Search

OBJECTIVE: Memory impairment is common in patients with temporal lobe epilepsy and seriously affects life quality. Chronic stress is a recognized cofactor in epilepsy and can also impair memory function. Furthermore, increased cortisol levels have been reported in epilepsy patients. Animal models have suggested that aggravating effects of stress on memory and synaptic plasticity were mediated via glucocorticoids. The aim of this study was, therefore, to investigate the effect of glucocorticoid receptor (GR) modulation on synaptic plasticity in the human cortex of epilepsy patients. METHODS: We performed field potential recordings in acute slices from the temporal neocortex of patients who underwent surgery for drug-resistant temporal lobe epilepsy. Synaptic plasticity was investigated by a theta-burst stimulation (TBS) protocol for induction of long-term potentiation (LTP) in the presence of GR modulators. RESULTS: LTP was impaired in temporal cortex from epilepsy patients. Pretreatment of the slices with the GR antagonist mifepristone (RU486) improved LTP induction, suggesting that LTP impairment was due to baseline GR activation in the human cortex. The highly potent GR agonist dexamethasone additionally weakened synaptic strength in an activity-dependent manner when applied after TBS. SIGNIFICANCE: Our results show a direct negative glucocorticoid effect on synaptic potentiation in the human cortex and imply chronic activation of GRs. Chronic stress may therefore contribute to memory impairment in patients with temporal lobe epilepsy. Furthermore, the activity-dependent acute inhibitory effect of dexamethasone suggests a mechanism of synaptic downscaling by which postictally increased cortisol levels may prevent pathologic plasticity upon seizures.

Background Chronic exposure to stress or alcohol can drive neuroadaptations that alter cognition. Alterations in cognition may contribute to alcohol use disorders by reducing cognitive control over drinking and maintenance of abstinence. Here we examined effects of combined ethanol (EtOH) and stress exposure on prefrontal cortex (PFC)-dependent cognition. Methods Adult male C57BL/6J mice were trained to drink EtOH (15%, v/v) on a 1 h/d 1-bottle schedule. Once stable, mice were exposed to cycles of chronic intermittent EtOH (CIE) or air-control vapor exposure (Air), followed by test cycles of 1 h/d EtOH drinking. During test drinking, mice received no stress (NS) or 10 minutes of forced swim stress (FSS) 4 hours before each test. This schedule produced 4 experimental groups: control, Air/NS; EtOH-dependent no stress, CIE/NS; nondependent stress, Air/FSS; or EtOH-dependent stress, CIE/FSS. After 2 cycles of CIE and FSS exposure, we assessed PFC-dependent cognition using object/context recognition and attentional set shifting. At the end of the study, mice were perfused and brains were collected for measurement of c-Fos activity in PFC and locus coeruleus (LC). Results CIE/FSS mice escalated EtOH intake faster than CIE/NS and consumed more EtOH than Air/NS across all test cycles. After 2 cycles of CIE/FSS, mice showed impairments in contextual learning and extradimensional set-shifting relative to other groups. In addition to cognitive dysfunction, CIE/FSS mice demonstrated widespread reductions in c-Fos activity within prelimbic and infralimbic PFC as well as LC. Conclusions Together, these findings show that interactions between EtOH and stress exposure rapidly lead to disruptions in signaling across cognitive networks and impairments in PFC-dependent cognitive function.

This study assessed the relative contributions of dorsal (dHPC) and ventral (vHPC) hippocampus regions in mediating the rapid effects of an acute stress on contextual memory retrieval. Indeed, we previously showed that an acute stress (3 electric footschocks; 0.9 mA each) delivered 15 min before the 24h-test inversed the memory retrieval pattern in a contextual discrimination task. Specifically, mice learned in a four-hole board two successive discriminations (D1 and D2) varying by the color and texture of the floor. Twenty-four hours later, non-stressed animals remembered accurately D1 but not D2 whereas stressed mice showed an opposite memory retrieval pattern, D2 being more accurately remembered than D1. We showed here that, at the time of memory testing in that task, stressed animals exhibited no significant changes neither in pCREB activity nor in the time-course evolution of corticosterone into the vHPC; in contrast, a significant decrease in pCREB activity and a significant increase in corticosterone were observed in the dHPC as compared to non-stressed mice. Moreover, local infusion of the anesthetic lidocain into the vHPC 15 min before the onset of the stressor did not modify the memory retrieval pattern in non-stress and stress conditions whereas lidocaine infusion into the dHPC induced in non-stressed mice an memory retrieval pattern similar to that observed in stressed animals. The overall set of data shows that memory retrieval in non-stress condition involved primarily the dHPC and that the inversion of memory retrieval pattern after stress is linked to a dHPC but not vHPC dysfunction. This article is protected by copyright. All rights reserved.

