Regulation of Motor Function in Parkinson's Disease

项目摘要 本项目研究在慢性脑缺血过程中发育的纹状体神经元的功能变化。 帕金森病(PD)与谷氨酸能信号转导密切相关。在PD中，DA调制的损失 纹状体导致纹状体投射神经元(SPN)功能的显著变化，然后起到 在运动症状中的关键病理生理学作用。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。 在帕金森病动物模型和患者中，这种上调是由皮质和 丘脑。然而，这些变化背后的机制还没有完全了解，以及 具体的NMDAR和AMPAR信令尚不清楚。在这里，我们将详细介绍SPN在 并确定NMDAR和AMPAR亚单位成分对病理信号转导的影响。 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中进行细胞识别 和新的药理工具，以测试高选择性的谷氨酸机制。这样做的最终目的是 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 警察。 该项目包括三个具体目标。在第一个目标中，我们将确定异常活动模式 在复制全面性帕金森病的灵长类动物模型中利用光遗传学确定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 啮齿动物和灵长类动物多巴胺丢失后谷氨酸受体亚单位的变化以确定其潜在的参与 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， 行为范式分析和亚基选择性抑制剂的测试。在第三个目标中，我们将利用 对亚基作用的广泛分析，以确定可能解释功能性SPN的机制 灵长类动物的变化，并用选定的抑制物直接在纹状体进行生理学挑战 和行为影响。 该项目采用了跨越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到体外和体内评估 在啮齿动物和灵长类帕金森病模型中识别神经元，以最终评估 帕金森症灵长类动物。来自这些翻译研究的数据将在该领域产生影响，推动我们的 了解疾病的病理生理机制，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.