Time-of-day-dependent adaptation of the HPA axis to predictable social defeat stress.

In modern societies, the risk of developing a whole array of affective and somatic disorders is associated with the prevalence of frequent psychosocial stress. Therefore, a better understanding of adaptive stress responses and their underlying molecular mechanisms is of high clinical interest. In response to an acute stressor, each organism can either show passive freezing or active fight-or-flight behaviour, with activation of sympathetic nervous system and the hypothalamus-pituitary-adrenal (HPA) axis providing the necessary energy for the latter by releasing catecholamines and glucocorticoids (GC). Recent data suggest that stress responses are also regulated by the endogenous circadian clock. In consequence, the timing of stress may critically affect adaptive responses to and/or pathological effects of repetitive stressor exposure. In this article, we characterize the impact of predictable social defeat stress during daytime versus nighttime on bodyweight development and HPA axis activity in mice. While 19 days of social daytime stress led to a transient reduction in bodyweight without altering HPA axis activity at the predicted time of stressor exposure, more detrimental effects were seen in anticipation of nighttime stress. Repeated nighttime stressor exposure led to alterations in food metabolization and reduced HPA axis activity with lower circulating adrenocorticotropic hormone (ACTH) and GC concentrations at the time of predicted stressor exposure. Our data reveal a circadian gating of stress adaptation to predictable social defeat stress at the level of the HPA axis with impact on metabolic homeostasis underpinning the importance of timing for the body's adaptability to repetitive stress.

Stress and animal models of inflammatory bowel disease--an update on the role of the hypothalamo-pituitary-adrenal axis.

Chronic psychosocial stress has been repeatedly shown in humans to be a risk factor for the development of several affective and somatic disorders, including inflammatory bowel diseases (IBD). There is also a large body of evidence from rodent studies indicating a link between stress and gastrointestinal dysfunction, resembling IBD in humans. Despite this knowledge, the detailed underlying neuroendocrine mechanisms are not sufficiently understood. This is due, in part, to a lack of appropriate animal models, as most commonly used rodent stress paradigms do not adequately resemble the human situation and/or do not cause the development of spontaneous colitis. Therefore, our knowledge regarding the link between stress and IBD is largely based on rodent models with low face and predictive validity, investigating the effects of unnatural stressors on chemically induced colitis. These studies have consistently reported that hypothalamo-pituitary-adrenal (HPA) axis activation during stressor exposure has an ameliorating effect on the severity of a chemically induced colitis. However, to show the biological importance of this finding, it needs to be replicated in animal models employing more clinically relevant stressors, themselves triggering the development of spontaneous colitis. Important in view of this, recent studies employing chronic/repeated psychosocial stressors were able to demonstrate that such stressors indeed cause the development of spontaneous colitis and, thus, represent promising tools to uncover the mechanisms underlying stress-induced development of IBD. Interestingly, in these models the development of spontaneous colitis was paralleled by decreased anti-inflammatory glucocorticoid (GC) signaling, whereas adrenalectomy (ADX) prior to stressor exposure prevented its development. These findings suggest a more complex role of the HPA axis in the development of spontaneous colitis. In the present review I summarize the available human and rodent data in order to provide a comprehensive understanding of the biphasic role of the HPA axis and/or the GC signaling during stressor exposure in terms of spontaneous colitis development.

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.

Adrenal insufficiency and colonic inflammation after a novel chronic psycho-social stress paradigm in mice: implications and mechanisms.

We investigated chronic psycho-social stress effects on stress-related parameters and on pathohistological changes in the murine colon. Moreover, we aimed to reveal the involvement of adrenal glucocorticoids in chronic stress effects. Chronic subordinate colony housing (CSC, 19 d) resulted in reduced body weight gain, thymus atrophy, adrenal hypertrophy, increased plasma norepinephrine, and increased anxiety. With respect to the time course of CSC effects, CRH mRNA in the hypothalamic paraventricular nucleus, light phase corticosterone and tyrosine hydroxylase expression in colonic tissue were found to be increased, whereas tyrosine hydroxylase expression in the locus coeruleus was found to be decreased on d 2 of CSC; these parameters returned to control levels thereafter. Nevertheless, after 19 d of CSC exposure, the adrenal corticosterone responses in vivo and in vitro, and glucocorticoid sensitivity of isolated splenic cells were found to be decreased. Importantly, in CSC mice a significant histological damage of the colon was found beginning on d 14 of CSC exposure. Additionally, pro- and antiinflammatory cytokine secretion by mesenteric lymph node cells was increased after CSC exposure. Adrenalectomy before CSC at least partially prevented these chronic stress effects as reflected by less increase in proinflammatory cytokine secretion and an equal histological damage score in adrenalectomized compared with sham-operated CSC mice. In conclusion, chronic exposure to CSC alters relevant neuronal, neuroendocrine and immune functions that could be directly or indirectly involved in the damage of the histological integrity of the colon comparable with that seen during the development of colitis.

Chronic intermittent psychosocial stress (social defeat/overcrowding) in mice increases the severity of an acute DSS-induced colitis and impairs regeneration.

Ulcerative colitis is a multifactorial disease, with immunological, genetic, and environmental factors playing an important role in its pathogenesis. Here we investigated the consequences of exposure to chronic psychosocial stress on the severity of a dextran sulfate sodium (DSS)-induced colitis in male C57BL/6 mice. Chronic stress was induced by repeated exposure to social defeat (SD, 2 h) and overcrowding (OC, 24 h) during 19 consecutive days. SD/OC mice showed a diminished body weight gain, thymus-atrophy, and adrenal hypertrophy, but similar light-phase plasma corticosterone concentrations, compared with unstressed mice. In contrast, the rise in dark-phase corticosterone concentration was significantly attenuated in SD/OC mice, whereas plasma ACTH concentrations and hypothalamic CRH mRNA expression did not differ between stressed and nonstressed groups. Additionally, adrenal cells from SD/OC mice showed a decreased in vitro response to ACTH stimulation. Subsequent treatment with 1% DSS for 7 d resulted in a more severe intestinal inflammation in SD/OC mice, as reflected by an increase in body weight loss, histological damage scores, and secretion of IL-6, TNFalpha, and interferon-gamma from mesenteric lymph node cells and by decreased colon length. The impaired health status of stressed mice was also reflected by a significantly lower survival rate after termination of the DSS treatment. In conclusion, the present findings demonstrate that chronic intermittent exposure to a psychosocial stressor before the induction of acute DSS-colitis results in adrenal insufficiency, increases in the severity of the acute inflammation, and impairs the healing phase.