The Primate External Globus Pallidus as a Critical Node in Normal and Parkinsonian Basal Ganglia Circuits

灵长类外苍白球作为正常和帕金森基底神经节回路的关键节​​点

• 批准号: 10213846
• 负责人: Adriana Galvan
• 金额: $ 39.05万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-28 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10213846
• 关键词: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Anatomy; Animal Model; Animals; Antiparkinson Agents; Autopsy; Basal Ganglia; Biochemical; Biochemical Markers; Brain; Cell Nucleus; Characteristics; Corpus striatum structure; Data; Descriptor; Electric Stimulation; Electrophysiology (science); Engineering; FOXP2 gene; Functional disorder; Future; Genetic; Globus Pallidus; Goals; Histological Techniques; Human; Individual; Knowledge; Label; Lead; Literature; Macaca mulatta; Measures; Methods; Modeling; Molecular; Monkeys; Motor; Movement; Neurons; Neurotoxins; Opsin; Parkinson Disease; Parkinsonian Disorders; Parvalbumins; Pathologic; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Physiological; Population; Presynaptic Terminals; Primates; Proteins; Research; Rodent; Rodent Model; Role; Severities; Specificity; Structure; Structure of subthalamic nucleus; Study models; Subgroup; Substantia nigra structure; Therapeutic; Tracer; Translating; base; brain abnormalities; disability; experience; experimental study; extracellular; improved; in vivo; motor deficit; motor impairment; nonhuman primate; novel; novel therapeutics; optogenetics; parkinsonian animal; parkinsonian non-human primate; promoter; protein expression; response; side effect; therapy development; tool; trait

PROJECT SUMMARY Patients with Parkinson’s disease (PD) experience progressive motor impairments that lead to severe disability. The motor impairments of PD are associated with abnormal neuronal activity in the basal ganglia, a group of brain structures involved in movement planning and execution. The long-term goal of our research is to elucidate how the abnormal activity of the basal ganglia relates to the motor deficits in PD, with the goal of developing novel therapies to treat parkinsonism with improved specificity and fewer unwanted side effects. The proposed studies are focused on the external segment of the globus pallidus (GPe), a key structure in the basal ganglia circuitry. Traditionally, the GPe was thought to be composed of a single neuron type; it is now established that this nucleus contains different types of neurons that can be classified based on their projection targets (‘upstream’ to the striatum, or ‘downstream’ to the subthalamic nucleus or internal pallidum). In rodent models of PD, there is evidence that PD-related abnormalities occur selectively in specific types of GPe neurons, raising the possibility that different GPe neuron populations might make distinct contributions to the normal and pathological roles of the GPe. However, the translational relevance of these findings is limited by functional and anatomical differences between the rodent and primate GPe. Our experiments will define functional differences between classes of GPe neurons in normal rhesus monkeys and in monkeys rendered parkinsonian by treatment with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Monkeys are an excellent animal model for studying PD-related changes in brain activity, because their basal ganglia and connected brain structures closely resemble those in humans, and because MPTP-treated monkeys show the majority of the motor impairments seen in PD patients. We will use electrophysiological in vivo recordings to evaluate differences in the firing rates and patterns of GPe-upstream and GPe-downstream neurons. The projections of individual GPe neurons will be identified by their antidromic responses to electrical stimulation of the target structures (aim 1). To determine how GPe neurons modulate the activity in the striatum, subthalamic nucleus or internal pallidum, we will selectively silence GPe axonal terminals in each of these nuclei, using optogenetic methods. We will also determine whether selective silencing of GPe terminals alters PD-motor impairments in monkeys (aim 2). Finally, we will use histologic techniques to identify proteins whose expression reveals specific GPe neuron projection patterns (aim 3). Our studies will begin to determine how the activities of primate GPe neuron subtypes differ, how they regulate the activity in other basal ganglia neurons in the normal and parkinsonian states, and whether they are involved in the pathophysiology of parkinsonism. The knowledge gained from these studies is significant, as it may enable us to develop new treatments for PD that harness functional and anatomical differences of GPe neuron types.

项目摘要 帕金森氏病（PD）患者经历了导致严重残疾的渐进运动障碍。 PD的运动障碍与Bassal神经节中的神经元活性异常有关，这是一组 涉及运动计划和执行的大脑结构。我们研究的长期目标是阐明 基底神经节的异常活性与电动机在PD中的定义如何，目的是开发 以改善特异性和较少不需要的副作用来治疗帕金森氏症的新型疗法。提议 研究的重点是Globus Pallidus（GPE）的外部段，这是基底神经节中的关键结构 电路。传统上，GPE被认为是由单个神经元组成的。现在确定 该核包含不同类型的神经元，可以根据其投影靶标进行分类 （“上游”到纹状体，或“下游”到丘脑下核us或内部粒子）。在啮齿动物模型中 PD，有证据表明与PD相关的异常有选择地发生在特定类型的GPE神经元中，并升高 不同的GPE神经元种群可能对正常和 GPE的病理作用。但是，这些发现的翻译相关性受功能的限制和 啮齿动物和灵长类动物GPE之间的解剖学差异。我们的实验将定义功能差异 在正常恒河猴和猴子中的GPE神经元之间的类别之间 与神经毒素1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）。猴子是一只出色的动物 用于研究与PD相关的大脑活动变化的模型，因为它们的基本神经节和连接的大脑 结构与人类密切相似，因为经MPTP处理的猴子显示了大多数 PD患者看到的运动障碍。我们将使用电生理记录来评估 GPE-UPSTREAM和GPE下游神经元的点火速率和模式的差异。项目的项目 单个GPE神经元将通过其对靶标的电刺激的抗体反应来识别 结构（目标1）。确定GPE神经元如何调节纹状体，丘脑下核或 内部pallidum，我们将使用光遗传学选择性地静音GPE GPE轴突末端 方法。我们还将确定GPE终端的选择性沉默是否改变了PD运动障碍 猴子（目标2）。最后，我们将使用组织学技术来鉴定其表达揭示特定的蛋白质 GPE神经元投影模式（AIM 3）。我们的研究将开始确定灵长类动物GPE的活动 神经元亚型不同，它们如何调节正常和 帕金森氏派国家，以及他们是否参与帕金森主义的病理生理学。知识 从这些研究中获得的意义很大，因为它可能使我们能够为PD开发新的治疗方法 GPE神经元类型的功能和解剖学差异。