RHYTHMICITY AND SYNCHRONY IN THE PALLIDO/SUBTHALAMIC RECURRENT FEEDBACK LOOP

帕金森氏病(PD)，以运动功能障碍为代表，是 最常见的神经退行性疾病，由退行性变引起 投射到纹状体(Str)的多巴胺能细胞。在MPTP模型中 对于帕金森病来说，清醒猴子的录音已经证明了这种类型 震颤的频率与节律同步爆发活动(RSBA)相关 丘脑下部(STN)和苍白球(GP)。 我们的主要假设是STN之间的一个循环反馈环路 而GP在缺乏多巴胺的情况下产生RSBA。为了测试 在这个假说中，我们将考察四个主要观点。首先，什么是 本质上的形态和电生理特性 爆裂的GP和STN细胞？第二，全科医生对于这一代是必要的吗？ RSBA的？第三，电压门控钙通道的功能是什么？ GABAA受体在RSBA？第四，做多巴胺能输入 会影响STN-GP电路中RSBA的生成吗？我们将雇用四名员工 回答这些问题的不同方法。首先，在 GP的电生理和形态特征神经元 和STN，我们将研究STN和GP之间的RSBA 使用同时的细胞内和细胞外记录。第二， 我们将通过比较两种协议来研究GP对STN中RSBA的贡献 有或没有GP培养STN的培养系统 使用长期的器官类型培养。第三，钙通道的作用 在天生爆发的神经元中会产生RSBA 用全细胞路径钳和钙成像方法分析 GABA受体亚单位组成与STN-GP通路的作用 将用免疫细胞化学对RSBA的生成进行分析，在 原位杂交组织化学和RT-PCR。第四，我们将增加 CX-Str-GP-STN器官型培养黑质(SN)培养 为纹状体提供主要的多巴胺能输入。我们将分析 RSBA的变化作为多巴胺输入的函数通过操纵 系统敏锐且长期使用多巴胺受体拮抗剂 或6-羟基多巴胺(6-OHDA)引起的多巴胺耗竭。RSBA中的更改将 与单细胞反弹爆发率的变化相关 和/或伴随GABAA受体亚单位表达的变化。 该项目将提供基本的神经元框架关于 基底节律性同步神经元活动的产生 神经节与帕金森病患者的运动功能障碍有关。

Parkinson's disease (PD), typified by motor dysfunction, is one of the most common neurodegenerative disorders and arises from a degeneration of dopaminergic cells which project to the striatum (Str). In the MPTP model for PD, recordings from the awake monkey have demonstrated that this type of tremor is correlated with rhythmic synchronized burst activity (RSBA) in the subthalamic (STN) and the globus pallidus (GP). Our primary hypothesis is that a recurrent feedback loop between the STN and the GP generates the RSBA in the absence of dopamine. In order to test this hypothesis, we will examine four major points. First, what are the morphological and electrophysiological properties of intrinsically bursting GP and STN cells? Second, is the GP necessary for the generation of RSBA? Third, what is the function of voltage-gated calcium channels and GABAa receptors in the generation of RSBA? Fourth, do dopaminergic inputs affect the generation of RSBA in the STN-GP circuitry? We will employ four different methodological approaches to answer these questions. First, in electrophysiologically and morphologically characterized neurons from GP and STN, we will study the RSBA within and between the STN and the GP using simultaneous intra- and extracellular recording. Second, the contribution of the GP to RSBA in the STN will be studied by comparing two culture systems in which the STN is cultured either with or without the GP using long-term organotypic cultures. Third, the role of calcium channels in intrinsically bursting neurons in the generation of RSBA will be analyzed with whole cell path clamp and calcium imaging methods and the function of GABA receptor subunit compositions with the STN-GP circuitry in the generation of RSBA will be analyzed with immunocytochemistry, in situ hybridization histochemistry, and RT-PCR. Fourth, we will add to the Cx-Str-GP-STN organotypic culture a substantia nigra (SN) culture which provides for the main dopaminergic inputs to the striatum. We will analyze the changes in RSBA as a function of dopamine inputs by manipulating the system acutely and chronically using either dopamine receptor antagonists, or dopamine depletion by 6-hydroxydopamine (6-OHDA). Changes in RSBA will be correlated with changes in rebound burst activity of single cells and/or with changes in the expression of GABAa receptor subunits. This project will provide the basic neuronal frame work regarding the generation of rhythmically synchronized neuronal activity in the basal ganglia that has been related to motor dysfunction in PD.