Prenatal stress alters early neurobehavior, stress reactivity and learning in non-human primates: a brief review

In this paper we review three prospective longitudinal studies from our laboratory examining the effects of prenatal stress on early neuro behavior, stress reactivity and learning performance in rhesus monkeys. Either a noise stressor or ACTH treatment was administered to pregnant monkeys during specific periods of pregnancy and offspring were examined repeatedly across development. In all three studies, the prenatally stressed monkeys showed reduced attention and impaired neuromotor functioning during the first month of life compared to controls from undisturbed pregnancies. When the monkeys were separated from their mothers or peers at 6-8 months of age, prenatally stressed monkeys exhibited more disturbance behavior and showed hypothalamic-pituitary-adrenal axis dysregulation. During adolescence, they exhibited impairments in learning, compared to controls.     

Hypothalamo-pituitary-adrenocortical axis function and hedonic behavior in adult male and female rats prenatally stressed by maternal food restriction

Neuroendocrine activation during stress is affected by many factors contributing to the variability of the stress response. The present study was aimed at evaluating long-term changes in hypothalamo-pituitary-adrenocortical (HPA) axis function and in hedonic behavior in adult offspring prenatally stressed by maternal food restriction, with attention on possible gender differences. Adult offspring were blood sampled via a tail artery cannula. Prenatally stressed females had significantly higher adrenal weights compared to males. Plasma ACTH levels, which rose in response to acute stress induced by handling, were significantly higher in females compared to those in males. A similar pattern was found in plasma corticosterone. The rise in ACTH levels was more pronounced in prenatally stressed rats though the rise in corticosterone failed to be modified. Corticotropin releasing hormone (CRH) and proopiomelanocortin mRNA levels in the hypothalamic paraventricular nucleus and anterior pituitary, respectively, were found to be unchanged. The present experiments failed to reveal a decrease in hedonic behavior in prenatally stressed rats. In contrast, in male offspring a tendency to a higher sucrose preference was observed. These data together with observed changes in hormone and CRH mRNA levels indicate that the gestational stress used did not result in a depression-like state in adult offspring.     

Testosterone prevents synaptic loss in the perineal motoneuron pool in the spinal cord in male rats exposed to chronic stress

Chronic stress is known to induce disorders of reproductive neuroendocrine functions. Motoneurons of the spinal nucleus of the bulbocavernosus (SNB) in male rats play an important role in copulatory behavior. In the present study, it was examined whether chronic stress would alter synaptic organization of the SNB motoneurons and whether androgen would modify the changes under chronic stress. Five male rats were under restraint stress for 5 days per week for 3 weeks, and five males implanted subcutaneously with Silastic capsules containing testosterone were also exposed to stress. Five males served as unstressed controls. After 3 weeks of restraint stress, cholera toxin-horseradish peroxidase (CT-HRP) was injected into the bulbocavernosus muscles and animals were killed 2 days later. The spinal cords containing the SNB were dissected, processed with a modified tetramethylbenzidine (TMB) method for visualization of retrogradely transported CT-HRP, and examined ultrastructurally. Neuronal structures apposing the membranes of 150 SNB motoneurons (total for three groups) were analyzed by measuring the percentage of somatic membranes covered by synaptic contacts. The mean percentage of somatic membranes covered by synapses in males exposed to chronic stress was significantly less than that in controls or stressed males treated with testosterone. Size and number of synaptic contacts per unit length of somatic membranes in males exposed to stress were also significantly less than those in controls or stressed males treated with testosterone. There was no significant difference in any of the parameters between controls and stressed males treated with testosterone. Changes in plasma levels of testosterone showed the same profile as changes in the synaptic contacts. These results suggest that the SNB motoneurons of male rats exposed to chronic stress retain a considerable synaptic plasticity in response to androgen, and that androgen treatment can rescue the SNB system in male rats when under chronic restraint stress.     

Exogenous androgen activates female behavior in noncopulating, prenatally stressed male rats

Male copulatory behavior was severely impaired in the male offspring of female rats stressed during pregnancy. This deficiency persisted even after castration and prolonged treatment with testosterone propionate and after exposure to electric skin shock. However, androgen treatment effectively activated female lordotic behavior in a large percentage of prenatally stressed males but not in any control animals and in only a negligible number of postnatally stressed males. Although prenatal stress demasculinizes and feminizes behavior, no modifications of reproductive morphology were detectable. It is postulated that prenatal stress alters normal sexual behavior differentiation by attenuating testosterone secretion from the fetal testes.     

