Spinal cord neural circuits for left-right and flexor-extensor coordination

描述（申请人提供）：脊髓内的神经网络组织和驱动有节奏的运动，如步行和游泳。这些电路代表了控制运动活动节奏和模式的中枢模式发生器（CPG）。由于互补的遗传、分子和生理方法的最先进的结合，这些电路的组织最近开始被揭示。本项目的总体目标是解剖脊髓CPG的组织，重点是屈-伸交替和左右协调回路的组织。所有工作都将在转基因小鼠中通过遗传标记标记的可识别类别的脊髓中间神经元和/或通过解剖或电生理标记进行分类，以获得CPG组织的统一图像。我们建议确定功能连接体和CPG这些基本组成部分之间的相互作用。实验将结合电生理、成像和分子生物学技术，并辅以先进的计算机建模。参与该项目的三位pi在脊髓研究方面具有强大的背景和经验，在生理、遗传和分子方法（Martyn Goulding和Ole Kiehn）和计算建模（Ilya Rybak）方面具有独特的专业知识。该项目的具体目标包括：研究运动过程中负责左右协调的基因鉴定的脊髓中间神经元的活动模式和连通性（目的1），研究负责屈伸交替的基因鉴定的脊髓中间神经元及其连通性及其与提供左右协调的回路的相互作用（目的2），开发脊髓回路的综合计算模型（目的3）。基于最新的方法和三个领先实验室之间的密切合作，提出的多学科方法将调查和分析左右和屈伸协调神经元回路及其相互作用对运动模式的产生和控制的具体贡献，并为哺乳动物脊髓的神经组织提供重要见解。导致治疗脊髓损伤和退行性脊髓疾病的新策略。

DESCRIPTION (provided by applicant): Neuronal networks within the spinal cord organize and drive rhythmic movements like walking and swimming. These circuits represent the central pattern generator (CPG) that controls both the rhythm and the pattern of the locomotor activity. The organization of these circuits has recently begun to be revealed due to the state-of- art combination of complementary genetic, molecular and physiological methods. The overall goal of this project is to dissect the organization of the spinal CPG with focus on the organization of flexor-extensor alternating and left-right coordinating circuits. All work will be done on identifiable classes of spinal interneurons labeled by genetic markers in transgenic mice and/or classified by anatomic or electrophysiological labeling needed to obtain a unified picture of the CPG organization. We propose to identify the functional connectome and the interactions between these fundamental components of the CPG. The experiments performed will use a combination of electrophysiological, imaging, and molecular biology techniques complemented with advanced computer modeling. The three PIs involved in this project have strong background and experience in spinal cord studies and unique expertise in physiological, genetic and molecular methods (Martyn Goulding and Ole Kiehn) and computational modeling (Ilya Rybak). The Specific Aims of the project include: investigation of activity patterns and connectivity of the genetically identified spinal interneurons responsible for left-right coordinaton during locomotion (Aim 1), investigation of the genetically identified spinal interneurons and thei connectivity responsible for flexor-extensor alternation and their interactions with the circuits providing left-right coordination (Aim 2), development of a comprehensive computational model of spinal cord circuits (Aim 3). The proposed multidisciplinary approach based on the state-of-art methods and close collaboration between the three leading labs will investigate and analyze the specific contributions of left-right and flexor-extensor coordinating neuronal circuits and their interactions to the generation and control of the locomotor pattern and provide important insights into the neural organization of the mammalian spinal cord, leading to new strategies to treat spinal cord injury and degeneration spinal cord disorders.