Regulation of basal ganglia output neurons

描述(申请人提供)：帕金森氏病(PD)是一种常见的神经系统疾病，主要损害基底节运动控制电路。它是由中脑多巴胺神经元的退化引起的，特别是黑质(SN)的神经元。SN有两个截然不同的组成部分：SN Pars Comacta(SNC)和SN Pars reNetata(SNR)。黑质-纹状体-多巴胺投射神经元在帕金森病中受到损害。SNR是基底神经节的关键输出核，其大部分神经元是含有3-氨基丁酸(GABA)的抑制性投射神经元，这些神经元发出的高频棘波在帕金森病中往往是异常的。过去的研究已经阐明了基底节生理学和帕金森病的病理生理学的许多重要方面。然而，许多关键问题仍然没有得到回答，许多重要的运动异常在帕金森病中不能以我们目前的知识得到充分的解释。美国国立卫生研究院的帕金森氏病研究议程指出，“一个鲜为人知的领域涉及纹状体外多巴胺丢失的后果”。这个应用程序正是专注于这些鲜为人知的领域。我们的假设和我们的高质量初步数据支持，从黑质多巴胺神经元树突释放的多巴胺可能直接作用于SNR 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-黑质环相比)可能为这个关键的基底节输出核提供了一种快速、直接的多巴胺控制。特别是，强直的多巴胺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规则的放电模式。多巴胺神经元变性后这种直接的多巴胺影响的丧失可能是帕金森病患者脑内SNR-GABA输出神经元活性异常和运动障碍的原因之一。我们设计了实验来检验我们的假设。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。转基因小鼠品系也将被用来帮助实验。这些项目所获得的新知识将促进我们对基底节运动控制回路和帕金森病的病理生理学的理解，并为治疗帕金森病等基底节起源的运动障碍提供潜在的途径。公共卫生相关性：帕金森氏病是一种常见的基底节运动控制神经元回路的神经性疾病。利用一系列先进技术，拟议的实验试图描绘出一条新的、重要的多巴胺途径，该途径直接影响关键的基底节输出核。这一结果将促进我们对帕金森病的病理生理学的理解，并为帕金森病等基底节起源的运动障碍的治疗干预提供一条潜在的途径。

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.