Sex differences in spatial and non-spatial Y-maze performance after chronic stress

Chronic restraint is known to alter hippocampal CA3 dendritic morphology and spatial memory in male rats. The present study examined whether female rats, which exhibit different anatomical adaptations to chronic stress than those of males, would also show spatial memory impairments. Male and female Sprague-Dawley rats were restrained for 6 h/day for 21 days, a time frame previously demonstrated to cause hippocampal CA3 dendritic atrophy. The day after the last restraint session, rats were tested on a Y-maze, a habituation task that can be used to assess spatial memory. Chronic stress impaired Y-maze performance in both sexes without affecting levels of locomotion as measured by total arm entries in the first minute. However, Y-maze performance of stressed females improved in 2-5 min when chronically stressed males continued to show poor Y-maze performance. The enhanced Y-maze performance of chronically stressed females occurred when total arm entries were higher compared to the entries made by males. Therefore, correlations were performed between total arm entries and spatial memory in 1 and 2-5 min. In the first minute when control females demonstrated functional spatial memory, female controls with the lowest locomotor levels exhibited the best performance. The correlations for stressed females were not significant, and neither were the correlations for any group in 2-5 min. Overall, these results show important sex differences in response to chronic stress with females exhibiting an ability to recover quickly from deficits in Y-maze performance.     

Crucial role of the postnatal maternal environment in the expression of prenatal stress effects in the male rats

Methodological and conceptual problems common in prenatal stress experiments were analyzed, and an experiment incorporating solutions to those problems were designed and executed. Rats were prenatally stressed or served as controls and then were cross-fostered within or between treatment groups. In adulthood, one male from each litter was tested over 20 trials in an open-field box and then tested over 20 successive discrimination reversals in a T-maze. A T-factor analysis was performed on each of the two sets of observations, and factors scores were subjected to elevational analyses. Major hypotheses generated from the results are the following: (a) Male rats subjected to prenatal stress acquire emotional reactivity levels in adulthood that are either elevated or reduced depending on the postnatal maternal environment. (b) Male rats subjected to prenatal stress acquire reversal learning sets in adulthood with a rapidity that parallels and indeed is produced by the pattern of emotional reactivity reflected in the above a and as mediated by cognitive processes. (c) T-factor analysis of trials is required in order to avoid construct validity problems as well as internal validity problems, both brought about by the confounding of trial variables, and in addition, it may generate valuable hypotheses giving further meaning to the dependent variables under observation.     

Maternal gestational stress alters adaptive and social behavior in adolescent rhesus monkey offspring

Data from rodent studies have indicated that stress experienced by pregnant mothers may result in behavioral and biological abnormalities in their offspring. However, few studies have examined the effects of prenatal stress on the offspring beyond the childhood period. In this study, 7 prenatally stressed (PNS) monkeys and 7 monkeys from undisturbed pregnancies were tested under mildly challenging conditions at 4 years of age. Following separation from cagemates and group formation, PNS monkeys showed more locomotion, abnormal and disturbance behavior than controls. Controls showed approximately six times more play than PNS animals. The PNS males showed the most clinging to others and the largest increase in contact with other animals over the period. Group differences were also found when the monkeys were observed as groups or alone in a playroom. Controls showed more explanatory behavior in the playroom, whereas PNS monkeys showed more inactivity. Control animals showed a decrease in distress vocalizations over time in the playroom, whereas PNS animals showed the opposite pattern. Control animals spent more time in proximity to and contact with cagemates than PNS animals. These results indicate that prenatal stress can have effects on adaptive and social behavior that persist into adolescence.     

