Negative feedback functions in chronically stressed rats: role of the posterior paraventricular thalamus

A gradual decrement in hypothalamic-pituitary-adrenal (HPA) activity is observed following repeated exposure to the same stressor, such as repeated restraint. This decrement, termed habituation, may be partly due to alterations in corticosterone-mediated negative feedback inhibition of the HPA axis. We have previously found that the posterior division of the paraventricular thalamus (pPVTh) regulates habituated HPA activity without altering HPA responses to acute stress. Therefore, in the present study, we examined the role of the pPVTh in delayed feedback inhibition of plasma corticosterone responses to repeated restraint. Dexamethasone was administered subcutaneously 2 h prior to 30 min restraint to induce delayed negative feedback inhibition of the HPA axis. In the first experiment, we determined that a 0.05-mg/kg dose of dexamethasone produced submaximal suppression of corticosterone responses to acute restraint and used this dose in the remainder of the experiments. In Experiment 2, we examined dexamethasone-induced feedback inhibition to corticosterone responses to a single or eighth restraint exposure since negative feedback functions in chronically stressed rats are not well studied. We found that corticosterone levels following dexamethasone treatment were similar in repeatedly restrained compared to acutely restrained rats. In Experiment 3, we lesioned the pPVTh and examined dexamethasone-induced feedback inhibition of corticosterone responses to a single or eighth exposure to restraint. pPVTh lesions attenuated dexamethasone-induced inhibition of corticosterone at 30 min in chronically stressed rats but had no effect in acutely stressed rats. These data suggest that negative feedback functions are maintained in rats exposed to repeated restraint and implicate the pPVTh as a site that contributes to these negative feedback functions specifically under chronic stress conditions.     

Effects of moderate and intensive training on the hypothalamo–pituitary–adrenal axis in rats

The influence of the two distinct training programmes, moderate (M) and intensive (I), on hypothalamo–pituitary–adrenal (HPA) axis was investigated, in rats. Changes in plasma concentrations of adrenocorticotropin hormone (ACTH) and corticosterone were followed in response to (i) a 60‐min acute running session performed on 2nd, 4th and 6th of the seven training weeks (ii) an acute restraint stress of 40 min applied after the final training programme. After 2nd, 4th and 6th week of the two training programmes, a 60‐min running resulted in an enhanced secretion of ACTH and corticosterone, compared with both the baseline values (i.e. before running) and to the sedentary (S) group. However, on 4th and 6th weeks compared with 2nd week, ACTH and corticosterone remained elevated in intensive group when they are significantly reduced in moderate group. We could suggest that a moderate training resulted in an adapted hormonal response whereas a deadapted process occurred for the intensive programme. The day after the last training session, basal ACTH, corticosterone and corticosteroid‐binding globulin (CBG) capacity were not affected by training. Hypothalamic corticotropin‐releasing factor tissue‐content (CRF) was increased significantly in the two trained groups. When compared with the sedentary group, the body weight of the rats in the two trained groups was significantly decreased with a total adrenal mass increasing but only in intensive group. The surimposed restraint stress resulted in significant increases in plasma ACTH and corticosterone both in trained and in sedentary animals. This result suggests that the adapted HPA axis response induced by both a moderate and intensive training do not prevent against the effects of a novel stress such as restraint stress.     

Maternal care affects male and female offspring working memory and stress reactivity

Variations in maternal care affect the development of individual differences in learning and memory and neuroendocrine responses to stress in adult male offspring, but it is not known how variations in maternal care affect adult female offspring. The present study investigated the performance of adult Sprague-Dawley male and female offspring exposed to either low or high levels of maternal licking/grooming on a spatial memory task (Experiment 1) and the effects of acute stress on corticosterone levels and spatial memory performance (Experiment 2). In Experiment 1 rats were trained for 24 days on the spatial working/reference memory version of the radial arm maze (RAM). In Experiment 2, rats were trained on the same RAM task, exposed to an acute stress, and the effect of stress on corticosterone levels and subsequent spatial memory was examined. In Experiment 1, adult female offspring of low licking/grooming dams had enhanced working memory compared to all other groups. In Experiment 2, all groups of male and female offspring had enhanced working memory 24 h after exposure to acute 2 h restraint stress while reference memory was enhanced after stress in male and female offspring of low licking/grooming dams. Furthermore, female offspring of low licking/grooming dams showed the largest corticosterone response to the acute restraint stress compared to all other groups. Male offspring of low licking/grooming dams showed a flattened corticosterone response to stress. Thus variations in maternal care differentially affect working memory and stress reactivity in male and female offspring.     