Acute stress has been shown to modulate memory for recently learned information, an effect attributed to the influence of stress hormones on medial temporal lobe (MTL) consolidation processes. However, little is known about which memories will be affected when stress follows encoding. One possibility is that stress interacts with encoding processes to selectively protect memories that had elicited responses in the hippocampus and amygdala, two MTL structures important for memory formation. There is limited evidence for interactions between encoding processes and consolidation effects in humans, but recent studies of consolidation in rodents have emphasized the importance of encoding "tags" for determining the impact of consolidation manipulations on memory. Here, we used functional magnetic resonance imaging in humans to test the hypothesis that the effects of post-encoding stress depend on MTL processes observed during encoding. We found that changes in stress hormone levels were associated with an increase in the contingency of memory outcomes on hippocampal and amygdala encoding responses. That is, for participants showing high cortisol reactivity, memories became more dependent on MTL activity observed during encoding, thereby shifting the distribution of recollected events toward those that had elicited relatively high activation. Surprisingly, this effect was generally larger for neutral, compared to emotionally negative, memories. The results suggest that stress does not uniformly enhance memory, but instead selectively preserves memories tagged during encoding, effectively acting as mnemonic filter. © 2016 Wiley Periodicals, Inc.

Stress influences emotional learning and memory processes. These effects are thought to underlie stress-associated mental disorders. Sex differences in stress reactivity and in central nervous system stress sensitivity illustrate the important modulatory role of sex hormones. This Review outlines how stress hormones influence different stages of the fear conditioning process, such as fear acquisition, extinction, and retrieval. Results will be compared with findings on the impact of stress on episodic memory. The focus is on the available human data on sex differences and the impact sex hormones have on the stress effects on emotional learning and memory. It will become apparent that the menstrual cycle but also the intake of hormonal contraceptives modulates the impact of stress on brain and behavior. Additional basic research is needed for a deeper insight regarding the interplay between stress and sex hormones in emotion and cognition. In addition, new treatment options might be derived to optimize existing strategies such as exposure therapy, which relies on the principles of fear conditioning. © 2016 Wiley Periodicals, Inc.

Oral contraceptive (OC) users typically show a blunted or no cortisol response to psychosocial stress. Although most OC regimens include both an inactive (dummy) and active pill phase, studies have not systematically investigated cortisol responses during these pill phases. Further, high levels of cortisol following a stressor diminish retrieval of emotional material, but the effects of stress on memory among OC users are poorly understood. We examined the effects of a psychosocial stressor, the Trier Social Stress Test, vs. a control condition on cortisol responsivity and emotional memory retrieval in women tested either during their active (n = 18) or inactive pill phase (n = 21). In secondary analyses, we quantitatively compared OC users with normally cycling women and showed a significant lack of cortisol response during both active and inactive pill phase. Emotional recall did not differ between active and inactive pill phases. Stress differentially diminished recall of negative words compared with positive or neutral words, but cortisol levels were unrelated to memory performance. These findings indicate that OC users have distinct cortisol and memory responses to stress that are similar between the active and inactive pill phases. © 2016 Wiley Periodicals, Inc.

It is well established that stress impacts the underlying processes of learning and memory. The effects of stress on memory are thought to involve, at least in part, effects on the hippocampus, which is particularly vulnerable to stress. Chronic stress induces hippocampal alterations, including but not limited to dendritic atrophy and decreased neurogenesis, which are thought to contribute to chronic stress-induced hippocampal dysfunction and deficits in learning and memory. Changes in synaptic transmission, including changes in GABAergic inhibition, have been documented following chronic stress. Recently, our laboratory demonstrated shifts in EGABA in CA1 pyramidal neurons following chronic stress, compromising GABAergic transmission and increasing excitability of these neurons. Interestingly, here we demonstrate that these alterations are unique to CA1 pyramidal neurons, since we do not observe shifts in EGABA following chronic stress in dentate gyrus granule cells. Following chronic stress, there is a decrease in the expression of the GABAA receptor (GABAA R) δ subunit and tonic GABAergic inhibition in dentate gyrus granule cells, whereas there is an increase in the phasic component of GABAergic inhibition, evident by an increase in the peak amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs). Given the numerous changes observed in the hippocampus following stress, it is difficult to pinpoint the pertinent contributing pathophysiological factors. Here we directly assess the impact of a reduction in tonic GABAergic inhibition of dentate gyrus granule cells on learning and memory using a mouse model with a decrease in GABAA R δ subunit expression specifically in dentate gyrus granule cells (Gabrd/Pomc mice). Reduced GABAA R δ subunit expression and function in dentate gyrus granule cells is sufficient to induce deficits in learning and memory. Collectively, these findings suggest that the reduction in GABAA R δ subunit-mediated tonic inhibition in dentate gyrus granule cells contributes, at least in part, to deficits in learning and memory associated with chronic stress. These findings have significant implications regarding the pathophysiological mechanisms underlying impairments in learning and memory associated with stress and suggest a role for GABAA R δ subunit containing receptors in dentate gyrus granule cells. © 2016 Wiley Periodicals, Inc.

