Estradiol‐Specific Neural Regulation of Social Stress Susceptibility in Female Rats

Abstract

Repeated exposure to social stress is a common risk factor for development of anxiety disorders. Women are twice as likely as men to suffer from anxiety. However, this increased susceptibility in females is confined between the onset of puberty and the end of menopause. This suggests that ovarian hormones may contribute to the disproportionate development of stress-related anxiety disorders among women. We have previously shown that witness stress (WS), a model of social stress in which a female rat is subjected to witnessing an aggressive social defeat encounter between a male intruder and a novel male resident, produces anxiety-like behaviors selectively in intact, cycling female rats. Ovariectomized (OVX) females are largely resistant to witness stress. Moreover, intact females exposed to WS exhibit a distinct increase in corticotropin releasing factor (CRF) expression in the CeA. The current study seeks to understand specific 17-β estradiol-induced neural regulation that may contribute to the heightened susceptibility to social stress among females. Following recovery from implantation of an intravenous catheter and OVX or sham surgery, female rats were treated with either 17-β estradiol (17-βE, 10μg/rat, s.c.) or vehicle (veh, 0μg/rat, s.c.). One hour after injection, female rats were exposed to WS or control handling and video-recorded for 15 minutes. Witness stress-evoked burying, freezing, and rearing behaviors were subsequently quantified to assess stress-induced anxiety-like responses. To quantify CRF expression, frozen brains were sliced coronally, immunohistochemistry was conducted, and brains were double labeled for CRF and cfos in various stress-sensitive regions. Behavioral responses showed WS rats spent significantly more time burying compared to control rats. Veh-treated OVX rats were less behaviorally reactive to WS as evidenced by decreased WS-evoked burying durations compared with intact veh-treated witnesses. However, OVX rats treated with 17-βE exhibited WS-induced anxiety-like responses similar to those of intact females as demonstrated by similar stress-evoked burying durations during stress. There was no effect of stress or treatment on freezing or rearing behaviors. Furthermore, cfos positive CRF expression in the CeA was increased for intact WS rats. Analysis of stress sensitive brain regions such as the hippocampus and locus coeruleus are ongoing. Taken together, these finding suggest that 17-βE plays a paramount role in facilitating the anxiety-like behaviors to witness stress and points towards specific neural regulation of these responses. These studies will lay the foundation for identifying pharmacological targets to increase stress resilience.