Coordination of Structure and Function in Corticospinal and Corticostriatal Pathways

皮质脊髓和皮质纹状体通路结构和功能的协调

• 批准号: 10619115
• 负责人: ANDERS NELSON
• 金额: $ 24.91万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10619115
• 关键词: Address; Anatomy; Axon; Basal Ganglia; Basic Science; Behavioral; Brain; Calcium; Clinical; Code; Collaborations; Corpus striatum structure; Disease; Dopamine Receptor; Dystonia; Electrophysiology (science); Ensure; Foundations; Ganglia; Image; Interneurons; Intuition; Knowledge; Logic; Maps; Measures; Mediating; Mentorship; Mind; Motor; Motor Cortex; Motor output; Movement; Movement Disorders; Muscle Contraction; Nervous System; Neurons; Neurosciences; Output; Parkinson Disease; Pathway interactions; Phase; Population; Property; Proteins; Research; Research Personnel; Role; Shapes; Signal Transduction; Spinal; Spinal Cord; Structure; Supervision; Synapses; System; Techniques; Technology; Testing; Training; Universities; Vertebral column; Vertebrates; Work; brain behavior; brain dysfunction; career; cell type; cellular targeting; cohesion; experimental study; imaging modality; innovative technologies; motor control; nerve supply; optogenetics; post-doctoral training; presynaptic; programs; rabies viral tracing; recruit; success; tool; two-photon

How the brain and spinal cord transform neuronal activity into coordinated movement is a central question in neuroscience. Corticospinal neurons, the principle output of motor cortex, project to the spinal cord, where they shape motor output by synapsing on a diversity of spinal interneurons. Corticospinal neurons also send axon collaterals to the striatum, where they synapse on two populations of neurons with opponent roles in motor control. Intuitively, cortical projections the spinal cord and the striatum should be coordinated in the cell types they target, in order to direct coherent motor output. Experimentally addressing this possibility been restricted by an inability to map, measure, and manipulate interconnected circuits defined by their synaptic targets. Our narrow understanding of how these motor control circuits are coordinated has undoubtedly limited clinicians’ ability to treat movement disorders that originate in brain dysfunction, particularly Parkinson’s disease and dystonia. In this proposal, I will use recently developed technologies to uncover the anatomical and functional organization of cortical outputs to the basal ganglia and the spinal cord, and how these circuits are coordinated during movement. This proposal is organized in three Aims split across a K99 training phase and an R00 independent phase. In the first Aim, I will combine anatomical and electrophysiological tools to map the organization of synapses made by corticospinal neurons in both the spinal cord and the striatum. Experiments in this Aim will uncover a circuit through which these motor control structures are coordinated. In Aim 2, I will use two-photon imaging methods to define the logic by which corticospinal neurons, and their cellular targets in basal ganglia, encode salient features of movement. Finally, in Aim 3, I will combine anatomical, electrophysiological, and behavioral tools to determine how corticospinal neurons with collaterals in the striatum influence circuits in the spinal cord to shape motor output. Critically, experiments in all three Aims will capitalize on innovative technology developed and mastered at Columbia University, as well as interactions with expert collaborators. This work will be conducted in the newly developed and thriving Zuckerman Mind Brain Behavior Institute under the supervision of Drs. Rui Costa and Mark Churchland. Their technical and professional mentorship, along with that of expert collaborators in the Institute, will ensure I am fully equipped to lead a successful research program as an independent investigator. The experiments outlined in this proposal will become the foundation for my research program as an independent investigator and will have profound basic science and clinical implications for our understanding of motor control.

大脑和脊髓如何将神经元活性转化为协调运动是神经科学中的一个核心问题。皮质脊髓神经元是运动皮层的主要输出，投影到脊髓，在那里它们通过在多样的脊髓中间神经元上突触来塑造运动输出。皮质脊髓神经元还将轴突calter骨发送到纹状体，在那里它们在运动控制中具有可选作用的两个神经元中突触。从直觉上讲，皮质项目脊髓和纹状体应在其靶向细胞类型中进行协调，以指导连贯的运动输出。在实验上解决这种可能性的限制受到无法映射，测量和操纵由其突触目标定义的相互联系的电路。我们对这些运动控制电路如何进行协调的狭narth毫无疑问，毫无疑问，临床医生能够治疗起源于脑功能障碍的运动障碍，尤其是帕金森氏病和肌张力障碍。在该建议中，我将使用最近开发的技术来揭示基本神经节和脊髓的皮质输出的解剖和功能组织，以及在运动过程中如何协调这些电路。该提案以在K99训练阶段和R00独立阶段分裂的三个目标组织。在第一个目标中，我将结合解剖学和电生理工具，以绘制脊髓和纹状体中皮质脊髓神经元的突触组织。在此目标中的实验将发现这些电机控制结构协调的电路。在AIM 2中，我将使用两光子成像方法来定义皮质脊髓神经元及其在基底神经节中的细胞靶标的逻辑，并编码运动的显着特征。最后，在AIM 3中，我将结合解剖学，电生理和行为工具，以确定纹状体中与colter骨的皮层神经元如何影响脊髓中的电路以塑造运动输出。至关重要的是，所有三个目标的实验都将利用在哥伦比亚大学开发和掌握的创新技术，以及与专家合作者的互动。这项工作将在Drs的监督下在新开发和蓬勃发展的Zuckerman Mind Brain行为研究所进行。 Rui Costa和Mark Churchland。他们的技术和专业思想以及研究所的专家合作者的心态将确保我有能力领导成功的研究计划。该提案中概述的实验将成为我作为独立研究者研究计划的基础，并将对我们对运动控制的理解具有深远的基础科学和临床意义。