Functional organization of neural circuits underlying movement control

项目摘要/摘要 纹状体是基底节的主要输入区，整合感觉和运动。 大脑皮质和丘脑输入所传递的信息。该电路的完整性对于各种类型的 功能，包括运动、运动学习和动作选择。How电机的当前型号 命令是通过基底节回路处理的，这一理论建立在两个 互补通路(直接通路和间接通路)为信息的不同方面提供中介 通过特定突触连接的继电器控制运动。然而，人们对此几乎一无所知 在直接和间接途径MSN的发育过程中如何形成特定的突触连接。 同样不清楚的是，与解剖学相关的纹状体神经元是否形成了与 皮质柱，其中兴奋性皮质神经元的放射状克隆优先发展为特定的 突触连接。 基底节神经网络活动障碍导致过多的精神运动障碍， 包括帕金森氏症(PD)、亨廷顿病(HD)和毒瘾。其中最 正常纹状体功能不可或缺的神经调节剂是多巴胺(DA)，这表明 帕金森病黑质致密部(SNC)中的多巴胺能神经元，在那里运动指令启动 和执行力严重受损。 这项研究的长期目标是定义调节细胞功能的机制 神经回路中的特定突触连接及其潜在的分子和细胞机制 这就决定了突触在发育过程中形成的特殊性。 我目前是加州大学伯纳多·萨巴蒂尼博士实验室的博士后研究员 哈佛医学院神经生物学专业。该部门为我提供了一个很好的环境来进行 在这里提出的研究项目。 在本计划的指导阶段，我们尝试解决两个具体目标：1.确定 选择性激活多巴胺轴突后纹状体神经元兴奋性的调节。 2.多巴胺能对LTS-中间神经元介导的GABA能抑制的调制作用 纹状体MSN中的传入神经。尽管人们普遍认为DA通过D1受体兴奋 直接途径和通过D2受体抑制的间接途径，究竟多巴胺是如何 调节不同途径的纹状体功能仍是个谜。我们的目标是通过组合使用 电生理、成像、光遗传技术和各种遗传操作以识别 纹状体中特定突触连接的特性。 在独立阶段，我们的目标是实施我拥有的尖端技术 在指导阶段学习，以解决我们对发展的理解中的基本问题 以及形成作为自主运动控制基础的功能神经回路。要解决这些问题 问题，我们建议解决的具体目标：3：研究分子机制决定 纹状体内特定谷氨酸能突触连接的形成。4：为了刻画 纹状体基本功能模块的组织。拟议的研究将由同一机构进行 一套用于识别神经元的电生理、成像工具和病毒基因操作工具 无论是转基因BAC小鼠还是条件性KO小鼠。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特征应该 提供对调节突触形成的机制的基本理解以及 了解精细运动控制和动作选择的神经基础。 这里拟议的研究将提供培训经验，这些经验对于从 博士后至独立PI。有了这个拟议的培训计划，我不仅将在以下方面获得重要培训 开发实验所需的技术，但也开发成功运行实验室的管理技能 在一家大型研究机构工作。我一直并将继续与萨巴蒂尼博士就各个方面进行讨论 这些目标，并获得有关拨款撰写和寻找教员职位的建议。

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.