A critical role for rapid estrogen signaling in alcohol addiction and anxiety

项目概要/摘要 酗酒和高应激反应是焦虑和酒精使用障碍的主要危险因素， 而女性患这些疾病的风险是男性的两倍。性激素雌激素 参与在焦虑和酒精/药物使用中发挥调节作用，并可能与伸缩 通过放大酗酒的积极和消极成分， 消费和退出。此外，饮酒本身可能会刺激雌激素的合成 促进饮酒行为，表明雌激素信号可能是成瘾的重要机制 无论是男性还是女性。然而，雌激素调节神经元功能的机制， 控制这些行为是未知的。我们假设雌激素信号在膜结合受体 位于边缘系统电路的离散突触节点，以调节其对行为的控制， 在女性基线时，该机制很突出，但在饮酒的男性中变得更重要 exposure.在拟议的工作中，我们研究了内源性雌激素信号传导的位点和机制，其 对回路功能和相应行为影响，以及酒精诱导的雌激素调节可塑性， 无论是男性还是女性。

Project Summary/Abstract Binge alcohol drinking and high stress reactivity are leading risk factors for anxiety and alcohol use disorders, and women are at twice the risk for co-expression of these diseases. The sex hormone estrogen has been implicated in playing a modulatory role in anxiety and alcohol/drug use and may be related to the telescoping of addiction observed in women by amplifying the positive and negative components of binge alcohol consumption and withdrawal. Further, alcohol consumption itself may be able to stimulate estrogen synthesis to promote drinking behavior, suggesting that estrogen signaling may be an important mechanism in addiction for both males and females. However, the mechanisms by which estrogen regulates neuronal function to control these behaviors is unknown. We hypothesize that estrogen signals at membrane-bound receptors located at discrete synaptic nodes of limbic circuitry to modulate their control of behavior, and that this mechanism is prominent at baseline in females but becomes more important in males across alcohol drinking exposure. In the proposed work, we examine the locus and mechanism of endogenous estrogen signaling, its effect on circuit function and corresponding behavior, and alcohol-induced plasticity in estrogen modulation in both males and females.