Synaptic Mechanisms of Nucleus Accumbens Disinhibition by Ethanol

项目摘要 酒精滥用会对公众健康造成重大影响，但其背后的大脑机制 物质驱动了它的滥用，人们对此知之甚少。这项提议试图发现一种新的机制 酒精有益的特性的基础。从这项研究中得出的数据将提供新的治疗方法 旨在削弱酒精对酒精使用障碍患者的有益影响的战略。这个 寻求和获得奖励的动机由大脑中关键的奖励整合中心的输出编码， 伏隔核。这个结构中的抑制性突触有力地控制了它的输出。我们的预赛 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。这一新机制将酒精定位为一种病理增强剂 伏隔核的输出和奖赏编码。为了进一步阐明这一点，我们提出了三个目标 使用尖端方法进行研究：1)确定驱动所需的神经电路组件 乙醇增强突触可塑性；2)确定乙醇介导的分子机制 增强这种形式的可塑性；3)因果确定乙醇如何增强NAC-iLTD奖赏 体内编码。这项研究的结果将极大地促进我们对酒精在 并为涉及伏核的无数神经精神障碍提供了重要的洞察力 突触可塑性障碍。

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.