Sex differences in chronic social stress models in mice

Abstract Chronic stress creates an allostatic overload that may lead to mood disorders such as anxiety and depression. Modern causes of chronic stress in humans are mostly social in nature, relating to work and relationship stress. Research into neural and molecular mechanisms of vulnerability and resilience following chronic social stress (CSS) is ongoing and uses animal models to discover efficient prevention strategies and treatments. To date, most CSS studies have neglected the female sex and used male-focused aggression-based animal models such as chronic social defeat stress (CSDS). Accumulating evidence on sex differences suggests differences in the stress response, the prevalence of stress-related illness and the treatment response, indicating that researchers should expand CSS investigation to include female-focused protocols alongside the popular CSDS protocols. Here, we describe a novel female mouse model of CSS and a parallel modified male mouse model of CSDS in C57BL/6 mice. These new models enable the investigation of vulnerability, coping and downstream effectors mediating long-term consequences of CSS in both sexes. Our data demonstrate sex differences during CSS and for many weeks following CSS. Female mice are more prone to body weight loss during CSS and hyperactive anxious behavior following CSS. Both sexes show disturbances in social interaction, but only stressed male mice show long-term changes in neuroendocrine function and memory performance after fear conditioning. We discuss future avenues of research using these models to investigate mechanisms pertaining to sensitivity to CSS as well as treatment response profiles, in a sex-suitable manner.