Striatal Microcircuit Dynamics of Ethanol Habits

项目摘要 这项研究计划探讨了大脑中的习惯中心--背外侧纹状体是如何被解除抑制的 通过长期酒精暴露来培养习惯。了解这个过程是如何在分子， 神经回路和行为水平对于设计针对酗酒的新型治疗策略至关重要，因为 以及合并习惯性使用其他滥用物质。背外侧纹状体的输出 由抑制性快速尖峰中间神经元（FSI）群体控制。FSI的丰度相对较高， 与其他纹状体亚区相比，背外侧纹状体将这些细胞定位为关键 背外侧纹状体输出和习惯表达的调节剂。作为大脑中的少数神经元， 纹状体、FSI及其在慢性乙醇胁迫诱导的习惯形成中的作用还远远没有得到充分研究。这 一项提案旨在了解慢性乙醇暴露如何抑制FSI功能， 纹状体去抑制和习惯性动作表达。这将在三个具体的实验中进行研究。 目的是采用尖端技术，允许前所未有的观点到这些功能， 老鼠的神经元在第一个目标中，我们测试了慢性乙醇暴露抑制释放的假设。 抑制性神经递质GABA从FSI到突触后中棘神经元，这是输出 纹状体的神经元这将使用光遗传学结合脑切片来完成 电生理学在第二个目标，我们探讨FSI同步。FSI同步其活动，以增强 他们对背外侧纹状体输出的抑制能力。因此，我们将检验FSI是否 在慢性乙醇暴露后去酒精化。我们将使用切片电生理学和钙离子来测试这一点 在暴露于慢性酒精的清醒行为小鼠中的FSI活动的成像。最后，我们将测试贡献 抑制FSI释放GABA和FSI抑制饮酒和广义习惯学习， 小鼠通过研究乙醇如何劫持习惯形成的神经回路，这项研究的结果应该 显著推进了我们对针对酒精中毒的新治疗策略的认识， 对涉及纹状体功能障碍的无数神经精神疾病的新见解。

Project Summary The research proposal explores how a habit center in the brain, the dorsolateral striatum, is disinhibited by chronic alcohol exposure to foster habit formation. Understanding how this process works at molecular, neural circuit and behavioral levels is critical to devising novel therapeutic strategies targeting alcoholism, as well as comorbid habitual use of other substances of abuse. Dorsolateral striatum output is powerfully governed by the inhibitory fast-spiking interneuron (FSI) population. FSIs are in relatively high abundance in the dorsolateral striatum as compared to other striatal subregions, which positions these cells to be key modulators of dorslolateral striatum output and habit expression. As a minority population of neurons in the striatum, FSIs and their role in chronic ethanol exposure-induced habit formation is vastly understudied. This proposal seeks to understand how chronic ethanol exposure dampens FSI function to allow for dorsolateral striatum disinhibition and habitual action expression. This will be investigated in three specific experimental aims employing cutting-edge technology that allows for an unprecedented view into the function of these neurons in mice. In the first aim we test the hypothesis that chronic ethanol exposure depresses the release of the inhibitory neurotransmitter GABA from FSIs onto postsynaptic medium spiny neurons, which are the output neurons of the striatum. This will be accomplished using optogenetics coupled with brain slice electrophysiology. In the second aim we explore FSI synchrony. FSIs synchronize their activity to enhance their inhibitory authority over dorsolateral striatum output. Thus, we will test the hypothesis that FSIs desynchronize following chronic ethanol exposure. We will test this using slice electrophysiology and calcium imaging of FSI activity in awake behaving mice exposed to chronic alcohol. Finally, we will test the contribution of dampened FSI release of GABA and FSI asynchrony on alcohol drinking and generalized habit learning in mice. By examining how ethanol hijacks the neural circuitry of habit formation, the results of this study should significantly advance our knowledge toward novel therapeutic strategies targeting alcoholism and provide novel insight to myriad neuropsychiatric disorders involving striatal dysfunction.