Organization and Function of Striatal Microcircuits in Health and Disease

项目摘要/摘要 基底节是一系列相互连接的脑核，通过 两个平行神经回路的协调，即促进运动的直接路径和间接路径 抑制运动的路径。这两条路径之间的不平衡被认为是 运动障碍，如帕金森氏症、亨廷顿氏症、抽动症和肌张力障碍。 我的长期目标是确定直接和间接途径调节的细胞机制，以更好地 了解在健康和疾病中运动控制的神经基础。纹状体中的神经元回路， 基底神经节的传入核在决定直接和间接通路方面尤为重要。 活动，但它们的组织原则仍然鲜为人知。这项提案的目标是确定 快速放电中间神经元在调节纹状体输出中的作用。在《目标1》中，我将用一本小说 FS中间神经元调节的电路水平和行为学分析的药理学方法 直接和间接途径的活性。因为中间神经元是电路功能的强大调节器， 与几种基底节疾病的病理密切相关，这种对它们的药物解剖 角色将为帕金森氏病和其他障碍提供新的见解，并可能导致新的 药物治疗。在目标2-3中，我将使用切片和体内相结合的光遗传学 电生理学挑战关于FS微电路组织的长期假设。长- 关于皮层和丘脑对FS中间神经元的输入的长期理论塑造了人们对 纹状体微电路的组织，但这些教条理论主要是基于其他 系统，还没有在纹状体直接测试。利用目标2中的光遗传学，我将直接测量 皮质和丘脑传入纹状体直接挑战旧观念的前馈抑制 前馈抑制在纹状体功能和疾病中的作用。在目标3中，我将从 苍白球(GPE)；尽管来自GPE的输入在十多年前就被解剖学识别，但 对这一计划的详细功能描述一直非常缺乏。新型神经细胞的鉴定 连接GPE和纹状体的回路可能会挑战长期以来关于信息的假设 在基底节进行加工。总而言之，所有这些实验都将促进我们对 神经回路是运动控制的基础，并可能识别疾病治疗的新靶点。

Project Summary/Abstract The basal ganglia are a series of inter-connected brain nuclei that control voluntary movement through the coordination of two parallel neural circuits, the 'direct pathway' that facilitates movement and the 'indirect pathway' that suppresses movement. Imbalances between these two pathways are hypothesized to underlie movement disorders such as Parkinson's disease, Huntington's disease, Tourette syndrome, and dystonia. My long-term goal is to identify cellular mechanisms of direct and indirect pathway regulation to better understand the neuronal basis of motor control in both health and disease. Neuronal circuits in the striatum, the input nucleus of the basal ganglia, are particularly important in determining direct and indirect pathway activity, but their organizing principles remain poorly understood. The objective of this proposal is to identify the role of fast-spiking (FS) interneurons in regulating striatal output. In Aim 1, I will use a novel pharmacological approach to perform circuit-level and behavioral analyses of FS interneuron regulation of direct and indirect pathway activity. Because interneurons are powerful regulators of circuit function and are intimately involved in the pathology of several basal ganglia disorders, this pharmacological dissection of their role will provide new insights into Parkinson's disease and other disorders and may lead to new pharmaceutical treatments. In Aim 2-3, I will use optogenetics combined with slice and in vivo electrophysiology to challenge long-standing hypotheses about the organization of FS microcircuits. Long- standing theories about inputs to FS interneurons from the cortex and thalamus have shaped thinking about the organization of striatal microcircuits, but these dogmatic theories are based largely on experiments in other systems and have not been directly tested in the striatum. Using optogenetics in Aim 2, I will directly measure feedforward inhibition recruited by cortical and thalamic inputs to the striatum to directly challenge old ideas about the role of feedforward inhibition in striatal function and disease. In Aim 3, I will turn to FS inputs from the globus pallidus (GPe); although inputs from the GPe were identified anatomically over ten years ago, a detailed functional characterization of this projection has been sorely lacking. The identification of novel neural circuits that connect the GPe and striatum could challenge long-standing assumptions about information processing in the basal ganglia. Together, all of these experiments will advance our understanding of the neural circuitry that underlies motor control and potentially identify new targets for disease therapy.