Model Of Chronic Psychosocial Stress Research Articles

Chronic psychosocial stress results in sensitization of the HPA axis to acute heterotypic stressors despite a reduction of adrenal in vitro ACTH responsiveness

Although chronic psychosocial stress is often accompanied by changes in basal hypothalamo-pituitary-adrenal (HPA) axis activity, it is vital for a chronically-stressed organism to mount adequate glucocorticoid (GC) responses when exposed to acute challenges. The main aim of the present study was to test whether this is true or not for the chronic subordinate colony housing (CSC, 19 days) paradigm, an established and clinically relevant mouse model of chronic psychosocial stress. As shown previously, CSC mice are characterized by unaffected morning and decreased evening plasma corticosterone (CORT) levels despite enlarged adrenals, suggesting a maladaptive breakdown of adrenal functioning. Plasma CORT levels, determined by repeated blood sampling via jugular vein catheters, as well as relative right adrenal CORT content were increased in CSC compared with single-housed control (SHC) mice in response to acute elevated platform (EPF, 5min) exposure. However, in vitro stimulation of adrenal explants with physiological and pharmacological doses of ACTH revealed an attenuated responsiveness of both the left and right adrenal glands following CSC, despite mRNA and/or protein expression of melanocortin 2 receptor (Mc2r), Mc2r accessory protein (MRAP), and key enzymes of steroidogenesis were not down-regulated. Taken together, we show that chronic psychosocial stressor exposure impairs in vitro ACTH responsiveness of both the left and right adrenal glands, whereas it increases adrenal responsiveness to an acute heterotypic stressor in vivo. This suggests that an additional factor present during acute stressor exposure in vivo rescues left and right adrenal ACTH sensitivity, or itself acts as CORT secretagogue in chronically stressed CSC mice.

Chronic psychosocial stress induces visceral hyperalgesia in mice

Experimental and clinical evidence has shown that chronic stress plays an important role in the onset and/or exacerbation of symptoms of functional gastrointestinal disorders. Here, we aimed to investigate whether exposure to a chronic and temporally unpredictable psychosocial stressor alters visceral and somatic nociception as well as anxiety-related behaviour. In male C57BL/6J mice, chronic stress was induced by repeated exposure to social defeat (SD, 2 h) and overcrowding (OC, 24 h) during 19 consecutive days. Visceral and somatic nociception was evaluated by colorectal distension and a hot plate, respectively. The social interaction test was used to assess social anxiety. Mice exposed to psychosocial stress developed visceral hyperalgesia and somatic hypoalgesia 24 h following the last stress session. SD/OC mice also exhibited social anxiety-like behaviour. All these changes were also associated with physiological alterations, measured as a decreased faecal pellet output and hypothalamic-pituitary-adrenal (HPA) axis disruption. Taken together, these data confirm that this mouse model of chronic psychosocial stress may be useful for studies on the pathophysiological mechanisms underlying such stress-associated disorders and to further test potential therapies.

Mucosal immunosuppression and epithelial barrier defects are key events in murine psychosocial stress-induced colitis

Chronic psychosocial stress is a risk factor for many affective and somatic disorders, including inflammatory bowel diseases. In support chronic subordinate colony housing (CSC, 19days), an established mouse model of chronic psychosocial stress, causes the development of spontaneous colitis. However, the mechanisms underlying the development of such stress-induced colitis are poorly understood. Assessing several functional levels of the colon during the initial stress phase, we show a pronounced adrenal hormone-mediated local immune suppression, paralleled by impaired intestinal barrier functions, resulting in enhanced bacterial load in stool and colonic tissue. Moreover, prolonged treatment with broad-spectrum antibiotics revealed the causal role of these early maladaptations in the development of stress-induced colitis.Together, we demonstrate that translocation of commensal bacteria is crucial in the initiation of stress-induced colonic inflammation. However, aggravation by the immune-modulatory effects of fluctuating levels of adrenal hormones is required to develop this into a full-blown colitis.

