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 ovarian hormones 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 estrogen's role in stress-related behavioral outcomes. Estrogen signaling through estrogen receptor beta (ERβ) has been traditionally thought of as anxiolytic, but recent studies suggest estrogen exhibits distinct effects in the context of stress. Furthermore, ERβ 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 ERβ 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 WS, rats exhibited stress-induced anxiety-like behaviors in the marble burying taskand brain analysis revealed increased ERβ 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 ERβ antagonist, PHTPP, prior to each stress session. During WS, estrogen signaling through ERβ was responsible for the behavioral sensitization to repeated social stress. Sucrose preference, acoustic startle, and marble burying tasks determined that blocking ERβ 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 rats. These experiments indicate that ERβ signaling in the CeA, likely through its effects on CRF, contributes to the development of negative valence behaviors that result from exposure to repeated social stress in female rats.