Striatal Microcircuits: Regulation and Function

描述(由申请人提供)：这是一份多重PI R01提案，旨在对纹状体进行协调研究，纹状体是一种与正常运动和动机密切相关的大脑结构。纹状体功能的改变是一系列严重、常见的神经疾病的基础，包括帕金森氏症和肌张力障碍。然而，这种结构通常处理信息的机制，以及这种机制如何出错，还没有被很好地理解。一种特殊的细胞类型，快速尖峰中间神经元(FSI)，是罕见的，但对其他纹状体神经元有不成比例的影响。在肌张力障碍的动物模型和人类多发性抽动症中已经观察到FSIS的丢失。在最近的研究中，我们观察到FSIS的激活是经过高度训练的，但不想要的选择需要被抑制，并且选择性地抑制FSIS会导致肌张力障碍样症状。因此，FSIS似乎在纹状体网络中起着关键的协调作用，迫切需要更好地了解它们的 生理和行为功能。拟议的脑片和清醒行为动物的补充实验充分利用了先进的电生理学、药理学和光遗传学方法。目的1研究大脑皮质、丘脑和苍白球的不同输入如何自发地和在选择任务绩效的关键时刻影响FSI放电模式。目的2研究FSIS控制两条主要输出通路的纹状体投射细胞的条件，以及FSI抑制如何影响网络动力学和行为。最后，Aim 3研究了多巴胺丢失对纹状体微回路的影响，检查了局部连接和放电模式的变化，这些变化可能是帕金森氏病核心运动困难的基础。该研究计划的长期目标是确定纹状体电路从亚细胞到网络级别的基本工作原理。这些知识将对设计帕金森氏症、肌张力障碍、抽动症和其他严重脑部疾病的改进疗法具有巨大价值。 与公共健康相关：这项提议旨在揭示特定大脑结构中的微电路如何有助于正常的行为控制，以及该结构的功能障碍如何导致异常行为。更好地了解这一回路将对设计改进帕金森氏病、肌张力障碍、抽动症和其他严重大脑疾病的治疗方法具有巨大价值。

DESCRIPTION (provided by applicant): This is a Multiple-PI R01 proposal for coordinated investigation of the striatum, a brain structure critically involved in normal movement and motivation. Altered striatal function underlies a range of serious, common neurological disorders, including Parkinson's Disease and dystonia. Yet the mechanisms by which this structure normally processes information, and how this can go awry, are not well understood. One particular cell type, the fast-spiking interneuron (FSI), is rare but has a disproportionate influence over other striatal neurons. Loss of FSIs has been observed in animal models of dystonia and in human Tourette syndrome. In recent studies we have observed activation of FSIs as highly trained yet unwanted choices need to be suppressed, and that selective suppression of FSIs results in dystonia-like symptoms. FSIs thus appear to have a key coordinating role within striatal networks, and there is a pressing need to better understand their physiological and behavioral functions. The proposed complementary experiments in brain slices and awake behaving animals make full use of advanced electrophysiological, pharmacological and optogenetic methods. Aim 1 examines how distinct inputs from cortex, thalamus, and globus pallidus influence FSI firing patterns, both spontaneously and at critical moments of choice task performance. Aim 2 examines the conditions under which FSIs control striatal projection cells of the two major output pathways, and how FSI suppression affects network dynamics and behavior. Finally, Aim 3 investigates the consequences of dopamine loss on striatal microcircuits, examining changes in local connectivity and firing patterns that may underlie core movement difficulties in Parkinson's Disease. The long-term goals of this research program are to determine the fundamental operational principles of striatal circuits from sub-cellular to network levels. This knowledge would be of immense value in designing improved therapies for Parkinson's Disease, dystonia, Tourette Syndrome and other serious brain disorders. PUBLIC HEALTH RELEVANCE: This proposal aims to reveal how microcircuitry within a specific brain structure contributes to normal behavioral control, and how dysfunction of this structure results in abnormal behavior. Greater understanding of this circuitry would be of immense value in designing improved therapies for Parkinson's Disease, dystonias, Tourette Syndrome and other serious brain disorders.