Juvenile offspring of rats exposed to restraint stress in late gestation have impaired cognitive performance and dysregulated progestogen formation

Gestational stress may have lasting effects on the physical and neurocognitive development of offspring. The mechanisms that may underlie these effects are of interest. Progesterone and its 5α-reduced metabolites, dihydroprogesterone and 5α-pregnan-3α-ol-20-one (3α,5α-THP), maintain pregnancy, have neurotrophic effects, and can enhance cognitive performance. We hypothesized that some of the deleterious effects of gestational stress on the cognitive performance of offspring may be related to progestogen formation. Pregnant rat dams were exposed to restraint under a bright light (thrice daily for 45 min) on gestational days 17-21 or were minimally handled controls. Dams that were exposed to restraint had lower circulating levels of 3α,5α-THP and significantly greater concentrations of corticosterone at the time of birth than did control dams. Male and female offspring, that were gestationally stressed or not, were cross-fostered to non-manipulated dams. Between postnatal days 28-30, offspring were assessed for object recognition, a prefrontal cortex (PFC)-dependent cognitive task. Restraint-exposed offspring performed more poorly in the object recognition task than did control offspring, irrespective of sex. As well, progesterone turnover to its 5α-reduced metabolites in the medial PFC (but not the diencephalon) was significantly reduced among restraint-exposed, compared to control, offspring. Progesterone turnover, and levels of 3α,5α-THP, positively correlated with performance in the object recognition task. Thus, restraint stress in late pregnancy impaired cognitive development and dysregulated progestogen formation in brain.     

Altered grooming responses to stress in rats exposed prenatally to ethanol

The effects of prenatal alcohol exposure on grooming, locomotion, and rearing in response to stress were examined in adult rats whose mothers consumed a liquid diet containing 35% ethanol-derived calories (EDC). Offspring of both pair-fed 0% EDC mothers and ad libitum chow-fed mothers were included as controls. In Experiment 1, females groomed more than males following placement into a novel test chamber, but no differences due to prenatal treatment were observed. Ethanol-exposed animals groomed more than controls following the stress of a forced 1-min swim (Experiment 2), but when rats tested in Experiment 1 were observed again after forced swim stress (Experiment 3), no differences due to prenatal treatment or sex were observed. Experiment 4 examined the effects of pretreatment with 1 mg/kg naloxone on novelty-induced grooming and as in Experiment 1 prenatal treatment did not affect grooming responses. Females again groomed significantly more than males and naloxone reduced grooming equally for all groups. The results suggest that novelty-induced grooming is a sex-influenced behavior, with females grooming more than males, and that animals exposed prenatally to alcohol and tested as adults may have altered responses to certain stressors (i.e., forced swim) under specific conditions. The altered grooming response of alcohol-exposed rats to swim stress can be eliminated by preexposing them to novelty stress.     

Sex-dependent changes induced by prenatal stress in cortical and hippocampal morphology and behaviour in rats: an update

Recent prospective studies have shown that gestational stress in humans is more likely to cause cognitive and emotional problems in the offspring if it occurs during weeks 12-20 of pregnancy. There are also suggestions that such problems may be gender dependent. This review describes recent studies that found sex differences in the behaviour and brain morphology of rats stressed prenatally during the equivalent period of neuronal development in humans. Learning deficits are more prevalent in males and anxious behaviour in females but their appearance depends also on the timing and intensity of the stress and the age when the offspring were tested. Cognitive deficits and anxiety are linked to a sex-dependent reduction in neurogenesis and in measures of dendritic morphology in the prefrontal cortex and hippocampal formation. Maternal adrenalectomy prior to the stress prevents the anxiety in both sexes and learning deficits in males. Corticosterone administration to the dam to mimic levels induced by stress reinstates only the anxiety, indicating that it arises from foetal exposure to corticosterone from the maternal circulation. Learning deficits in males may result from a combination of a reduction in testosterone and in aromatase activity, together with the action of other adrenal hormones.     

Substance P is involved in terminating the hypothalamo- pituitary-adrenal axis response to acute stress through centrally located neurokinin-1 receptors

The neurokinin substance P (SP) has been previously shown to inhibit basal hypothalamo-pituitary-adrenal (HPA) axis activity. This study was designed to investigate the effects of central injection of the specific neurokinin-1 receptor antagonist RP67580 on the HPA axis response to acute restraint stress. In non-restrained rats injected with RP67580, plasma ACTH and corticosterone levels were elevated at 30 and 60 min compared to rats injected with vehicle, but there were no differences between vehicle and RP67580 groups at 4h. In restrained rats injected with vehicle, plasma ACTH and corticosterone levels were significantly elevated at 30 min and 60 min following initiation of the stress but had returned to basal levels at 4h. In restrained rats injected icv with RP67580, plasma corticosterone and ACTH levels were significantly elevated at 30 min and 60 min, with no significant differences compared to the restraint stressed vehicle-injected group. However, in the RP67580-injected group, corticosterone and ACTH levels remained significantly elevated at 4h following onset of restraint compared to those in the restraint stressed vehicle-injected group. Corticotrophin-releasing factor mRNA levels in the parvocellular subdivision of the paraventricular nucleus of the hypothalamus and POMC mRNA levels in the anterior pituitary were significantly increased in the stressed group 4h following injection with RP67580 compared to the stressed group injected with vehicle alone. These data show that endogenous SP does not inhibit the initial magnitude of the HPA axis response to restraint stress, but does act through neurokinin-1 receptors at a central level to reduce the duration of the response to stress. This suggests that SP may be an important central agent controlling the transition between acute and chronic stress.     

