develop depression, anxiety, or even PTSD, but a relatively low percentage (5–10%) of the general population is affected. It is important to emphasize that specific traumatic memory, even after formation, is still fragile and prone to disruption (Nader et al., 2000), pharmacologically and nonpharmacologically. The neural response involves increased activity in the amygdala and underactivity in the mPFC, probably related to a failure of top–down regulation of emotion and arousal by the mPFC (Nitschke et al., 2006; Cruwys and O’Kearney, 2008; but see Bruce et al., 2013). Under an insufficient top–down control, the amygdala may form the basic structure underlying the flashbacks and re-experiencing, through its extensive connections to the visual association cortex (Simmons et al., 2004). PSTD patients rely more strongly on the last few items in a test; hence, they may show an increase in recency scores on memory tests (Johnsen and

Asbjørnsen, 2008), but may have limited executive resources, which are insufficient for multitask or dualtask performance (Honzel et al., 2013). Social aversion in PTSD might be mediated by GRs in dopaminoceptive neurons, not dopamine-releasing neurons (Barik et al., 2013). The cognitive models emphasize individual differences in cognitive vulnerability in response to stress. Such analysis may identify those trauma survivors who are at risk of development of depression or PTSD and offer those with a particular cognitive profile access to specific treatments or interventions. For example, chronic psychosocial stress makes rats more pessimistic in cognitive judgment bias (Papciak et al., 2013). Thus, the trait pessimism could predict vulnerability to stress-induced behavioral changes (Rygula et al., 2013).

Pharmacology Targeting the critical role of the HPA axis in stress responses, agents that directly block GRs or MRs or glucocorticoid release would seem to be among the first line of effective therapeutics for treating stress-induced cognitive impairment (Fig. 1), although reduction in glucocorticoid tonus may not necessarily have protective effects under certain circumstances. Such agents have in fact been developed. RU486 (mifepristone) and cyproterone are GR antagonists. Progesterone and DHEA have antagonist effects on the GR. Their clinical use, however, faces several severe concerns. One is that blocking GR-dependent processes interferes with glucocorticoid negative feedback and leads to counteractive consequences, such as inducing excessive glucocorticoid secretion (Ratka et al., 1989; Spiga et al., 2007). These agents also disrupt circadian rhythmic hormone secretion (Ikeda et al., 2013). These issues, however, do not preclude the use of these agents as effective therapeutics for stress, as long as the negative feedback system is also effectively targeted and impact on circadian rhythmic hormonal secretion is sufficiently spared. The stressrelated and circadian rhythmic hormonal secretions should be dissociable in drug targeting. From the pharmacological point of view, it would be more desirable to develop agents that selectively reduce the stress-evoked increase in glucocorticoid release and activity. Enhancing the cannabinoid signaling system with CB1 receptor agonists, such as WIN55212-2, can prevent stressinduced increase in glucocorticoid levels (Ganon-Elazar and Akirav, 2009; Hill et al., 2009) and the effects of acute stress on emotional memory (Akirav, 2013) or coping with PTSD symptoms (Passie et al., 2012). Oxytocin inhibits stress-induced activity in the HPA axis. Agents that increase the release of oxytocin from the paraventricular nucleus of the hypothalamus or its actions (intranasal oxytocin) may reduce the impact of stressful events, such as those evoked in social buffering, or poststress social contact (Gordon et al., 2011; Smith and Wang, 2013).



Exercise and mindfulness training may also have beneficial effects. Stress-related undesirable impacts on cognition could be reduced or reversed through several strategies (Fig. 1), based on our understanding of the inter-relationship between stress and cognition: (1) Enhancing neurotrophic activity and memories. (2) Blocking fear memory formation and inhibiting fear reconsolidation. (3) Enhancing extinction of chronic fear. Rescuing stress-related cognitive impairment can be achieved through reversing or reducing stress-induced deficits or enhancing the targeted memory systems (Fig. 1). Neurotrophins, such as BDNF, are highly involved in synaptic plasticity and cognition. Stress, especially chronic stress, reduces brain BDNF activity (Lakshminarasimhan and Chattarji, 2012) in the mPFC and the hippocampus. Brain BDNF activity can be enhanced by exercise, rich environment, and pharmacological agents, such as PKCε activators and other agents (Sun and Alkon, 2008; Sun et al., 2008; Hongpaisan et al., 2011). These agents can directly enhance cognition, probably through their direct action on memory cascades and networks to reverse synaptic and memory deficits. Administration of α-1-receptor antagonists in the PFC or systemically can prevent stress-induced cognitive deficits (Birnbaum et al., 1999) and may be useful in treating PSTD (Taylor and Raskind, 2002; Raskind et al., 2003). Similar effects can also be achieved by D1 receptor antagonists. β-Receptor antagonists, in contrast, have been shown to prevent stress-induced impairment of cognitive flexibility (Fig. 1; Alexander et al., 2007). Restoring the stress-induced loss of hippocampal growth hormone through viral-mediated gene transfer completely reverses stress-induced hippocampal impairment, assayed by contextual fear conditioning and auditory trace conditioning (Vander Weele et al., 2013). Endocannabinoids in the rat BLA enhance memory consolidation (Campolongo et al., 2009; Hill and McEwen, 2009). Cannabinoid agonists have been found to markedly reduce amygdala reactivity to social threats in humans (Phan et al., 2008). Lithium pretreatment has been shown to protect adult mice against traumatic brain injury-induced impairment of spatial memory (Zhu et al., 2010). Postinjury treatment with lithium is also effective in improving performance in spatial memory tasks and the Y-maze test (Dash et al., 2011; Yu et al., 2012). Docosahexaenoic acid [22:6 (n-3)] has been found to increase the levels of GAP43 and BDNF in the hippocampus (Wu et al., 2008) and effectively prevent stressinduced cognitive impairment (measured by the recognition memory task and spatial working memory task) in rats (Trofimiuk and Braszko, 2013). Docosahexaenoic acid makes up 20–50% of cell membrane phospholipids,

promotes neurogensis and synaptogenesis (Calderon and Kim, 2004; Cao et al., 2009), and plays an essential role in maintaining the structural and functional integrity of biological membranes. Its actions on protein kinase C, although underinvestigated, may include the inhibition of translocation of some PKC isoforms (Kim et al., 2001) and activation of others to induce intracellular Ca2 + release (Aires et al., 2007). Regular exercise at appropriate levels and relaxation may reduce the extent of stress (Li et al., 2013; Schoenfeld et al., 2013). Overexercise, however, may be stressful, resulting in a negative effect on neurogenesis and oxidative stress (Schefer and Talan, 1996; Holmes et al., 2004). Blocking fear memory (Fig. 1) might be achieved in several ways. Memory could be impaired by postevent administration of an agent to block the conversion from short-term memory to long-term memory. In this setting, the short-term fear memory will decay quickly. Maldonado et al. (2013) showed that 5 min after restraint in rats activation of ERK2 was observed in the BLA, lasting for at least 1 day after the stressful experience. The increase in ERK2 could be prevented by midazolam (administered either intra-BLA or systemically), a shortacting benzodiazepine ligand. Positive GAGAA receptor modulators should have similar effects. Intra-BLA infusion of U0126, an MEK inhibitor that inhibits ERK1/2 phosphorylation, has been shown to prevent stressinduced influence on fear memory formation (Maldonado et al., 2013). Memories can also be disrupted during their reconsolidation. The neurochemical responses during stress exposure, such as dopamine release, are transient and affect outcomes of cognitive testing in a time-dependent manner (Pabst et al., 2013). Stress at the onset of memory retrieval impairs memory updating, whereas stress that occurs long before memory retrieval does not impair memory updating (Dongaonkar et al., 2013). Low doses of cortisol can inhibit memory retrieval (Roozendaal, 2002) or expression and thus dampen the strength of traumatic memories in PTSD (Aerni et al., 2004; De Quervain and Margraf, 2008). When a protein synthesis inhibitor is administered after retrieval, long-term memory is impaired on subsequent tests (Nader et al., 2000). The therapy would be similar to administration of a combined memory-impairing drug with retrieval of the memory (Brunet et al., 2008), in which propranolol was administered after PTSD patients described a traumatic experience, as fear memory consolidation involves activation of β-adrenergic receptors in the amygdala (LaLumiere et al., 2003). Although propranolol appears to decrease amygdalar activation in humans (Pitman et al., 2002), a larger study found no significant effect after trauma (Sharp et al., 2010). HDAC-targeting inhibitors might also be used during reconsolidation to attenuate even remote fear memories (Graff et al., 2014). Postretrieval inhibition of GRs with systemic RU38486



