Chronic Subordinate Colony Housing Paradigm: A Mouse Model to Characterize the Consequences of Insufficient Glucocorticoid Signaling

Abstract

Chronic, in particular chronic psychosocial, stress is a burden of modern societies and known to be a risk factor for numerous somatic and affective disorders (in detail referenced below). However, based on the limited existence of appropriate, and clinically relevant, animal models for studying the effects of chronic stress, the detailed behavioral, physiological, neuronal, and immunological mechanisms linking stress and such disorders are insufficiently understood. To date, most chronic stress studies in animals employ intermittent exposure to the same (homotypic) or to different (heterotypic) stressors of varying duration and intensity. Such models are only of limited value, since they do not adequately reflect the chronic and continuous situation that humans typically experience. Furthermore, application of different physical or psychological stimuli renders comparisons to the mainly psychosocial stressors faced by humans, as well as between the different stress studies almost impossible. In contrast, rodent models of chronic psychosocial stress represent situations more akin to those faced by humans and consequently seem to hold more clinical relevance. Our laboratory has developed a model in which mice are exposed to social stress for 19 continuous days, namely the chronic subordinate colony housing (CSC) paradigm, to help bridge this gap. The main aim of the current review article is to provide a detailed summary of the behavioral, physiological, neuronal, and immunological consequences of the CSC paradigm, and wherever possible relate the findings to other stress models and to the human situation.

Immunization with a heat-killed preparation of the environmental bacterium Mycobacterium vaccae promotes stress resilience in mice

“…These findings are consistent with other studies showing that glucocorticoid hormones decrease IgA (which normally inhibits bacterial adherence to intestinal epithelial cells), increase bacterial adherence to the intestinal epithelium over twofold, and increase bacterial translocation to mesenteric lymph nodes (17). Mice exposed to the CSC procedure experience a profound activation of the HPA axis, with persistent adrenal hypertrophy that is evident within 24 h and persists through days 2, 7, 14, and 20 of the CSC procedure, exaggerated ACTH and corticosterone release to novel stressors, and in vitro adrenal insufficiency, as measured by decreased sensitivity to ACTH (26). Glucocorticoid insensitivity of effector immune cells, as indicated by glucocorticoid insensitivity of lipopolysaccharide-stimulated splenocytes and anti-CD3-stimulated T cells, may contribute to the exaggerated inflammatory responses in CSC mice (26).…”

“…Mice exposed to the CSC procedure experience a profound activation of the HPA axis, with persistent adrenal hypertrophy that is evident within 24 h and persists through days 2, 7, 14, and 20 of the CSC procedure, exaggerated ACTH and corticosterone release to novel stressors, and in vitro adrenal insufficiency, as measured by decreased sensitivity to ACTH (26). Glucocorticoid insensitivity of effector immune cells, as indicated by glucocorticoid insensitivity of lipopolysaccharide-stimulated splenocytes and anti-CD3-stimulated T cells, may contribute to the exaggerated inflammatory responses in CSC mice (26). Immunization with M. vaccae had no effect on the CSC-induced adrenal hypertrophy or the in vitro adrenal insensitivity, suggesting that, although HPA axis changes may contribute to stress-induced exaggerations of inflammation, they do not mediate the protective effects of M. vaccae immunization.…”

“…Oral or intraperitoneal administration of immunomodulatory bacterial products have been shown to both prevent and treat experimental colitis in animal models (46,47), suggesting that these substances can act through gut-dependent and gut-independent mechanisms to attenuate chemically induced colitis. Chronic subordinate colony housing exposure reproducibly induces spontaneous colitis and aggravates chemically induced colitis (26). Importantly, although immunization with M. vaccae did not prevent the CSC-induced increase in colitogenic Helicobacter spp.…”

“…Likewise, PTSD subjects (9) and subjects with major depressive disorder (53) have reduced Treg, which is reversed 1 y following effective narrative exposure therapy (54) or treatment with antidepressants, respectively (53). Given these findings and studies showing that CSC reduces Treg in peripheral lymph nodes (26) and M. vaccae immunization induces Treg (22), we investigated a potential role for Treg in the stress-protective effects of M. vaccae (Exp. 4) (Fig.…”

„Old Friends“, Immunregulation und Stressresilienz

“…Chronischer psychosozialer Stress ist eine der Hauptbelastungen des modernen Lebens und stellt einen akzeptierten Risikofaktor für eine Vielzahl von stressbedingten somatischen und affektiven Störungen dar [2]. Obwohl die Verbreitung von stressbedingten somatischen und affektiven Störungen in den letzten Jahrzehnten zugenommen hat, sind die Faktoren, die zu dieser Zunahme beitragen, insbesondere bei stressbedingten psychischen Störungen, noch längst nicht vollständig verstanden.…”