Acute exposure to a novel stressor further reduces the habituated corticosterone response to restraint in rats

The present study sought to identify dishabituation of the hypothalamic-pituitary-adrenal(HPA) axis response to different psychological stressors. Young adult male Sprague Dawley rats were exposed to five, 1 h sessions of restraint stress on five consecutive days. On the sixth day, and 2 h before additional exposure to restraint, animals were subjected to 30 min of a small (27cm square), elevated open field stressor (pedestal), which served as the dishabituating stimulus. We predicted HPA axis response dishabituation in chronically restrained rats exposed to the novel pedestal. Rats which underwent five days of restraint stress showed significantly blunted plasma corticosterone levels to restraint (habituation) as compared to restraint-nai've rats. However, rats which underwent five sessions of restraint responded with an enhanced habituation response when confronted with restraint shortly after exposure to the novel pedestal. Instead of HPA axis response dishabituation, we observed enhanced habituation. Subsequent experiments determined that a 1.25 mgkg corticosterone injection could substitute for pedestal exposure to produce enhanced restraint habituation.Combined treatment with both the glucocorticoid receptor antagonist RU40555 (30 mgkg)and the mineralocorticoid receptor antagonist RU283 18 (50 mgkg) blocked the expression of enhanced habituation after pedestal exposure. Thus, the delayed corticosterone negative feedback produced by novel stress led to enhanced expression of corticosterone response habituation.     

Metyrapone reveals that previous chronic stress differentially impairs hippocampal-dependent memory

Chronic stress facilitates fear conditioning in rats with hippocampal neuronal atrophy and in rats in which the atrophy is prevented with tianeptine, a serotonin re-uptake enhancer. The purpose of this study was to determine whether the lack of dissociation between fear conditioning performance and hippocampal integrity was masked by the presence of endogenous corticosteroids during training. As in previous studies, rats were stressed by daily restraint (6 h/day for 21 days), trained in the conditioning chamber (day 23), and then assessed for conditioned fear (day 25) at a time when hippocampal dendritic atrophy persists. On the training day, half of the control and stressed rats were. injected with metyrapone to reduce corticosterone release. Two hours later, two paired or unpaired presentations of tone and footshock were delivered. Although metyrapone reduced conditioned fear in all rats, only stressed rats showed dissociated fear conditioning (i.e. tone conditioning was reduced while contextual conditioning was eliminated). Chronically stressed rats, regardless of metyrapone treatment displayed more rearing in the open field when tested immediately after the completion of fear conditioning. These data support the hypothesis that increased emotionality and enhanced fear conditioning exhibited by chronically stressed rats maybe due to endogenous corticosterone secretion at the time of fear conditioned training. Moreover,these data suggest that chronic stress impairs hippocampal-dependent processes more robustly than hippocampal-independent processes after metyrapone to reduce corticosterone secretion during aversive training.     

Immune stress in late pregnant rats decreases length of gestation and fecundity, and alters later cognitive and affective behaviour of surviving pre-adolescent offspring

Immune challenge during pregnancy is associated with preterm birth and poor perinatal development. The mechanisms of these effects are not known. 5α-Pregnan-3α-ol-20-one (3α,5α-THP), the neuroactive metabolite of progesterone, is critical for neurodevelopment and stress responses, and can influence cognition and affective behaviours. To develop an immune challenge model of preterm birth, pregnant Long-Evans rat dams were administered lipopolysaccharide [LPS; 30?μg/kg/ml, intraperitoneal (IP)], interleukin-1β (IL-1β; 1?μg/rat, IP) or vehicle (0.9% saline, IP) daily on gestational days 17-21. Compared to control treatment, prenatal LPS or IL-1β reduced gestational length and the number of viable pups born. At 28-30 days of age, male and female offspring of mothers exposed to prenatal IL-1β had reduced cognitive performance in the object recognition task compared to controls. In females, but not males, prenatal IL-1β reduced anxiety-like behaviour, indicated by entries to the centre of an open field. In the hippocampus, progesterone turnover to its 5α-reduced metabolites was lower in prenatally exposed IL-1β female, but not in male offspring. IL-1β-exposed males and females had reduced oestradiol content in hippocampus, medial prefrontal cortex and diencephalon compared to controls. Thus, immune stress during late pregnancy reduced gestational length and negatively impacted birth outcomes, hippocampal function and central neurosteroid formation in the offspring.     