Episodic retrieval allows people to access memories from the past to guide current thoughts and decisions. In many real-world situations, retrieval occurs under conditions of acute stress, either elicited by the retrieval task or driven by other, unrelated concerns. Memory under such conditions may be hindered, as acute stress initiates a cascade of neuromodulatory changes that can impair episodic retrieval. Here, we review emerging evidence showing that dissociable stress systems interact over time, influencing neural function. In addition to the adverse effects of stress on hippocampal-dependent retrieval, we consider how stress biases attention and prefrontal cortical function, which could further affect controlled retrieval processes. Finally, we consider recent data indicating that stress at retrieval increases activity in a network of brain regions that enable reflexive, rapid responding to upcoming threats, while transiently taking offline regions supporting flexible, goal-directed thinking. Given the ubiquity of episodic memory retrieval in everyday life, it is critical to understand the theoretical and applied implications of acute stress. The present review highlights the progress that has been made, along with important open questions.

It has been suggested that extinction-based therapy benefits from administration of the stress hormone cortisol. However, it is unclear whether similar effects can be obtained by inducing stress instead of administering cortisol, and whether the effects also persist if memory is tested in a different context (renewal test) or after exposure to an aversive stimulus (reinstatement). The present study therefore applied a fear conditioning (contextA, day 1) and extinction (context B, day 2) paradigm in healthy men. After fear extinction, participants were exposed to a stress or control procedure (n = 20 each). Fear retrieval was tested in contextsAand B on day 3. Postextinction stress increased skin conductance responses to the extinguished stimulus in the retrieval and reinstatement test especially in the acquisition context. The contextdependent return of fear may reflect enhancing effects of stress on the consolidation of contextual cues. Descriptors: Conditioning, Normal volunteers, Electrodermal, Learning/Memory, Emotion, Biochemical

Stress alters the function of many physiological processes throughout the body, including in the brain. A neural circuit particularly vulnerable to the effects of stress is the hippocampus, a key component of the episodic and spatial memory system in both humans and rodents. Earlier studies have provided snapshots of morphological, molecular, physiological and behavioral changes in the hippocampus following either acute or repeated stress. However, the cumulative impact of repeated stress on in vivo hippocampal physiology remains unexplored. Here we report the stress-induced modulation of the spatially receptive fields of the hippocampal CA1 'place cells' as mice explore familiar and novel tracks after 5 and 10 days of immobilization stress. We find that similar to what has been observed following acute stress, five days of repeated stress results in decreased excitability of CA1 pyramidal cells. Following ten days of chronic stress, however, this decreased hippocampal excitability is no longer evident, suggesting adaptation may have occurred. In addition to these changes in neuronal excitability, we find deficient context discrimination, wherein both short-term and chronic stress impair the ability of the hippocampus to unambiguously distinguish novel and familiar environments. These results suggest that a loss of network flexibility may underlie some of the behavioral deficits accompanying chronic stress.

Learning and memory can be controlled by distinct mem- ory systems. How these systems are coordinated to optimize learning and behavior has long been unclear. Accumulating evidence indicates that stress may modulate the engagement of multiple memory systems. In par- ticular, rodent and human studies demonstrate that stress facilitates dor- sal striatum-dependent "habit" memory, at the expense of hippocampus- dependent "cognitive" memory. Based on these data, a model is proposed which states that the impact of stress on the relative use of multiple mem- ory systems is due to (i) differential effects of hormones and neurotrans- mitters that are released during stressful events on hippocampal and dorsal striatal memory systems, thus changing the relative strength of and the interactions between these systems, and (ii) a modulatory influence of the amygdala which biases learning toward dorsal striatum-based mem- ory after stress. This shift to habit memory after stress can be adaptive with respect to current performance but might contribute to psychopa- thology in vulnerable individuals. V C 2013 Wiley Periodicals, Inc.

