Striatal fast-spiking interneurons regulate compulsive alcohol consumption

项目摘要 酒精使用障碍对公共卫生有重大影响，但导致酒精滥用的大脑机制是 不太了解。习惯是重复的运动序列，尽管奖励贬值，但仍会持续存在，并形成 强迫行为背后的行动策略。慢性酒精暴露促进习惯学习， 慢性使用者的习惯性行为增加。背外侧纹状体（人类的壳核）调节 习惯学习和它的常驻抑制细胞，快速尖峰中间神经元（FSI），是酒精的目标 exposure.为了确定酒精是否利用FSI来促进强迫性饮酒，我选择性地消融了 自愿间歇性饮酒（在黑暗中饮酒）动物的纹状体FSI， 用掺杂的奎宁刺激动物，以测量强迫性消费。FSI消融取消 强迫性饮酒和显著破坏有组织的乙醇舔序列行为。下一 将这一发现推进到临床应用的重要步骤是确定特定的时间窗， 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学和机器学习方法进行研究的两个目标： 1)以确定纹状体FSI是否是强迫性乙醇的有组织行为的发展所必需的 消费和; 2）以确定是否纹状体FSI是必要的维持有组织的行动 潜在的强迫性酒精消费这项研究的结果将显着推进我们的 了解运动序列学习，运动序列在强迫行为中的作用，并将表明 未来针对强迫性饮酒的治疗干预措施的必要时间窗口。

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.