RHYTHMICITY AND SYNCHRONY IN THE PALLIDO/SUBTHALAMIC RECURRENT FEEDBACK LOOP

以运动功能障碍为典型特征的帕金森病（PD）是帕金森病的一种。 最常见的神经退行性疾病，并产生于退化的 投射到纹状体（Str）的多巴胺能细胞。在MPTP模型中 对于PD，清醒猴子的记录表明，这种类型的PD 震颤的发生与节律性同步爆发活动（RSBA）相关 在丘脑底核（subthalamic，简称STH）和苍白球（globus pallidus，简称GP）。 我们的主要假设是，一个经常性的反馈回路之间的 GP在没有多巴胺的情况下产生RSBA。为了测试 这个假设，我们将研究四个主要点。首先， 固有神经元的形态学和电生理特性 GP细胞和胰岛细胞破裂其次，全科医生对于一代人来说是必要的吗 RSBA？第三，电压门控钙通道的功能是什么， GABAa受体在RSBA的产生？第四，多巴胺能输入 影响STN-GP电路中RSBA的生成？我们将雇用四名 不同的方法来回答这些问题。一是在 GP神经元的电生理和形态学特征 在第二次世界大战期间，我们将研究RSBA内部和与GP之间的RSBA 同时进行细胞内和细胞外记录。二是 将通过比较两种方法来研究GP对RSBA的贡献。 培养系统，在该培养系统中，在有或没有GP的情况下培养大肠杆菌 使用长期的器官型培养。三、钙通道的作用 在产生RSBA的内在爆发神经元中， 用全细胞通道钳夹和钙离子成像方法分析， GABA受体亚单位组成与STN-GP回路的功能 将用免疫细胞化学分析RSBA产生中的 原位杂交组织化学和RT-PCR。第四，我们将增加 Cx-Str-GP-B1器官型培养黑质（SN）培养物， 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 系统急性和慢性使用多巴胺受体拮抗剂， 或通过6-羟基多巴胺（6-OHDA）消耗多巴胺。RSBA的变化将 与单个细胞的反弹爆发活性的变化相关 和/或GABA α受体亚单位表达的变化。 这个项目将提供基本的神经元框架工作， 在基底节中产生节律同步的神经元活动 与PD运动功能障碍相关的神经节。

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.