Underlying mechanisms of adrenal insufficiency after exposure to chronic psychosocial stress in mice

The chronic subordinate colony housing (CSC) has been established as clinically relevant model of chronic psychosocial stress for male mice and as such shown to cause behavioural, immunological as well as neuroendocrine changes. One of the most striking findings was that 19 days of CSC exposure affects proper hypothalamo-pituitary-adrenal (HPA) axis function, mainly at the level of the adrenal glands. This was indicated by the finding that adrenal corticosterone response upon in vivo and in vitro ACTH stimulation was strongly dampened following CSC, despite a concurrent increase in adrenal mass. Here, we investigated the mechanisms underlying the CSC-induced adrenal insufficiency, which was found to be body side specific. As shown before, CSC resulted in a significant reduction in body weight gain, as well as in an increase in absolute and relative adrenal mass, when compared with single housed control (SHC) mice. However, when distinguishing between left and right body side, adrenal mass was only found to be significantly increased on the right side. In the left adrenal there was only a slight trend towards an increased mass. Oil red/ nissel staining, followed by computerized analysis, revealed that the CSC-induced increased right adrenal mass was due to an enlargement of cortical areas, mainly of the glucocorticoids-producing zona fasciculata. In contrast, the trend towards an increased mass in the left adrenal was due to an enlargement of the medulla. Furthermore, oil red staining, followed by computerized analysis, showed that the amount of cholesterol containing, cortical lipid vesicles was increased in the right adrenal, whereas no changes were found after CSC in the left adrenal. In addition, real-time PCR indicated that the ACTH receptor mRNA expression in CSC mice was strongly reduced, but only in the left adrenal. Furthermore, after in vitro ACTH-stimulation of adrenals, we found decreased corticosterone levels in the supernatants of the left, but not the right, adrenal gland compared with SHC. In summary, our data suggest that 19 days of CSC result in a decreased sensitivity to ACTH of the left adrenal and that the right adrenal tries to compensate this loss of adrenal functionality by an increase in the number of cortical zona fasciculata cells.

Sildenafil counteracts the inhibitory effect of social subordination on competitive aggression and sexual motivation in male mice

The effects of chronic intra-peritoneal administration of 10 mg/kg (t.i.w., for 5 weeks) of sildenafil on competitive aggression, sexual behaviour and body weight gain was tested in CD1 subordinate male mice in two experimental contexts: 1) “low levels of aggression”, i.e. housing in dyads of siblings 2) “high levels of aggression”, i.e. exposure to a model of chronic psychosocial stress with an unfamiliar mice. Subordinate mice in both experimental contexts were injected with sildenafil or saline. After 2 weeks of sildenafil administration, a subgroup of subordinates exposed to “high levels of aggression” began to counterattack their dominant counterparts at higher rates than saline-injected subordinates. This effect was essentially similar but faster in subordinates subjected to “low levels of aggression”. As far as sexual behaviour is concerned, in both experimental contexts, sildenafil-injected subordinated mice showed significant lower latencies to mount a proceptive female when compared to saline-injected subjects. Furthermore, in the “high levels of aggression” context, Sildenafil reduced stress-induced body weight gain. Sildenafil showed no effects in individually housed males serving as controls. In conclusion, chronic Sildenafil treatment counteracts the inhibitory effects of social subordination on male competitive aggression, sexual behaviour and body weight gain. Overall our data suggests that sildenafil could be acting in the central nervous system to modulate sexual and agonistic motivation.

