CRCNS: Organization of the locomotor CPG in the rodent spinal cord

CRCNS：啮齿动物脊髓中运动 CPG 的组织

• 批准号: 8443579
• 负责人: Ronald M Harris-Warrick
• 金额: $ 34.52万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8443579
• 关键词: Affect; Automobile Driving; Behavior; Chest; Clinical; Collaborations; Computer Analysis; Computer Simulation; Cues; Data; Education; Excision; Experimental Models; Felis catus; Female; Flexor; Frequencies; Future; Generations; Genetic; Genetic Markers; Goals; Hindlimb; Human; Inhibitory Synapse; Injury; Institution; Instruction; Interneuron function; Interneurons; Investigation; Label; Laboratories; Left; Literature; Locomotion; Lumbar spinal cord structure; Mammals; Medical; Medical Students; Mentors; Methods; Modeling; Monitor; Motor; Motor Activity; Motor Neurons; Movement; Mus; Muscle; Neonatal; Neurons; Neurosciences; Participant; Pattern; Pattern Formation; Phase; Phase Transition; Research; Research Infrastructure; Rodent; Role; Science; Scientist; Senior Scientist; Series; Shapes; Side; Source; Spinal; Spinal Cord; Spinal Cord Lesions; Spinal cord injury; Students; Synapses; Technical Expertise; Techniques; Testing; Time; Underrepresented Minority; Universities; Validation; Vertebrates; Voltage-Clamp Technics; Work; base; career; central pattern generator; computer framework; computer studies; graduate student; insight; mouse model; multidisciplinary; neural circuit; neuroregulation; novel; operation; relating to nervous system; research study; response; restoration; simulation; synaptic inhibition; tool; undergraduate student; web site

DESCRIPTION (provided by applicant): This project combines electrophysiological and modeling approaches to study the organization and neuronal composition of the Central Pattern Generator (CPG) neural circuits in the mammalian spinal cord that coordinate rhythmic neural activity driving locomotion. This study will take a general approach that utilizes various spontaneous and evoked perturbations in the locomotor pattern (including deletions of motoneuron activity, spinal cord lesions and pharmacological manipulations) as probes to understand CPG organization and function. It is proposed that analysis of the influences of these perturbations on the rhythmic motor pattern and the activity of identified spinal interneurons will provide important insights on the spinal CPG organization and operation. These data will be used to develop a comprehensive computational model of the spinal locomotor CPG, and to refine and validate this model, so that it can reproduce both normal locomotor activity and the consequences of experimental perturbations. In turn, the model will serve as a computational framework to formulate predictions to guide subsequent experimental investigations. The project brings together two senior scientists with complementary and overlapping expertise in experimental (Dr. Harris-Warrick at Cornell University) and computational (Dr. Rybak at Drexel University) neuroscience. It has three interlocking objectives: 1) Explore alterations in behavior of, and synaptic drive to, motoneurons and genetically defined interneurons during spontaneous and evoked deletions in flexor and/or extensor rhythmic motor activity, to define the possible function of these interneurons in the locomotor CPG. 2) Explore the consequences of reducing CPG complexity by spinal cord hemisection and removal of spinal segments, and compare the behavior of identified interneurons in the reduced cord during deletions and after pharmacological blockade of synaptic inhibition. 3) Develop a comprehensive computational model of the neural circuits forming the locomotor CPG in the neonatal mouse spinal cord that includes genetically identified interneurons and suggests their roles in the generation of the locomotor pattern. Validate this model in simulations reproducing the specific transformations in motoneuron and interneuron activity and the entire locomotor pattern during experimental perturbations proposed in objectives 1 and 2.The model will be progressively developed by continuous interaction with the experimental studies, and will serve both as a testbed for working concepts on spinal cord organization and as a source of predictions for subsequent experimental validation. Intellectual Merit: This proposal represents an important step toward a mechanistic understanding of the organization of the neural circuits forming the spinal locomotor CPG in mammals. The proposed experimental and modeling studies will also provide novel insights into the general principles of neural control of rhythmic motor behaviors. Broader Impacts: (1) Integration of research and education: At Cornell and Drexel, this work will be included in several courses on basic neuroscience and neuroengineering for students at many levels, from undergraduate to graduate and medical students. Undergraduate and graduate students will participate in this project at both institutions. At Cornell, Dr. Harris-Warrick will invite an underrepresented minority student to work on this project each year, and the project will support two female scientists who will be given careful mentoring for a future career in science. (2) Enhance infrastructure for research and education: Two laboratories with mostly nonoverlapping technical expertise will collaborate to understand the neural circuitry for locomotion. This collaboration will help both laboratories to combine computational and electrophysiological approaches to the study of neural circuits. The simulation package NSM 3.0, developed at Drexel, and all models developed in this project will be shared between project participants and made available to other research groups via a specially developed website at Drexel. (3) Medical Impact: It is now clear that all vertebrates, including humans, have spinal CPGs that drive and coordinate locomotor movements. These CPGs survive upper spinal cord injuries, and are in principle capable of restoring locomotion after injury, as demonstrated in rodents and cats. Better understanding of the organization and function of such CPGs will provide essential insights into future clinical strategies for restoration of locomotor function after spinal cord injury.

描述（申请人提供）：本项目结合电生理学和建模方法，研究哺乳动物脊髓中协调有节奏的神经活动驱动运动的中枢模式发生器（CPG）神经回路的组织和神经元组成。本研究将采用一种通用的方法，利用运动模式中的各种自发和诱发扰动（包括运动神经元活动的缺失、脊髓病变和药物操作）作为探针来了解CPG的组织和功能。建议分析这些扰动对节律性运动模式和识别脊髓活动的影响