Estrogen receptor beta in the central amygdala regulates the deleterious behavioral and neuronal consequences of repeated social stress in female rats

Abstract

While over 95% of the population has reported experiencing extreme stress or trauma, females of reproductive age develop stress-induced neuropsychiatric disorders at twice the rate of males. This suggests that estrogen may facilitate neural processes that increase stress susceptibility and underlie the heightened rates of these disorders, like depression and anxiety, that result from stress exposure in females. However, there is contradicting evidence in the literature regarding estrogens role in stress-related behavioral outcomes. Estrogen signaling through estrogen receptor beta (ER{beta}) has been traditionally thought of as anxiolytic, but recent studies suggest estrogen exhibits distinct effects in the context of stress. Furthermore, ER{beta} is found abundantly in many stress-sensitive brain loci, including the central amygdala (CeA), in which transcription of the vital stress hormone, corticotropin releasing factor (CRF), can be regulated by an estrogen response element. Therefore, these experiments sought to identify the role of CeA ER{beta} activity during stress on behavioral outcomes in naturally cycling, adult, female Sprague-Dawley rats. Rats were exposed to an ethological model of vicarious social stress, witness stress (WS), in which they experienced the sensory and psychological aspects of an aggressive social defeat encounter between two males. Following stress, rats exhibited stress-induced anxiety-like behaviors in the marble burying task, and, finally, brain analysis revealed increased ER{beta} and CRF specifically within the CeA following exposure to stress cues. Subsequent experiments were designed to target this receptor in the CeA using microinjections of the ER{beta} antagonist, PHTPP, prior to each stress session. Sucrose preference, acoustic startle, and marble burying tasks determined that blocking ER{beta} in the CeA during WS prevented the development of depressive-,anxiety-like, and hypervigilant behaviors. Additionally, brain analysis revealed a long-term decrease of intra-CeA CRF expression in PHTPP-treated WS rats compared to vehicle. These experiments indicate that ER{beta} signaling in the CeA, through its effects on CRF, contribute to the development of negative valence behaviors that result from exposure to repeated social stress in female rats.