has been shown to disrupt reconsolidation of traumatic memory in rats (Tronel and Alberini, 2007) and in PTSD patients (Taubenfeld, et al., 2009). Caution, however, needs to be taken as replaying the traumatic events may sensitize the disorders and lead to deterioration. In PTSD, an important pathological role is indicated for impairment or loss of fear extinction (Milad et al., 2009), which might be augmented by memory-enhancers, alone or in combination with cognitive therapy (Foa et al., 2007), including cognitive exposure therapy (imaginal exposure; Powers et al., 2010). Cognitive behavioral therapy is the current treatment of choice for PSTD. The downside of cognitive therapy is that stress markedly impairs the cognitive regulation of emotion (Raio et al., 2013), although extensive experimental studies have shown that emotional responses can be cognitively altered. Nevertheless, 30–50% of patients do not respond to the treatment. The therapy involves extinction learning and might be improved significantly by the addition of pharmacological agents (Fig. 1). The learning process, known as extinction, is context dependent and only reduces fear in the context in which extinction occurs. Extinction of fear conditioning decreases fear responses with repeated presentations of the conditioned stimulus without unconditioned stimulus reinforcement. Extinction of fear conditioning involves the amygdala and hippocampus, both of which are involved in acquiring fear memories, and the ventromedial PFC, which is not normally involved in the formation of fear memories. The extinction silences the basal amygdala neurons that are activated by fear conditioning (Trouche et al., 2013) and decreases the efficacy of excitatory synaptic transmission in projections from the mPFC to the BLA (Cho et al., 2013). The extinction procedures apparently suppress fear but do not erase fear memories, as fear may relapse either spontaneously, be renewed, or be reinstated (Bouton, 1993). BDNF could be an effective molecular target for facilitating extinction learning (Egan et al., 2003; Heldt et al., 2007; Peters et al., 2010; Soliman et al., 2010; Andero and Ressler, 2012), as well as PKCε activators. The BDNF Val66Met polymorphism has been found to predict the response to exposure therapy in PTSD patients (Felmingham et al., 2013), with patients with the BDNF Met-66 low-activity-dependent secretion allele showing poorer response to exposure therapy. Activation of the µ-opioid pathway or blocking κ-opioid receptors has been found to oppose fear consolidation and enhance fear extinction (Good and Westbrook, 1995; McNally and Westbrook, 2003; Holbrook et al., 2010; Knoll et al., 2011). In addition to cognitive therapy, psychopharmacological treatment for PTSD may include selective serotonin reuptake inhibitors (SSRIs), such as sertraline, the only FDA-approved medication for the treatment of PTSD, which is effective in blocking the impact of cortisol on the hippocampus (Vermetten et al., 2006), reducing hyperarousal symptoms

and improving memory (De Quervain, 2006). Although the WHO guidelines recommend against the use of antidepressants in children and adolescents, and benzodiazepine in children, adolescents, and adults (World Health Organization, 2012), benzodiazepine is still prescribed to PTSD patients (Lund et al., 2012). Drugs such as D-cycloserine (Davis et al., 2006), a partial NMDA receptor agonist, may also be used to enhance fear extinction in exposure therapy for treating PTSD (De Kleine et al., 2013). Nabilone, a synthetic cannabinoid, has been found to lead to either cessation of nightmares or reduction in nightmare intensity in the majority of PTSD patients in one clinical trial (Fraser, 2009). The use of agents that activate brain cannabinoid receptors is, however, limited by their abuse potential (Economidou et al., 2007; Ashton, 2012). Vorinostat, an HDAC inhibitor, has been found to ameliorate impaired fear extinction in rats following a single prolonged stress paradigm (Matsumoto et al., 2013). Other HDAC inhibitors, including sodium butyrate, trichostatin A, and valproic acid, are expected to produce similar effects (Kilgore et al., 2010; Stafford et al., 2012; Whittle et al., 2013). However, high doses of the inhibitors themselves might act as pharmacological stressors (Gagliano et al., 2013). Selective PKCε activators possess some pharmacological characteristics that are potentially beneficial to patients suffering from stress disorders. The biological roles of PKC are complex, depending on brain regions, isoforms, or activity. Appropriate levels of activation of certain PKC isoforms may be neuroprotective and synaptogenic (Sun et al., 2008, 2009; Hongpaisan et al., 2011), for their involvement in synaptic remodeling and cognition (Alkon et al., 2005). Yet, the opposite impacts can be easily evoked, depending on the PKC isoform involved (Birnbaum et al., 2004; Hains et al., 2009). The PKCε activators are cognitive enhancers (Alkon et al., 2005; Nelson and Alkon, 2009), when appropriately dosed. They increase BDNF activity and induce synaptogenesis in the hippocampus and could reverse stress-related memory deficits and enhance fear extinction. PKCε activators also rapidly desensitize mGluR5 in vivo (Gereau and Heinemann, 1998), a mechanism through which cognitive impairment induced by social stress can be rescued (Wagner et al., 2013). However, overactivity of some unidentified PKC isoforms may lead to the inhibition of PFC-mediated working memory (Birnbaum et al., 2004). Some antioxidants may have therapeutic effects on stress-induced cognitive impairment (Fig. 1). Vitamin E can prevent stress-induced memory impairment in rats (Fukui et al., 2002). Resveratrol (trans-3,4′,5-trihydroxystilbene), a phenolic compound produced by grapes, mulberries, and peanuts, has been found to protect primary rat cortical neurons from oxidative stress-induced



injury (Zhuang et al., 2003). At a dose of 80 mg/kg (intraperitoneally for 5 weeks), resveratrol prevents cognitive impairment (tested by water maze) induced by chronic unpredictable mild stress in rats (Liu et al., 2013). Conclusion

Stress, especially acute stress, can quickly mobilize multiple organs and systems to respond to the emerging challenge(s) and improve the chance of survival. However, the systems are not built to handle sustained stress challenges. The adverse impacts of stress on human lives are increasingly recognized. Stress not only causes cardiovascular problems (Park et al., 2005; Wideman et al., 2013) and increases the risk of developing inflammatory and autoimmune diseases, but also accelerates the process of cellular aging (Moreno-Villaneva et al., 2013) and results in psychological suffering and cognitive impairment. Although most studies on stress psychology focus on the involvement of glucocorticoids, the dimension of stress is not restricted to glucocorticoid activity. Stress-related cognitive impairment and bias can be treated using pharmacological therapeutic agents, which may enhance cognitive functions, reverse disorder-related damages to the networks, help regain cognitive balance, or enhance fear extinction. Conversion of short-term fear memory to longterm memory could be blocked pharmacologically in the process. One concern is that the induced amnesia might block memory of an event that is important to remember for future safety. With our rapidly increasing understanding of a variety of molecular players in the cognitive process, the potential of behavioral and pharmacological therapies to address stress-related cognitive impairment holds a greater future than today’s imagination.

Acknowledgements Conflicts of interest

There are no conflicts of interest.

References Abercrombie HC, Kalin NH, Thurow ME, Rosenkranz MA, Davidson RJ (2003). Cortisol variation in humans affects memory for emotionally laden and neutral information. Behav Neurosci 117:505–516. Aerni A, Traber R, Hock C, Roozendaal B, Schelling G, Papassotiropoulos A, et al. (2004). Low-dose cortisol for symptoms of posttraumatic stress disorder. Am J Psychiatry 161:1488–1490. Aires V, Hichami A, Filomenko R, Plé A, Rébé C, Bettaieb A, Khan NA (2007). Docosahexaenoic acid induces increases in [Ca2 + ]i via inositol 1,4,5-triphosphate production and activates protein kinase C gamma and -delta via phosphatidylserine binding site: implication in apoptosis in U937 cells. Mol Pharmacol 72:1545–1556. Akirav I (2013). Cannabinoids and glucocorticoids modulate emotional memory after stress. Neurosci Behav Rev 37 (10 Pt 2):2554–2563. Akirav I, Kozenicky M, Tal D, Sandi C, Venero C, Richter-Levin G (2004). A facilitative role for corticosterone in the acquisition of a spatial task under moderate stress. Learn Mem 11:188–195. Akirav I, Segev A, Motanis H, Maroun M (2009). D-cycloserine into the BLA reverses the impairing effects of exposure to stress on the extinction of contextual fear, but not conditioned taste aversion. Learn Mem 16:682–686. Alexander JK, Hillier A, Smith RM, Tivarus ME, Beversdorf DQ (2007). Betaadrenergic modulation of cognitive flexibility during stress. J Cogn Neurosci 19:468–478.

