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）中的多巴胺神经元的变性引起的。SN有两个不同的组成部分：SN pars reticulata（SNc）和SN pars reticulata（SNr）。SNc包含大多数在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，并且其大多数神经元是抑制性的含有3-氨基丁酸（GABA）的投射神经元，其发射在PD中通常异常的高频尖峰。过去的研究已经阐明了基底神经节生理学和PD的病理生理学的许多重要方面。然而，许多关键的问题仍然没有得到解答，许多重要的运动异常的PD不能充分解释与我们目前的知识。美国国立卫生研究院的帕金森病研究议程指出，“一个知之甚少的领域涉及纹状体外多巴胺损失的后果”。这个应用程序正好集中在这些知之甚少的领域。我们假设和我们的高质量的初步数据支持，从黑质多巴胺神经元的树突释放多巴胺可能直接作用于SNr GABA输出神经元。与长距离的黑质-纹状体-黑质环路相比，这种超短的SNc-SNr多巴胺通路可能提供了对这个关键的基底节输出核的快速、直接的多巴胺控制。特别是，紧张性多巴胺D1/D5受体介导的直接兴奋可能有助于SNr GABA输出神经元去极化和规则的放电模式。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病患者大脑中SNr GABA输出神经元活动异常和运动缺陷。我们设计了实验来测试我们的假设。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。转基因小鼠系也将用于辅助实验。从拟议的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。使用一系列先进的技术，拟议的实验试图描绘一个新的，重要的多巴胺通路，直接影响一个关键的基底神经节输出核。这些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.