Functional organization of neural circuits underlying movement control

项目总结/摘要 纹状体是基底神经节的主要输入区，整合了感觉和运动 由皮层和丘脑输入的信息。这种电路的完整性对于各种 包括运动、运动学习和动作选择。当前的电动机模型 命令是通过基底神经节回路处理的，这一理论建立在两个 互补途径（直接和间接途径）介导不同方面的信息， 通过特定突触连接的中继进行运动控制。然而，事实上， 在直接和间接通路MSN的发育过程中，特定的突触连接是如何形成的。 同样不清楚的是，解剖学上相关的纹状体神经元是否形成了类似于图1中所见的功能模块。 皮质柱，其中兴奋性皮质神经元的放射状克隆优先发育特异性的 突触连接 基底神经节神经网络活动的功能障碍会导致大量的精神障碍， 包括帕金森病（PD）、亨廷顿病（HD）和成瘾。一个最 正常纹状体功能不可或缺的神经调质是多巴胺（DA）， PD患者黑质多巴胺能神经元（SNc），其中运动指令启动 和执行力都严重受损 这项研究的长期目标是确定调节神经元功能的机制。 神经回路中的特异性突触连接及其潜在的分子和细胞机制 在发育过程中控制突触形成的特异性。 我目前是博士后研究员博士贝尔纳多萨巴蒂尼实验室在系 神经生物学，哈佛医学院。这个部门为我提供了一个很好的环境， 这里提出的研究项目。 在本建议的指导阶段，我们试图解决两个具体目标：1。表征 多巴胺轴突选择性激活后纹状体神经元兴奋性的调节。 2：表征多巴胺能神经元对LTS-中间神经元介导的GABA能抑制的调制。 纹状体MSNs中的传入神经。虽然一般认为DA通过D1受体起作用， 直接途径和通过D2受体来抑制间接途径， 调节不同通路的纹状体功能仍然是个谜。我们的目标是通过结合使用 电生理学、成像、光遗传学技术和各种遗传操作来鉴定 纹状体中特定突触连接的特性。 在独立阶段，我们的目标是实现我所拥有的尖端技术， 在指导阶段学习，以解决我们对发展的理解中的基本问题 以及形成自主运动控制的功能性神经回路。解决这些 问题，我们提出解决具体目标：3：调查分子机制， 在纹状体中形成特异性突触连接。4：描述 纹状体中基本功能模块的组织。拟议的研究将由同样的 一套应用于已识别神经元的电生理学、成像工具和病毒基因操作工具 在转基因BAC小鼠和条件性KO小鼠中。详细的电生理分析， 条件性KO小鼠的突触功能和随后的电路功能表征应 提供调节突触形成的机制的基本理解和框架， 理解精细运动控制和动作选择的神经基质。 这里提议的研究将提供培训经验，这对于从 博士后独立PI。有了这个拟议的培训计划，我不仅将获得重要的培训， 开发实验所需的技术，但也有管理技能，运行一个成功的实验室 在一家大型研究机构工作。我已经并将继续与萨巴蒂尼博士讨论各个方面的问题 这些目标，并获得有关申请拨款和寻找教师职位的建议。

Project Summary/Abstract The striatum is the main input zone of the basal ganglia, which integrates the sensory and motor information conveyed by cortical and thalamic inputs. The integrity of this circuitry is critical for a variety of functions, including locomotion, motor learning and action selection. The current model of how motor command is processed through basal ganglia circuits has been built upon the theory that two complementary pathways (direct and indirect pathways) mediate different aspects of information for motor control through relays of specific synaptic connections. However, virtually nothing is known about how specific synaptic connections are formed during development in direct and indirect pathway MSNs. It is also unclear if anatomically related striatal neurons form functional modules like those seen in cortical columns, where radial clones of excitatory cortical neurons preferentially develop specific synaptic connections. Dysfunction of basal ganglia neural network activity leads to a plethora of psychomotor disorders, including Parkinson's disease (PD), Huntington's disease (HD), and addiction. One of the most indispensable neuromodulators for normal striatal function is dopamine (DA) as suggested by loss of dopaminergic neurons in substantia nigra parc compacta (SNc) in PD, where motor command initiation and execution are severely impaired. The long-term objectives of this study are to define mechanisms that regulate function of the specific synaptic connection in the neural circuit and the underlying molecular and cellular mechanism that governs the specificity of synapse formation during developement. I am currently a postdoctoral fellow at Dr. Bernardo Sabatini laboratory at Department of Neurobiology, Harvard Medical School. The department offers a great environment for me to conduct the research projects proposed here. During mentored phase of this proposal, we try to address two specific aims: 1. To characterize the modulation of neuronal excitability in striatal neurons following selective activation of dopamine axons. 2: To characterize the modulation of LTS-interneuron mediated GABAergic inhibition by dopaminergic afferents in striatal MSNs. Although it is generally accepted that DA acts through D1 receptors to excite the direct pathway and through D2 receptors to inhibit the indirect pathway, precisely how dopamine modulates the different pathway striatal function remains enigmatic. We aim to by using a combination of electrophysiological, imaging, optogenetic techniques and various genetic manipulations to identify properties of specific synaptic connections in the striatum. During the Independent phase, we aim to implement the cutting-edge techniques that I have learned during the mentored phase to tackle fundamental questions in our understanding of development and formation of functional neural circuits underlying voluntary movement control. To address these questions, we propose to address specific aims: 3: To investigate the molecular mechanism governing formation of specific glutamatergic synaptic connectivity in the striatum. 4: To characterize the organization of basic functional modules in the striatum. The proposed studies will be pursued by same set of electrophysiological, imaging tools and viral gene manipulation tools applied to identified neurons either in transgenic BAC mice and conditional KO mice. Detailed electrophysiological analyses of these synapse function and subsequent characterization of the circuit function in conditional KO mice should provide a basic understanding of mechanisms regulating synapse formation and a framework for understanding the neural substrate for fine motor control and action selection. The proposed studies here will provide training experience that will be critical for transition from postdoc to independent PI. With this proposed training plan, I will not only gain important training in developing techniques necessary for experiments, but also managerial skills for running a successful lab at a major research institution. I have been and will continue to discuss with Dr. Sabatini on every aspect of these goals and get advice on grant writing and finding a faculty position.