Insular cortex-BNST neural circuit regulation of chronic alcohol abstinence-induced negative affect

项目摘要/摘要 酒精使用障碍(AUD)每年困扰着数百万人及其家人。澳元经常被 同时伴有焦虑和抑郁，表明饮酒动机的潜在来源。 酗酒者通常将压力源和负面情感状态列为渴望和复发的主要触发因素， 疾病状态的严重程度与复发易感性相关。健康和经济负担 与AUD相关突出了更多专注于理解相互作用的研究的迫切需要 在澳元和负性情感障碍之间。确定导致这种衰弱的关键神经适应 疾病对于开发更好的诊断工具和治疗酒精中的情感症状至关重要 禁欲。越来越多的证据表明，从社会使用向负面强化驱动的转变 酗酒涉及一组大脑结构，统称为延伸的杏仁核。那张床 终纹核(BNST)是杏仁核延伸网络的一个组成部分，是中枢神经系统的关键节点。 与压力相关的疾病，如焦虑、抑郁和成瘾。BNST在许多项目中发挥着突出的作用 酒精成瘾的几个方面，包括酗酒和戒酒渴望。BNST与许多人互动 皮质、皮质下、中脑和后脑区域，以确定一般影响。我们最近的研究发现了一个 岛叶皮质(岛)和BNST之间的功能联系。脑岛参与了内源性感觉神经 意识、认知控制和感觉处理，以及越来越多的证据表明，脑岛在 酗酒和消极情感障碍。我们使用了一种慢性饮酒的小鼠模型，然后强迫 戒断(CDFA)概述岛-BNST通路在戒断诱导的负性反应中的明确作用 这项提议将在很大程度上建立在这一基本证据的基础上。我们将结合体内的钙 纤维光度法和体外电生理学与遗传小鼠品系和各种复杂的病毒- 分离电路特异性神经元群的基因技术。指导(K99)阶段将提供 纤维光度学和复杂的病毒基因操作策略方面的培训，以确定功能和 接受胰岛输入的BNST神经元的生理状态(目标1)和投射到 BNST(目的2)，在CDFA的长期戒断阶段。独立(R00)阶段将识别二阶 传入脑岛BNST神经元，目的是进一步描绘复杂的神经回路调节 禁欲引发的负面情绪。拟于本年度进修及相关的职业发展培训计划 通向独立之路奖共同提供了理想的机制，将申请者转变为 独立成瘾神经学家的职业生涯。研究结果将极大地促进我们对 慢性酒精滥用后长期戒酒后发生的神经适应。

PROJECT SUMMARY/ABSTRACT Alcohol use disorder (AUD) afflicts millions of individuals and their families each year. AUD is frequently comorbid with anxiety and depression, indicating potential sources for the motivation to consume alcohol. Alcoholics commonly list stressors and negative affective states as leading triggers of cravings and relapse, and severity of the disease state correlates with relapse susceptibility. The health and financial burden associated with AUD highlights the pressing need for more research focused on understanding the interaction between AUD and negative affective disturbances. Identifying key neuroadaptations driving this debilitating disease is essential for developing better diagnostic tools and treatments for affective symptoms in alcohol abstinence. Converging evidence suggests the transition from social use to negative reinforcement-driven alcohol seeking involves a set of brain structures collectively referred to as the extended amygdala. The bed nucleus of the stria terminalis (BNST), a component of the extended amygdala network, is a critical node for stress-related disorders such as anxiety, depression, and addiction. The BNST plays a prominent role in many facets of alcohol addiction including binge drinking and cravings in withdrawal. The BNST interacts with many cortical, subcortical, midbrain, and hindbrain regions to determine general affect. Our recent work identified a functional connection between the insular cortex (insula) and the BNST. The insula is involved in interoceptive awareness, cognitive control, and sensory processing, and mounting evidence suggests a role for the insula in alcoholism and negative affective disturbances. We used a mouse model of chronic drinking followed by forced abstinence (CDFA) to outline a definitive role for the insula-BNST pathway in abstinence-induced negative affect, and this proposal will significantly build on this foundational evidence. We will combine in vivo calcium fiber photometry and ex vivo electrophysiology with genetic mouse lines and a variety of sophisticated viral- genetic techniques to isolate circuit-specific neuronal ensembles. The mentored (K99) phase will provide training in fiber photometry and complex viral-genetic manipulation strategies to determine the functional and physiological state of BNST neurons receiving insular inputs (Aim 1) and insular neurons that project to the BNST (Aim 2) in the protracted abstinence phase of CDFA. The independent (R00) phase will identify 2nd order inputs onto insulaàBNST neurons, with the goal of further delineating the complex neurocircuitry regulating abstinence-induced negative affect. The proposed studies and related career development training plan in this Pathway to Independence Award collectively provide the ideal mechanism to transition the applicant to a career as an independent addiction neuroscientist. The results will significantly advance our understanding of the neural adaptations that occur in protracted abstinence following chronic alcohol abuse.