Opposing effects of chronic stress and weight restriction on cardiovascular, neuroendocrine and metabolic function

Chronic stress is associated with dysregulation of energy homeostasis, but the link between the two is largely unknown. For most rodents, periods of chronic stress reduce weight gain. We hypothesized that these reductions in weight are an additional homeostatic challenge, contributing to the chronic stress syndrome. Experiment #1 examined cardiovascular responsivity following exposure to prolonged intermittent stress. We used radio-telemetry to monitor mean arterial pressure and heart rate in freely moving, conscious rats. Three groups of animals were tested: chronic variable stress (CVS), weight-matched (WM), and controls. Using this design, we can distinguish between effects due to stress and effects due to the changing body weight. WM, but not CVS, markedly reduced basal heart rate. Although an acute stress challenge elicited similar peak heart rate, WM expedited the recovery to baseline heart rate. The data suggest that CVS prevents the weight-induced attenuation of cardiovascular stress reactivity. Experiment #2 investigated hypothalamic-pituitary-adrenal axis and metabolic hormone reactivity to novel psychogenic stress. WM increased corticosterone area under the curve. CVS blunted plasma glucose, leptin, and insulin levels in response to restraint. Experiment #3 tested the effects of WM and CVS on PVN oxytocin and corticotrophin-releasing hormone mRNA expression. CVS increased, while WM reduced PVN CRH mRNA expression, whereas both CVS and WM reduced dorsal parvocellular PVN oxytocin mRNA. Overall, the data suggest that weight loss is unlikely to account for the deleterious effects of chronic stress on the organism, but in fact produces beneficial effects that are effectively absent or indeed, reversed in the face of chronic stress exposure.     

Extensive subpial cortical demyelination is specific to multiple sclerosis

Cortical demyelinated lesions are frequent and widespread in chronic multiple sclerosis (MS) patients, and may contribute to disease progression. Inflammation and related oxidative stress have been proposed as central mediators of cortical damage, yet meningeal and cortical inflammation is not specific to MS, but also occurs in other diseases. The first aim of this study was to test whether cortical demyelination was specific for demyelinating CNS diseases compared to other CNS disorders with prominent meningeal and cortical inflammation. The second aim was to assess whether oxidative tissue damage was associated with the extent of neuroaxonal damage. We studied a large cohort of patients diagnosed with demyelinating CNS diseases and non‐demyelinating diseases of autoimmune, infectious, neoplastic or metabolic origin affecting the meninges and the cortex. Included were patients with MS, acute disseminated encephalomyelitis (ADEM), neuromyelitis optica (NMO), viral and bacterial meningoencephalitis, progressive multifocal leukoencephalopathy (PML), subacute sclerosing panencephalitis (SSPE), carcinomatous and lymphomatous meningitis and metabolic disorders such as extrapontine myelinolysis, thus encompassing a wide range of adaptive and innate cytokine signatures. Using myelin protein immunohistochemistry, we found cortical demyelination in MS, ADEM, PML and extrapontine myelinolysis, whereby each condition showed a disease‐specific histopathological pattern. Remarkably, extensive ribbon‐like subpial demyelination was only observed in MS, thus providing an important pathogenetic and diagnostic cue. Cortical oxidative injury was detected in both demyelinating and non‐demyelinating CNS disorders. Our data demonstrate that meningeal and cortical inflammation alone accompanied by oxidative stress are not sufficient to generate the extensive subpial cortical demyelination found in MS, but require other MS‐specific factors.     

