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

描述(申请人提供)：该项目结合电生理学和建模方法，研究哺乳动物脊髓中协调节律性神经活动驱动运动的中央模式生成器(CPG)神经电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的扰动(包括运动神经元活动的缺失、脊髓损伤和药物操作)作为探针，以了解CPG的组织和功能。建议分析这些扰动对节律性运动模式和已识别脊髓活动的影响 中间神经元将为脊髓CPG的组织和操作提供重要的信息。这些数据将被用来开发脊髓运动CPG的全面计算模型，并对该模型进行改进和验证，以便它能够再现正常的运动活动和实验扰动的后果。反过来，该模型将作为一个计算框架来制定预测，以指导后续的实验研究。该项目汇集了两位在实验(康奈尔大学的Harris-Warrick博士)和计算(Drexel大学的Rybak博士)神经科学领域具有互补和重叠专业知识的资深科学家。它有三个相互关联的目标：1)探索运动神经元和神经元的行为变化和突触驱动 在自发性和诱发性屈肌和/或伸肌节律性运动活动缺失过程中对中间神经元进行基因定义，以确定这些中间神经元在运动CPG中的可能功能。2)探索脊髓降低CPG复杂性的后果 半切和移除脊髓节段，并比较被识别的中间神经元在缺失和药物阻断突触抑制后在被减少的脊髓中的行为。3)建立一个包括遗传识别中间神经元在内的形成新生小鼠脊髓运动CPG的神经回路的综合计算模型，并提出它们在运动模式产生中的作用。在模拟目标1和2中提出的实验扰动期间运动神经元和神经元间活动的特定变化以及整个运动模式的模拟中验证该模型。该模型将通过与实验研究的持续交互逐步发展，并将作为脊髓组织工作概念的试验床和后续实验验证的预测来源。 智力价值：这一提议代表着迈向机械论的重要一步 对构成脊髓中央皮质运动神经元的神经回路组织的认识 哺乳动物。拟议的实验和建模研究还将为有节奏的运动行为的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 为多个层次的学生开设的几门基础神经科学和神经工程课程， 本科生到研究生和医学本科生。本科生和研究生将 在这两个机构参与这个项目。在康奈尔大学，哈里斯-沃里克博士将邀请一位 该项目将支持两名女科学家，她们将在未来的科学职业生涯中得到认真的指导。 (2)加强研究和教育的基础设施：两个技术专长基本不重叠的实验室将合作了解运动的神经回路。这种合作将有助于两个实验室将计算和电生理学方法结合起来，研究神经回路。在Drexel开发的模拟包NSM 3.0和在该项目中开发的所有模型将在项目参与者之间共享，并通过在Drexel上专门开发的网站提供给其他研究小组。(3)医学影响：现在很明显，所有脊椎动物，包括人类，都有脊椎CPG来驱动和协调运动。这些CPG在上脊髓损伤后存活下来，原则上能够恢复受伤后的运动，就像在啮齿动物和猫身上证明的那样。更好地了解这类CPG的组织和功能将为未来恢复脊髓损伤后运动功能的临床策略提供必要的见解。

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.