Alkon DL, Epstein H, Kuzirian A, Bennett MC, Nelson TJ (2005). Protein synthesis required for long-term memory is induced by PKC activation on days before associative learning. Proc Natl Acad Sci USA 102:16432–16437. Alvarez-Crespo M, Skibicka KP, Farkas I, Molnár CS, Egecioglu E, Hrabovszky E, et al. (2012). The amygdala as a neurobiological target for ghrelin in rats: neuroanatomical, electrophysiological and behavioral evidence. PLoS One 7: e46321. Andero R, Ressler KJ (2012). Fear extinction and BDNF: translating animal models of PTSD to the clinic. Genes Brain Behav 11:503–512. Arnsten AF (2009). Stress signaling pathways that impair prefrontal cortex structure and function. Nat Rev Neurosci 10:410–422. Arnsten AF, Wang MJ, Paspalas CD (2012). Neuromodulation of thought: flexibilities and vulnerabilities in prefrontal cortical network synapses. Neuron 76:223–239. Ashton JC (2012). Synthetic cannabinoids as drugs of abuse. Curr Drug Abuse Rev 5:158–168. Atsak P, Roozendaal B, Campolongo P (2012). Role of the endocannabinoid system in regulating glucocorticoid effects on memory for emotional experiences. Neuroscience 204:104–116. Baram TZ, Davis EP, Obenaus A, Sandman CA, Small SL, Solodkin A, Stern H (2012). Fragmentation and unpredictability of early-life experience in mental disorders. Am J Psychiatry 169:907–915. Barbier E, Vendruscolo LF, Schlosburg JE, Edwards S, Juergens N, Park PE, et al. (2013). The NK1 receptor antagonist L822429 reduces heroin reinforcement. Neuropsychopharmacology 38:976–984. Barense MD, Fox MT, Baxter MG (2002). Aged rats are impaired on an attentional set-shifting task sensitive to medial frontal cortex damage in young rats. Learn Mem 9:191–201. Barik J, Marti F, Morel C, Fernandez SP, Lanteri C, Godeheu G, et al. (2013). Chronic stress triggers social aversion via glucocorticoid receptor in dopaminoceptive neurons. Science 339:332–335. Barrós-Loscertales A, Meseguer V, Sanjuán A, Belloch V, Parcet MA, Torrubia R, Avila C (2006). Behavioural inhibition system activity is associated with increased amygdala and hippocampal grey matter volume: a voxel-based morphometry study. Neuroimage 33:1011–1015. Bentz D, Michael T, De Quervain DJ, Wilhelm FH (2010). Enhancing exposure therapy for anxiety disorders with glucocorticoids: from basic mechanisms of emotional learning to clinical applications. J Anxiety Disord 24:223–230. Berghorst LH, Bogdan R, Frank MJ, Pizzagalli DA (2013). Acute stress selectively reduces reward sensitivity. Front Human Neurosci 7:133. Bertoglio L J, Joca SR, Guimarães FS (2006). Further evidence that anxiety and memory are regionally dissociated within the hippocampus. Behav Brain Res 175:183–188. Bian Y, Pan Z, Hou Z, Huang C, Li W, Zhao B (2012). Learning, memory, and glial cell changes following recovery from chronic unpredictable stress. Brain Res Bull 88:471–476. Birnbaum SG, Gobeske KT, Auerbach J, Taylor JR, Arnsten AF (1999). A role for norepinephrine in stress-induced cognitive deficits: α-1-adrenoceptor mediation in prefrontal cortex. Biol Psychiatry 46:1266–1274. Birnbaum SB, Yuan PX, Wang M, Vujayraghavan S, Bloom AK, Davis DJ, et al. (2004). Protein kinase C overactivity impairs prefrontal cortical regulation of working memory. Science 306:882–884. Birrell JM, Brown VJ (2000). Medial frontal cortex mediates perceptual attentional set shifting in the rat. J Neurosci 20:4320–4324. Bloss EB, Janssen WG, Ohm DT, Yuk FJ, Wadsworth S, Saardi KM, et al. (2011). Evidence for reduced experience-dependent dendritic spine plasticity in the aging prefrontal cortex. J Neurosci 31:7831–7839. Boudaba C, Szabo K, Tasker JG (1996). Physiological mapping of local inhibitory inputs to the hypothalamic paraventricular nucleus. J Neurosci 16:7151–7160. Bouton ME (1993). Context, time, and memory retrieval in the interference paradigms of Pavlovian learning. Psychol Bull 114:80–99. Boyle LM (2013). A neuroplasticity hypothesis of chronic stress in the basolateral amygdala. Yale J Biol Med 86:117–125. Breslau N, Kessler RC, Chilcoat HD, Schultz LR, Davis GC, Andreski P (1998). Trauma and posttraumatic stress disorder in the community: the 1996 Detroit Area Survey of Trauma. Arch Gen Psychiatry 55:626–632. Brown SM, Henning S, Wellman CL (2005). Mild, short-term stress alters dendritic morphology in rat medial prefrontal cortex. Cereb Cortex 15:1714–1722. Bruce SE, Buchholz KR, Brown WJ, Yan L, Durbin A, Sheline YI (2013). Altered emotional interference processing in the amygdala and insula in women with post-traumatic stress disorder. Neuroimage Clin 2:43–49. Brunet A, Orr SP, Tremblay J, Robertson K, Nader K, Pitman RK (2008). Effect of post-retrieval propranolol on psychophysiologic responding during



subsequent script-driven traumatic imagery in post-traumatic stress disorder. J Psychiatr Res 42:503–506. Cahill L, Gorski L, Le K (2003). Enhanced human memory consolidation with postlearning stress: interaction with the degree of arousal at encoding. Learn Mem 10:270–274. Calderon F, Kim HY (2004). Docosahexaenoic acid promotes neurite growth in hippocampal neurons. J Neurochem 904:979–988. Campolongo P, Roozendaal B, Trezza V, Hauer D, Schelling G, McGaugh JL, et al. (2009). Endocannabinoids in the rat basolateral amygdala enhance memory consolidation and enable glucocorticoid modulation of memory. Proc Natl Acad Sci USA 106:4888–4893. Cao D, Kevala K, Kim J, Moon HS, Jun SB, Lovinger D, et al. (2009). Docosahexaenoic acid promotes hippocampal neuronal development and synaptic function. J Neurochem 1112:510–521. Cerqueira JJ, Pego JM, Taipa R, Bessa JM, Almeida OFX, Sousa N (2005). Morphological correlates of corticosteroid-induced changes in prefrontal cortex-dependent behaviors. J Neurosci 25:7792–7800. Cerqueira JJ, Mailliet F, Almeida OF, Jay TM, Sousa N (2007). The prefrontal cortex as a key target of the mal-adaptive response to stress. J Neurosci 27:2781–2787. Chaplin TM, Hong K, Fox HC, Siedlarz KM, Bergquist K, Sinha R (2010). Behavioral arousal in response to stress and drug cue in alcohol and cocaine addicted individuals versus healthy controls. Hum Psychopharmacol 25:368–376. Chen Y, Dubé CM, Rice CJ, Baram TZ (2008). Rapid loss of dendritic spines after stress involves derangement of spine dynamics by corticotropin-releasing hormone. J Neurosci 28:2903–2911. Chen Y, Rex CS, Rice CJ, Dube CM, Gall CM, Lynch G, et al. (2010). Correlated memory defects and hippocampal dendritic spine loss after acute stress involve corticotropin-releasing hormone signaling. Proc Natl Acad Sci USA 107:13123–13128. Chen Y, Andres AL, Frotscher M, Baram TZ (2012). Tuning synaptic transmission in the hippocampus by stress: the CRH system. Front Cell Neurosci 6:13. Chen Y, Kramár EA, Chen LY, Babayan AH, Andres AL, Gall CM, et al. (2013). Impairment of synaptic plasticity by the stress mediator CRH involves selective destruction of thin dendritic spines via RhoA signaling. Mol Psychiatry 18:485–496. Childers SR, Breivogel CS (1998). Cannabis and endogenous cannabinoid systems. Drug Alcohol Depend 51:173–187. Cho J-H, Deisseroth K, Bolshakov VY (2013). Synaptic encoding of fear extinction in mPFC amygdala circuits. Neuron 80:1491–1507. Ciccocioppo R, De Guglielmo G, Hansson AC, Ubaldi M, Kallupi M, Cruz MT, et al. (2014). Restraint stress alters nociceptin/orphanin FQ and CRF systems in the rat central amygdala: Significance for anxiety-like behavior. J Neurosci 34:363–372. Cohen MM, Jing DQ, Tottenham N, Lee FS, Casey BJ (2013). Early-life stress has persistent effects on amygdala function and development in mice and humans. Proc Natl Acad Sci USA 110:18274–18278. Cordero MI, Kruyt ND, Merino JJ, Sandi C (2002). Glucocorticoid involvement in memory formation in a rat model for traumatic memory. Stress 5:73–79. Courtin J, Chaudun F, Rozeske RR, Karalis N, Gonzalez-Campo C, Wurtz H, et al. (2014). Preforntal parvalbumin interneurons shape neuronal activity to drive fear expression. Nature 505:92–96. Cruwys T, O’Kearney R (2008). Implications of neuroscientific evidence for the cognitive models of post-traumatic stress disorder. Clin Psychologist 12:67–76. Dash PK, Johnson D, Clark J, Orsi SA, Zhang M, Zhao J, et al. (2011). Involvement of the glycogen synthase kinase-3 signaling pathway in TBI pathology and neurocognitive outcome. PLoS One 6:e24648. Davis M, Ressler K, Rothbaum BO, Richardson R (2006). Effects of D-cycloserine on extinction: Translation from preclinical to clinical work. Biol Psychiatry 60:369–375. Debiec J, LeDoux J (2006). Noradrenergic signalling in the amygdala contributes to the reconsolidation of fear memory: treatment implications for PTSD. Annals NY Acad Sci 1071:521–524. De Fockert JW, Rees G, Frith CD, Lavie N (2001). The role of working memory in visual selective attention. Science 291:1803–1806. De Kleine RA, Hendriks G-J, Smits JAJ, Broekman TG, van Minnen A (2014). Prescriptive variables for D-cycloserine augmentation of exposure therapy for posttraumatic stress disorder. J Psychiatric Res 48:40–46. De Kloet ER, Oitzl MS, Joels M (1999). Stress and cognition: are corticosteroids good or bad guys? Trends Neurosci 22:422–426. De Kloet ER, Joels M, Holsboer F (2005). Stress and the brain: from adaptation to disease. Nature Rev Neurosci 6:463–475.

