The role of a nucleus tractus solitarius-central amygdala circuit in alcohol-induced plasticity and drinking behavior

孤束核-中央杏仁核回路在酒精诱导的可塑性和饮酒行为中的作用

• 批准号: 10608946
• 负责人: Melissa A Herman
• 金额: $ 34.99万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-10 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10608946
• 关键词: Acute; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Amygdaloid structure; Behavior; Behavioral; Biological; Brain; Brain Stem; Brain region; Calcium-Binding Proteins; Cell Nucleus; Chronic; Clozapine; Complex; Development; Disease; Electrophysiology (science); Emotional; Ethanol; Ethanol dependence; Female; Functional disorder; Genetic; Genetic study; Goals; In Vitro; Individual; Interneurons; Label; Maps; Mediating; Microspheres; Molecular; Neurons; Oxides; Pathology; Peripheral; Phase; Population; Prevalence; Property; Rattus; Receptor Inhibition; Role; Signal Transduction; Source; Stomach; Synaptic Transmission; alcohol effect; alcohol exposure; behavioral outcome; behavioral study; designer receptors exclusively activated by designer drugs; drinking; drinking behavior; experimental study; genetic approach; genetic manipulation; in vivo; insight; mad itch virus; male; neuroadaptation; neurobiological mechanism; optogenetics; protein biomarkers; receptor; sensory input; social; therapeutic target; transmission process; vector control

Alcoholism is a complex disorder characterized by neuroadaptive changes in specific brain regions and circuits that promote adverse behavioral outcomes associated with alcohol dependence. Previous studies have focused on the role of the central amygdala (CeA) in the extended amygdala, however, CeA connections with other brain regions can also influence CeA responsivity to ultimately alter behavior. One region that forms reciprocal connections with the CeA is the Nucleus Tractus Solitarius (NTS). The NTS receives sensory input from the periphery and acts as an integrative autonomic center. The CeA confers emotional relevance to internal and external sensory input. Thus, the NTS  CeA circuit represents a potential conduit by which peripheral state can influence emotional reactivity and emotional state can impact peripheral function. In that context, the NTS CeA circuit may also represent an important target for acute and chronic ethanol and an understudied source of circuit dysfunction that alters drinking behavior. The overarching goal of this proposal is to employ a combined electrophysiological, molecular, and behavioral approach with functional circuit mapping using optogentics and chemogenetics to examine NTS microcircuitry, the sensitivity of NTS neurons to ethanol exposure, and the role of the NTSCeA circuit in drinking behavior and the development of alcohol dependence. Molecular and electrophysiological studies will be used to identify distinct components of NTS microcircuitry and the impact of acute in vitro and chronic in vivo ethanol on synaptic transmission and activity in NTS circuit components. Retrograde tracing, electrophysiological, optogenetic, and chemogenetic studies will be used to identify specific components of the NTS CeA circuit in the NTS and CeA to determine the impact of chronic ethanol on these specific components at a cellular and circuit level. Chemogenetic and behavioral studies of voluntary ethanol consumption will be used to assess the role of the NTS CeA circuit in drinking. Collectively, these studies will provide new information on the role of the NTS and the NTS CeA circuit in the cellular and circuit mechanisms underlying ethanol dependence.

酒精中毒是一种复杂的疾病，其特征是特定脑区和回路的神经适应性变化 会导致与酒精依赖相关的不良行为结果。以前的研究都集中 关于中央杏仁核（CeA）在扩展杏仁核中的作用，然而，CeA与其他大脑的联系， 区域也可以影响CeA反应性，最终改变行为。一个区域，形成互惠 与CeA相连的是孤束核（NTS）。NTS接收来自 外围，并作为一个综合自主中心。CeA赋予情感相关性的内部和 外部感官输入因此，NTS旁路电路代表了一个潜在的管道，通过该管道， 可以影响情绪反应，情绪状态可以影响外周功能。在这方面，NTS CeA回路也可能是急性和慢性乙醇的重要靶点，也是未充分研究的 改变饮酒行为的回路功能障碍。该提案的总体目标是采用一种组合的 电生理学、分子学和行为学方法，使用光遗传学进行功能电路映射， 化学遗传学检查NTS微电路，NTS神经元对乙醇暴露的敏感性，以及 在饮酒行为和酒精依赖的发展中的NTS神经元CeA回路。分子和 电生理学研究将用于识别NTS微电路的不同组成部分以及 急性体外和慢性体内乙醇对NTS回路组件中突触传递和活性的影响。 逆行追踪、电生理学、光遗传学和化学遗传学研究将用于鉴定特定的 NTS和CeA中的NTS-CeA回路的组成部分，以确定慢性乙醇对这些 在蜂窝和电路级别的特定组件。自愿性乙醇的化学发生学和行为学研究 消耗量将被用来评估NTS神经元CeA回路在饮酒中的作用。总的来说，这些研究 将提供新的信息的作用，NTS和NTS SCRENCEA电路在蜂窝和电路 乙醇依赖的潜在机制。