Synaptic Transmissions in the Basal Ganglia

描述（由申请人提供）：帕金森病（PD）是第二常见的破坏性神经退行性疾病，影响高达25%的65岁以上个体。来自PD患者和动物模型的数据表明，帕金森病的发展与中脑含多巴胺神经元变性后基底节区异常强烈和广泛同步的振荡活动（OS）的出现有关。根据最近的研究，我们假设PD患者多巴胺缺失的基底神经节的异常OS严重依赖于白球外节核（GPe）异常OS的发展，该核与基底神经节中大多数其他核具有强的神经元连接。该项目的主要目标是揭示GPe的功能和解剖连通性的改变，这是异常OS产生的基础。具体来说，这项资助的目的是揭示多巴胺消耗如何改变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的丘脑下-GPe环路的特性，所有这些都将为设计实验治疗策略提供信息，以减少PD受试者的行为缺陷。这些研究结果将促进我们对病理状态下基底神经节功能组织的理解，并为未来的研究提供明确的方向，包括制定人类帕金森病的治疗策略。

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.