Synaptic Transmissions in the Basal Ganglia

描述(申请人提供)：帕金森病(PD)是第二种最常见的破坏性神经退行性疾病，影响高达25%的65岁以上的人。来自患者和帕金森病动物模型的数据表明，帕金森综合症的发生与基底节异常强烈和广泛同步的振荡活动(OS)的出现有关，这些振荡活动是在中脑多巴胺神经元变性后发展起来的。根据最近的研究，我们假设PD患者多巴胺耗竭的基底节中OS的异常发展严重依赖于苍白球外段(GPE)核中OS的异常发展，该核与基底节中的大多数其他核团有很强的神经元联系。这个项目的主要目的是揭示导致异常OS发生的GPE的功能和解剖连接的改变。具体地说，这项拨款的目的是揭示多巴胺耗竭如何改变1)GPE神经元的放电行为，2)皮质-纹状体-GPE通路中异常OS的传导性，以及3)放大异常OS的丘脑-GPE环路的特性，所有这些都将为设计实验治疗策略以减少PD患者的行为缺陷提供信息。这些研究结果将促进我们对病理条件下基底神经节功能组织的理解，并为未来的研究包括制定人类帕金森综合征的治疗策略提供明确的方向。

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is the second most common devastating neurodegenerative disorder affecting up to 25% of individuals over 65 years of age. Data from patients and animal models of PD have shown that the development of parkinsonisms is associated with the emergence of abnormally strong and widely synchronized oscillatory activity (OS) of the basal ganglia that developed after degeneration of midbrain dopamine containing neurons. Based on recent studies, we hypothesize that abnormal OS in the dopamine-depleted basal ganglia of PD patients is critically dependent on the development of abnormal OS in a nucleus called the external segment of the globus pallidus (GPe), which has strong neuronal connections with most of other nuclei in the basal ganglia. The main goal of this project is to reveal alterations of the functional and anatomical connectivity of GPe that underlie the generation of abnormal OS. Specifically, the aims of this grant are to reveal how dopamine depletion alters 1) the firing behavior of GPe neurons, 2) the conductivity of abnormal OS in the cortico-striato- GPe pathway, and 3) the properties of subthalamo-GPe loop that amplifies abnormal OS, all of which will provide information for designing experimental therapeutic strategies to reduce behavioral deficits in PD subjects. The results of the proposed studies will advance our understanding of the functional organization of the basal ganglia in pathological conditions and provide clear directions for future investigations including the formulation of treatment strategies of human parkinsonisms.