Synaptic Mechanisms of Nucleus Accumbens Disinhibition by Ethanol

乙醇对伏核去抑制的突触机制

• 批准号: 10544526
• 负责人: BRIAN NEIL MATHUR
• 金额: $ 49.92万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-20 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10544526
• 关键词: Address; Alcohol consumption; Alcoholism; Alcohols; Area; Automobile Driving; Brain; Brain-Derived Neurotrophic Factor; Chronic; Consumption; Data; Disease; Disinhibition; Dynamin; Electrophysiology (science); Enhancers; Ethanol; Fostering; Functional disorder; Genetic; Goals; Inhibitory Synapse; Investigation; Knowledge; Long-Term Depression; Mediating; Mental Depression; Molecular; Motivation; Neurons; Nucleus Accumbens; Output; Pathologic; Positioning Attribute; Prefrontal Cortex; Property; Protein Tyrosine Kinase; Public Health; Receptor Protein-Tyrosine Kinases; Research; Rewards; Role; Signal Transduction; Slice; Source; Structure; Synapses; Synaptic Transmission; Synaptic plasticity; System; Testing; Therapeutic; Ventral Tegmental Area; Viral; alcohol effect; alcohol exposure; alcohol misuse; alcohol reward; alcohol use disorder; behavior prediction; cell type; chronic alcohol ingestion; chronic pain; comorbidity; conditioned place preference; drinking behavior; effective therapy; in vivo; innovation; insight; knock-down; neural circuit; neuropsychiatric disorder; novel; optogenetics; pharmacologic; postsynaptic; preference; receptor; stem; tool; treatment strategy; vapor

Project Summary Alcohol misuse levies a major impact on public health, yet the brain mechanisms underlying how this substance drives its misuse are poorly understood. This proposal seeks to discover a novel mechanism underlying the rewarding properties of alcohol. Data derived from this study stand to provide novel treatment strategies aimed at blunting the rewarding effects of alcohol in those suffering from alcohol use disorders. The motivation to seek and acquire rewards is encoded by the output of a key reward integration center in the brain, the nucleus accumbens. Inhibitory synapses in this structure powerfully gate its output. Our preliminary experimentation indicates that alcohol pathologically disinhibits the nucleus accumbens by hijacking a form of synaptic plasticity at inhibitory synapses. This novel mechanism positions alcohol as a pathological enhancer of nucleus accumbens output and reward encoding. To elucidate this further, we propose three aims of investigation using cutting-edge approaches: 1) to determine the neural circuit components necessary for driving ethanol enhancement of this synaptic plasticity; 2) to determine the molecular mechanism mediating ethanol enhancement of this form of plasticity and; 3) to causally determine how ethanol enhances NAc-iLTD reward encoding in vivo. The results of this study stand to significantly advance our understanding of alcohol action in the brain and provide important insight to myriad neuropsychiatric disorders involving nucleus accumbens synaptic dysplasticity.

项目摘要 酒精滥用对公共健康产生重大影响，但大脑机制如何导致这种情况 物质驱动其滥用的原因知之甚少。这项提案旨在发现一种新的机制， 酒精的奖赏特性的基础。从这项研究中获得的数据可以提供新的治疗方法 旨在减弱酒精对患有酒精使用障碍的人的奖励作用的策略。的 寻求和获得奖励的动机是由大脑中关键奖励整合中心的输出编码的， 脑桥核这个结构中的抑制性突触有力地控制了它的输出。我们的初步 实验表明，酒精通过劫持一种形式的 抑制性突触的突触可塑性。这种新的机制将酒精定位为一种病理性的增强剂， 输出和奖赏编码。为了进一步阐明这一点，我们提出了三个目标， 使用尖端方法进行调查：1）确定驾驶所需的神经回路组件 乙醇增强这种突触可塑性; 2）确定乙醇介导的分子机制 增强这种形式的可塑性和3）因果关系，以确定乙醇如何增强NAc-iLTD奖励 体内编码。这项研究的结果将大大促进我们对酒精作用的理解， 并为涉及脑髓核的无数神经精神疾病提供了重要的见解 突触可塑性障碍