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

项目摘要 帕金森病（PD）患者会出现进行性运动障碍，导致严重残疾。 PD的运动障碍与基底神经节异常神经元活动有关，基底神经节是一组神经元活动异常的神经元。 参与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动如何与PD中的运动缺陷相关，目的是发展 具有改进的特异性和更少的不良副作用的治疗帕金森综合征的新疗法。拟议 研究集中在苍白球（GPe）的外部部分，这是基底神经节中的一个关键结构 电路传统上，GPe被认为是由单一神经元类型组成;现在已经确定， 这个核团包含不同类型的神经元，可以根据它们的投射目标进行分类 （纹状体的“上游”，或丘脑底核或内苍白球的“下游”）。在啮齿动物模型中， PD，有证据表明PD相关异常选择性地发生在特定类型的GPe神经元中， 不同的GPe神经元群体可能对正常和 GPe的病理作用。然而，这些发现的翻译相关性受到功能和 啮齿类动物和灵长类动物之间的解剖学差异。我们的实验将定义功能差异 正常恒河猴和因治疗而患帕金森病的猴子的GPe神经元类别之间的差异 与神经毒素1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）。猴子是一种极好的动物 研究PD相关的大脑活动变化的模型，因为他们的基底神经节和连接的大脑 结构与人类非常相似，因为MPTP治疗的猴子显示出大多数的 PD患者中出现的运动障碍。我们将使用体内电生理记录来评估 GPe上游和GPe下游神经元的放电率和模式的差异。的投影 单个GPe神经元将通过它们对靶的电刺激的逆向反应来识别 结构（目标1）。为了确定GPe神经元如何调节纹状体、丘脑底核或纹状体内的活动， 内部苍白球，我们将选择性沉默GPe轴突终末在每个这些核，使用光遗传学 方法.我们还将确定GPe末端的选择性沉默是否会改变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蛋白质，其表达揭示了特定的 GPe神经元投射模式（aim 3）。我们的研究将开始确定灵长类GPe的活动是如何 神经元亚型不同，它们如何调节正常和 帕金森状态，以及它们是否参与帕金森症的病理生理学。知识 从这些研究中获得的信息是重要的，因为它可能使我们能够开发新的PD治疗方法， GPe神经元类型的功能和解剖差异。

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.