Pituitary adrenocortical response to chronic intermittent stress

Two experiments were conducted to investigate the pituitary adrenocortical response to stress. In the first experiment, rats received chronic and/or acute cold stress over a period of three weeks or three months. Plasma corticosterone, adrenal wet weight, and body weight were assessed. Three month chronically stressed rats had large adrenals, weighed less, and secreted less corticosterone in response to an acute stressor than did control rats stressed for the first time. Furthermore, their basal level of plasma corticosterone equalled the level secreted after acute stress. In Experiment two, repeated ACTH measures were taken in rats chronically stressed for three weeks. Plasma ACTH was significantly elevated after stress with no change in baseline levels. Taken together, these experiments suggested that rats adapt to stress and that a decreased hormonal stress response reflects conditioning and metabolic conservation rather than exhaustion of resources.     

Stress-induced preproenkephalin mRNA expression in the amygdala changes during early ontogeny in the rat

Peripheral infections in mammals are characterised by local, systemic and CNS effects. The latter give rise to sickness behaviour. Pro-inflammatory cytokines such as interleukin-1beta (IL-1beta) are thought to be important mediators of this neuro-immune signalling (Cartmell et al., 1999). There is anecdotal evidence suggesting that peripheral infections in patients with Alzheimer's disease have more severe behavioural consequences than those in otherwise healthy elderly subjects, and it is well known that brain microglia are activated in the elderly and in Alzheimer's disease (McGeer et al., 1987). Using ME7-induced murine prion disease as a model of chronic neurodegeneration that displays chronic microglial activation, and the intra-peritoneal injection of bacterial lipopolysaccharide to mimic a peripheral infection, we have shown that the temperature and activity responses of animals with pre-clinical prion disease were exaggerated compared with controls, and that this was associated with a significant increase in brain levels of IL-1beta. We hypothesise that prior priming of microglia by the degenerative process, followed by further activation through signalling from the periphery, resulted in increased brain IL-1beta synthesis and the consequent acute sickness behavioural responses.These findings demonstrate an interaction between peripheral infection and pre-existing CNS inflammation and suggest that further stimulation of an already primed microglial population by a peripheral infection may drive disease progression in chronic inflammatory conditions such as Alzheimer's disease and prion disease.     

Increased glucocorticoid response to a novel stress in rats that have been restrained

Rats exposed to repeated restraint stress (3 h of restraint on each of 3 days) lose weight during stress and do not return to the weight of nonstressed controls once stress ends. Others have reported that chronic stress raises the daily nadir of corticosterone release and increases the adrenal response to subsequent stress; therefore, we examined glucocorticoid release in rats that had been exposed to repeated restraint. Repeated restraint had no effect on the diurnal pattern of corticosterone or insulin release, measured 12 days after restraint had ended, indicating that the reduced weight of the rats is not associated with an elevated corticosterone-insulin ratio. In contrast, rats that had been exposed to repeated restraint, 12 days previously, showed a blunted corticosterone release during a second restraint stress, a normal response to the novel physiological stress of 2-deoxy glucose (2-DG) injection, but an exaggerated corticosterone response to the novel mild stress (MS) of either placement in a unfamiliar environment or an intraperitoneal injection of saline. Mice exposed to repeated restraint showed a similar hyperresponsiveness to novel MS, suggesting that repeated restraint lowers the threshold for stress-induced activation of the adrenal gland. MS caused a small, but significant, degree of hypophagia in rats that had been exposed to repeated restraint stress. Therefore, multiple aspects of the stress response may be exaggerated in these animals and contribute to the chronic reduction in body weight.     

Overexpression of agouti protein and stress responsiveness in mice

Ectopic overexpression of agouti protein, an endogenous antagonist of melanocortin receptors' linked to the beta-actin promoter (BAPa) in mice, produces a phenotype of yellow coat color, Type II diabetes, obesity and increased somatic growth. Spontaneous overexpression of agouti increases stress-induced weight loss. In these experiments, other aspects of stress responsiveness were tested in 12-week-old male wild-type mice and BAPa mice. Two hours of restraint on three consecutive days produced greater increases in corticosterone and post-stress weight loss in BAPa than wild-type mice. In Experiment 2, anxiety-type behavior was measured immediately after 12 min of restraint. This mild stress did not produce many changes indicative of anxiety, but BAPa mice spent more time in the dark side of a light-dark box and less time in the open arms of an elevated plus maze than restrained wild-type mice. In a defensive withdrawal test, grooming was increased by restraint in all mice, but the duration of each event was substantially shorter in BAPa mice, possibly due to direct antagonism of the MC4-R by agouti protein. Thus, BAPa mice showed exaggerated endocrine and energetic responses to restraint stress with small differences in anxiety-type behavior compared with wild-type mice. These results are consistent with observations in other transgenic mice in which the melanocortin system is disrupted, but contrast with reports that acute blockade of central melanocortin receptors inhibits stress-induced hypophagia. Thus, the increased stress responsiveness in BAPa mice may be a developmental compensation for chronic inhibition of melanocortin receptors.     

