Striatal fast-spiking interneurons regulate compulsive alcohol consumption

项目摘要 酒精使用障碍对公众健康有重大影响，但导致酒精滥用的大脑机制是 人们对此知之甚少。习惯是重复的运动序列，即使报酬贬值也会持续存在，并形成 作为强迫性行为基础的行动策略。长期饮酒有助于习惯学习和引导 导致长期使用者的习惯性行为增加。背外侧纹状体(人类的壳核)调节 习惯性学习及其驻留的抑制细胞--快速放电中间神经元(FSIS)是酒精的靶标 曝光。为了确定酒精是否利用FSIS促进强迫性酒精消费，我选择性地消融了 接受自愿间歇饮酒范例(在黑暗中饮酒)的动物纹状体FSIS 用掺入的奎宁测试动物的强迫性消费。FSI消融被取消 强迫饮酒并显著扰乱了有组织的酒精舔序列行为。下一个 将这一发现推广到临床应用的关键步骤是确定特定的时间窗口 FSI被招募来形成或维持作为强迫性饮酒基础的运动序列。 为此，我提出了使用创新的光遗传和机器学习方法进行研究的两个目标： 1)确定纹状体FSIS是否对强迫性酒精的有组织行为的发展是必要的 消耗和；2)确定纹状体FSIS是否是维持有组织行动所必需的 潜在的强迫性酒精消费。这项研究的结果将大大推进我们的 了解运动序列学习，运动序列在强迫行为中的作用，并将指示 未来针对强迫性饮酒的治疗干预的必要时间窗口。

Project Summary Alcohol use disorder has a major impact on public health, yet the brain mechanisms driving alcohol misuse are poorly understood. Habits are repetitive motor sequences that persist despite reward devaluation and form the action strategy that underlies compulsive behavior. Chronic alcohol exposure facilitates habit learning and leads to increased habitual behavior in chronic users. The dorsolateral striatum (the putamen in humans) regulates habit learning and its resident inhibitory cells, the fast-spiking interneurons (FSIs), are targeted by alcohol exposure. To determine if alcohol utilizes FSIs to promote compulsive alcohol consumption, I selectively ablated striatal FSIs in animals undergoing a voluntary intermittent drinking paradigm (Drinking in the Dark) and challenged animals with the adulterant quinine to measure compulsive consumption. FSI ablation abolished compulsive alcohol consumption and significantly disrupted organized ethanol lick sequence behavior. The next essential step toward advancing this finding to a clinical application is to determine the specific time window that FSIs are recruited for the formation or maintenance of the motor sequences that underlie compulsive drinking. To this end I propose two aims of investigation using innovative optogenetic and machine learning approaches: 1) to determine if striatal FSIs are necessary for the development of the organized actions of compulsive ethanol consumption and; 2) to determine if striatal FSIs are necessary for the maintenance of organized actions underlying compulsive ethanol consumption. The results of this study will significantly advance our understanding of motor sequence learning, the role of motor sequences in compulsive behavior, and will indicate the necessary time window for future therapeutic interventions targeting compulsive drinking.