Chronological assessment of mast cell-mediated gut dysfunction and mucosal inflammation in a rat model of chronic psychosocial stress

Life stress and mucosal inflammation may influence symptom onset and severity in certain gastrointestinal disorders, particularly irritable bowel syndrome (IBS), in connection with dysregulated intestinal barrier. However, the mechanism responsible remains unknown. Crowding is a validated animal model reproducing naturalistic psychosocial stress, whose consequences on gut physiology remain unexplored. Our aims were to prove that crowding stress induces mucosal inflammation and intestinal dysfunction, to characterize dynamics in time, and to evaluate the implication of stress-induced mast cell activation on intestinal dysfunction. Wistar-Kyoto rats were submitted to 15 days of crowding stress (8 rats/cage) or sham-crowding (2 rats/cage). We measured spontaneous and corticotropin-releasing factor-mediated release of plasma corticosterone. Stress-induced intestinal chrono-pathobiology was determined by measuring intestinal inflammation, epithelial damage, mast cell activation and infiltration, and intestinal barrier function. Corticosterone release was higher in crowded rats throughout day 15. Stress-induced mild inflammation, manifested earlier in the ileum and the colon than in the jejunum. While mast cell counts remained mostly unchanged, piecemeal degranulation increased along time, as the mucosal content and luminal release of rat mast cell protease-II. Stress-induced mitochondrial injury and increased jejunal permeability, both events strongly correlated with mast cell activation at day 15. Taken together, we have provided evidences that long-term exposure to psychosocial stress promotes mucosal inflammation and mast cell-mediated barrier dysfunction in the rat bowel. The notable resemblance of these findings with those in some IBS patients, support the potential interest and translational validity of this experimental model for the research of stress-sensitive intestinal disorders, particularly IBS.

Chronic psychosocial stress promotes systemic immune activation and the development of inflammatory Th cell responses

Recent studies indicate that chronic psychosocial stress favors the development of generalized immune dysfunction. During stressor exposure neuroendocrine factors affect numbers and functionality of leukocytes. However, the exact mechanisms leading to systemic changes in immune functions during stress are still not clear. During chronic subordinate colony housing, a model of chronic psychosocial stress, mice developed spontaneous colonic inflammation. Decreased glucocorticoid signaling, induced by a combination of adrenal insufficiency and glucocorticoid resistance, was thought to prevent tempering of local immune cells, and to promote tissue inflammation. In this study we investigated changes in the systemic immune status after chronic subordinate colony housing and analyzed potential mechanisms underlying those alterations. Analysis of T helper cell subsets in peripheral lymph nodes revealed a reduction of regulatory T cells, accompanied by increased T cell effector functions. Generalized activation of T cells was shown by elevated cytokine production upon stimulation. In addition, we observed no apparent shift towards T helper type 2 responses. It is likely, that the previously reported hypocorticism in this stress model led to a steady production of inflammatory Th1, Th2, and Th17 cytokines and obstructed the shift towards an anti-inflammatory response. In conclusion, we established chronic subordinate colony housing as a model to investigate the outcome of stress on the systemic immune status. We also provide evidence that distinct T helper cell subtypes react differentially to the suppressive effect of glucocorticoids.

Effect of chronic psychosocial stress-induced by subordinate colony (CSC) housing on brain neuronal activity patterns in mice

Chronic subordinate colony (CSC) housing has been recently validated as a murine model of chronic psychosocial stress which induces alterations of stress-related parameters including decreased body-weight gain and an increased level of anxiety in comparison with single housed control (SHC) mice. By using immunohistochemical immediate early gene (IEG) mapping we investigated whether CSC housing causes alterations in neuronal activation patterns in limbic areas including the amygdala, hippocampus, septum and the periaqueductal gray (PAG) and hypothalamic paraventricular nucleus (PVN). While CSC housing increased basal Zif-268 expression in the nucleus accumbens shell compared to SHC, IEG responses to subsequent open arm (OA) exposure were attenuated in the ventral and intermediate sub-regions of the lateral septum, parvocellular PVN and the dorsal CA3 region of the hippocampus of CSC compared with SHC mice. In contrast, a potentiated c-Fos response in CSC mice was observed in the dorsomedial PAG after OA exposure. Confirming previous findings obtained on the elevated plus-maze, an enhanced anxiety-related behavior in CSC compared with SHC mice was also observed during OA exposure. In order to investigate the appropriate control conditions for CSC housing, group housed control (GHC) mice were additionally included in the behavioral testing. Interestingly, GHC as well as CSC mice showed significantly less risk assessment/exploratory behavior during OA exposure compared with SHC mice indicating that group housing itself is stressful for mice and not an adequate control for the CSC paradigm. Overall, CSC housing is an ethologically relevant chronic psychosocial stressor which results in an elevated sensitivity to a subsequent novel, aversive challenge. However, the CSC-induced increase in anxiety-related behavior was accompanied by differences in neuronal activation, compared with SHC, in defined sub-regions of brain areas known to be involved in the processing of emotionality and stress responses.

