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: 8881347
• 负责人: Ronald M Harris-Warrick
• 金额: $ 33.27万
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8881347
• 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; Universities; Validation; Vertebrates; Voltage-Clamp Technics; Work; base; career; central pattern generator; computer framework; computer studies; graduate student; insight; locomotor control; mouse model; multidisciplinary; neural circuit; neuroregulation; novel; operation; relating to nervous system; research study; response; restoration; simulation; synaptic inhibition; tool; undergraduate student; underrepresented minority 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（由申请人提供）：该项目结合了研究中央模式发生器（CPG）神经回路的组织和神经元组成的电生理学和建模方法，在哺乳动物的脊髓中，可以协调节奏神经活动驱动机车的节奏神经活动。这项研究将采用一种通用方法，该方法利用运动模式（包括运动神经元活动的缺失，脊髓病变和药理操纵）作为探针来了解CPG组织和功能。有人提出，分析这些扰动对节奏运动模式的影响和已识别的脊柱活性 中间神经元将提供有关脊柱CPG组织和操作的重要见解。这些数据将用于开发脊柱运动CPG的综合计算模型，并完善和验证该模型，以便它可以重现正常的运动活性和实验扰动的后果。反过来，该模型将作为一个计算框架，以制定预测以指导后续的实验研究。该项目汇集了两位高级科学家，具有实验性的补充和重叠专业知识（康奈尔大学的哈里斯·沃里克博士）和计算机（Drexel University的Rybak博士）神经科学。它具有三个互锁的目标：1）探索对运动神经元的行为和突触驱动器的变化 在屈肌和/或伸肌节奏运动活动中自发和诱发缺失期间的基因定义的中间神经元，以定义这些神经元在运动CPG中的可能功能。 2）探索通过脊髓降低CPG复杂性的后果 脊柱片段的半分和去除，并比较缺失期间绳索中鉴定出的中间神经元的行为，并在突触抑制的药理学阻断后进行了比较。 3）开发了一个全面的计算模型，该模型的神经回路形成新生小鼠脊髓中的运动CPG，其中包括遗传鉴定的中间神经元，并提出了它们在运动模式的生成中的作用。在模拟中验证该模型在目标1和2中提出的实验性扰动期间的运动神经元和间神经元活动的特定转换以及整个运动模式。该模型将通过与实验研究的持续相互作用而逐步开发，并且将作为脊髓组织的工作概念和预测的源进行验证的测试概念。 智力优点：该提议代表了迈向机械的重要一步 了解形成脊柱运动CPG的神经回路的组织 哺乳动物。提出的实验和建模研究还将为节奏运动行为神经控制的一般原理提供新的见解。更广泛的影响：（1）研究和教育的整合：在康奈尔和德雷克塞尔，这项工作将包括在 许多级别的学生的基本神经科学和神经工程的课程，从 毕业生和医学生的本科生。本科生和研究生将 在这两个机构都参加这个项目。在康奈尔（Cornell），哈里斯·沃里克（Harris Warrick）博士将邀请 每年代表不足的少数族裔学生从事该项目，该项目将为两位女科学家提供支持，他们将在科学领域的未来职业中进行仔细的指导。 （2）增强研究和教育的基础设施：两个具有非重叠技术专长的实验室将合作了解运动的神经电路。这种合作将有助于两个实验室将计算和电生理方法结合在一起，以研究神经回路的研究。在Drexel开发的仿真软件包NSM 3.0，该项目中开发的所有模型将在项目参与者之间共享，并通过Drexel的特殊开发的网站提供给其他研究小组。 （3）医疗影响：现在很明显，包括人类在内的所有脊椎动物都具有驱动和协调运动运动的脊髓CPG。这些CPG在上脊髓损伤上幸存下来，原则上能够在受伤后恢复运动，如啮齿动物和猫所示。更好地了解此类CPG的组织和功能将为脊髓损伤后恢复运动功能的未来临床策略提供基本见解。