Chronic restraint or variable stresses differently affect the behavior, corticosterone secretion and body weight in rats

Organisms are constantly subjected to stressful stimuli that affect numerous physiological processes and activate the hypothalamo-pituitary-adrenal (HPA) axis, increasing the release of glucocorticoids. Exposure to chronic stress is known to alter basic mechanisms of the stress response. The purpose of the present study was to compare the effect of two different stress paradigms (chronic restraint or variable stress) on behavioral and corticosterone release to a subsequent exposure to stressors. Considering that the HPA axis might respond differently when it is challenged with a novel or a familiar stressor we investigated the changes in the corticosterone levels following the exposure to two stressors: restraint (familiar stress) or forced novelty (novel stress). The changes in the behavioral response were evaluated by measuring the locomotor response to a novel environment. In addition, we examined changes in body, adrenals, and thymus weights in response to the chronic paradigms. Our results showed that exposure to chronic variable stress increased basal plasma corticosterone levels and that both, chronic restraint and variable stresses, promote higher corticosterone levels in response to a novel environment, but not to a challenge restraint stress, as compared to the control (non-stressed) group. Exposure to chronic restraint leads to increased novelty-induced locomotor activity. Furthermore, only the exposure to variable stress reduced body weights. In conclusion, the present results provide additional evidence on how chronic stress affects the organism physiology and point to the importance of the chronic paradigm and challenge stress on the behavioral and hormonal adaptations induced by chronic stress.     

Corticosterone modulates autonomic responses and adaptation of central immediate-early gene expression to repeated restraint stress.

We have tested the role of elevated corticosterone in modulating the responses to either a single (acute) or chronic (repeated daily) restraint stress. Male rats were adrenalectomised, and received subcutaneous corticosterone pellets that resulted in either low (ca. 60 ng/ml) or higher (ca. 130-150 ng/ml) levels of plasma corticosterone. They were also implanted with telemetric transmitters relaying heart rate and core temperature. Control rats were unoperated and untreated. In the first experiment, rats were exposed to daily (60 min) restraint stress for 9 days whereas in the second experiments, rats were only exposed to a single restraint stress. Heart rate and core temperature were recorded every 10 min during each stress session. Brains were removed 1 h after the end of the final stress, and stained immunocytochemically for Fos, Fos-b. Plasma corticosterone was measured by radioimmunoassay.Control rats showed marked tachycardia, peaking at about 10 min and declining thereafter (habituation). This pattern did not change significantly across the 9 days of repeated stress. Rats with low dose corticosterone replacement showed a different pattern: maximal heart rate responses were similar, but elevated heart rate persisted during the period of stress. This effect was most marked on the first exposure to restraint. In contrast, high dose replacement rats showed similar heart rate responses to controls. Restraint stress induced a transient hypothermia, which in control rats was reduced during repeated stress (adaptation). High dose corticosterone resulted in accelerated adaptation of this response.As expected, an acute stress increased Fos expression in a range of limbic structures including the lateral septum, lateral preoptic area, bed nucleus of the stria terminalis, and three divisions of the hypothalamic paraventricular nucleus and in the raphe, locus coeruleus and solitary nucleus of the brainstem. After 9 days, there was no longer increased Fos expression in any of these areas. There was no effect of corticosterone treatment on Fos expression after an acute stress, and following repeated stress the low dose group showed increased expression in the lateral preoptic area only. Results with Fos-b were quite different. The effects of an acute stress in control animals was similar to that observed for Fos. Corticosterone had no effects on Fos-b expression after a single stress. Following repeated stress, there were still elevations of Fos-b (compared to controls) in the lateral septum, and in the basolateral and medial amygdala. Rats receiving low dose corticosterone showed increased Fos-b expression following 9 days stress in the lateral septum and in the dorsal and medial parts of the paraventricular nucleus compared to either control, stressed rats or those receiving the higher corticosterone dose and repeated stress.From these results we suggest that persistently elevated corticosterone acts to reduce ('shut-off') stress-induced responses as assessed both by the reaction of the autonomic system and by the expression of immediate-early genes in the brain. However, there are marked differences in the relations between corticosterone and the parameters measured in our experiments. In particular, there are distinctions between Fos and Fos-b both in the way they adapt to repeated restraint stress, and the effect corticosterone has on this adaptive process.     

