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

项目总结 帕金森氏病(PD)患者经历进行性运动障碍，导致严重残疾。 帕金森病的运动障碍与基底节神经元活动异常有关，一组 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 基底节活动异常与帕金森病患者运动功能障碍的关系 治疗帕金森症的新疗法具有更好的特异性和更少的不良副作用。建议数 研究集中在苍白球外段(GPE)，这是基底节的关键结构 电路。传统上，GPE被认为是由单一的神经元类型组成的；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。 (“上游”至纹状体，或“下游”至丘脑底核或内侧苍白球)。在啮齿动物模型中 PD，有证据表明PD相关的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功能的限制 啮齿动物和灵长类GPE的解剖学差异。我们的实验将定义功能差异 正常恒河猴和治疗帕金森病猴的GPE神经元类型之间的差异 神经毒素1-甲基-4-苯基-1，2，3，6-四氢吡啶(MPTP)。猴子是一种很棒的动物 研究帕金森病相关脑活动变化的模型，因为它们的基底节和连接的大脑 结构与人类非常相似，因为MPTP治疗的猴子表现出大部分的 帕金森病患者的运动障碍。我们将使用电生理活体记录来评估 GPE上游和下游神经元的放电频率和模式的差异。的预测 单个GPE神经元将通过它们对目标的电刺激的反向反应来识别 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 在苍白球内部，我们将选择性地沉默每个核团中的GPE轴突终末，使用光遗传 方法：研究方法。我们还将确定选择性沉默GPE终末是否改变PD-运动损伤 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基因的蛋白质 GPE神经元投射模式(目标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，它们是如何调节正常和正常基底神经节其他神经元的活动的 帕金森氏症状态，以及它们是否参与了帕金森氏症的病理生理学。《知识》 从这些研究中获得的成果是重要的，因为它可能使我们能够开发出治疗帕金森病的新方法 GPE神经元类型的功能和解剖学差异。

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.