Effects of chronic social stress during lactation on maternal behavior and growth in rats

Maternal mood disorders such as depression and chronic anxiety can negatively affect the lives of not only mothers, but also of partners, offspring, and future generations. Chronic exposure to psychosocial stress is common in postpartum mothers, and one of the strongest predictors of postpartum depression is social conflict. The objective of the current study was to evaluate the effects of chronic social stress (CSS) during lactation on the maternal behavior (which consists of maternal care and aggression toward a novel conspecific) of lactating rats, as well as on the growth of the dams and their offspring. It was hypothesized that chronic daily exposure to a novel male intruder would alter the display of maternal behavior and impair growth in both the dam and offspring during lactation due to the potentially disruptive effects on maternal behavior and/or lactation. The data indicate that CSS during lactation attenuates maternal care and the growth of both dams and pups, and increases self-grooming and maternal aggression toward a novel male intruder. These results support the use of CSS as a relevant model for disorders that impair maternal behavior and attenuate growth of the offspring, such as postpartum depression and anxiety.     

Sex differences in prenatally programmed anxiety behaviour in rats: differential corticotropin-releasing hormone receptor mRNA expression in the amygdaloid complex

We recently reported that male, but not female, offspring born to mothers exposed to social stress during late gestation show heightened anxiety-type behaviour in adulthood. The amygdala organises anxious behaviour, which involves actions of corticotropin-releasing hormone (CRH). CRH gene expression and/or its release are increased in the amygdala in prenatally stressed (PNS) rats. CRH type 1 receptor (CRH-R1) mediates actions of CRH and urocortin I to promote anxiety-like behaviour, whereas the CRH type 2 receptor (CRH-R2) may mediate anxiolytic actions, through actions of urocortins 2 and 3. Here, using quantitative in situ hybridisation, we investigated whether altered CRH receptor mRNA expression in the amygdaloid nuclei may explain the sex differences in anxiety behaviour in adult male and female PNS rats. CRH-R1 mRNA expression was significantly greater in the central amygdala and basolateral amygdala (BLA) in male PNS rats compared with controls, with no change in the basomedial amygdala (BMA) or medial amygdala (MeA). In PNS females, CRH-R1 mRNA expression was greater than controls only in the MeA. Conversely, CRH-R2 mRNA expression was significantly lower in the BMA of male PNS rats compared with controls, but greater in female PNS rats, with no change in the BLA or MeA in either sex. The ratio of CRH-R1:CRH-R2 mRNA in the amygdaloid nuclei was generally increased in PNS males, but not in the PNS females. In conclusion, sex differences in anxiety-type behaviour in PNS rats may be explained by differential mRNA expression for CRH-R1 (pro-anxiogenic) and CRH-R2 (pro-anxiolytic) in the amygdaloid complex.     

Gender differences in acute and chronic stress in Wistar Kyoto (WKY) rats

While females are considered more susceptible to depressive behavior, this assertion is not strongly supported by the experimental literature. Since stress contributes to depressive behavior, male and female Wistar Kyoto (WKY) rats were exposed to either one session (acute stress) or 5 sessions (chronic stress) of restraint plus cold in order to study depressive behavior in male and female rats. After their respective treatment exposure, rats were tested in the open field test (OFT) and for retention of a passive-avoidance (P-A) task. One stress session resulted in significant immobility in the OFT for males, whereas 5 sessions were required to produce similar immobility in female rats. Acute stress interfered with the retention of the P-A response for males, while both acute and chronic stress produced poor P-A responses in female rats. Food consumption decresed, progressively, as a function of stress sessions, in female rats, whereas feeding in males returned to control levels after five stress days. Both acute and chronic stress exacerbated the stress ulcer response in male rats, but not in female rats. Chronic, but not acute, stress resulted in an increase in serotonin transporter mRNA levels in the dorsal raphe nucleus of both male and, female rats. The general consensus from these data suggested that female rats were more vulnerable to chronic stress and consequently supported the notion that females may be more susceptible to stress induced behavioral depression.     

