Novel role of beta2-adrenergic receptor signaling in vBNST CRF-mediated stress-induced ethanol intake

项目总结 酒精使用障碍(AUD)影响着美国约1600万人。不幸的是，尽管有少数几个 目前可用的治疗方法，复发率非常高。压力是旧病复发的常见诱因； 因此，它是AUD治疗的主要靶点。这项提案将研究压力的综合影响。 酒精对边缘系统神经回路的影响，边缘系统是参与情绪的主要结构群 正在处理。这项提议的第一个具体目标是检验压力和乙醇相互作用的假设 促进终纹床核的β2-肾上腺素能受体(b2-AR)信号转导 增加自愿的乙醇摄入量。这将使用全细胞膜片钳电生理学进行测试， BNST神经元的化学遗传操作和荧光原位杂交。第二个目标是测试 靶向糖皮质激素受体(GR)介导的BNST信号转导将减轻b2-AR的假说 应激和酒精摄入后依赖的行为和神经回路的变化。这将会实现的 通过染色质免疫沉淀(CHIP)、电生理学和药物操作 GR.与国家酒精滥用和酒精中毒研究所(NIAAA)的使命保持一致， 这项研究计划将通过识别神经回路来调查酒精对健康和幸福的影响 压力与酒精暴露的小鼠和幼稚的小鼠之间的差异。归根结底，这些发现 研究将有助于开发与压力相关的酒精使用障碍的预防和治疗。

PROJECT SUMMARY Alcohol use disorder (AUD) affects about 16 million people in the United States. Unfortunately, despite the few currently-available treatments, the rate of relapse is extraordinarily high. Stress is a common trigger of relapse; therefore it is a prime target for AUD treatment. This proposal will investigate the combined effects of stress and alcohol use on neurocircuitry in the limbic system, the primary group of structures involved in emotional processing. The first specific aim of this proposal is to test the hypothesis that stress and ethanol interact to promote beta2-adrenergic receptor (b2-AR) signaling in the bed nucleus of the stria terminalis (BNST) and increase voluntary ethanol intake. This will be tested using whole-cell patch-clamp electrophysiology, chemogenetic manipulations of BNST neurons, and fluorescent in situ hybridization. The second aim is to test the hypothesis that targeting glucocorticoid receptor (GR)-mediated signaling in the BNST will mitigate b2-AR dependent behavioral and neurocircuit changes following stress and ethanol intake. This will be achieved through chromatin immunoprecipitation (ChIP), electrophysiology, and pharmacological manipulations of the GR. Keeping consistent with the mission of the National Institute on Alcohol Abuse and Alcoholism (NIAAA), this research proposal will investigate alcohol’s effect on health and well-being by identifying neurocircuitry differences between stress and alcohol-exposed mice and naïve mice. Ultimately the findings from these studies will help when developing prevention and treatments for stress-related alcohol use disorder.