De Quervain D (2006). Glucocorticoid-induced inhibition of memory retrieval: Implications for posttraumatic stress disorder. Annals NY Acad Sci 1071:216–220. De Quervain DJ, Margraf J (2008). Glucocorticoids for the treatment of posttraumatic stress disorder and phobias: A novel therapeutic approach. Eur J Pharmacol 583:365–371. De Quervain DJ, Roozendaal B, McGaugh JL (1998). Stress and glucocorticoids impair retrieval of long-term spatial memory. Nature 394:787–790. Deutch AY, Roth RH (1990). The determinants of stress-induced activation of the prefrontal cortical dopamine system. Prog Brain Res 85:367–403. Di S, Malcher-Lopes R, Halmos KC, Tasker JG (2003). Nongenomic glucocorticoid inhibition via endocannabinoid release in the hypothalamus: a fast feedback mechanism. J Neurosci 23:4850–4857. Di S, Malcher-Lopes R, Marcheselli VL, Bazan NG, Tasker JG (2005). Rapid glucocorticoid-mediated endocannabinoid release and opposing regulation of glutamate and gamma-aminobutyric acid inputs to hypothalamic magnocellular neurons. Endocrinology 146:4292–4301. Dias-Ferreira E, Sousa JC, Melo I, Morgado P, Mesquita AR, Cerqueira JJ, et al. (2009). Chronic stress causes frontostriatal reorganization and affects decision-making. Science 325:621–625. Dickerson SS, Kemeny ME (2004). Acute stressors and cortisol responses: a theoretical integration and synthesis of laboratory research. Psychol Bull 130:355–391. Dinneen S, Alzaid A, Miles J, Rizza R (1993). Metabolic effects of the nocturnal rise in cortisol on carbohydrate metabolism in normal humans. J Clin Invest 92:2283–2290. Diorio D, Viau V, Meaney MJ (1993). The role of the medial prefrontal cortex (cingulate gyrus) in the regulation of hypothalamic–pituitary–adrenal responses to stress. J Neurosci 13:3839–3847. Dongaonkar B, Hupbach A, Gomez R, Nadel L (2013). Effects of psychosocial stress on episodic memory updating. Psychopharmacology (Berl) 226:769–779. Drevets WC, Price JL, Simpson JR, Todd RD, Reich T, Vannier M, et al. (1997). Sub-genual prefrontal cortex abnormalities in mood disorders. Nature 386:824–827. Eagle AL, Fitzpatrick CJ, Perrine SA (2013). Single prolonged stress impairs social and object novelty recognition. Behav Brain Res 256:591–597. Ebner K, Rupniak NM, Saria A, Singewald N (2004). Substance P in the medial amygdala: emotional stress-sensitive release and modulation of anxietyrelated behavior in rats. Proc Natl Acad Sci USA 101:4280–4285. Ebner K, Singewald GM, Whittle N, Ferraguti F, Singewald N (2008). Neurokinin 1 receptor antagonism promotes active stress coping via enhanced septal 5-HT transmission. Neuropsychopharmacology 33:1929–1941. Economidou D, Mattioli L, Ubaldi M, Lourdusamy A, Soverchia L, Hardiman G, et al. (2007). Role of cannabinoidergic mechanisms in ethanol selfadministration and ethanol seeking in rat adult offspring following perinatal exposure to Delta9-tetrahydrocannabinol. Toxicol Appl Pharmacol 223:73–85. Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, et al. (2003). The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 112:257–269. Elzinga BM, Roelofs K (2005). Cortisol-induced impairments of working memory require acute sympathetic activation. Behav Neurosci 119:98–103. Enoch MA (2011). The role of early life stress as a predictor for alcohol and drug dependence. Psychopharmacol (Berl) 214:17–31. Fanselow M, Poulos A (2005). The neuroscience of mammalian associative learning. Annu Rev Psychol 56:207–234. Felix-Ortiz AC, Tye KM (2014). Amygdala inputs to the ventral hippocampus bidirectionally modulate social behavior. J Neurosci 34:586–595. Felmingham KL, Dobson-Stone C, Schofield PR, Quirk GJ, Bryant RA (2013). The brain-derived neurotrophic factor Val66Met polymorphism predicts responses to exposure therapy in posttraumatic stress disorder. Biol Psychiatry 73:1059–1063. Finlay JM, Zigmond MJ, Abercrombie ED (1995). Increased dopamine and norepinephrine release in medial prefrontal cortex induced by acute and chronic stress: effects of diazepam. Neuroscience 64:619–628. Finsterwald C, Alberini CM (2013). Stress and glucocorticoid receptordependent mechanisms in long-term memory: From adaptive response to psychopathologies. Neurobiol Learn Mem pii: S1074-7427:00194-9. Flavin SA, Winder DG (2013). Noradrenergic control of the bed nucleus of the stria terminalis in stress and reward. Neuropharmacology 70:324–330. Foa EB, Hembree EA, Rothbaum BO (2007). Prolonged exposure therapy for PTSD: emotional processing of traumatic experiences. Oxford: Oxford University Press.



Fraser GA (2009). The use of a synthetic cannabinoid in the management of treatment-resistant nightmares in posttraumatic stress disorder (PTSD). CNS Neurosci Ther 15:84–88. Frisone DF, Frye CA, Zimmerberg B (2002). Social isolation stress during the third week of life has age-dependent effects on spatial learning in rats. Behav Brain Res 128:153–160. Fukui K, Omoi NO, Hayasaka T, Shinnkai T, Suzuki S, Abe K, et al. (2002). Cognitive impairment of rats caused by oxidative stress and aging, and its prevention by vitamin E. Ann NY Acad Sci 959:275–284. Funahashi S, Bruce CJ, Goldman-Rakic PS (1989). Mnemonic coding of visual space in the monkey’s dorsolateral prefrontal cortex. J Neurophysiol 61:331–349. Gagliano H, Delgado-Morales R, Sanz-Garcia A, Armario A (2013). High doses of the histone deacetylase inhibitor sodium butyrate triggers a stress-like response. Neuropharmacology 79C:75–82. Galliot E, Levaillant M, Beard E, Millot J-L, Pouri´e G (2010). Enhancement of spatial learning by predator odor in mice: involvement of amygdala and hippocampus. Neurobiol Learn Mem 93:196–202. Gamaro GD, Manoli LP, Torres ILS, Silveira R, Dalmaz C (2003). Effects of chronic variant stress on feeding behavior and on monoamine levels in different rat brain structures. Neurochem Int 42:107–114. Ganon-Elazar E, Akirav I (2009). Cannabinoid receptor activation in the basolateral amygdala blocks the effects of stress on the conditioning and extinction of inhibitory avoidance. J Neurosci 29:11078–11088. Gazzaley A, Nobre AC (2012). Top-down modulation: bridging selective attention and working memory. Trends Cogn Sci 16:129–135. Genud-Gabai R, Klavir O, Paz R (2013). Safety signals in the primate amygdala. J Neurosci 33:17986–17994. Gereau RW 4th, Heinemann SF (1998). Role of protein kinase C phosphorylation in rapid desensitization of metabolic glutamate receptor 5. Neuron 20:143–151. Gerecke KM, Kolobova A, Allen S, Fawer JL (2013). Exercise protects against chronic restraint stress-induced oxidative stress in the cortex and hippocampus. Brain Res 1509:66–78. Ghosh S, Laxmi TR, Chattarji S (2013). Functional connectivity from the amygdala to the hippocampus grows stronger after stress. J Neurosci 33:7234–7244. Gomez JL, Luine VN (2013). Female rats exposed to stress and alcohol show impaired memory and increased depressive-like behaviors. Physiol Behav 123:47–54. Good AJ, Westbrook RF (1995). Effects of a microinjection of morphine into the amygdala on the acquisition and expression of conditioned fear and hypoalgesia in rats. Behav Neurosci 109:631–641. Gordon I, Martin C, Feldman R, Leckman JF (2011). Oxytocin and social motivation. Dev Cogn Neurosci 1:471–493. Gould E, Tanapat P (1999). Stress and hippocampal neurogenesis. Biol Psychiatry 46:1472–1479. Graff J, Joseph NF, Horn ME, Samiei A, Meng J, Seo J, et al. (2014). Epigenetic priming of memory updating during reconsolidation to attenuate remote fear memories. Cell 156:261–276. Guez J, Cohen J, Naveh-Benjamin M, Shiber A, Yankovsky Y, Saar R, et al. (2013). Associative memory impairment in acute stress disorder: Characteristics and time course. Psychiatry Res 209:479–484. Haddadi M, Jahromi SR, Sagar BKC, Patil RK, Shivanadappa T, Ramesh SR (2013). Brain aging, memory impairment and oxidative stress: A study in Drosophila melanogaster. Behav Brain Res 259:60–69. Hains AB, Vu MA, Maciejewski PK, van Dyck CH, Gottron M, Arnsten AF (2009). Inhibition of protein kinase C signaling protects prefrontal cortex dendritic spines and cognition from the effects of chronic stress. Proc Natl Acad Sci USA 106:17957–17962. Hamacher-Dang TC, Engler H, Schedlowski M, Wolf OT (2013). Stress enhances the consolidation of extinction memory in a predictive learning task. Front Behav Neurosci 7:108. Heatherton TF, Wagner DD (2011). Cognitive neuroscience of self-regulation failure. Trends Cogn Sci 15:132–139. Heldt SA, Stanek L, Chhatwal JP, Ressler KJ (2007). Hippocampus-specific deletion of BDNF in adult mice impairs spatial memory and extinction of aversive memories. Mol Psychiatry 12:656–670. Heldt SA, Zimmermann K, Parker K, Gaval M, Ressler KJ (2014). BDNF deletion or TrkB impairment in amygdala inhibits both appetitive and aversion learning. J Neurosci 34:2444–2450. Herman JP, Adams D, Prewitt C (1995). Regulatory changes in neuroendocrine stress integrative circuitry produced by a variable stress paradigm. Neuroendocrinology 61:180–190. Herman JP, Tasker JG, Ziegler DR, Cullinan WE (2002). Local circuit regulation of paraventricular nucleus stress integration: glutamate-GABA connections. Pharmacol Biochem Behav 71:457–468.

