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

描述（由申请人提供）：哺乳动物的大脑由多种神经回路组成，这些神经回路必须在发育期间正确连接才能发挥正常功能。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性方面起着重要作用，特别是在出生后早期（Hooks & Chen 2007）。比较活动如何塑造不同回路类型的神经线路，为了解回路如何组织和最终发挥功能提供了有价值的见解。我们建议解剖突触活动如何影响基底神经节（BG）的布线，参与运动行为，记忆和习惯形成的前脑核团的集合。BG通过长距离抑制投射神经元将大脑网络化。这些投射被组织成一系列平行的通路，这些通路将神经信息分开和隔离（Romanelli et al 2005）。两个主要的分支，称为直接和间接途径，对BG输出产生相反的影响，并被认为平衡运行以实现正常功能（阿尔宾et al 1989）。这个提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。具体来说，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，突触活动如何促进平衡通路生理学的发展？我们将通过使用转基因小鼠进行实验来研究这些问题，这些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每个通路的MSN中。几种临床上重要的疾病由BG功能障碍引起。神经退行性疾病，如帕金森病和亨廷顿病，被认为与直接和间接途径的失衡有关（DeLong & Wichmann 2007; Romanelli et al 2005）。BG还在产生成瘾行为中具有已知作用（贝林et al 2009），并在认知障碍如精神分裂症中具有推测作用（Romanelli et al 2005）。确定电路功能的哪些方面在疾病状态下发生改变，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以组织电路。

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.