Influence of rearing conditions on voluntary ethanol intake and response to stress in rats

The effects of exposure to four environmental rearing conditions on subsequent voluntary ethanol intake and response to immobilization stress were examined. Male weanling rats were reared in an enriched environment, with a female partner, with a male partner, or individually, for 90 days. At 111 days of age, voluntary consumption of ethanol in increasing concentrations (3 to 9%, v/v) was assessed. Following the ethanol-exposure period, rats were randomly divided into stressed and nonstressed groups and exposed to 3 h of immobilization. Results indicated that the enriched animals consumed greater amounts of ethanol as compared to all other groups, suggesting that the enriched environment and not handling, housing conditions, or the presence of another male or female is responsible for the observed increase in ethanol drinking behavior. Ulcer data indicated that among environmentally enriched rats, ethanol attenuated stress ulcer development relative to their non-ethanol-exposed but stressed controls. In nonstressed enriched rats, ethanol alone exacerbated stomach damage. We suggest that environmental rearing conditions markedly influence the complex interaction between ethanol intake and the response to stress.     

Effect of stress on hippocampal nociceptin expression in the rat

Nociceptin/orphanin FQ (N/OFQ) peptide and its receptor are not only ubiquitously expressed in mammalian brain and spinal cord but are also abundant in limbic structures, particularly in the hippocampus. The widespread distribution of N/OFQ reflects the broad spectrum of its biological actions such as nociception, food intake, spontaneous locomotor activity, and learning and memory processes. Since the hippocampus is involved in the control of adrenocortical activity, its role in stress-related phenomena is well characterized. In male Wistar rats, we first examined the effects of acute restraint stress (120?min) on the brain immunohistochemical localization of N/OFQ. The analysis carried out on sections obtained at the onset of stress revealed enhanced expression of N/OFQ in CA1, CA3, and the dentate gyrus as well as increased plasma corticosterone concentrations. Next, we examined whether endogenous glucocorticoid hormone plays a role in the modulation of hippocampal N/OFQ expression in response to stress. To this end, rats were injected with corticosterone (1?mg/kg) or subjected to restraint stress 1 week after adrenalectomy. Two hours after corticosterone administration, plasma glucocorticoid concentrations were comparable to those observed after restraint stress, while N/OFQ expression had significantly increased in all the hippocampal subfields examined. By contrast, in adrenalectomized rats, stress did not modify protein expression. These results confirm that stress can affect N/OFQ expression and that glucocorticoids may constitute hormonal mediators of this complex interplay.     

Environmental enrichment protects against the effects of chronic stress on cognitive and morphological measures of hippocampal integrity

Chronic stress has detrimental effects on hippocampal integrity, while environmental enrichment (EE) has beneficial effects when initiated early in development. In this study, we investigated whether EE initiated in adulthood would mitigate chronic stress effects on cognitive function and hippocampal neuronal architecture, when EE started one week before chronic stress began, or two weeks after chronic stress onset. Adult male Sprague Dawley rats were chronically restrained (6h/d) or assigned as non-stressed controls and subdivided into EE or non-EE housing. After restraint ended, rats were tested on a radial arm water maze (RAWM) for 2-d to assess spatial learning and memory. The first study showed that when EE began prior to 3-weeks of chronic stress, EE attenuated chronic stress-induced impairments in acquisition, which corresponded with the prevention of chronic stress-induced reductions in CA3 apical dendritic length. A second study showed that when EE began 2-weeks after the onset of a 5-week stress regimen, EE blocked chronic stress-induced impairments in acquisition and retention at 1-h and 24-h delays. RAWM performance corresponded with CA3 apical dendritic complexity. Moreover, rats in EE housing (control or stress) exhibited similar corticosterone profiles across weeks, which differed from the muted corticosterone response to restraint by the chronically stressed pair-housed rats. These data support the interpretation that chronic stress and EE may act on similar mechanisms within the hippocampus, and that manipulation of these factors may yield new directions for optimizing brain integrity and resilience under chronic stress or stress related neuropsychological disorders in the adult.