Chronic Variable Stress Induces Sex-Specific Alterations in Social Behavior and Neuropeptide Expression in the Mouse

Chronic exposure to stressors impairs the function of multiple organ systems and has been implicated in increased disease risk. In the rodent, the chronic variable stress (CVS) paradigm has successfully modeled several stress-related illnesses. Despite striking disparities between men and women in the prevalence and etiology of disorders associated with chronic stress, most preclinical research examining chronic stressor exposure has focused on male subjects. One potential mediator of the consequences of CVS is oxytocin (OT), a known regulator of stress neurocircuitry and behavior. To ascertain the sex-specific effects of CVS in the C57BL/6 mouse on OT and the structurally similar neuropeptide arginine vasopressin (AVP), the numbers of immunoreactive and mRNA-containing neurons in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) were determined using immunohistochemistry and in situ hybridization, respectively. In addition, the mice underwent a battery of behavioral tests to determine whether CVS affects social behaviors known to be regulated by OT and AVP. Six weeks of CVS increased sociability in the female mouse and decreased PVN OT immunoreactivity (ir) and AVP mRNA. In the male mice, CVS decreased PVN OT mRNA but had no effect on social behavior, AVP, or OT-ir. CVS also increased the soma volume for PVN OT neurons. In contrast, OT and AVP neurons in the SON were unaffected by CVS treatment. These findings demonstrate clear sex differences in the effects of CVS on neuropeptides in the mouse, suggest a pathway through which CVS alters sociability and stress-coping responses in females and reveals a vulnerability to CVS in the C57BL/6 mouse strain.