Herman JP, Ostrander MM, Mueller NK, Figueiredo H (2005). Limbic system mechanisms of stress regulation: hypothalamo–pituitary–adrenocortical axis. Prog Neuropsychopharmacol Biol Psychiatry 29:1201–1213. Hill MN, McEwen BS (2009). Endocannabinoids: the silent partner of glucocorticoids in the synapse. Proc Natl Acad Sci USA 106:4579–4580. Hill MN, McLaughlin RJ, Morrish AC, Viau V, Floresco SB, Hillard CJ, et al. (2009). Suppression of amygdalar endocannabinoid signaling by stress contributes to activation of the hypothalamic–pituitary–adrenal axis. Neuropsychopharmacology 34:2733–2745. Hill MN, Kumar SA, Filipski SB, Iverson M, Stuhr KL, Keith JM, et al. (2013). Disruption of fatty acid amide hydrolase activity prevents the effects of chronic stress on anxiety and amygdalar microstructure. Mol Psychiatry 10:1125–1135. Hofer M, Pagliusi SR, Hohn A, Leibrock J, Barde YA (1990). Regional distribution of brain-derived neurotrophic factor mRNA in the adult mouse brain. EMBO J 9:2459–2464. Holbrook TL, Galarneau MR, Dye JL, Quinn K, Dougherty AL (2010). Morphine use after combat injury in Iraq and post-traumatic stress disorder. N Engl J Med 362:110–117. Holmes MM, Galea LA, Mistlberger RE, Kempermann G (2004). Adult hippocampal neurogenesis and voluntary running activity: circadian and dosedependent effects. J Neurosci Res 76:216–222. Hongpaisan J, Sun M-K, Alkon DL (2011). PKC ε activation prevents synaptic loss, Aβ elevation, and cognitive deficits in Alzheimer’s disease transgenic mice. J Neurosci 31:630–643. Honzel N, Justuss T, Swick D (2013). Posttraumatic stress disorder is associated with limited executive resources in a working memory task. Cogn Affect Behav Neurosci [Epub ahead of print]. Hu L, Yang J, Song T, Hou N, Liu Y, Zhao X, et al. (2013). A new stress model, a scream sound, alters learning and monoamine levels in rat brain. Physiol Behav 123:105–113. Ikeda Y, Kumagai H, Skach A, Sato M, Yanagisawa M (2013). Modulation of circadian glucocorticoid oscillation via adrenal opioid-CXCR7 signaling alters emotional behavior. Cell 155:1323–1336. Ilango A, Kesner A, Keller KL, Stuber GD, Bonci A, Ikemoto S (2014). Similar roles of substantia nigra and ventral tegmental dopamine neurons in reward and aversion. J Neurosci 34:817–822. Izquierdo A, Wellman CL, Holmes A (2006). Brief uncontrollable stress causes dendritic retraction in infralimbic cortex and resistance to fear extinction in mice. J Neurosci 26:5733–5738. Jacinto LR, Reis JS, Dias NS, Cerqueira JJ, Correia JH, Sousa N (2013). Stress affects theta activity in limbic networks and impairs novelty-induced exploration and familiarization. Front Behav Neurosci 7:127. Jankord R, Herman JP (2008). Limbic regulation of hypothalamo–pituitary adrenocortical functions during acute and chronic stress. Ann NY Acad Sci 1148:64–73. Johnsen GE, Asbjørnsen AE (2008). Consistent impaired verbal memory in PTSD: a meta-analysis. J Affect Disord 111:74–82. Kalisch R (2009). The functional neuroanatomy of reappraisal: time matters. Neurosci Biobehav Rev 33:1215–1226. Kamal A, Ramakers GMJ, Altinbilek B, Kas MJH (2013). Social isolation stress reduces hippocampal long-term potentiation: effects of animal strain and involvement of glucocorticoid receptors. Neuroscience 256:262–270. Kass MD, Rosenthal MC, Pottachal J, McGann JP (2013). Fear learning enhances neural responses to threat-predictive sensory stimuli. Science 342:1389–1392. Katona I, Rancz EA, Acsady L, Ledent C, Mackie K, Hajos N, et al. (2001). Distribution of CB1 cannabinoid receptors in the amygdala and their role in the control of GABAergic transmission. J Neurosci 21:9506–9518. Kesner RP, Churchwell JC (2011). An analysis of rat prefrontal cortex in mediating executive function. Neurobiol Learn Mem 96:417–431. Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CB (1995). Posttraumatic stress disorder in the National Comorbidity Survey. Arch Gen Psychiatry 52:1048–1060. Kessler RC, Chiu WT, Demler O, Merikangas KR, Walters EE (2005). Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 62:617–627. Kilgore M, Miller CA, Fass DM, Hennig KM, Haggarty SJ, Sweatt JD, et al. (2010). Inhibitors of class 1 histone deacetylases reverse contextual memory deficits in a mouse model of Alzheimer’s disease. Neuropsychopharmacology 35:870–880. Kim HFS, Weeber EJ, Sweatt JD, Stoll AL, Marangell LB (2001). Inhibitory effects of megega-3 acids on protein kinase C activity in vitro. Mol Psychiatry 6:246–248.



Kim P, Evans GW, Angstadt M, Ho SS, Sripada CS, Swain JE, et al. (2013). Effects of childhood poverty and chronic stress on emotion regulatory brain function in adulthood. Proc Natl Acad Sci USA 110:18442–18447. Kim JI, Lee JW, Kee YA, Lee DH, Han NS, Choi YK, et al. (2013). Sexual activity counteracts the suppressive effects of chronic stress on adult hippocampal neurogenesis and recognition memory. Brain Res 1538:26–40. Kirschbaum C, Pirke KM, Hellhammer DH (1993). The ‘Trier Social Stress Test’ – a tool for investigating psychobiological stress responses in a laboratory setting. Neuropsychobiology 28:76–81. Kleim B, Ehlers A, Glucksman E (2012). Investigating cognitive pathways to psychopathology: predicting depression and posttraumatic stress disorder from early responses after assault. Psychol Trauma 4:527–537. Knoll AT, Muschamp JW, Sillivan SE, Ferguson D, Dietz DM, Meloni EG, et al. (2011). Kappa opioid receptor signaling in the basolateral amygdala regulates conditioned fear and anxiety in rats. Biol Psychiatry 70:425–433. Koolhaas J, Bartolomucci A, Buwalda B, De Boer SF, Flügge G, Korte SM, et al. (2011). Stress revisited: a critical evaluation of the stress concept. Neurosci Biobehav Rev 35:1291–1301. Kosten TR, Rounsaville BJ, Kleber HD (1986). A 2.5-year follow-up of depression, life crises, and treatment effects on abstinence among opioid addicts. Arch Gen Psychiatry 43:733–738. Kouzarides T (2007). Chromatin modifications and their function. Cell 128:693–705. Kuhlmann S, Piel M, Wolf OT (2005). Impaired memory retrieval after psychosocial stress in healthy young men. J Neurosci 25:2977–2982. Lakshminarasimhan H, Chattarji S (2012). Stress leads to contrasting effects on the levels of brain-derived neurotrophic factor in the hippocampus and amygdala. PLoS One 7:e30481. LaLumiere RT, Buen TV, McGaugh JL (2003). Post-training intra-basolateral amygdala infusions of norepinephrine enhance consolidation of memory for contextual fear conditioning. J Neurosci 23:6754–6758. Lazarus RS (1966). Psychological stress and the coping process. New York: McGraw-Hill. LeDoux JE (2000). Emotion circuits in the brain. Annu Rev Neurosci 23:155–184. Li HW, Liang A, Guan FX, Fan RT, Chi LK, Yang B (2013). Regular treadmill running improves spatial learning and memory performance in young mice through increased hippocampal neurogenesis and decreased stress. Brain Res 1531:1–8. Lipton R (1997). The relationship between alcohol, stress, and depression in Mexican Americans and non-Hispanic whites. Behav Med 23:101–111. Liston C, Miller MM, Goldwater DS, Radley JJ, Rocher AB, Hof PR, et al. (2006). Stress-induced alterations in prefrontal cortical dendritic morphology predict selective impairments in perceptual attentional set-shifting. J Neurosci 26:7870–7874. Liu D, Zhang Q, Gu J, Wang X, Xie K, Xian X, et al. (2014). Reveratrol prevents impaired cognition induced by chronic unpredictable mild stress rats. Prog Neuropsychopharmacol Biol Psychiatry 49:21–29. Lovett-Barron M, Kaifosh P, Kheirbek MA, Danielson N, Zaremba JD, Reardon TR, et al. (2014). Dendritic inhibition in the hippocampus supports fear learning. Science 343:857–863. Lu L, Bao G, Guobin B, Chen H, Xia P, Fan X, et al. (2003). Modification of hippocampal neurogenesis and neuroplasticity by social environments. Exp Neurol 183:600–609. Lund BC, Bernardy NC, Alexander B, Friedman MJ (2012). Declining benzodiazepine use in veterans with posttraumatic stress disorder. J Clin Psychiatry 73:292–296. Lupien SJ, Maheu F, Tu M, Fiocco A, Schramek TE (2007). The effects of stress and stress hormones on human cognition: implications for the field of brain and cognition. Brain Cogn 65:209–237. Lutter M, Sakata I, Osborne-Lawrence S, Rovinsky SA, Anderson JG, Jung S, et al. (2008). The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress. Nat Neurosci 11:752–753. Maldonado NM, Espejo PJ, Martijena ID, Molina VA (2013). Activation of ERK2 in basolateral amygdala underlies the promoting influence of stress on fear memory and anxiety: influence of midazolam pretreatment. Eur Neuropsychopharmacol 24:262–270. Mantsch JR, Vranjkovic O, Twining RC, Gasser PJ, McReynolds JR, Blacktop JM (2014). Neurobiological mechanisms that contribute to stress-related cocaine use. Neuropharmacology 76:383–394. Maras PM, Baram TZ (2012). Sculpting the hippocampus from within: stress, spines and CRH. Trends Neurosci 35:315–324. Maren S, Phan KL, Liberzon I (2013). The contextual brain: implications for fear conditioning, extinction and psychopathology. Nat Rev Neurosci 14:417–428. Maroun M, Ioannides PJ, Bergman KL, Kavushansky A, Holmes A, Wellman CL (2013). Fear extinction deficits following acute stress associate with