Protective and Detrimental Roles for Regulatory T Cells in a Viral Model for Multiple Sclerosis

Multiple sclerosis (MS) has been proposed to be an immune‐mediated disease in the central nervous system (CNS) that can be triggered by virus infections. In Theiler's murine encephalomyelitis virus (TMEV) infection, during the first week (acute stage), mice develop polioencephalomyelitis. After 3 weeks (chronic stage), mice develop immune‐mediated demyelination with virus persistence, which has been used as a viral model for MS. Regulatory T cells (Tregs) can suppress inflammation, and have been suggested to be protective in immune‐mediated diseases, including MS. However, in virus‐induced inflammatory demyelination, although Tregs can suppress inflammation, preventing immune‐mediated pathology, Tregs may also suppress antiviral immune responses, leading to more active viral replication and/or persistence. To determine the role and potential translational usage of Tregs in MS, we treated TMEV‐infected mice with ex vivo generated induced Tregs (iTregs) on day 0 (early) or during the chronic stage (therapeutic). Early treatment worsened clinical signs during acute disease. The exacerbation of acute disease was associated with increased virus titers and decreased immune cell recruitment in the CNS. Therapeutic iTreg treatment reduced inflammatory demyelination during chronic disease. Immunologically, iTreg treatment increased interleukin‐10 production from B cells, CD4⁺ T cells and dendritic cells, which may contribute to the decreased CNS inflammation.     

Exercise reverses chronic stress-induced Bax oligomer formation in the cerebral cortex

Chronic stress may lead to neuronal atrophy and functional impairments within the CNS, and increasing evidence indicates that exercise can protect the brain from these changes. Bax is a key protein of the B-cell lymphoma (Bcl) family that complexes within the mitochondrial membrane and forms pores to initiate cellular apoptosis. Herein, we measured cortical Bax levels following chronic and acute stress via immunoblotting. We reveal that chronic, but not acute, stress increases cortical levels of Bax oligomer 270, a complex revealed in previous studies to be associated with apoptosis. Several recent studies have revealed that physical exercise can protect rodents from neurochemical and/or behavioral changes occurring with stress. Previous studies have also revealed that voluntary exercise enhances the expression and activation of cellular proteins associated with enhanced neuronal survival. Herein, we reveal that 3 weeks of daily restraint led to increased oligomerization of Bax within the cerebral cortex, and that chronic corticosterone administration had a similar effect. Voluntary wheel running, concurrent with chronic restraint, prevented an increase in Bax oligomer 270. Analysis of subcellular fractions also revealed that the combination of exercise with chronic stress reduced the percent of total Bax localized to the mitochondria. Ours is the first study to investigate dynamic molecule complexes associated with the initiation of apoptosis with stress, and the influence of exercise upon the levels of these complexes, suggesting that exercise is an effective preventative measure that can promote neuronal survival and protect the brain against the damaging effects of chronic stress.     

