Striatal Microcircuits: Regulation and Function

描述（由申请人提供）：这是一项多PI R01提案，用于协调研究纹状体，纹状体是一种与正常运动和动机密切相关的大脑结构。纹状体功能改变是一系列严重的常见神经系统疾病的基础，包括帕金森病和肌张力障碍。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，还没有得到很好的理解。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的影响不成比例。在肌张力障碍的动物模型和人类抽动秽语综合征中已经观察到FSI的丧失。在最近的研究中，我们已经观察到FSI的激活，因为需要抑制高度训练但不想要的选择，并且选择性抑制FSI会导致肌张力障碍样症状。因此，FSI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作用。 生理和行为功能。 脑切片和清醒动物的互补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探讨不同的输入从皮层，丘脑，苍白球的影响FSI放电模式，无论是自发的，并在关键时刻的选择任务的表现。目的2研究FSI控制两个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，目标3研究纹状体微电路多巴胺损失的后果，检查局部连接和放电模式的变化，可能是帕金森病核心运动困难的基础。 这项研究计划的长期目标是确定从亚细胞到网络水平的纹状体回路的基本操作原理。这些知识将在设计帕金森氏病、肌张力障碍、抽动秽语综合征和其他严重脑部疾病的改进疗法方面具有巨大价值。

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.