Sensory cortical control of movement in health and disease

脊髓包含负责执行各种运动任务的神经网络，这些运动任务涉及 移动。这些脊髓网络接受来自大脑和脑干的下行命令。脊髓 损伤(SCI)破坏了大脑和脊髓运动网络之间的连接，导致 严重丧失对运动的控制。尽管迫切需要找到恢复脊髓损伤后运动功能的方法， 治疗选择仍然有限。我们最近证实，初级躯体感觉皮质(SI)可以 通过颈椎兴奋直接控制腰髓运动中枢模式发生器 中间神经元(SI运动通路)，独立于运动皮质。基于范式转换的发现 感觉皮质可以直接调节脊髓运动网络，这一提议旨在定义 这种感觉皮质控制运动的机制，并利用这一途径恢复脊髓损伤后的行走。 首先，在目标1中，使用头戴式微型显微镜，我们将使用特定于电路的单细胞分辨率 自由活动小鼠SI颈锥体神经元的钙显象。这一战略将使我们能够识别和 破译与运动起始和速度相关的神经元活动模式。此外，使用 电路特异性光遗传学方法，我们将确定该通路的直接和特异性刺激是否 足以在健康和脊髓损伤后启动运动。目标2将确定这条通路的解剖连通性 使用横断面病毒示踪实验和SI-颈椎锥体综合标测的完整性 轴突侧支。在目标3中，确定该通路在运动功能恢复中的治疗潜力 对于脊髓损伤，我们将采用急性光遗传和化学遗传策略。总体而言，理解 SI-运动通路的功能意义及其解剖连通性和完整性 后SCI将增进我们对这一新发现的电路的了解，并促进 运动受损的脊髓损伤和其他神经疾病后恢复运动的策略。

The spinal cord houses the neuronal networks responsible for executing various motor tasks involved in locomotion. These spinal networks receive descending commands from the brain and brain stem. Spinal cord injury (SCI) disrupts the connectivity between the brain and the spinal cord locomotor networks, leading to a significant loss of motor control. Despite a dire need to develop ways to restore motor function after SCI, treatment options remain limited. We recently demonstrated that the primary somatosensory cortex (SI) could directly control the locomotor central pattern generator in the lumbar spinal cord via cervical excitatory interneurons (SI locomotor pathway), independent of the motor cortex. Based on the paradigm-shifting discovery that the sensory cortex can directly modulate spinal locomotor networks, this proposal aims to define the mechanism of this sensory cortical control of locomotion and harness this pathway to restore walking after SCI. First, in Aim 1, using a head-mounted miniature microscope, we will use circuit-specific single-cell resolution calcium imaging of SI-cervical pyramidal neurons in freely moving mice. This strategy will allow us to identify and decipher the neuronal activity patterns correlated to the initiation and speed of locomotion. Moreover, using a circuit-specific optogenetic approach, we will determine if direct and specific stimulation of this pathway is sufficient to initiate movement in health and after SCI. Aim 2 will determine this pathway's anatomical connectivity and integrity using intersectional viral tracing experiments and comprehensive mapping of SI-cervical pyramidal axon collaterals. In Aim 3, to determine the therapeutic potential of this pathway for locomotor recovery after spinal cord injury, we will employ acute optogenetic and chemogenetic strategies. Overall, understanding the functional significance of the SI-locomotor pathway and delineating the anatomical connectivity and integrity post-SCI will enhance our knowledge of this newly discovered circuitry and facilitate the development of strategies to restore movement after SCI and other neurological conditions with impaired movement.