Prior work suggests that hippocampus-dependent memory undergoes a systems consolidation process such that recent memories are stored in the hippocampus, while older memories are independent of the hippocampus and instead dependent on cortical areas. One problem with interpreting these studies is that memory for the contextual stimuli weakens as time passes between the training event and testing and older memories are often less detailed, making it difficult to determine if memory storage in the hippocampus is related to the age or to the accuracy of the memory. Activity of the mammalian target of rapamycin (mTOR) signaling pathway is known to be important for controlling protein translation necessary for both memory consolidation after initial learning and for the reconsolidation of memory after retrieval. We tested whether p70s6 kinase (p70s6K), a key component of the mTOR signaling pathway, is activated following retrieval of context fear memory in the dorsal hippocampus (DH) and anterior cingulate cortex (ACC) at 1, 10, or 36 days after context fear conditioning. We also tested whether strengthening memory for the contextual stimuli changed p70s6K phosphorylation in these structures 36 days after training. We show that under standard training conditions retrieval of a recently formed memory is initially precise and involves the DH. Over time it loses detail, becomes independent of the DH and depends on the ACC. In a subsequent experiment, we preserved the accuracy of older memories through pre-exposure to the training context. We show that remote memory still involved the DH in animals given pre-exposure. These data support the notion that detailed memories depend on the DH regardless of their age.

Item does not contain fulltext Stress causes a neuroendocrine response cascade, leading to the release of catecholamines and glucocorticoids (GCs). GCs influence learning and memory by acting on mineralocorticoid (MR) and glucocorticoid (GR) receptors. Typically, GCs enhance the consolidation of memory processing at the same time as impairing the retrieval of memory of emotionally arousing experiences. The present selective review addresses four recent developments in this area. First, the role of the endocannabinoid system in mediating the rapid, nongenomic effects of GCs on memory is illustrated in rodents. Subsequently, studies on the impact of the selective stimulation of MRs on different memory processes in humans are summarised. Next, a series of human experiments on the impact of stress or GC treatment on fear extinction and fear reconsolidation is presented. Finally, the clinical relevance of the effects of exogenous GC administration is highlighted by the description of patients with anxiety disorders who demonstrate an enhancement of extinction-based therapies by GC treatment. The review highlights the substantial progress made in our mechanistic understanding of the memory-modulating properties of GCs, as well as their clinical potential.

The cerebral serotonin (5-HT) system is involved in cognitive functions such as memory and learning and animal studies have repeatedly shown that stimulation of the 5-HT type 4 receptor (5-HT4 R) facilitates memory and learning and further that the 5-HT4 R modulates cellular memory processes in hippocampus. However, any associations between memory functions and the expression of the 5-HT4 R in the human hippocampus have not been investigated. Using positron emission tomography with the tracer [(11) C]SB207145 and Reys Auditory Verbal Learning Test we aimed to examine the individual variation of the 5-HT4R binding in hippocampus in relation to memory acquisition and consolidation in healthy young volunteers. We found significant, negative associations between the immediate recall scores and left and right hippocampal BPND , (p = 0.009 and p = 0.010 respectively) and between the right hippocampal BPND and delayed recall (p = 0.014). These findings provide evidence that the 5-HT4 R is associated with memory functions in the human hippocampus and potentially pharmacological stimulation of the receptor may improve episodic memory.

Objective In comparison with basal physiological levels, acute, high levels of cortisol affect learning and memory. Despite reports of cortisol-induced episodic memory effects, no study has used a comprehensive battery of tests to evaluate glucocorticoid effects on the multicomponent model of working memory. Here, we report the results of a double-blind, placebo-controlled, between-subjects study. Methods Twenty healthy young men were randomly assigned to either acute cortisol (30 mg hydrocortisone) or placebo administration. Participants were subjected to an extensive cognitive test battery that evaluated all systems of the multicomponent model of working memory, including various executive domains (shifting, updating, inhibition, planning and access to long-term memory). Results Compared with placebo, hydrocortisone administration increased cortisol blood levels and impaired working memory in storage of multimodal information in the episodic buffer and maintenance/reverberation of information in the phonological loop. Hydrocortisone also decreased performance in planning and inhibition tasks, the latter having been explained by changes in storage of information in working memory. Conclusions Thus, hydrocortisone acutely impairs various components of working memory, including executive functioning. This effect must be considered when administering similar drugs, which are widely used for the treatment of many clinical disorders. Copyright © 2011 John Wiley & Sons, Ltd.

