Striatal Microcircuit Dynamics of Ethanol Habits

项目摘要 这项研究计划探索大脑中的习惯中枢--背外侧纹状体--是如何被抑制的 通过长期饮酒养成习惯。了解这个过程是如何在分子水平上进行的， 神经回路和行为水平对于设计针对酒精中毒的新治疗策略至关重要，因为 以及共病习惯性使用其他滥用物质。背外侧纹状体输出很强 受抑制性快速放电中间神经元(FSI)群体的支配。FSIS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性表达的调节器。作为一个少数的神经元群体 纹状体、FSIS及其在慢性酒精暴露诱导的习惯形成中的作用被广泛地研究得很少。这 一项提案试图了解慢性酒精暴露如何抑制FSI功能，以允许背外侧 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 旨在采用尖端技术，以前所未有的视角了解这些 老鼠体内的神经元。在第一个目标中，我们检验了这样的假设，即长期接触乙醇会抑制脑组织中 从FSIS到突触后中棘神经元的抑制性神经递质GABA是 纹状体的神经元。这将使用光遗传学和脑切片相结合的方法来完成 电生理学。在第二个目标中，我们探索FSI同步。FSIS同步它们的活动以增强 它们对背外侧纹状体输出的抑制作用。因此，我们将检验FSIS的假设 慢性酒精暴露后的去同步化。我们将使用切片电生理和钙离子来测试这一点 慢性酒精暴露下清醒行为小鼠FSI活性的成像。最后，我们将测试贡献 饮酒和一般习惯学习抑制FSI释放GABA和FSI的异步性 老鼠。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是 极大地提高了我们针对酒精中毒的新治疗策略的知识，并提供 对涉及纹状体功能障碍的无数神经精神障碍的新见解。

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.