increased spine density and dendritic retraction in basolateral amygdala neurons. Eur J Neurosci 38:2611–2620. Matsumoto Y, Morinobu S, Yamamoto S, Matsumoto T, Takei S, Fujita Y, et al. (2013). Varinostat ameliorates impaired fear extinction possibly via the hippocampal NMDA-CaMKII pathway in an animal model of posttraumatic stress disorder. Psychopharmacology (Berl) 229:51–62. McCoy SK, Hutchinson S, Hawthorne L, Cosley BJ, Ell SW (2013). Is pressure stressful? The impact of pressure on the stress response and category learning. Cogn Affact Behav Neurosci. doi: 10.3758/s13415-013-0215-1. [Epub ahead of print]. McEwen BS (2004). Protection and damage from acute and chronic stress: allostasis and allostatic overload and relevance to the pathophysiology of psychiatric disorders. Ann NY Acad Sci 1032:1–7. McEwen BS (2005). Glucocorticoids, depression, and mood disorders: structural remodeling in the brain. Metabolism 54:20–23. McEwen BS, Morrison JH (2013). The brain on stress: vulnerability and plasticity of the prefrontal cortex over the life course. Neuron 79:16–29. McGaugh JL (2013). Making lasting memories: remembering the significant. Proc Natl Acad Sci USA 110 (Suppl 2):10402–10407. McNally GP, Westbrook RF (2003). Opioid receptors regulate the extinction of Pavlovian fear conditioning. Behav Neurosci 117:1292–1301. Meller E, Shen C, Nikolao TA, Jensen C, Tsimberg Y, Chen J, et al. (2003). Regionspecific effects of acute and repeated restraint stress on the phosphorylation of mitogen-activated protein kinases. Brain Res 979:57–64. Meyer RM, Burgos-Robles A, Liu E, Correia SS, Goosens KA (2013). A ghrelingrowth hormone axis drives stress-induced vulnerability to enhanced fear. Mol Psychiatry. doi: 10.1038/mp.2013.135 [Epub ahead of print]. Michelsen KA, van den Hove DL, Schmitz C, Segers O, Prickaerts J, Steinbusch HW (2007). Prenatal stress and subsequent exposure to chronic mild stress influence dendritic spine density and morphology in the rat medial prefrontal cortex. BMC Neurosci 8:107. Mika A, Mazur GJ, Hoffman AN, Talboom JS, Bimonte-Nelson HA, Sanabria F, et al. (2012). Chronic stress impairs prefrontal cortex-dependent response inhibition and spatial working memory. Behav Neurosci 126:605–619. Milad MR, Pitman RK, Ellis CB, Gold AL, Shin LM, Lasko NB, et al. (2009). Neurobiological basis of failure to recall extinction memory in posttraumatic stress disorder. Biol Psychiatry 66:1075–1082. Mirescu C, Gould E (2006). Stress and adult neurogenesis. Hippocampus 16:233–238. Mitra R, Jadhav S, McEwen BS, Vyas A, Chattarji S (2005). Stress duration modulates the spatiotemporal patterns of spine formation in the basolateral amygdala. Proc Natl Acad Sci USA 102:9371–9376. Moreno-Villaneva M, Morath J, Vanhooren J, Elbert T, Libert C, Burkle A, et al. (2013). N-glycosylation profiling of plasma provides evidence for accelerated physiological aging in post-traumatic stress disorder. Tansl Psychiatry 3:e320. Murakami S, Imbe H, Morikawa Y, Kubo C, Senba E (2005). Chronic stress, as well as acute stress, reduces BDNF mRNA expression in the rat hippocampus but less robustly. Neurosci Res 53:129–139. Nader K, Schafe GE, Le Doux JE (2000). Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature 406:722–726. Nater UM, Ditzen B, Strahler J, Ehler U (2013). Effects of orthostasis on endocrine response to psychosocial stress. Intern J Psychophysiol 90:341–346. Nava-Mesa M, Lamprea MR, Munera A (2013). Divergent short- and long-term effects of acute stress in object recognition memory are mediated by endogenous opioid system activation. Neurobiol Learning Mem 106:185–192. Nelson TJ, Alkon DL (2009). Neuroprotective versus tumorigenic protein kinase C activators. Trends Biochem Sci 34:136–145. Nitschke J, Sarinopoulos I, Mackiewicz K, Schaefe H, Davidson R (2006). Functional neuroanatomy of aversion and its anticipation. Neuroimage 29:106–116. Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, et al. (2001). Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol 60:759–767. Ochsner KN, Silvers JA, Buhle JT (2012). Functional imaging studies of emotion regulation: a synthetic review and evolving model of the cognitive control of emotion. Ann NY Acad Sci 1251:E1–E24. Olijslagers JE, DeKloet ER, Elgersma Y, Van Woerden GM, Joels M, Karst H (2008). Rapid changes in hippocampal CA1 pyramidal cell function via pre-as well as postsynaptic membrane mineralocorticoid receptors. Eur J Neurosci 27:2542–2550. Olsavsky AK, Telzer EH, Shapiro M, Humphreys KL, Flannery J, Goff B, et al. (2013). Indiscriminate amygdala response to mothers and strangers after early maternal deprivation. Biol Psychiatry 74:853–860. Pabst S, Brand M, Wolf OT (2013). Stress and decision making: a few minutes make all the difference. Behav Brain Res 250:39–45.