The past two decades have been witness to extensive research providing considerable insight into the neurobiological basis of stress–memory interactions. For some time there was a tendency for researchers to view stress as exerting a global impairment of hippocampal function, perhaps via increased levels of glucocorticoids (Metcalfe and Jacobs, 1998; Metcalfe and Mischel, 1999; Nadel and Jacobs, 1998). However, this view has slowly been replaced with a significant body of work which has shown that the effects of stress on hippocampal function, as well as memory in general, are much more complex. Numerous studies have shown that acute stress can enhance, impair, or have no effect on learning and memory, depending on several factors related to the stressor, the learning experience, and the subjects under investigation (Akirav and Richter-Levin, 2006; Joels et al., 2006; Joels and Baram, 2009; Sandi and Pinelo-Nava, 2007; Schwabe et al., 2010). Moreover, stress or corticosteroid administration have been shown to enhance, as well as to impair, hippocampusspecific memory and synaptic plasticity (Ahmed et al., 2006; Almaguer-Melian et al., 2005; Bangasser and Shors, 2010; Davis et al., 2004; Frey, 2001; Joels et al., 2006, 2009; Joels and Baram, 2009; Kim and Diamond, 2002; Li et al., 2003; Schwabe et al., 2010; Seidenbecher et al., 1997; Smeets et al., 2009; Straube et al., 2003; Uzakov et al., 2005). Thus, a major challenge to behavioral neuroscientists is to develop an understanding of the conditions by which stress enhances or impairs learning and memory and to identify the cellular and molecular mechanisms that mediate these effects.

Summary The effects of stress on memory were examined through a study of 33 3 to 12-year-old maltreated children removed from their biological parents by the Child Protective Services because of an emergency (acute) or normal (planned) care order. Children's stress levels were rated by a researcher present during the removal and children's memory of the removal investigated at a later time. The type of removal significantly predicted children's level of stress. ‘Acute removal’ children remembered more from high-stress phases of the removal than the ‘planned removal’ children. All children had more accurate memories of the low-stress phases. Details remembered were rated as central or peripheral; more central information was recalled than peripheral information. The ‘acute removal’ children recalled more peripheral information from the high-stress phases of the removal than the low-stress phases, a difference, which was not present for the ‘planned removal’ children. Copyright © 2011 John Wiley & Sons, Ltd.

Neurogenesis in the hippocampus occurs throughout life in a wide range of species and could be associated with hippocampus-dependent learning and memory. Stress is well established to seriously perturb physiological/psychological homeostasis and affect hippocampal function. In the present study, to investigate the effect of chronic restraint stress in early life on hippocampal neurogenesis and hippocampus-dependent memory, 3-week-old mice were subjected to restraint stress 6 days a week for 4 weeks. The chronic restraint stress significantly decreased the hippocampal volume by 6.3% and impaired hippocampal neurogenesis as indicated by the reduced number of Ki67-, 5-bromo-2'-deoxyuridine- and doublecortin-positive cells in the dentate gyrus. The chronic restraint stress severely impaired hippocampus-dependent contextual fear memory without affecting hippocampus-independent fear memory. The expression level of brain-specific transcription factor neuronal PAS domain protein 4 (Npas4) mRNA in the hippocampus was down-regulated by the restraint stress or by acute corticosterone treatment. Npas4 immunoreactivity was detected in progenitors, immature and mature neurons of the dentate gyrus in control and stressed mice. Our findings suggest that the chronic restraint stress decreases hippocampal neurogenesis, leading to an impairment of hippocampus-dependent fear memory in mice. Corticosterone-induced down-regulation of Npas4 expression may play a role in stress-induced impairment of hippocampal function.

Drug addiction is a chronic brain disorder, characterized by the loss of the ability to control drug consumption. The neurobiology of addiction is traditionally thought to involve the mesocorticolimbic system of the brain. However, the hippocampus has received renewed interest for its potential role in addiction. Part of this attention is because of the fact that drugs of abuse are potent negative regulators of neurogenesis in the adult hippocampus and may as a result impair learning and memory. We investigated the effects of different dosages of contingent cocaine on cell proliferation and neurogenesis in the dentate gyrus of the hippocampus and on working memory during abstinence, using the water T-maze test, in adult rats. We found that cocaine, in addition to the changes it produces in the reward system, if taken in high doses, can attenuate the production and development of new neurons in the hippocampus, and reduce working memory.

