Estradiol Promotes Social Stress Susceptibility in Female Rats in a Region‐ and CRF‐Specific Manner

Abstract

Repeated exposure to social stress is a common risk factor for anxiety disorders. Women are twice as likely as men to suffer from anxiety. However, the mechanisms behind this increased risk remain unclear, which limits targeted therapeutic options. Interestingly, this increased susceptibility in females is confined between the onset of puberty and the end of menopause, suggesting that ovarian hormones may contribute to this disproportionate risk of stress‐related disorders. 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 lasting anxiety‐like behaviors selectively in intact, cycling female rats. Ovariectomized (OVX) females are largely resistant to WS‐evoked behaviors, but estradiol replacement reinstates these anxiety‐like behaviors. Moreover, intact females, but not OVX, exposed to WS exhibit a distinct and long‐lasting increase in corticotropin releasing factor (CRF) expression in the central amygdala (CeA), a stress sensitive brain region. The current study seeks to understand specific 17‐β estradiol (17‐βE)‐induced neural regulation that may contribute to the heightened susceptibility to social stress among females to identify a druggable target to promote stress resilience. Following recovery from OVX or sham surgery, adult female rats were treated with either 17‐βE (10μg/rat, s.c.) or vehicle (0μg/rat, s.c.) and one hour later, were exposed to WS or control handling. WS/control episodes were video recorded to measure burying, freezing, and rearing behaviors, and blood samples were collected one hour after WS/control to assess corticosterone (CORT) levels. Brains were collected two hours after WS/control. To quantify activity of CRF neurons, immunohistochemistry was used to double label for CRF and cFos in various stress sensitive regions. Behavioral responses were shown to be regulated by 17‐βE; WS‐evoked burying evident in intact females was decreased by OVX and reinstated by 17‐βE. However, there was no effect of WS or 17‐βE on freezing or rearing behaviors. Additionally, 17‐βE increased WS‐induced plasma CORT levels. cFos positive CRF expression in the CeA was robustly enhanced by 17‐βE during WS, but not control. This effect was not globally observed as there was no effect of WS or 17‐βE on cFos expression in CRF positive neurons within the paraventricular nucleus of the hypothalamus and the hippocampus. Analysis of stress‐ and CRF‐sensitive brain regions including the locus coeruleus are ongoing. Taken together, these findings suggest that an interaction between 17‐βE and CRF is paramount in facilitating the anxiety‐like responses to WS. Given the controversial impact of CRF1 receptor antagonists to date, this study provides evidence of conditions under which anxiety‐like behaviors are associated with enhanced CRF responses and may serve as a personalized viable target to treat increased sensitivity to stress‐related disorders in females.