Organization and Function of Striatal Microcircuits in Health and Disease

描述：基底神经节是一系列相互连接的大脑核，通过协调两个平行的神经回路来控制随意运动，“直接通路”促进运动，“间接通路”抑制运动。这两种途径之间的不平衡被认为是帕金森病、亨廷顿病、图雷特综合症和肌张力障碍等运动障碍的基础。我的长期目标是确定直接和间接通路调节的细胞机制，以更好地了解健康和疾病中运动控制的神经元基础。纹状体（基底神经节的输入核）中的神经元回路在决定直接和间接通路活动方面尤为重要，但它们的组织原理仍然知之甚少。本研究的目的是确定快速尖峰（FS）中间神经元在调节纹状体输出中的作用。在Aim 1中，我将使用一种新的药理学方法对FS中间神经元对直接和间接通路活性的调节进行回路水平和行为分析。由于中间神经元是电路功能的强大调节器，并且与几种基底神经节疾病的病理密切相关，因此对其作用的药理学解剖将为帕金森病和其他疾病提供新的见解，并可能导致新的药物治疗。在Aim 2-3中，我将使用光遗传学结合切片和体内电生理学来挑战关于FS微电路组织的长期假设。长期以来，关于皮层和丘脑向FS中间神经元输入的理论已经形成了对纹状体微电路组织的思考，但这些教条理论主要基于其他系统的实验，尚未在纹状体中进行直接测试。在Aim 2中，我将使用光遗传学直接测量皮层和丘脑输入纹状体的前馈抑制，以直接挑战关于前馈抑制在纹状体功能和疾病中的作用的旧观点。在目标3中，我将转向来自苍白球（GPe）的FS输入；尽管十多年前从解剖学角度确定了GPe的输入，但严重缺乏该投影的详细功能特征。连接GPe和纹状体的新神经回路的识别可能会挑战长期以来关于基底神经节信息处理的假设。总之，所有这些实验将促进我们对运动控制基础的神经回路的理解，并有可能确定疾病治疗的新靶点。

DESCRIPTION: 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. PUBLIC HEALTH RELEVANCE: Movement disorders of the basal ganglia, including Parkinson's disease, Huntington's disease, dystonia, and Tourette syndrome, affect millions of Americans but their etiology remains poorly understood. This proposal seeks to advance our understanding of inhibitory neural circuits in the basal ganglia that regulate motor control and contribute to the pathology of these diseases. Elucidation of these understudied neural circuits could lead to the development of more specific targets for disease therapy.