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.

项目摘要/摘要 纹状体是基底神经节的主要输入区域，它整合了感官和电动机 由皮质和丘脑输入传达的信息。该电路的完整性对于多样性至关重要 功能，包括运动，运动学习和动作选择。电机的当前模型 命令是通过基底神经节电路来处理的 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控制电动机。但是，几乎一无所知 在直接和间接途径MSN的开发过程中，如何形成特定的突触连接。 还不清楚解剖学相关的纹状体神经元是否形成功能模块 皮质柱，其中兴奋性皮质神经元的径向克隆优先发展特定 突触连接。 基底神经神经网络活动的功能障碍导致过多的心理疾病， 包括帕金森氏病（PD），亨廷顿氏病（HD）和成瘾。最大的 正常纹状体功能必不可少的神经调节剂是多巴胺（DA） PD的底底尼格拉parc Commacta（SNC）的多巴胺能神经元，马力指挥启动 执行严重受损。 这项研究的长期目标是定义调节功能的机制 神经回路的特定突触连接以及基础分子和细胞机制 控制着在发展过程中突触形成的特异性。 我目前是Bernardo Sabatini博士实验室的博士后研究员 哈佛医学院神经生物学。该部为我提供了一个很好的环境 研究项目在这里提出。 在该提案的指导阶段，我们尝试解决两个具体目标：1。 多巴胺轴突选择性激活后，纹状体神经元中神经元兴奋性的调节。 2：表征LTS interneuron介导的GABA能抑制多巴胺能的调节 纹状体MSN中的传入。尽管普遍认为DA通过D1受体起作用以激发 直接途径并通过D2受体抑制间接途径，正是多巴胺如何 调节不同的途径纹状体功能仍然神秘。我们的目标是结合 电生理学，成像，光遗传技术和各种遗传操纵以识别 纹状体中特定突触连接的特性。 在独立阶段，我们旨在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 并形成了自愿运动控制基础的功能神经回路。解决这些 问题，我们建议解决特定目的：3：调查控制分子机制 纹状体中特定的谷氨酸能突触连通性的形成。 4：表征 纹状体中基本功能模块的组织。拟议的研究将由同一研究 用于鉴定神经元的电生理，成像工具和病毒基因操纵工具 在转基因BAC小鼠和有条件的KO小鼠中。这些的详细电生理分析 有条件的KO小鼠中电路函数的突触功能和随后的表征应 提供对调节突触形成的机制的基本理解和一个​​框架 了解精细运动控制和动作选择的神经基板。 拟议的研究将提供培训经验，这对于从 博士后到独立pi。有了这个拟议的培训计划，我不仅会获得重要的培训 开发实验所需的技术，也是运行成功实验室的管理技能 在一个主要的研究机构。我曾经并且将继续在各个方面与Sabatini博士讨论 在这些目标中，并获得有关赠款写作和寻找教师职位的建议。