Defensive Behavioral Strategies and Enhanced State Anxiety during Chronic Subordinate Colony Housing Are Accompanied by Reduced Hypothalamic Vasopressin, But Not Oxytocin, Expression

Chronic subordinate colony (CSC) housing has recently been shown to be a clinically relevant model of chronic psychosocial stress for male mice and to cause an increase in the animals' anxiety-related behavior on the plus-maze. Here, we investigated (1) the detailed subordinate/dominant behavior during CSC housing, (2) the anxiety-related behavior of CSC and control mice in two independent tests, and (3) whether CSC exposure also influences the hypothalamic expression of oxytocin (OXT) and/or arginine vasopressin (AVP), specifically within the paraventricular nucleus. Both neuropeptides are known to be involved in the regulation of anxiety and stress responses. Behavioral observation revealed that all male CSC mice that were co-housed with a slightly larger male mouse obtained a subordinate status within their colonies over 19 consecutive days. Furthermore, CSC exposure resulted in diminished body weight gain and increased anxiety-related behavior as quantified both on the elevated plus-maze and in the light-dark box. Hypothalamic mRNA levels of OXT remained unchanged, whereas AVP mRNA was found to be decreased on day 20 of CSC exposure. In conclusion, exposure to CSC enhances anxiety, an effect that seems to be independent of the hypothalamic expression of the neuropeptides OXT and AVP.

Examining SLV-323, a novel NK1 receptor antagonist, in a chronic psychosocial stress model for depression

Substance P antagonists have been proposed as candidates for a new class of antidepressant compounds. We examined the effects of SLV-323, a novel neurokinin 1 receptor (NK1R) antagonist, in the chronic psychosocial stress paradigm of adult male tree shrews. Animals were subjected to a 7 day period of psychosocial stress before being treated daily with SLV-323 (20 mg kg(-1) day(-1)). The psychosocial stress continued throughout the treatment period of 28 days. Brain metabolite concentrations were determined in vivo by proton magnetic resonance spectroscopy. Norepinephrine excretion was monitored from daily urine samples, and serum testosterone concentrations were measured at the end of the experiment. All animals were videotaped daily to analyze scent-marking behavior and locomotor activity. Cell proliferation in the dentate gyrus and hippocampal volume were measured postmortem. Stress significantly decreased cerebral concentrations of N-acetyl-aspartate, total creatine, and choline-containing compounds in vivo and resulted in an increase of urinary norepinephrine and decrease of serum testosterone concentrations. Moreover, stressed animals displayed decreased scent-marking behavior and locomotor activity. The proliferation rate of the granule precursor cells in the dentate gyrus was reduced, and hippocampal volume was mildly decreased. The stress-induced alterations in the central nervous system were partially prevented by concomitant administration of SLV-323, while drug treatment had only a minor effect on the stress-induced behavioral changes. The novel NK1R antagonist SLV-323 has certain antidepressant-like effects in a valid animal model of depression.

