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。

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.