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

岛皮层-BNST神经回路对慢性戒酒引起的负面情绪的调节

• 批准号: 9976199
• 负责人: Samuel William Centanni
• 金额: $ 14.97万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9976199
• 关键词: Abstinence; Affect; Affective; Affective Symptoms; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Amygdaloid structure; Anterior; Antidepressive Agents; Anxiety; Anxiety Disorders; Automobile Driving; Award; Awareness; Behavior; Brain; Brain imaging; Calcium; Cell Nucleus; Characteristics; Chronic; Chronic Phase; Complex; Coupled; Data; Diagnostic; Disease; Electrophysiology (science); Emotional; Exhibits; Family; Fiber; Financial Hardship; Food; Foundations; Genetic; Genetic Recombination; Genetic Techniques; Goals; Health; Heterogeneity; Human; Hyperactive behavior; Individual; Insula of Reil; Interneurons; Link; Major Depressive Disorder; Mental Depression; Mental disorders; Mentors; Midbrain structure; Motivation; Mus; Negative Reinforcements; Neural Pathways; Neurons; Output; Pathway interactions; Patients; Pattern; Phase; Photometry; Physiological; Play; Post-Traumatic Stress Disorders; Predisposition; Regulation; Relapse; Reporting; Research; Role; Sensory; Severities; Severity of illness; Somatosensory Cortex; Source; Stress; Structure; Structure of terminal stria nuclei of preoptic region; Symptoms; Testing; Thalamic structure; Therapeutic; Time; Training; Viral; Virus; Withdrawal; Work; addiction; affective disturbance; alcohol abstinence; alcohol seeking behavior; alcohol use disorder; associated symptom; base; binge drinking; career; career development; cell type; cognitive control; comorbidity; craving; drinking; feeding; genetic approach; genetic manipulation; hindbrain; in vivo; mouse model; negative affect; neural circuit; neuroadaptation; neuroimaging; novel; problem drinker; prophylactic; relating to nervous system; side effect; social; stress related disorder; stressor; therapeutic target; tool; virus genetics

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.

项目概要/摘要 酒精使用障碍（AUD）每年困扰着数百万人及其家庭。澳元经常 与焦虑和抑郁共病，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诱因， 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 的相关性凸显了迫切需要进行更多专注于理解相互作用的研究 澳元与负面情感障碍之间的关系。识别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情感症状至关重要 节制。越来越多的证据表明，从社会使用到负强化驱动的转变 寻求酒精涉及一组统称为扩展杏仁核的大脑结构。床 终纹核 (BNST) 是杏仁核扩展网络的一个组成部分，是 与压力相关的疾病，例如焦虑、抑郁和成瘾。 BNST 在许多方面发挥着重要作用 酒精成瘾的各个方面，包括酗酒和戒酒的渴望。 BNST 与许多机构互动 皮质、皮质下、中脑和后脑区域以确定一般情感。我们最近的工作确定了 岛叶皮质（岛叶）和 BNST 之间的功能连接。岛叶参与内感受 意识、认知控制和感觉处理，越来越多的证据表明岛叶在 酗酒和消极情感障碍。我们使用了慢性饮酒后强迫的小鼠模型 戒断 (CDFA) 概述了岛-BNST 通路在戒断引起的负面影响中的明确作用 影响，并且该提案将在很大程度上建立在这一基础证据的基础上。我们将体内的钙结合起来 纤维光度测定和离体电生理学与遗传小鼠系和各种复杂的病毒 分离特定电路神经元群的遗传技术。指导（K99）阶段将提供 纤维光度测定和复杂的病毒遗传操作策略的培训，以确定功能和 接收岛叶输入（目标 1）的 BNST 神经元和投射到岛叶神经元的生理状态 CDFA 长期禁欲阶段的 BNST（目标 2）。独立 (R00) 阶段将识别二阶 输入到岛BNST神经元上，目的是进一步描绘复杂的神经回路调节 禁欲引起的负面影响。本次拟研究及相关职业发展培训计划 独立之路奖共同提供了将申请人转变为独立人士的理想机制 作为一名独立的成瘾神经科学家。结果将显着增进我们对 长期酗酒后长期戒酒时发生的神经适应。