Behavioral and physiological characterization of male mice under chronic psychosocial stress

Social stress is a major factor in the etiology of several psychopathologies, with individuals greatly differing in vulnerability. The development of appropriate animal models of social stress is, thus, a major challenge of modern bio-medical research. Adult male mice were subjected to a new model of chronic psychosocial stress in which resident/intruder dyads live chronically in sensory contact and physically interact on a daily basis. Four behavioral categories were identified: Resident Dominants (RD), Resident Subordinates (RS), Intruder Dominants (InD), Intruder Subordinates (InS). Here we investigated: behavior during aggressive interactions; gross physiological components of mice metabolism; organ physiology; response to dexamethasone suppression test (DST). RD and InD mice showed persistently high levels of aggression. All four categories of mice showed robust lack of suppression of corticosterone level when challenged with the DST. Although food intake was not altered under chronic stress, body weight decreased in RD and InD mice while increased in InS and, even more so, in RS mice, suggesting an alteration of their metabolic functions. In conclusion, social status and territory ownership were factors determining individual vulnerability to stress exposure. Our model could, thus, be regarded as a valid model to investigate the biological basis of the individual differences in the response to stressful events.

Chronic psychosocial stress-induced down-regulation of immunity depends upon individual factors

The effect of chronic stress on immune functions is strongly biased by individual factors. Mice were subjected to a new model of chronic psychosocial stress in which four different subcategories of stressed animals may be identified: Resident Dominants (RD), Resident Subordinates (RS), Intruder Dominants (InD), and Intruder Subordinates (InS). After 7 days of stress, mice were immunized with keyhole limpet hemocyanine (KLH). Their immune functions were investigated 14 days later with stress continuing trough. Importantly, RS mice, which are mice losing territory ownership, were the more affected, having lower IgG, proliferation, and IL-2. RD and InD showed lower IgG while InS showed no immune alteration. In conclusion, loss of resources could be a key factor in determining individual vulnerability to stressful events.

Blockade of glucocorticoid receptors with ORG 34116 does not normalize stress-induced symptoms in male tree shrews

Glucocorticoid receptors play an important role in the regulation of the activity of the hypothalamo–pituitary–adrenal axis, and are thought to be involved in the pathophysiology of depressive disorders. The present study investigated the effect of the specific glucocorticoid receptor antagonist ORG 34116 (a substituted 11,21 bisarylsteroid compound) in the tree shrew ( Tupaia belangeri) chronic psychosocial stress model, an established animal model for depressive disorders. Animals were stressed for 10 days before treatment with ORG 34116 started (25 mg/kg p.o. for 28 days). Stress induced a decrease in body weight, which just failed significance, whereas ORG 34116 did not affect body weight in stress and control animals. ORG 34116 enhanced the stress-induced increase in the concentration of urinary-free cortisol, although no differences between the different experimental groups existed during the last week of treatment. In stressed animals, ORG 34116 did not affect marking behavior, but decreased locomotor activity. Post mortem analysis of 5-HT 1A receptors revealed a decreased affinity of 3[H]-8-OH-DPAT ( 3[H]-8-hydroxy-2-[di- n-propylamino]tetralin) binding sites in the hippocampus of animals treated with the glucocorticoid receptor antagonist. In conclusion, under our experimental conditions, the glucocorticoid receptor antagonist ORG 34116 did not normalize the depressive-like symptoms in the psychosocial stress model of male tree shrews. This finding, however, does not exclude that specific central, neuroendocrine and behavioral features are affected by the compound.

The Chronic Psychosocial Stress Paradigm in Male Tree Shrews: Evaluation of a Novel Animal Model for Depressive Disorders

To improve our knowledge of the causal mechanisms of stress-related disorders such as depression, we need animal models that mirror the situation in patients. One promising model is the chronic psychosocial stress paradigm in male tree shrews, which is based on the territorial behaviour of these animals that can be used to establish naturally occurring challenging situations under experimental control in the laboratory. Co-existence of two males in visual and olfactory contact leads to a stable dominant-subordinate relationship, with subordinates showing distinct stress-induced behavioural and neuroendocrine alterations that are comparable to the symptoms observed during episodes of depression in patients such as constantly elevated circulating glucocorticoid hormones due to a chronic hyperactivity of the hypothalamic-pituitary-adrenal axis. To elucidate whether the chronic psychosocial stress model in tree shrews besides its "face validity" for depression also has "predictive validity", we treated subordinate tree shrews with the tricyclic antidepressant clomipramine and found a time-dependent restoration of both endocrine and behavioural parameters. In contrast, the anxiolytic diazepam was ineffective. Although the chronic psychosocial stress model in tree shrews requires further validation, it has sufficient face, predictive, and construct validity to become an interesting non-rodent model for research on the etiology and pathophysiology of depression.