Padival M, Quinette D, Rosenkranz JA (2013). Effects of repeated stress on excitatory drive of basal amygdala neurons in vivo. Neuropsychopharmacology 38:1748–1762. Papciak J, Popik P, Fuchs E, Rygula R (2013). Chronic psychosocial stress makes rats more ‘pessimistic’ in the ambiguous interpretation paradigm. Behav Brain Res 256:305–310. Papp M, Nalepa I, Antkiewicz-Micaluk L, Sanchez C (2002). Behavioural and biochemical studies of citalopram and WAY 100635 in rat chronic mild stress model. Pharmacol Biochem Behav 72:465–474. Park JH, Kang SJ, Song JK, Kim HK, Lim CM, Kang DH, et al. (2005). Left ventricular apical ballooning due to severe physical stress in patients admitted to the medical ICU. Chest 128:296–302. Passie T, Emrich HM, Karst M, Brandt SD, Halpern JH (2012). Mitigation of posttraumatic stress symptoms by Cannabis resin: a review of the clinical and neurobiological evidence. Drug Test Anal 4:649–659. Patterson TK, Craske MG, Knowlton BJ (2013). The effect of early-life stress on memory systems supporting instrumental behavior. Hippocampus 23:1025–1034. Payne JD, Jackson ED, Hoscheidt S, Ryan L, Jacobs WJ, Nadel L (2007). Stress administered prior to encoding impairs neutral but enhances emotional longterm episodic memories. Learn Memory 14:861–868. Peters J, Dieppa-Perea LM, Melendez LM, Quirk GJ (2010). Induction of fear extinction with hippocampal-infralimbic BDNF. Science 328:1288–1290. Phan L, Angstadt M, Golden J, Onyewuenyi I, Popovska A, De Wit H (2008). Cannabinoid modulation of amygdala reactivity to social signals of threat in humans. J Neurosci 28:2313–2319. Pitman RK, Sanders KM, Zusman RM, Healy AR, Cheema F, Lasko NB, et al. (2002). Pilot study of secondary prevention of posttraumatic stress disorder with propranolol. Biol Psychiatry 51:189–192. Plessow F, Fischer R, Kirschbaum C, Goschke T (2011). Inflexibly focused under stress: acute psychosocial stress increases shielding of action goals at the expense of reduced cognitive flexibility with increasing time lag to the stressor. J Cogn Neurosci 23:3218–3227. Plessow F, Kiesel A, Kirschbaum C (2012). The stressed prefrontal cortex and goal-directed behaviour: acute psychosocial stress impairs the flexible implementation of task goals. Exp Brain Res 216:397–408. Powers MB, Halpern JM, Ferenschak MP, Gillihan SJ, Foa EB (2010). A metaanalytic review of prolonged exposure for posttraumatic stress disorder. Clin Psychol Rev 30:635–641. Pratico D, Clark CM, Lee VM, Trojanowski JQ, Rokach J, FitzGerald GA (2000). Increased 8,12-iso-iPF2alpha-VI in Alzheimer’s disease: correlation of a noninvasive index of lipid peroxidation with disease severity. Ann Neurol 48:809–812. Radecki DT, Brown LM, Martinez J, Teyler TJ (2005). BDNF protects against stress-induced impairments in spatial learning and memory and LTP. Hippocampus 15:246–253. Radley JJ, Williams B, Sawchenko PE (2008a). Noradrenergic innervation of the dorsal medial prefrontal cortex modulates hypothalamo–pituitary–adrenal responses to acute emotional stress. J Neurosci 28:5806–5816. Radley JJ, Rocher AB, Rodriguez A, Ehlenberger DB, Dammann M, McEwen BS, et al. (2008b). Repeated stress alters dendritic spine morphology in the rat medial prefrontal cortex. J Comp Neurol 507:1141–1150. Raio CM, Orederu TA, Palazzolo L, Shurick AA, Phelps EA (2013). Cognitive emotion regulation fails the stress test. Proc Natl Acad Sci USA 110:15139–15144. Raskind MA, Peskind ER, Kanter ED, Petrie EC, Radant A, Thompson CE, et al. (2003). Prazosin reduces nightmares and other PTSD symptoms in combat veterans: a placebo-controlled study. Am J Psychiatry 160:371–373. Ratka A, Sutanto W, Bloemers M, De Kloet ER (1989). On the role of brain mineralocorticoid (type I) and glucocorticoid (type II) receptors in neuroendocrine regulation. Neuroendocrinology 50:117–123. Resstel LB, Joca SR, Corrêa FM, Guimarães FS (2008). Effects of reversible inactivation of the dorsal hippocampus on the behavioral and cardiovascular responses to an aversive conditioned context. Behav Pharmacol 19:137–144. Rifkin-Graboi A, Bai J, Chen H, Hameed WB, Sim LW, Tint MT, et al. (2013). Prenatal maternal depression associates with microstructure of right amygdala in neonates at birth. Biol Psychiatry 74:837–844. Rizza RA, Mandarino LJ, Gerich JE (1982). Cortisol-induced insulin resistance in man: impaired suppression of glucose production and stimulation of glucose utilization due to a postreceptor detect of insulin action. J Clin Endocrinol Metab 54:131–138. Roozendaal B (2000). Glucocorticoids and the regulation of memory consolidation. Psychoneuroendocrinology 25:213–238.

Roozendaal B (2002). Stress and memory: opposing effects of glucocorticoids on memory consolidation and memory retrieval. Neurobiol Learn Mem 78:578–595. Roozendaal B, Bohus B, McGaugh JL (1996). Dose-dependent suppression of adrenocortical activity with metyrapone: effects on emotion and memory. Psychoneuroendocrinology 21:681–693. Roozendaal B, Okuda S, Van der Zee E, McGaugh JL (2006). Glucocorticoid enhancement of memory requires arousal-induced noradrenergic activation in the basolateral amygdala. Proc Natl Acad Sci USA 103:6741–6746. Roozendaal B, McEwen BS, Chattarji S (2009). Stress, memory and the amygdala. Nat Rev Neurosci 10:423–433. Roth RH, Tam S-Y, Ida Y, Yang J-X, Deutch AY (1988). Stress and the mesocorticolimbic dopamine systems. Ann NY Acad Sci 537:138–147. Rygula R, Papciak J, Popik P (2013). Trait pessimism predicts vulnerability to stress-induced anhedonia in rats. Neuropsychopharmacology 38: 2188–2196. Sakata K, Duke SM (2014). Lack of BDNF expression through promoter IV disturbs expression of monoamine genes in the frontal cortex and hippocampus. Neuroscience 260:265–275. Sarro EC, Sullivan RM, Barr G (2014). Unpredictable neonatal stress enhances adult anxiety and alters amygdala gene expression related to serotonin and GABA. Neuroscience 258:147–161. Sato H, Takahashi T, Sumitani K, Takatsu H, Urano S (2010). Glucocorticoid generates ROS to induce oxidative injury in the hippocampus leading to impairment of cognitive function of rats. J Clin Biochem Nutr 47:224–232. Schafe GE, Atkins CM, Swank MW, Bauer EP, Sweatt JD, LeDoux JE (2000). Activation of ERK/MAP kinase in the amygdala is required for memory consolidation of Pavlovian fear conditioning. J Neurosci 20:8177–8187. Schank JR, Ryabinin AE, Giardino WJ, Ciccocioppo R, Heilig M (2012). Stressrelated neuropeptides and addictive behaviors: beyond the usual suspects. Neuron 76:192–208. Schank J, Schulteis G, Koob GF, Heilig M (2013). The NK1 receptor antagonist L822429 reduces heroin reinforcement. Neuropsychopharmacology 38:976–984. Schank JR, King CE, Sun H, Cheng K, Rice KC, Heilig M, et al. (2014). The role of the neurokinin-1 receptor in stress-induced reinstatement of alcohol and cocaine seeking. Neuropsychopharmacology 39:1093–1101. Schefer V, Talan MI (1996). Oxygen consumption in adult and aged C57BL/6J mice during acute treadmill exercise of different intensity. Exp Gerontol 31:387–392. Schoenfeld TJ, Rada P, Pieruzzini PR, Hsueh B, Gould E (2013). Physical exercise prevents stress-induced activation of granule neurons and enhances local inhibitory mechanisms in the dentate gyrus. J Neurosci 33:7770–7777. Schonfeld P, Ackermann K, Schwabe L (2013). Remembering under stress: different roles of autonomic arousal and glucocorticoids in memory retrieval. Psychoneuroendocrinology 39:249–256. Schoofs D, Pabst S, Brand M, Wolf OT (2013). Working memory is differentially affected by stress in men and women. Behav Brain Res 241:144–153. Schwabe L, Wolf OT (2009). The context counts: congruent learning and testing environments prevent memory retrieval impairment following stress. Cogn Affect Behav Neurosci 9:229–236. Schwabe L, Wolf OT (2012). Stress modulates the engagement of multiple memory systems in classification learning. J Neurosci 32:11042–11049. Schwabe L, Wolf OT (2013). Stress and multiple memory systems: from ‘thinking’ to ‘doing’. Trends Cogn Sci 17:60–68. Schwabe L, Tegenthoff M, Hoffken O, Wolf OT (2010). Concurrent glucocorticoid and noradrenergic activity shifts instrumental behavior from goal-directed to habitual control. J Neurosci 30:8190–8196. Schwabe L, Hoffken O, Tegenthoff M, Wolf OT (2011). Preventing the stressinduced shift from goal-directed to habit action with a beta-adrenergic antagonist. J Neurosci 31:17317–17325. Scopinho AA, Lisboa SFS, Guimaraes FS, Correa FMA, Resstel LBM, Joca SRL (2013). Dorsal and ventral hippocampus modulate autonomic responses but not behavioral consequences associated to acute restraint stress in rats. PLOS One 8:e77750. Sharp S, Thomas C, Rosenberg L, Rosenberg M, Meyer WIII (2010). Propranolol does not reduce risk for acute stress disorder in pediatric burn trauma. J Trauma 68:193–197. Shors TJ, Mieseqaes G, Beylin A, Zhao M, Rydel T, Gould E (2001). Neurogenesis in the adult is involved in the formation of trace memories. Nature 410:372–376. Simmons A, Matthews S, Stein M, Paulus M (2004). Anticipation of emotionally aversive visual stimuli activates right insula. NeuroReport 15:2261–2265. Singewald N, Chicchi GG, Thurner CC, Tsao KL, Spetea M, Schmidhammer H, et al. (2008). Modulation of basal and stress-induced amygdaloid substance P



