Striatal Microcircuits: Regulation and Function

描述（由申请人提供）：这是一份关于纹状体协调研究的多重pi R01提案，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，以及它是如何出错的，还没有得到很好的理解。有一种特殊的细胞类型，快速脉冲中间神经元（FSI），很少见，但对其他纹状体神经元有不成比例的影响。在肌张力障碍动物模型和人类图雷特综合征中观察到FSIs的丧失。在最近的研究中，我们观察到fsi的激活是高度训练的，但不需要的选择需要被抑制，选择性抑制fsi导致肌张力障碍样症状。因此，fsi似乎在纹状体网络中具有关键的协调作用，并且迫切需要更好地了解它们

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.