Antidepressant therapy prevents structural brain changes

Chronic stress leads to several structural changes in the brain, most notably a reduction in hippocampal volume. A recent study describes the effects of antidepressant therapy on hippocampal plasticity in a primate model of chronic psychosocial stress. Treatment with tianeptine prevented stress-induced changes in brain markers of neuronal viability, normalized the proliferation of adult hippocampal cells, and corrected the stress-induced changes in hippocampal volume. Tianeptine, an unusual antidepressant agent that is believed to promote rather than inhibit 5-HT uptake, joins the list of antidepressant drugs that have beneficial effects on neurogenesis. [Czeh, B. et al. (2001) Proc. Natl. Acad. Sci. U. S. A. 98, 12796–12801]. AB

Combination of hypothyroidism and stress abolishes early LTP in the CA1 but not dentate gyrus of hippocampus of adult rats

Clinical experience suggests that both hypothyroidism and stress interfere with mental concentration and memory. This electrophysiological study examined the effect of hypothyroidism and stress, separately or combined, on long-term potentiation (LTP), a widely accepted cellular model for learning and memory. Measurements of early LTP (E-LTP) were carried out in the hippocampus of urethane-anesthetized adult Wistar rats. Hypothyroidism was achieved by thyroidectomy, and the ‘intruder’ stress was used as a model of chronic psychosocial stress. Stimulating electrodes were placed in the left CA3 region and right angular bundle and a recording electrode was placed in the right CA1 or the dentate gyrus (DG). The results showed that in the CA1 region of the hippocampus, hypothyroid or stress partially blocked E-LTP. However, when hypothyroidism and stress were combined, they eliminated E-LTP. In contrast, no significant change in E-LTP was seen in the DG of the three groups of rats. These results suggest that impaired memory because of hypothyroidism or stress may be related to impairment of the E-LTP in the Schaffer collateral synapses but not of that of the perforant path synapses.

Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine.

Stress-induced structural remodeling in the adult hippocampus, involving debranching and shortening of dendrites and suppression of neurogenesis, provides a cellular basis for understanding the impairment of neural plasticity in the human hippocampus in depressive illness. Accordingly, reversal of structural remodeling may be a desirable goal for antidepressant therapy. The present study investigated the effect of tianeptine, a modified tricyclic antidepressant, in the chronic psychosocial stress model of adult male tree shrews (Tupaia belangeri), a model with high validity for research on the pathophysiology of major depression. Animals were subjected to a 7-day period of psychosocial stress to elicit stress-induced endocrine and central nervous alterations before the onset of daily oral administration of tianeptine (50 mg/kg). The psychosocial stress continued throughout the treatment period of 28 days. Brain metabolite concentrations were determined in vivo by proton magnetic resonance spectroscopy, cell proliferation in the dentate gyrus was quantified by using BrdUrd immunohistochemistry, and hippocampal volume was measured post mortem. Chronic psychosocial stress significantly decreased in vivo concentrations of N-acetyl-aspartate (-13%), creatine and phosphocreatine (-15%), and choline-containing compounds (-13%). The proliferation rate of the granule precursor cells in the dentate gyrus was reduced (-33%). These stress effects were prevented by the simultaneous administration of tianeptine yielding normal values. In stressed animals treated with tianeptine, hippocampal volume increased above the small decrease produced by stress alone. These findings provide a cellular and neurochemical basis for evaluating antidepressant treatments with regard to possible reversal of structural changes in brain that have been reported in depressive disorders.