Chronic exposure to random restraint stress retards the development of estrogen-induced pituitary prolactinoma in rats

The effects of stress on carcinogenesis have been equivocal. The present work examined the influence of an unpredictable pattern of chronic restraint stress on estradiol-induced pituitary hyperplasia in male Fischer 344 rats. The animals were grouped as follows: (1) control, (2) stressed, (3) estradiol (31 mg), subcutaneous implant for 40 days and (4) estradiol with stress, 1 h daily, randomly, for 40 days. The pituitaries increased markedly in mass in groups 3 and 4 compared to the first two groups. However, the gland weight in rats exposed to estradiol plus stress was significantly (P less than 0.04) reduced as compared to estradiol per se. Prolactin levels increased due to estradiol treatment and decreased following exposure to stress. Weights of adrenal glands increased as a result of estradiol treatment when compared to those in stressed or untreated animals. This adrenal hypertrophy correlated well with plasma corticosterone levels. The data demonstrate that chronic immobilization stress retarded estradiol-induced pituitary prolactinoma. Modulation of the immune response by stress-related factors may play a role in the inhibition of tumorigenesis.     

Stress-dependent changes in neuroinflammatory markers observed after common laboratory stressors are not seen following acute social defeat of the Sprague Dawley rat

Exposure to acute stress has been shown to increase the expression of pro-inflammatory cytokines in brain, blood and peripheral organs. However, the nature of the inflammatory response evoked by acute stress varies depending on the stressor used and species examined. The goal of the following series of studies was to characterize the consequences of social defeat in the Sprague Dawley (SD) rat using three different social defeat paradigms. In Experiments 1 and 2, adult male SD rats were exposed to a typical acute resident-intruder paradigm of social defeat (60 min) by placement into the home cage of a larger, aggressive Long Evans rat and brain tissue was collected at multiple time points for analysis of IL-1β protein and gene expression changes in the PVN, BNST and adrenal glands. In subsequent experiments, rats were exposed to once daily social defeat for 7 or 21 days (Experiment 3) or housed continuously with an aggressive partner (separated by a partition) for 7 days (Experiment 4) to assess the impact of chronic social stress on inflammatory measures. Despite the fact that social defeat produced a comparable corticosterone response as other stressors (restraint, forced swim and footshock; Experiment 5), acute social defeat did not affect inflammatory measures. A small but reliable increase in IL-1 gene expression was observed immediately after the 7th exposure to social defeat, while other inflammatory measures were unaffected. In contrast, restraint, forced swim and footshock all significantly increased IL-1 gene expression in the PVN; other inflammatory factors (IL-6, cox-2) were unaffected in this structure. These findings provide a comprehensive evaluation of stress-dependent inflammatory changes in the SD rat, raising intriguing questions regarding the features of the stress challenge that may be predictive of stress-dependent neuroinflammation.     

Effects of moderate and intensive training on the hypothalamo-pituitary-adrenal axis in rats

The influence of the two distinct training programmes, moderate (M) and intensive (I), on hypothalamo-pituitary-adrenal (HPA) axis was investigated, in rats. Changes in plasma concentrations of adrenocorticotropin hormone (ACTH) and corticosterone were followed in response to (i) a 60-min acute running session performed on 2nd, 4th and 6th of the seven training weeks (ii) an acute restraint stress of 40 min applied after the final training programme. After 2nd, 4th and 6th week of the two training programmes, a 60-min running resulted in an enhanced secretion of ACTH and corticosterone, compared with both the baseline values (i.e. before running) and to the sedentary (S) group. However, on 4th and 6th weeks compared with 2nd week, ACTH and corticosterone remained elevated in intensive group when they are significantly reduced in moderate group. We could suggest that a moderate training resulted in an adapted hormonal response whereas a deadapted process occurred for the intensive programme. The day after the last training session, basal ACTH, corticosterone and corticosteroid-binding globulin (CBG) capacity were not affected by training. Hypothalamic corticotropin-releasing factor tissue-content (CRF) was increased significantly in the two trained groups. When compared with the sedentary group, the body weight of the rats in the two trained groups was significantly decreased with a total adrenal mass increasing but only in intensive group. The surimposed restraint stress resulted in significant increases in plasma ACTH and corticosterone both in trained and in sedentary animals. This result suggests that the adapted HPA axis response induced by both a moderate and intensive training do not prevent against the effects of a novel stress such as restraint stress.     

