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.

脊髓容纳负责执行各种运动任务的神经元网络， 运动这些脊髓网络接收来自大脑和脑干的下行命令。脊髓 脊髓损伤（SCI）破坏了大脑和脊髓运动网络之间的连接，导致 严重失去运动控制。尽管迫切需要开发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，初级躯体感觉皮层（SI）可以 直接控制运动中枢模式发生器在腰脊髓通过颈部兴奋 中间神经元（SI运动通路），独立于运动皮层。基于范式转换的发现 感觉皮层可以直接调节脊髓运动网络，这项建议旨在定义 这一感觉皮层控制运动的机制，并利用这一途径恢复SCI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像。这一战略将使我们能够识别和 破译与运动的起始和速度相关的神经元活动模式。此外，使用A 电路特异性光遗传学方法，我们将确定是否直接和特异性刺激这一途径， 足以在健康和SCI后启动运动。目标2将确定这条通路的解剖连接 和完整性使用交叉病毒示踪实验和全面映射的SI-颈椎锥体 轴突侧支在目的3中，为了确定该途径在移植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。总的来说，了解 SI-运动通路的功能意义，并描绘解剖学连接和完整性 后SCI将提高我们对这一新发现的电路的认识，并促进 在SCI和其他神经系统疾病导致运动受损后，