Sensory and Supraspinal Control of Locomotion

描述（由申请人提供）：神经科学中一个根本性的重要问题是感觉反馈和脊髓上命令如何控制控制运动的脊髓运动程序。本研究将开始通过检查脊髓背侧兴奋性神经元的连接和功能来解决这个问题，主要关注表达核孤儿受体RORa的细胞。Goulding实验室的初步研究结果表明，这些感觉中间神经元从下行运动通路和皮肤感觉传入接受会聚输入。更重要的是，RORa中间神经元的丢失导致明显的运动缺陷，这表明这些细胞形成了一个重要的兴奋性中继，将感觉和下行通路连接到脊髓运动系统。在这项研究中，我们将使用RORa中间神经元来解决三个重要的问题，这些问题是理解感觉和下行控制通路如何与脊髓运动回路相互作用所必需的。第一个涉及识别RORa中间神经元的输入源，使用Goulding实验室开发的一种新的遗传跨突触追踪系统。这将导致更好地理解背角神经元如何整合感觉和下行命令（目标1）。第二个是识别脊髓中由RORa中间神经元支配的神经元，特别关注先前已被证明是运动回路的关键组成部分的神经元（目的2）。最后，RORa神经元和其他背侧中间神经元细胞类型在引发和塑造运动中发挥的作用将通过遗传操作进行分析，该遗传操作使用条件报告小鼠来消融和沉默神经元，或光遗传学地激活它们（目的3）。这项研究完成后，将是第一个全面分析感觉中间神经元对运动控制的贡献的研究。它将提供有关脊髓如何将触觉传感器刺激与来自大脑运动中心的下行信号整合以控制运动运动的见解。从这些研究中获得的信息将有助于脊髓损伤后功能恢复的新治疗方法的产生。它还将为控制运动和运动的下行命令通路提供新的见解，其功能在帕金森病等运动障碍中受到损害。

DESCRIPTION (provided by applicant): A fundamentally important question in neuroscience is how sensory feedback and supraspinal commands control the spinal motor programs that control movement. This study will begin to address this issue by examining the connectivity and function of excitatory neurons in the dorsal spinal cord, focusing primarily on cells that express the nuclear orphan receptor RORa. Preliminary findings from the Goulding lab indicate that these sensory interneurons receive convergent inputs from descending motor pathways and from cutaneous sensory afferents. More importantly, loss of the RORa interneurons results in a pronounced motor defect, suggesting these cells form an important excitatory relay that connects sensory and descending pathways to the spinal motor system. In this study, we will use the RORa interneurons to address three important questions that are required to understand how sensory and descending control pathways interface with the spinal motor circuitry. The first involves identifying the source of inputs to the RORa interneurons, using a new genetic transsynaptic tracing system that was developed in the Goulding lab. This will lead to a better understanding of how neurons in the dorsal horn integrate sensory and descending commands (Aim 1). The second is to identify the neurons in the spinal cord that are innervated by RORa interneurons, with a particular focus on neurons that have previously been demonstrated to be key components of the locomotor circuitry (Aim 2). Finally, the role that RORa neurons and other dorsal interneuron cell types play in eliciting and shaping movement will be analyzed by genetic manipulations that use conditional reporter mice to either ablate and silence neurons, or activate them optogenetically (Aim 3). This study, when completed, will be the first to comprehensively analyze the contribution that a population of sensory interneurons makes to motor control. It will provide insights into how the spinal cord integrates tactile sensor stimuli with descending signals from motor centers in the brain to control locomotor movements. The information gained from these studies will aid the generation of new therapeutic approaches for functional recovery following spinal cord injury. It will also provide novel insight into the descending command pathways that control movement and locomotion, whose functioning is compromised in motor disorders such as Parkinson's Disease.