Sensory cortical control of movement in health and disease

健康和疾病中运动的感觉皮层控制

• 批准号: 10733821
• 负责人: Kajana Satkunendrarajah
• 金额: $ 31.5万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-15 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733821
• 关键词: Acute; Anatomy; Axon; Brain; Brain Stem; Calcium; Cells; Cervical; Development; Disease; Electrophysiology (science); Genetic; Head; Health; Image; Interneurons; Knowledge; Locomotion; Locomotor Recovery; Lumbar spinal cord structure; Maps; Methods; Microscope; Motor; Motor Cortex; Movement; Mus; Neurologic; Neurons; Pathway interactions; Pattern; Resolution; Role; Somatosensory Cortex; Speed; Spinal; Spinal Cord; Spinal cord injury; Therapeutic; Treatment Efficacy; Vertebral column; Viral; Walking; central pattern generator; experimental study; genetic approach; hippocampal pyramidal neuron; locomotor control; motor control; motor impairment; neuroregulation; novel; optical imaging; optogenetics; sensory cortex; sensory mechanism

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.

脊髓容纳了负责执行各种运动任务的神经元网络 运动。这些脊柱网络接收来自大脑和脑干的下行命令。脊髓 损伤（SCI）会破坏大脑和脊髓运动网络之间的连接，导致 运动控制明显丧失。尽管迫切需要开发在 SCI 后恢复运动功能的方法， 治疗选择仍然有限。我们最近证明初级体感皮层（SI）可以 通过颈椎兴奋直接控制腰脊髓的运动中枢模式发生器 中间神经元（SI 运动通路），独立于运动皮层。基于范式转变的发现 感觉皮层可以直接调节脊髓运动网络，该提案旨在定义 这种感觉皮层控制运动的机制，并利用该途径在 SCI 后恢复行走。 首先，在目标 1 中，使用头戴式微型显微镜，我们将使用电路特定的单细胞分辨率 自由活动小鼠 SI 颈部锥体神经元的钙成像。该策略将使我们能够识别并 破译与运动的启动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是 足以在健康时和 SCI 后启动运动。目标 2 将确定该通路的解剖连接性 使用交叉病毒追踪实验和 SI-颈椎锥体综合绘图来确定完整性 轴突侧支。在目标 3 中，确定该途径对术后运动恢复的治疗潜力 脊髓损伤，我们将采用急性光遗传学和化学遗传学策略。总体而言，了解 SI 运动通路的功能意义以及描绘解剖连接性和完整性 post-SCI 将增强我们对这一新发现电路的了解，并促进 SCI 和其他运动受损的神经系统疾病后恢复运动的策略。