Regulation of Motor Function in Parkinson's Disease

项目摘要 本项目研究了纹状体神经元在慢性脑缺血过程中的功能变化。 帕金森病（Parkinson's disease，PD）的发病机制主要涉及神经递质信号转导.在PD中，DA调制的丢失在PD中是可能的。 纹状体导致纹状体投射神经元（SPN）功能的显著变化，然后发挥作用。 在运动症状中的关键病理生理作用。SPN的失调表现为大量的 包括主要形态和生理变化的数据。特别是，SPN明显过度活跃， 在动物模型和PD患者中，这种上调是由来自皮质的多巴胺能输入介导的， 丘脑然而，这些变化背后的机制尚未完全了解， 具体的NMDAR和AMPAR信令是未知的。在这里，我们将详细描述 并确定NMDAR和AMPAR亚基组分对病理信号传导的影响。 我们采用了一种新的方法，使用最近开发的技术，在灵长类动物的记录细胞识别 以及高选择性测试谷氨酸机制的新药理学工具。这个项目的最终目标 该项目旨在发现和验证新的治疗目标，以改善运动功能，并帮助患者 警局 该项目包括三个具体目标。在第一个目标中，我们将确定 在晚期PD的灵长类动物模型中使用光遗传学鉴定SPN亚型， 人类疾病的运动表型。在第二个目标中，我们将研究表达的调节 谷氨酸受体亚单位后，多巴胺损失在啮齿动物和灵长类动物，以确定潜在的参与 异常信号中的亚基。我们将使用啮齿动物模型进行体外生理学研究， 行为模式分析和亚基选择性抑制剂测试。在第三个目标中，我们将利用 对亚单位作用的广泛分析，以确定可能解释功能性SPN的机制， 灵长类动物的变化，并直接在纹状体中用所选抑制剂激发它们， 和行为效应。 该项目采用跨多个学科的不同实验方法来解决一个重要的健康问题， 问题，从使用新的病毒载体和药理学试剂，离体和体内评价 在啮齿动物和灵长类动物PD模型中鉴定神经元，以最终评估 患有帕金森病的灵长类动物这些翻译研究的数据将在该领域产生影响，推动我们的研究。 了解病理生理机制，并促进新的治疗策略的发展， 帕金森氏症。

Project Summary This project investigates the functional changes in striatal neurons that develop in the chronic course of Parkinson’s disease (PD) and largely involve the glutamatergic signaling. In PD, the loss of DA modulation in the striatum leads to significant changes in the function of striatal projection neurons (SPNs), which then play a key pathophysiological role in motor symptoms. The dysregulation of SPNs is evidenced by a significant amount of data including major morphological and physiological changes. In particular, SPNs are markedly hyperactive in animal models and patients with PD, and this upregulation is mediated by glutamatergic input from cortex and thalamus. However, the mechanisms underlying these changes are not fully understood, and the role of particular NMDAR and AMPAR signaling is not known. Here, we will profile thoroughly the SPN changes in advanced PD and determine the impact of NMDAR and AMPAR subunit components on pathological signaling. We take a novel approach using recently developed technologies for cellular identification in primate recordings and new pharmacological tools to test glutamate mechanisms with high selectivity. The ultimate goal of this project is to uncover and validate new therapeutic targets to improve motor functionality and help patients with PD. The project includes three specific aims. In the first aim, we will determine the abnormal activity pattern of identified SPN subtypes using optogenetics in the primate model of advanced PD that reproduces the full extent of the motor phenotype of the human disease. In the second aim, we will examine the regulation of expression of glutamate receptor subunits after dopamine loss in rodent and primates to determine the potential participation of subunits in the abnormal signaling. We will use rodent models for ex-vivo physiology with comprehensive analyses of behavioral paradigms and tests of subunit-selective inhibitors. In the third aim, we will take advantage of the extensive analysis of subunit roles to pinpoint the mechanisms that may account for functional SPN changes in the primate, and challenge them with the selected inhibitors directly in the striatum for physiologic and behavioral effects. This project employs diverse experimental approaches across multiple disciplines to address an important health problem, from the use of novel viral vectors and pharmacological agents, to the ex-vivo and in-vivo evaluation of identified neurons in rodent and primate PD models, to the final evaluations of pathophysiologic mechanisms in the parkinsonian primate. The data from these translational studies will be influential in the field, advance our understanding of pathophysiologic mechanisms, and catalyze the development of new therapeutic strategies in Parkinson’s disease.