Rhythmicity and Synchrony in the Basal Ganglia

帕金森氏症(PD)大约每1000名成年人中就有1人受到困扰，50岁后发病率呈指数级上升。人类和动物的研究表明，帕金森病是由中脑多巴胺能神经元的变性引起的。帕金森病患者和灵长类帕金森病动物模型苍白球和丘脑底核神经元的电活动 核(STN)异常。与正常动物的神经元不同，这些动物的GP和STN神经元表现出同步的、有节奏的爆发放电。据推测，这种异常活动是帕金森病患者运动症状的原因，这为手术干预提供了理论基础，无论是苍白球电解损伤还是对STN的脑深部刺激。这项计划提案的中心假设是，异常活动应对 帕金森病的症状可归因于多巴胺(DA)耗竭后GP和STN神经元的内在特性及其突触相互作用的适应。 为了验证这一假设，该计划汇集了四个在基底节功能电生理分析方面具有成熟专业知识的小组。前三个项目将结合分子、药理学和电生理学方法来研究支配GP和STN神经元活动模式的内在离子和突触机制，以及这些机制是如何被多巴胺调制的。项目1(Surmeier)首先将生成 对支配啮齿动物GP神经元放电的电压依赖和配基门控离子通道的分子和生物物理特征进行了描述，并展示了这些通道是如何被多巴胺调制的。单细胞RT-PCR、电压钳和电流钳方法的组合将用于急性分离的神经元和组织切片中的神经元。项目2(Bevan)除了解剖学策略外，还将使用一套常见的实验方法对已识别的啮齿动物STN神经元进行类似水平的分析？项目3(KITA)将重点研究STN谷氨酸能突触输入如何调节GP神经元的活动，以及这一输入的变化如何导致运动障碍。这些研究将在啮齿动物和行为灵长类动物中利用药理学、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，建立了正常状态和多巴胺非脱除状态下GP/STN电路的生物接地计算模型。 这些计划目标的成功实现将提供与帕金森病运动症状最直接相关的基底节神经元中DA耗竭诱导的适应的关键信息-使神经科学界处于更好的地位，为这种令人衰弱的疾病设计新的、更有效的药物和基因治疗方法。

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.