Striatal Microcircuit Dynamics of Ethanol Habits

项目摘要 我们最近证实，背外侧纹状体快速放电中间神经元(FSIS)是 强迫性饮酒，这是酒精使用障碍的一个基本特征。这项建议旨在 了解乙醇在分子、神经回路和神经通路中对这一关键中间神经元群体的影响 行为水平，以推进针对强迫性酒精使用的新治疗策略。虽然慢性 间歇性酒精暴露对FSIS和FSI固有兴奋性的兴奋性输入几乎没有影响，它 显著下调FSIS的抑制性突触控制-定位FSIS激活而不受调控 是病态强迫性饮酒行为的基础。我们大量的初步数据指向一个框架 其中，乙醇能显著增强对FSIS的GABA能输入，并在反复间歇暴露于 乙醇、GABA能输入受到细胞外基质降解的稳态下调 围绕着FSIS，即所谓的神经周围网络，稳定抑制输入到FSIS。因此，我们在此 假设到FSIS的GABA能输入的这种戏剧性损失是由周围神经细胞的退化所介导的 篮网。这将通过三个相互关联但完全独立的实验目标进行测试，使用尖端技术 接近了。目标1将研究控制急性乙醇增强的电路特异性突触机制 使用分子工具和全细胞膜片钳电生理学技术将GABA能输入FSIS。目标2将 确定慢性间歇性乙醇下调FSIS的GABA能输入的命运 一套先进的细胞和分子成像技术。目标3将探索急性胰腺炎的因果相互作用 乙醇对GABA能传入的增强作用及神经周神经网络介导的这些传入的下调 在使用切片电生理学的强大组合进行慢性间歇性酒精暴露后， 神经周网络成像、体内化学遗传学和强迫性饮酒分析。这个多层次的， 正交实验方法将该项目定位为产生新疗法的纵向进展 针对强迫性饮酒和对无数涉及背部的神经精神障碍的洞察 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.