Chronic restraint stress and chronic corticosterone treatment modulate differentially the expression of molecules related to structural plasticity in the adult rat piriform cortex

Stress and stress-related hormones induce structural changes in neurons of the adult CNS. Neurons in the hippocampus, the amygdala and the prefrontal cortex undergo neurite remodeling after chronic stress. In the hippocampus some of these effects can be mimicked with chronic administration of adrenal steroids. These changes in neuronal structure may be mediated by certain molecules related to plastic events such as the polysialylated form of the neural cell adhesion molecule (PSA-NCAM). The expression of PSA-NCAM persists in the adult hippocampus and it is up-regulated after chronic stress. The piriform cortex also displays considerable levels of PSA-NCAM during adulthood and indirect evidence suggests that it may also be the target of stress and stress related-hormones. Using immunohistochemistry we have studied the expression of PSA-NCAM and doublecortin (DCX; another protein implicated in neuronal structural plasticity) in the piriform cortex of adult rats subjected either to 21 days of chronic restraint stress or to oral corticosterone administration during the same period. Our results indicate that chronic stress and chronic corticosterone administration have differential effects on the expression of PSA-NCAM and DCX. While chronic stress increases the number of PSA-NCAM- and DCX-immunoreactive cells in the piriform cortex layer II, chronic corticosterone administration decreases these numbers. These findings indicate that stress and adrenal steroids affect the piriform cortex and suggest that in this region, as in the hippocampus, they may induce structural changes. This is a potential mechanism by which stress and corticosterone modulate functions of this limbic region, such as its participation in olfactory memory.     

Restraint stress is associated with changes in glucocorticoid immunoregulation

Psychological stress has been associated with activation of the hypothalamic-pituitary-adrenal (HPA) axis and impaired cell-mediated immune (CMI) responses. There is also evidence suggesting that intermittent chronic stress differentially alters CMI across different immune compartments, but the mechanisms underlying this phenomenon have not been explored in detail. In the present study, we investigated (i) acute and chronic restraint stress effects in Sprague-Dawley rats on both peripheral blood lymphocyte (PBL) and splenocyte mitogen-induced proliferation and (ii) also determined whether differential stress effects within these immune compartments might reflect alterations in lymphocyte sensitivity to glucocorticoids. It was found that while acute stress exposure significantly raised plasma corticosterone levels (1048% vs. controls, P<.001), this response was attenuated in the animals previously exposed to chronic intermittent stress (-79.66% vs. acute; P<.001). Acute stress increased phytohemagglutinin (PHA)-induced lymphocyte proliferation in the spleen (69.04%, P=.01) and suppressed PBL proliferation (-45.52%, P<.001). Neither of these changes were observed following chronic stress. We also demonstrated that reexposure to the stressor rapidly increased splenocyte sensitivity to in vitro dexamethasone (P<.05) and corticosterone (P<.05) in chronically stressed rats. Our data (1) confirm that acute stress is associated with compartment-specific changes in CMI function, (2) indicate that chronic stress is associated with habituated endocrine and immune responses and (3) that stressor exposure rapidly alters splenocyte sensitivity to glucocorticoids and we suggest that the latter may contribute to differential stress effects across immune compartments.     

Plasma corticosterone levels during repeated presentation of two intensities of restraint stress: chronic stress and habituation

This study measured plasma corticosterone levels in male rats during repeated daily presentations of two intensities of restraint stress. The corticosterone response to a stress session was defined as the change from pre-stress levels to levels after 60 minutes of restraint. With the relatively intense stress imposed by four limb prone restraint, the corticosterone response partially habituated over seven days due to increasing basal corticosterone levels. However, even on day 7, there was still a large corticosterone response. With the milder stress of immobilization in a tube, the corticosterone response did not habituate at all over 21 days of repeated stress despite rising basal levels. Stress levels of corticosterone did not show significant change over days in either of the two restraint groups. Further, rising basal corticosterone levels suggest that repeated restraint produced a chronic stress state in these rats which may vary in some qualitative way with stressor intensity. Control rats placed in the same room as the stressed rats during the two stresses initially had increased corticosterone levels that matched the levels achieved in the stressed rats. The responses in control rats for the intense stress did not habituate completely in 7 days, whereas those in the control rats for the mild stress habituated completely within 3 days. These data suggest intraspecific communication of the intensity of stress.