Functional organization of neural circuits underlying movement control

运动控制背后的神经回路的功能组织

• 批准号: 8695503
• 负责人: Jun Ding
• 金额: $ 24.07万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8695503
• 关键词: Address; Axon; Basal Ganglia; Behavior; Biological Neural Networks; Brain; Cells; Corpus striatum structure; Cortical Column; Defect; Development; Dopamine; Dopamine D1 Receptor; Dopamine D2 Receptor; Electrophysiology (science); Environment; Equilibrium; Event; Faculty; Foundations; Functional disorder; Gene Expression; Glutamates; Goals; Grant; Huntington Disease; Image; Imaging Device; Institution; Interneurons; Intraventricular Injections; Knockout Mice; Label; Laboratories; Laser Scanning Microscopy; Lasers; Learning; Locomotion; Maintenance; Mediating; Mentors; Modeling; Molecular; Mothers; Motor; Movement; Mus; Neurobiology; Neurodegenerative Disorders; Neuromodulator; Neurons; Neurotransmitters; Obsessive-Compulsive Disorder; Parkinson Disease; Pathway interactions; Pattern; Phase; Population; Positioning Attribute; Postdoctoral Fellow; Process; Property; Proteins; Psychomotor Disorders; Radial; Research; Research Project Grants; Retroviridae; Role; Running; Sensory; Signal Transduction; Slice; Specificity; Substantia nigra structure; Synapses; Techniques; Thalamic structure; Therapeutic; Tissues; Training; Transgenic Mice; Transgenic Organisms; Viral Genes; Work; Writing; abstracting; addiction; cell type; dopaminergic neuron; experience; genetic manipulation; in utero; insight; medical schools; motor control; motor learning; nerve supply; neural circuit; neuronal excitability; neuropeptide Y; neurotransmitter release; optogenetics; pars compacta; recombinase; relating to nervous system; research study; skills; synaptic function; synaptogenesis; theories; tool; two-photon

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.

项目概要/摘要 纹状体是基底神经节的主要输入区，集感觉和运动于一体 由皮质和丘脑输入传递的信息。该电路的完整性对于各种 功能，包括运动、运动学习和动作选择。目前电机型号如何 命令是通过基底神经节电路处理的，该理论建立在两个 互补途径（直接和间接途径）介导信息的不同方面 通过特定突触连接的继电器进行电机控制。然而，人们对此几乎一无所知 在直接和间接通路 MSN 的发育过程中如何形成特定的突触连接。 还不清楚解剖学上相关的纹状体神经元是否形成像在 皮质柱，兴奋性皮质神经元的放射状克隆优先发展出特定的 突触连接。 基底神经节神经网络活动功能障碍导致大量精神运动障碍， 包括帕金森病 (PD)、亨廷顿病 (HD) 和成瘾。最有之一 正常纹状体功能不可缺少的神经调节剂是多巴胺 (DA)，如 PD 中黑质致密区 (SNc) 的多巴胺能神经元，运动指令启动的地方 和执行力严重受损。 这项研究的长期目标是确定调节功能的机制 神经回路中的特定突触连接及其潜在的分子和细胞机制 它控制着发育过程中突触形成的特异性。 我目前是伯纳多·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。该部门为我提供了良好的环境 此处提出的研究项目。 在该提案的指导阶段，我们尝试实现两个具体目标： 1. 描述 多巴胺轴突选择性激活后纹状体神经元神经元兴奋性的调节。 图2：表征多巴胺能对LTS-中间神经元介导的GABA能抑制的调节 纹状体 MSN 中的传入。尽管人们普遍认为DA通过D1受体发挥作用来激发 直接途径和通过D2受体抑制间接途径，多巴胺到底是如何作用的 调节纹状体功能的不同途径仍然是个谜。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基因操作来识别 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所拥有的尖端技术 在指导阶段学到的知识来解决我们对发展的理解中的基本问题 以及自愿运动控制的功能性神经回路的形成。为了解决这些 问题，我们建议解决具体目标：3：研究控制的分子机制 纹状体中特定谷氨酸能突触连接的形成。 4：表征 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 应用于已识别神经元的一套电生理学、成像工具和病毒基因操作工具 转基因 BAC 小鼠和条件 KO 小鼠。对这些的详细电生理分析 条件 KO 小鼠中的突触功能和随后的电路功能表征应该 提供对调节突触形成的机制的基本理解和框架 了解精细运动控制和动作选择的神经基质。 这里提出的研究将提供培训经验，这对于从 博士后到独立PI。通过这个拟议的培训计划，我不仅将获得以下方面的重要培训 开发实验所需的技术，以及成功运营实验室的管理技能 在一个主要的研究机构。我已经并将继续与萨巴蒂尼博士就各个方面进行讨论 了解这些目标，并获得有关资助金写作和寻找教职职位的建议。