Striatal Microcircuit Dynamics of Ethanol Habits

项目摘要 我们最近证明，背外侧纹状体快速发放中间神经元（FSI）是必要的， 强迫性饮酒，这是酒精使用障碍的主要特征。这项建议旨在 了解乙醇对这一关键的中间神经元群体在分子，神经回路， 行为水平，以推进针对强迫性饮酒的新的治疗策略。而慢性 间歇性乙醇暴露对FSI的兴奋性输入和FSI的内在兴奋性几乎没有影响， 显著下调FSI的抑制性突触控制-使FSI在没有调节的情况下激活 导致了病态的强迫性饮酒行为我们大量的初步数据表明， 其中乙醇急性增强GABA能输入FSI，并且在重复间歇暴露于 乙醇，GABA能输入通过细胞外基质的降解被稳态下调， 围绕着FSI，所谓的神经元周围网络，稳定对FSI的抑制输入。因此， 我假设这种GABA能输入到FSI的急剧损失是由神经元膜的降解介导的， 网。这将通过三个相互关联但完全独立的实验目标进行测试， 接近。目的1将研究控制急性乙醇增强的回路特异性突触机制 使用分子工具和全细胞膜片钳电生理学检测GABA能输入FSI。目标2将 确定GABA能输入FSI的命运，FSI被慢性间歇性乙醇下调，使用 一套先进细胞和分子成像技术。目的3将探讨急性心肌梗死的因果关系， 乙醇增强GABA能输入和神经元周围网络介导的这些输入的下调 在使用切片电生理学的强有力组合的慢性间歇性乙醇暴露之后， 神经元周围网络成像、体内化学遗传学和强迫性饮酒分析。这个多层次的， 正交实验方法使该项目能够产生新疗法的纵向进展 针对强迫性饮酒和洞察力的无数神经精神疾病，涉及背 纹状体功能障碍

Project Summary We recently demonstrated that dorsolateral striatum fast-spiking interneurons (FSIs) are necessary for compulsive alcohol drinking, which is a cardinal feature of alcohol use disorder. This proposal seeks to understand the impact of ethanol on this critical interneuron population at molecular, neural circuit, and behavioral levels to advance novel therapeutic strategies targeting compulsive alcohol use. While chronic intermittent ethanol exposure exerts little effect on excitatory inputs to FSIs and FSI intrinsic excitability, it dramatically downregulates inhibitory synaptic control of FSIs – positioning FSIs to activate without regulation to underlie pathological compulsive drinking behavior. Our substantial preliminary data points to a framework wherein ethanol acutely potentiates GABAergic input to FSIs and, following repeated intermittent exposure to ethanol, GABAergic inputs are homeostatically downregulated by a degradation of the extracellular matrix that surrounds FSIs, the so-called perineuronal nets that stabilize inhibitory input onto FSIs. Thus, we herein hypothesize that this dramatic loss of GABAergic input to FSIs is mediated by a degradation of perineuronal nets. This will be tested with three interrelated yet fully independent experimental aims using cutting-edge approaches. Aim 1 will examine circuit-specific synaptic mechanisms governing the acute ethanol potentiation of GABAergic input to FSIs using molecular tools and whole-cell patch clamp electrophysiology. Aim 2 will determine the fate of GABAergic inputs to FSIs that are downregulated by chronic intermittent ethanol using a suite of advance cellular and molecular imaging techniques. Aim 3 will explore the causal interaction of acute ethanol potentiation of GABAergic input and the perineuronal net-mediated downregulation of these inputs following chronic intermittent ethanol exposure using a powerful combination of slice electrophysiology, perineuronal net imaging, in vivo chemogenetics, and compulsive alcohol drinking analyses. This multilevel, orthogonal experimental approach positions this project to yield vertical advances toward novel therapeutics targeting compulsive alcohol consumption and insight to myriad neuropsychiatric disorders involving dorsal striatal dysfunction.