Regulation of basal ganglia output neurons

描述（由申请人提供）：帕金森病（PD）是一种常见的神经系统疾病，主要损害基底神经节运动控制回路。它是由中脑多巴胺神经元，特别是黑质（SN）神经元的退化引起的。SN有两个不同的组成部分：SNc （SNc）和SNr （SNr）。SNc包含大部分在PD中受损的黑质纹状体多巴胺投射神经元。SNr是基底神经节的关键输出核，其大部分神经元是抑制性3-氨基丁酸（GABA）的投射神经元，这些神经元发射高频尖峰，这在PD中通常是异常的。过去的研究已经阐明了基底神经节生理和PD病理生理的许多重要方面。然而，许多关键问题仍未得到解答，PD中许多重要的运动异常无法用我们目前的知识充分解释。美国国立卫生研究院的帕金森氏症研究议程指出，“一个鲜为人知的领域涉及纹状体外多巴胺损失的后果”。这个应用程序精确地集中在这些知之甚少的领域。我们假设，我们的高质量的初步数据支持树突释放的多巴胺从黑质多巴胺神经元可能直接作用于信噪比GABA输出神经元。这种超短的SNc-SNr多巴胺通路（与长距离的黑质-纹状体-黑质回路相比）可能为这个关键的基底神经节输出核提供了快速、直接的多巴胺控制。特别是，强直性多巴胺D1/D5受体介导的直接兴奋可能有助于SNr - GABA输出神经元的去极化和正常的放电模式。多巴胺神经元变性后这种直接多巴胺影响的丧失可能导致帕金森脑和运动缺陷中SNr - GABA输出神经元活动异常。我们设计了实验来验证我们的假设。将使用多种最先进的方法，包括单细胞逆转录(RT)-PCR，定量电生理学，神经化学，神经药理学和免疫组织化学。转基因小鼠也将用于辅助实验。从这些项目中获得的新知识将促进我们对基底神经节运动控制回路和PD的病理生理学的理解，并为基底神经节起源的运动障碍（如PD）的治疗干预提供潜在的途径。公共卫生相关性：帕金森病是一种常见的基底神经节运动控制神经元回路的神经系统疾病。利用一系列先进的技术，提出的实验试图描绘一个新的，重要的多巴胺途径，直接影响一个关键的基底神经节输出核。该结果将促进我们对帕金森病病理生理学的理解，并为基底神经节起源的运动障碍（如帕金森病）的治疗干预提供潜在的途径。

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a common neurological disorder that primarily impairs the basal ganglia motor control circuit. It is caused by degeneration of midbrain dopamine neurons, particularly those in the substantia nigra (SN). The SN has two distinct components: SN pars compacta (SNc) and SN pars reticulata (SNr). The SNc contains the majority of nigrostriatal dopamine projection neurons that are compromised in PD. The SNr is a key output nucleus of the basal ganglia and the majority of its neurons are inhibitory 3-aminobutyric acid (GABA)-containing projection neurons that fire high frequency spikes that are often abnormal in PD. Past research has elucidated many important aspects of basal ganglia physiology and the pathophysiology of PD. However, many critical issues remain unanswered and many important motor abnormalities in PD can not be adequately explained with our current knowledge. NIH's Parkinson's Disease Research Agenda states that "One poorly understood area concerns the consequences of dopamine loss outside the striatum". This application focuses precisely on these poorly understood areas. We hypothesize and our high quality preliminary data support that dendritically released dopamine from nigral dopamine neurons may directly act on SNr GABA output neurons. This ultra-short SNc-SNr dopamine pathway (comparing with the long distance nigro-striato-nigral loop) may provide a fast, direct dopamine control over this key basal ganglia output nucleus. Particularly, a tonic dopamine D1/D5 receptor-mediated direct excitation may aid in SNr GABA output neuron depolarization and regular firing pattern. Loss of this direct dopamine influence after dopamine neuron degeneration may contribute to the abnormalities in SNr GABA output neuron activity in parkinsonian brain and motor deficits. We have designed experiments to test our hypotheses. Multiple state-of-the-art approaches will be used, including single cell reverse transcription (RT)-PCR, quantitative electrophysiology, neurochemistry, neuropharmacology, and immunohistochemistry. Genetically modified mouse lines will also be used to aid in the experiments. New knowledge gained from the proposed projects will advance our understanding of the basal ganglia motor control circuit and the pathophysiology of PD and provide a potential route for therapeutic intervention in movement disorders of basal ganglia origin such as PD. The Public Health Relevance: Parkinson's disease is a common neurological disorder of the basal ganglia motor control neuronal circuit. Using an array of advanced techniques, the proposed experiments seek to delineate a novel, important dopamine pathway that directly influences a key basal ganglia output nucleus. The results will advance our understanding of the pathophysiology of Parkinson's disease and provide a potential route for therapeutic intervention in movement disorders of basal ganglia origin such as Parkinson's disease.