r Abstract: Acute psychosocial stress in humans triggers the release of glucocorticoids (GCs) and influ- ences performance in declarative and working memory (WM) tasks. These memory systems rely on the hippocampus and prefrontal cortex (PFC), where GC-binding receptors are present. Previous stud- ies revealed contradictory results regarding effects of acute stress on WM-related brain activity. We combined functional magnetic resonance imaging with a standardized psychosocial stress protocol to investigate the effects of acute mental stress on brain activity during encoding, maintenance, and re- trieval of WM. Participants (41 healthy young men) underwent either a stress or a control procedure before performing a WM task. Stress increased salivary cortisol levels and tended to increase WM ac- curacy. Neurally, stress-induced increases in cortical activity were evident in PFC and posterior parie- tal cortex (PPC) during WM maintenance. Furthermore, hippocampal activity was modulated by stress during encoding and retrieval with increases in the right anterior hippocampus during WM encoding and decreases in the left posterior hippocampus during retrieval. Our study demonstrates that stress increases activity in PFC and PPC specifically during maintenance of items in WM, whereas effects on hippocampal activity are restricted to encoding and retrieval. The finding that psychosocial stress can increase and decrease activity in two different hippocampal areas may be relevant for understanding the often-reported phase-dependent opposing behavioral effects of stress on long-term memory. Hum Brain Mapp 00:000-000, 2010. V C 2010 Wiley-Liss, Inc.

Although it is generally agreed that Aβ contributes to the pathogenesis of AD, its precise role in AD and the reason for the varying intensity and time of onset of the disease have not been elucidated. In addition to genetic factors, environmental issues such as stress may also play a critical role in the etiology of AD. This study examined the effect of chronic psychosocial stress in an at-risk (treatment with a subpathogenic dose of Aβ; “subAβ”) rat model of AD on long-term memory by three techniques: memory tests in the radial arm water maze, electrophysiological recordings of synaptic plasticity in anesthetized rats, and immunoblot analysis of learning- and long-term memory-related signaling molecules. Chronic psychosocial stress was induced using a rat intruder model. The subAβ rat model of AD was induced by continuous infusion of 160 pmol/day Aβ1–42 via a 14-day i.c.v. osmotic pump. All tests showed that subAβ rats were not different from control rats. Result from behavioral tests and electrophysiological recordings showed that infusion of subAβ in chronically stressed rats (stress/subAβ group) caused significant impairment of cognitive functions and late-phase long-term potentiation (L-LTP). Molecular analysis of various signaling molecules after expression of L-LTP, revealed an increase in the levels of p-CREB in control, stress, and subAβ rats, but not in the stress/subAβ rats. These findings suggest that the chronic stress-induced molecular alteration may accelerate the impairment of cognition and synaptic plasticity in individuals “at-risk” for AD. © 2010 Wiley-Liss, Inc.

Summary Objective Glucocorticoid excess is commonly related to neuropsychiatric and neurological disorders, with memory impairment typically found among these disorders. The objective of this study is to offer a clinical profile of memory deficits resulting from exposure to chronic stress-level elevations of endogenous glucocorticoids in patients with Cushing's Syndrome (CS). Study subjects Thirty female participants of matching age and education level were studied: 15 had untreated CS (mean age 38 ± 14) and 15 were healthy. In all patients, CS was confirmed by histology of the lesion after surgery. Design Different learning and memory processes were assessed using an adapted version of Luria's Memory Words-Revised task (LMW-R). Participants’ performances were measured in an immediate condition and, 30 min later, in a delayed condition. Attentional and executive functions were also evaluated. Results Our data show that chronic exposure to elevated levels of cortisol is clinically associated with significant working memory deficits, which included less shot-term memory volume, slow learning rate, memory contamination and no accurate perception of own performance. Patients also show impairment in the delayed recall task. No relation was detected between learning and delayed conditions. CS group did not differ significantly from control group in basic attentional and executive functioning. Conclusions Our clinical profile of memory deficits related to CS relates chronic exposure to hypercortisolemia to impaired attentional-dependent working memory and delayed recall process, suggesting that cortisol levels play a critical role in the modulation of learning and memory. Possible damage to hippocampus and extrahippocampal areas is discussed.

