| Mammals respond to environmental threats through complex neuroendocrine processes, collectively referred to as the stress response. Once activated, the stress response affects the regulation of many other physiological systems, including the immune system. For people living in modern, developed nations, social stress is the most common stimulus for the induction of the stress response. Subjects reporting high levels of social stress are more likely to experience increased anxiety and depression and to engage in unhealthy coping strategies and high-risk behaviors. Social disruption (SDR) is an animal model of social stress in which mice are repeatedly attacked and defeated in their home cage by an aggressive conspecific, or member of the same species. Social disruption has been reported to cause increased production of proinflammatory cytokines and glucocorticoid (GC) insensitivity in splenic macrophages. To this point however, the behavioral consequences of SDR have not been thoroughly characterized. Because social defeat has been reported to cause anxiety- and depressive-like behaviors in humans and rodents, the first study was designed to assess whether SDR causes anxiety- and depressive-like behaviors. The light/dark preference test and the open field test were used as tools to measure behaviors characteristic of anxiety. Both C57BL/6 and CD-1 male mice subjected to SDR displayed increased anxiety-like behavior. The increase in anxiety-like behaviors persisted for at least one week after the cessation of the stressor. In contrast, depressive-like behaviors were not elicited by SDR, as assessed by the forced swim test and the tail suspension test.; The second study focused on the role of aging in social defeat. Previous research indicates that repeated social defeat of young adult mice causes increased lymphocyte trafficking to the spleen, elevated proinflammatory cytokine production, and glucocorticoid insensitivity in splenocytes. This study investigated whether repeated social defeat resulted in similar immunoregulatory changes in aged mice, as seen previously in young adults. Regardless of age, defeated mice displayed significantly higher anxiety-like behavior, as measured in the open field test, and more splenic CD11b+ Gr-1+ monocytes and neutrophils than controls. Supernatants harvested from cultured splenocytes from old mice contained comparatively higher IL-6 and TNF-alpha than supernatants from young animals. In addition, those same cells derived from aged defeated mice were hypersensitive to lipopolysaccharide and insensitive to glucocorticoids in vitro. These data indicate that repeated social defeat results in a proinflammatory state that is exacerbated in aged mice. The implications of these data are noteworthy, given that inflammation worsens symptoms of many age-related diseases, and is a possible root cause of Alzheimer's disease.; The third study presented herein determined whether pharmacologically blocking SDR-induced anxiety-like behaviors also blocked the development of GC insensitivity. Neither anxiolytic nor anxiogenic drug significantly affected the development of GC insensitivity, although the chosen dose of diazepam was sufficient to have sedative effects on the mice. These data suggest that the development of anxiety-like behavior does not directly cause the observed immunological effects of social disruption. Taken together, these data indicate that social disruption stress caused an increase in anxiety-like behaviors, but not depressive-like behaviors. This increase in anxiety-like behavior was also observed in aged mice, which were predisposed toward increased inflammation, and this effect was further exacerbated by social defeat. Pharmacologic blockade of anxiety-like behavior neither attenuated nor exacerbated the previously-observed defeat-induced changes to immune function, suggesting that the SDR-induced anxiety-like state does not causally affect immunity. |