release by the potent and selective NK1 receptor antagonist L-822429. J Neurochem 106:2476–2488. Smeets T, Giesbrecht T, Jelicic M, Merckelbach H (2007). Context-dependent enhancement of declarative memory performance following acute psychosocial stress. Biol Psychol 76:116–123. Smith AS, Wang Z (2013). Hypothalamic oxytocin mediates social buffering of the stress response. Biol Psychiatry pii S0006-3223:00858-5. Smith MA, Makino S, Kvetnansky R, Post RM (1995). Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J Neurosci 15:1768–1777. Soliman F, Glatt CE, Bath KG, Levita L, Jones RM, Pattwell SS, et al. (2010). A genetic variant BDNF polymorphism alters extinction learning in both mouse and human. Science 327:863–866. Spiga F, Harrison LR, Wood SA, Atkinson HC, MacSweeney CP, Thomson F, et al. (2007). Effect of the glucocorticoid receptor antagonist Org 34850 on basal and stress-induced corticosterone secretion. J Neuroendocrinol 19:891–900. Stafford JM, Raybuck JD, Ryabinin AE, Lattal KM (2012). Increasing histone acetylation in the hippocampus-infralimbic network enhances fear extinction. Biol Psychiatry 72:25–33. Steiner MA, Wotjak CT (2008). Role of the endocannabinoid system in regulation of the hypothalamic–pituitary–adrenocortical axis. Prog Brain Res 170:397–432. Storey JD, Robertson DAF, Beattie JE, Reid IC, Mitchell SN, Balfour DJK (2006). Behavioural and neurochemical responses evoked by repeated exposure to an elevated open platform. Behav Brain Res 166:220–229. Sun M-K, Alkon DL (2008). 4-Methylcatechol on spatial memory and depression. NeuroReport 19:355–359. Sun M-K, Hongpaisan J, Nelson TJ, Alkon DL (2008). Post-stroke neuronal rescue and synaptogenesis mediated in vivo by protein kinase C in adult brains. Proc Natl Acad Sci USA 105:13620–13625. Sun M-K, Hongpaisan J, Alkon DL (2009). Post-ischemic PKC activation rescues retrograde and anterograde long-term memory. Proc Natl Acad Sci USA 106:14676–14680. Sweatt JD (2001). The neuronal MAP kinase cascade: a biochemical signal integration system subserving synaptic plasticity and memory. J Neurochem 76:1–10. Tajiri N, Acosta SA, Shahaduzzaman M, Ishikawa H, Shinozuka K, Pabon M, et al. (2014). Intravenous transplants of human adipose-derived stem cell protect the brain from traumatic brain injury-induced neurodegeneration and motor and cognitive impairments: cell graft biodistribution and soluble factors in young and aged rats. J Neurosci 34:313–326. Taubenfeld SM, Riceberg JS, New AS, Alberini CM (2009). Preclinical assessment for selectively disrupting a traumatic memory via post-retrieval inhibition of glucocorticoid receptors. Biol Psychiatry 65:249–257. Taylor F, Raskind MA (2002). The α1-adrenergic antagonist prazosin improves sleep and nightmares in civilian trauma posttraumatic stress disorder. J Clin Psychopharmacol 22:82–85. Trofimiuk E, Braszko JJ (2013). Concomitant docosahexaenoic acid administration ameliorates stress-induced cognitive impairment in rats. Physiol Behav 118:171–177. Tronel S, Alberini CM (2007). Persistent disruption of a traumatic memory by postretrieval inactivation of glucocorticoid receptors in the amygdala. Biol Psychiatry 62:33–39. Trouche S, Sasaki JM, Tu T, Reijmers LG (2013). Fear extinction causes targetspecific remodeling of perisomatic inhibitory synapses. Neuron 80:1054–1065. Vander Weele CM, Saenz C, Yao J, Correia SS, Goosens KA (2013). Restoration of hippocampal growth hormone reverses stress-induced hippocampal impairment. Front Behav Neurosci 7:66. Vermetten E, Vythilingam M, Schmahl C, De Kloet C, Southwick SM, Charney DS, et al. (2006). Alterations in stress reactivity after long-term treatment with paroxetine in women with posttraumatic stress disorder. Annals NY Acad Sci 1071:184–202.

Vyas A, Mitra R, Shankaranarayana Rao BS, Chattarji S (2002). Chronic stress induces contrasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons. J Neurosci 22:6810–6818. Wagner KV, Hartmann J, Mangold K, Wang X-D, Labermaier C, Liebl C, et al. (2013). Homer1 mediates acute stress-induced cognitive deficits in the dorsal hippocampus. J Neurosci 33:3857–3864. Wang L, Wang W, Zhao M, Ma L, Li M (2008). Psychological stress induces dysregulation of iron metabolism in rat brain. Neuroscience 155:24–30. Wang X, Wang WZ, Li L, Perry G, Lee H-G, Zhu X (2013a). Oxidative stress and mitochondrial dysfunction in Alzheimer’s disease. Biochim Biophys Acta pii S0925-4439:00323-2. Wang XD, Su YA, Wagner KV, Avrabos C, Scharf SH, Hartmann J, et al. (2013b). Nectin-3 links CRHR1 signaling to stress-induced memory deficits and spine loss. Nat Neurosci 16:706–713. Weiss S (2007). Neurobiological alterations associated with traumatic stress. Perspect Psychiatr Care 43:114–122. Wellman CL (2001). Dendritic reorganization in pyramidal neurons in medial prefrontal cortex after chronic corticosterone administration. J Neurobiol 49:245–253. White AO, Wood MA (2013). Does stress remove the HDAC brakes for the formation and persistence of long-term memory? Neurobiol Learning Mem pii S1074-7427:00202-5. Whittle N, Schmuckermair C, Gunduz Cinar O, Hauschild M, Ferraguti F, Holmes A, Singewald N (2013). Deep brain stimulation, histone deacetylase inhibitors and glutamatergic drugs rescue resistance to fear extinction in a genetic mouse model. Neuropharmacology 64:414–423. Wideman CH, Cierniak KH, Sweet WE, Moravec CS, Murphy HM (2013). An animal model of stress-induced cardiomyopathy utilizing the social defeat paradigm. Physiol Behav 120:220–227. Willner P (2005). Chronic mild stress (CMS) revisited: consistency and behavioural-neurobiological concordance in the effects of CMS. Neuropsychobiology 52:90–110. Wirkner J, Weymar M, Low A, Hamm AO (2013). Effects of pre-encoding stress on brain correlates associated with the long-term memory for emotional scenes. PLoS One 8:e68212. World Health Organization (2012). WHO handbook for guideline development. Available at: http://apps.who.int/iris/bitstream/10665/75146/1/9789241548441_ eng.pdf. [Accessed 17 June 2014]. Wu A, Ying Z, Gomez-Pinilla F (2008). Docosahexaenoic acid dietary supplementation enhances the effects of exercise on synaptic plasticity and cognition. Neuroscience 155:751–759. Yoshioka M, Matsumoto M, Togashi H, Saito H (1995). Effects of conditioned fear stress on 5-ht release in the rat prefrontal cortex. Pharmacol Biochem Behav 51:515–519. Yu F, Zhang Y, Chuang DM (2012). Lithium reduces BACE1 overexpression, beta amyloid accumulation, and spatial learning deficits in mice with traumatic brain injury. J Neurotrauma 29:2342–2351. Zhao C, Deng W, Gage FH (2008). Mechanisms and functional implications of adult neurogenesis. Cell 132:645–660. Zhao Z, Liu H, Xiao K, Yu M, Cui L, Zhu Q, et al. (2014). Gherlin administration enhances neurogenesis but impairs spatial learning and memory in adult mice. Neuroscience 257:175–185. Zheng G, Zhang X, Chen Y, Zhang Y, Luo W, Chen J (2007). Evidence for a role of GABAA receptor in the acute restraint stress-induced enhancement of spatial memory. Brain Res 1181:61–73. Zhu ZF, Wang QG, Han BJ, William CP (2010). Neuroprotective effect and cognitive outcome of chronic lithium on traumatic brain injury in mice. Brain Res Bull 83:272–277. Zhuang H, Kim YS, Koehler RC, Dore S (2003). Potential mechanism by which resveratrol, a red wine constituent, protects neurons. Ann NY Acad Sci 993:276–286. Zoladz PR, Clark B, Warnecke A, Smith L, Tabar J, Talbot JN (2011). Pre-learning stress differentially affects long-term memory for emotional words, depending on temporal proximity to the learning experience. Physiol Behav 103:467–476.


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Impact of Stress on the Brain: Pathology, Treatment and Prevention.

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Brain mechanisms underlying the impact of attachment-related stress on social cognition.

Editorial: Impact of Diet on Learning, Memory and Cognition.

The Impact of Monaural Beat Stimulation on Anxiety and Cognition.

Impact of pharmacological and psychological treatment methods of depressive and anxiety disorders on cognitive functioning.

Pharmacological treatment and therapeutic perspectives of metabolic syndrome.

Recent studies on resveratrol and its biological and pharmacological activity.

Imipramine in the treatment of depressed Alzheimer's patients: impact on cognition.

A review on protocatechuic Acid and its pharmacological potential.

Impact of Quantified Smoking Status on Cognition in Young Adults.

Perspectives on stress resilience and adolescent neurobehavioral function.

The interaction between stress and exercise, and its impact on brain function.

Patient-reported outcomes in post-traumatic stress disorder. Part II: focus on pharmacological treatment.

Impact of benign prostatic hyperplasia pharmacological treatment on transrectal prostate biopsy adverse effects.

Editorial: Stress and Cognition.

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Oxidative stress in schizophrenia: a case-control study on the effects on social cognition and neurocognition.