Animal research on brain mechanisms involved in psychiatric disorders presents an enormous challenge because it is impossible to precisely model symptoms of a human disorder in a rat or mouse. Nevertheless, there are uses for animal models as long as the limitations are recognized. Animal research related to posttraumatic stress disorder (PTSD) points to acute and chronic stressors, such as restraint or immobilization as being the most relevant stimuli to study how neural and endocrine systems are affected, both immediately and long term. Of particular relevance are the onset and duration of effects of stressors on brain areas subserving emotional memories, such as the amygdala, prefrontal cortex, and hippocampus. The hippocampus plays a role in memory and in vegetative functions of the body. The hippocampus receives input from the amygdala and its function in spatial memory is altered by amygdala activity. Repeated stress in the rat suppresses dentate gyrus neurogenesis and causes dendrites of hippocampal and medial prefrontal cortical neurons to shrink. Conversely, it causes basolateral amygdala neurons to increase in dendritic complexity and sprout new synapses. Repeated stress also increases fear and aggression, reduces spatial memory, and alters contextual fear conditioning. Antidepressants and mood stabilizers have diverse effects on these processes. New data indicate that a single stress episode can cause a delayed alteration in synapse formation in the basolateral amygdala without changing dendritic length and branching. Further studies are examining the structural changes in prefrontal cortex and hippocampus as a result of single traumatic stressors, which may reflect the functional interactions with the amygdala. Together with mechanistic studies of the role of adrenal glucocorticoids and catecholamines, these results may tell us how the brain is shaped by acute and repeated uncontrollable stress in ways that then can be investigated in human anxiety disorders.

Stress promotes adaptation, but prolonged stress leads over time to wear-and-tear on the body (allostatic load). Neural changes mirror the pattern seen in other body systems, that is, short-term adaptation vs. long-term damage. Allostatic load leads to impaired immunity, atherosclerosis, obesity, bone demineralization, and atrophy of nerve cells in the brain. Many of these processes are seen in major depressive illness and may be expressed also in other chronic anxiety disorders. The brain controls the physiological and behavioral coping responses to daily events and stressors. The hippocampal formation expresses high levels of adrenal steroid receptors and is a malleable brain structure that is important for certain types of learning and memory. It is also vulnerable to the effects of stress and trauma. The amygdala mediates physiological and behavioral responses associated with fear. The prefrontal cortex plays an important role in working memory and executive function and is also involved in extinction of learning. All three regions are targets of stress hormones. In animal models, neurons in the hippocampus and prefrontal cortex respond to repeated stress by showing atrophy, whereas neurons in amygdala show a growth response. Yet, these are not necessarily "damaged" and may be treatable with the right medications.

The hippocampus has long been proved to be implicated in several learning and memory processes. Being integrated into the limbic-hypothalamus-pituitary-adrenal axis, the hippocampus also plays an active role in the regulation of the stress response. Long lasting elevated levels of glucocorticoids resulting from a prolonged stress exposure affect hippocampal functions and structure, inducing learning and memory alterations and suppressing cell proliferation in the adult dentate gyrus. Here, adult male tree shrews (Tupaia belangeri) exposed to chronic psychosocial stress were tested repeatedly on a holeboard apparatus using two different learning tasks devised to evaluate hippocampal-dependent and hippocampal-independent cognitive function. We show that chronic stress enhanced learning in animals performing the hippocampal-dependent task, whereas no stress-induced effect was found in the hippocampal-independent task. Additionally, after five weeks of stress, cell proliferation was reduced in the hippocampal dentate gyrus. These results indicate that specific memory processes not only may remain intact, but indeed are facilitated by chronic stress, despite elevated cortisol levels and suppressed hippocampal cell proliferation.

The hippocampal formation, a structure involved in declarative, spatial and contextual memory, is a particularly sensitive and vulnerable brain region to stress and stress hormones. The hippocampus shows a considerable degree of structural plasticity in the adult brain. Stress suppresses neurogenesis of dentate gyrus granule neurons, and repeated stress causes atrophy of dendrites in the CA3 region. In addition, ovarian steroids regulate synapse formation during the estrous cycle of female rats. All three forms of structural remodeling of the hippocampus are mediated by hormones working in concert with excitatory amino acids (EAA) and N-methyl-D-aspartate (NMDA) receptors. EAA and NMDA receptors are also involved in neuronal death that is caused in pyramidal neurons by seizures and by ischemia and prolonged psychosocial stress. In the human hippocampus, magnetic resonance imaging studies have shown that there is a selective atrophy in recurrent depressive illness, accompanied by deficits in memory performance. Hippocampal atrophy may be a feature of affective disorders that is not treated by all medications. From a therapeutic standpoint, it is essential to distinguish between permanent damage and reversible atrophy in order to develop treatment strategies to either prevent or reverse deficits. In addition, remodeling of brain cells may occur in other brain regions. Possible treatments are discussed. Copyright © 2001 John Wiley & Sons, Ltd.

