Rhythmicity and Synchrony in the Basal Ganglia

帕金森氏病（PD）大约每1000名成年人中就有1人患病，50岁后发病率呈指数级上升。人类和动物的研究表明，帕金森病的结果从中脑多巴胺能神经元的变性？在PD患者和灵长类PD模型中，苍白球（GP）和丘脑底核神经元的电活动 核（nucleus）异常。与正常动物的神经元不同，这些动物中的GP神经元和GBP神经元表现出同步的、有节奏的爆发放电。据推测，这种异常活动是PD运动症状的原因，这为以苍白球电解损伤或深部脑刺激的形式进行手术干预提供了依据。这是该计划提案的核心假设，即导致 PD的症状可归因于GP和P2P神经元的内在特性的适应以及多巴胺（DA）耗尽后它们的突触相互作用。 为了验证这一假设，该计划汇集了四个小组，在基底神经节功能的电生理分析方面具有良好的专业知识。前三个项目将使用分子，药理学和电生理学方法的组合来研究内在的离子和突触机制，这些机制控制着GP和P2P神经元的活动模式，以及这些机制如何被多巴胺调节。项目1（Surmeier）首先将产生 的分子和生物物理特性的电压依赖性和配体门控离子通道管理确定的啮齿动物GP的神经元放电，然后显示这些通道是如何调制多巴胺。一个组合！单细胞RT-PCR、电压钳和电流钳方法将用于急性分离的神经元和组织切片中的神经元。项目2（贝文）将提供一个类似的水平的分析确定啮齿类动物神经元使用一套共同的实验方法，除了解剖策略？项目3（Kita）将专注于多巴胺能突触输入如何调节GP神经元活动，以及这种输入的改变如何导致运动障碍。这些研究将利用啮齿动物和行为灵长类动物的药理学、解剖学和电生理学方法。项目4（威尔逊）将这些实验结果结合在一起，以建立正常和多巴胺依赖状态下GP/P2P电路的生物学基础计算模型。 这些计划目标的成功实现应该提供有关DA耗竭诱导的基底神经节神经元适应性的关键信息，这些适应性与PD的运动症状最直接相关-使神经科学界能够更好地为这种使人衰弱的疾病设计新的和更有效的药理学和遗传学治疗方法。

Parkinson's disease (PD) afflicts roughly 1 in 1000 adults, rising exponentially in incidence after the age of fifty. Human and animal studies have shown that parkinsonism results from the degeneration of the mesencephalic dopaminergic neurons ? In PD patients and in primate PD models, the electrical activity of neurons in globus pallidus (GP) and the subthalamic nucleus (STN) is abnormal. Unlike neurons from normal animals, GP and STN neurons in these animals exhibit synchronous, rhythmic burst discharges. It has been hypothesized that this abnormal activity is responsible for the motor symptoms in PD, providing a rationale for surgical intervention either in the form of pallidal electrolytic lesions or deep brain stimulation of the STN. It is the central hypothesis of this program proposal that the abnormal activity responsible for the symptoms of PD is attributable to adaptations in intrinsic properties of GP and STN neurons and their synaptic interaction following dopamine (DA) depletion. To test this hypothesis, the program brings together four groups with well-established expertise in the electrophysiological analysis of basal ganglia function. The first three projects will use a combination of molecular, pharmacological and electrophysiological approaches to study intrinsic ionic and synaptic mechanisms governing the activity patterns of GP and STN neurons and how these mechanisms are modulated by dopamine. Project 1 (Surmeier) first will generate a molecular and biophysical characterization of voltage-dependent and ligand-gated ion channels governing discharge in identified neurons of the rodent GP and then show how these channels are modulated by dopamine. A combination of !single cell RT-PCR, voltage-clamp and current clamp approaches will be used in acutely-isolated neurons and neurons in tissue slices. Project 2 (Bevan) will provide a similar level of analysis of identified rodent STN neurons using a common set of experimental approaches, in addition to anatomical strategies? Project 3 (Kita) will focus on how STN glutamatergic synaptic input regulates GP neuron activity and how alterations in this input might lead to dyskinesias. These studies will utilize pharmacological, anatomical and electrophysiological approaches in rodents and behaving primates. Project 4 (Wilson) brings these experimental results together to forge biologically grounded compuational model of the GP/STN circuit in normal and dopamine-depeleted states? The successful attainment of these program aims should provide critical information about DA-depletion induced adaptations in basal ganglia neurons most directly linked to the motor symptoms ofPD - placing the neuroscience community in a much better position to devise new and more effective pharmacological and genetic treatments for this debilitating disease.