Estrogen receptor beta in the central amygdala regulates the deleterious behavioral and neuronal consequences of repeated social stress in female rats.
Estrogen receptor beta in the central amygdala regulates the deleterious behavioral and neuronal consequences of repeated social stress in female rats.
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DOI：
10.1016/j.ynstr.2023.100531
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发表时间：
2023-03
影响因子：
5
通讯作者：
Wood, Susan K.
中科院分区：
文献类型：
--
作者：
Smiley, Cora E.;Pate, Brittany S.;Bouknight, Samantha J.;Francis, Megan J.;V. Nowicki, Alexandria;Harrington, Evelynn N.;Wood, Susan K.
虽然超过95%的人口报告说经历过极端的压力或创伤，但育龄女性患上压力引起的神经精神障碍的比率是男性的两倍。这表明卵巢激素可能促进神经过程，增加压力敏感性，并导致这些疾病的发病率升高，如抑郁和焦虑，这是由女性的压力暴露引起的。然而，关于雌激素在压力相关行为结果中的作用，文献中有相互矛盾的证据。通过雌激素受体β（ERβ）的雌激素信号传导传统上被认为是抗焦虑的，但最近的研究表明雌激素在压力的背景下表现出独特的作用。此外，ERβ大量存在于许多应激敏感的大脑位点，包括中央杏仁核（CeA），其中重要应激激素促肾上腺皮质激素释放因子（CRF）的转录可由雌激素反应元件调节。因此，这些实验试图确定CeA ERβ活性在自然循环的成年雌性Sprague-Dawley大鼠中应激期间对行为结果的作用。大鼠暴露于行为学模型的替代社会压力，证人压力（WS），在其中他们经历了感官和心理方面的积极的社会失败遇到两个男性之间。WS后，大鼠在埋大理石任务中表现出应激诱导的焦虑样行为，脑分析显示，暴露于应激线索后，CeA内的ERβ和CRF特异性增加。随后的实验设计为在每次应激前通过显微注射ERβ拮抗剂PHTPP靶向CeA中的该受体。在WS期间，通过ERβ的雌激素信号是对重复社会应激的行为敏感化的原因。蔗糖偏好、声音惊吓和大理石掩埋任务确定了WS期间阻断CeA中的ERβ可防止抑郁、焦虑样和过度警惕行为的发展。此外，脑分析显示，PHTPP治疗大鼠的CeA内CRF表达长期下降。这些实验表明，CeA中的ERβ信号可能通过其对CRF的影响，促进了雌性大鼠暴露于反复的社会应激导致的负价行为的发展。社会压力会增加焦虑，过度警惕和抑郁样行为。重复目击应激使女性CeA中ERβ和CRF增加。CeA内ERβ拮抗作用阻断了过度警觉的发展。ERβ拮抗作用导致CeA CRF表达持续降低。与压力相关的雌激素可能是女性压力易感性的一个靶点。
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. Social stress increases anxiety-, hypervigilant, and depressive-like behaviors. Repeated witness stress increases ERβ and CRF in the CeA of females. Intra-CeA ERβ antagonism blocks the development of hypervigilance. ERβ antagonism leads to persistent reductions in CeA CRF expression. Stress-related estrogen may represent a target for stress susceptibility in women.
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