The Role of GABAergic Transmission in the Development of Basal Ganglia Pathways

描述(申请人提供)：哺乳动物的大脑由多种神经回路组成，这些回路在发育过程中必须正确连接，才能正常发挥功能。对感觉系统中兴奋性突触的研究表明，突触活动在微调电路连接方面发挥着重要作用，特别是在出生后早期(Hooks&Chen 2007)。比较活动如何塑造不同电路类型的神经连线，有助于我们深入了解电路是如何组织并最终发挥作用的。我们建议解剖突触活动如何影响基底节(BG)的连接，基底节是参与运动行为、记忆和习惯形成的前脑核团的集合。BG通过长距离抑制性投射神经元网络连接大脑。这些投射被组织成一系列平行的路径，分离和分离神经信息(Romanelli等人，2005年)。这两个主要的分裂被称为直接和间接途径，对BG的输出产生相反的影响，并被认为是在平衡中运行以实现正常功能(Albin等人，1989)。这项建议的目的是确定突触活动如何影响通路分离和平衡的发展。具体地说，我们将使用产生直接和间接途径的细胞作为我们的模型。使用这个系统，我们将解决两个问题。首先，突触活动如何影响MSN解剖连接的发展？第二，突触活动对平衡通路生理学的发展有何贡献？我们将通过使用转基因小鼠来实验地探索这些问题，转基因小鼠允许突触传递所必需或足够的基因被删除或选择性地引入到每条路径的MSN中。一些临床上重要的疾病是由血糖功能障碍引起的。神经退行性疾病，如帕金森氏症和亨廷顿病，被认为与直接和间接通路的失衡有关(DeLong&Wichmann，2007；Romanelli等，2005)。BG在产生成瘾行为方面也有已知的作用(Belin等人，2009年)，在诸如精神分裂症等认知障碍中也有推测作用(Romanelli等人，2005年)。确定在疾病状态下电路功能的哪些方面发生变化，关键取决于了解活动和遗传程序如何在发育过程中相互作用来组织电路。 与公共健康相关：基底神经节(BG)通过一系列平行的抑制通路连接大脑，这些通路对BG的输出和运动行为产生相反的影响。毁灭性的神经退行性疾病，如帕金森氏症和亨廷顿病，被认为是由这些通路的不平衡引起的。在这里，我们从基因上剖析了突触活动如何在发育过程中对途径组织做出贡献。

DESCRIPTION (provided by applicant): The mammalian brain consists of a diversity of neural circuits which must be wired correctly during development for normal function. Studies of excitatory synapses in sensory systems suggest that synaptic activity plays an important role in fine-tuning circuit connectivity, especially during the early post-natal period (Hooks & Chen 2007). Comparing how activity shapes neural wiring across circuit types provides valuable insight into how circuits are organized and ultimately function. We propose to dissect how synaptic activity influences the wiring of the Basal Ganglia (BG), a collection of forebrain nuclei involved in motor behavior, memory and habit formation. The BG network the brain through long-distance inhibitory projection neurons. These projections are organized into a series of parallel pathways that split and segregate neural information (Romanelli et al 2005). The two major splits, called the direct and indirect pathway, exert opposite effects on BG output and are thought to operate in balance to achieve normal function (Albin et al 1989). The goal of this proposal is to determine how synaptic activity influences the development of pathway segregation and balance. Specifically, we will use the cells that give rise to the direct and indirect pathway as our model. Using this system, we will address two questions. First, how does synaptic activity affect the development of MSN anatomical connections? Second, how does synaptic activity contribute to the development of balanced pathway physiology? We will pursue these questions experimentally by using transgenic mice that allow genes necessary or sufficient for synaptic transmission to be deleted or introduced selectively into MSNs of each pathway. Several clinically important disorders arise from BG dysfunction. Neurodegenerative diseases, like Parkinson's and Huntington's disease, are thought to be related to imbalances in the direct and indirect pathway specifically (DeLong & Wichmann 2007; Romanelli et al 2005). The BG also have a known role in generating addictive behavior (Belin et al 2009) and a speculative role in cognitive disorders such as Schizophrenia (Romanelli et al 2005). Establishing which aspects of circuit function are altered in disease states depends critically on understanding how activity and genetic programs interact to organize the circuit during development. PUBLIC HEALTH RELEVANCE: The Basal Ganglia (BG) network the brain through a series of parallel inhibitory pathways that exert opposite effects on BG output and motor behavior. Devastating neurodegenerative diseases like Parkinson's and Huntington's Disease are thought to arise from imbalances in these pathways. Here we genetically dissect how synaptic activity contributes to pathway organization during development.