This paper reviews the literature on the relationship between glucocorticoids and cognitive functioning, including memory and selective attention. The main body of evidence suggests that hypothalamic-pituitary-adrenal (HPA) axis dysfunction or a state of hypercortisolaemia can be correlated with cognitive deficits specific to the medial temporal lobe declarative memory system. These impairments are discussed in relation to patients with HPA abnormalities, as seen in a significant number of patients with major depression or Cushing's syndrome, and also in relation to healthy volunteers after administration of glucocorticoids. It remains to be seen whether there are differential effects on acquisition, consolidation or retrieval processes. However, it would seem that glucocorticoids have a preferential effect on recall of information as opposed to recognition, possibly because recognition is more automatic.Type 2 glucocorticoid receptors (GRs), which are occupied by cortisol in humans in times of stress, are thought to be responsible for the glucocorticoid-induced memory impairment. GRs alter the feedback of the HPA axis, which in turn disrupts hippocampal functioning. While this can be reversible, animal studies suggest that chronic elevation of glucocorticoid levels can lead to the loss of hippocampal neurons and irreversible decline in declarative memory. Copyright 2001 John Wiley & Sons, Ltd.

Exposure to stressful experiences can increase vulnerability to adverse health outcomes. A potential neuroendocrine mechanism mediating the link between stress and health is the hypothalamic-pituitary-adrenal (HPA) system, with a key role attributed to the glucocorticoid hormone cortisol. Retrospective and cross sectional clinical stud- ies of humans and experimental studies with nonhuman primates and rodents suggest that traumatic experiences dur- ing critical periods in development may have permanent effects on HPA regulation, which in turn can have deleterious effects on health. Here I report results from a continuous 20-year study (1988-2009) of children in a rural community on Dominica. Sequential data on cortisol levels, social stressors, and health in naturalistic, everyday conditions are examined to assess developmental trajectories of HPA functioning. Saliva aliquots were assayed for cortisol in concert with monitoring of growth, morbidity, and social environment. Analyses here include data from 1989 to 1999 for 147 children aged 3-16 years with >100 saliva samples each. Cortisol values were standardized by elapsed time since wake-up. Results do not support the hypothesis that traumatic stress during childhood causes permanent general elevation of cortisol levels. Am. J. Hum. Biol. 21:769-771, 2009. ' 2009 Wiley-Liss, Inc. Humans, like most animals, have complex physiological systems that are responsive to stimuli from the social environment. The sensitivity of the neuroendocrine stress system to social challenges presents an evolutionary puz- zle. We do not have good explanations for why natural selection favored links between the neuropsychological mechanisms involved with assessment of the social envi- ronment and the neuroendocrine mechanisms that regu- late stress hormones such as cortisol. Furthermore, we do not understand why these links are modifiable during on- togeny, such that early traumatic experiences may have long-term effects on neuroendocrine stress response (Anisman et al., 1998; Mirescu et al., 2004). This puzzle is accentuated by the apparent negative consequences of social stress and concomitant abnormal cortisol levels for health and psychological development (Sapolsky, 2005). The dominant model in stress research has targeted the homeostatic mechanisms of the hypothalamic-anterior pituitary-adrenal cortex (HPA) system, which are posited to be permanently affected by exposure to high levels of glucocorticoids during ontogeny. Glucocorticoid receptors (GRs) in the hippocampus that are part of the negative feedback loop regulating release of corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) can be damaged by the neurotoxic levels of cortisol associ

To explore memory impairments in temporal lobe epilepsy, we used two experimental models in the rats : (a) kainate-induced status epilepticus (SE) resulting in excitotoxic damage and in later spontaneous seizures ; and (b) amygdala kindling, known to induce no lesions (or only minor) and neuronal reorganization. Long-term effects of these models on memory were investigated with a spatial learning task in a radial-arm maze, and a social interaction test that implies degree of short-term memory. An histological analysis was made to determine neuronal damage or loss caused by epileptic activity in brain regions that could be related to memory functions. Kainate-induced epilepsy produced large memory deficits in animals tested 5 months after the injection. The rats showed severe lesions in amygdala and hippocampus and piriform and entorhinal cortex. Spatial memory was strongly diminished. The social memory test was severely impaired, probably due to the extent of amygdala injury, which is known to disturb social behavior. On the contrary, kindled rats showed no evident lesion in any brain region and displayed performances as good as those of controls in both tests. These experiments demonstrated that memory deficits appear to be related to the severity of neuronal damage in limbic areas, and the ability to develop seizures (permanence) is not solely responsible for these memory disturbances.