Optical Dissection of Intracortical Circuits Supporting Motor Recovery After Spinal Cord Injury

支持脊髓损伤后运动恢复的皮质内回路的光学解剖

• 批准号: 10625358
• 负责人: Edmund R Hollis
• 金额: $ 45.06万
• 依托单位: WINIFRED MASTERSON BURKE MED RES INST
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10625358
• 关键词: Acute; Animal Model; Area; Axon; Behavior; Body Regions; Brain Stem; Cell Transplantation; Cerebral Palsy; Cervical spinal cord injury; Chronic; Dendritic Spines; Dissection; Forelimb; Foundations; Future; Goals; Growth; Hindlimb; Injury; Knowledge; Learning; Maps; Measures; Mediating; Mediator; Mission; Motor; Motor Cortex; Motor Evoked Potentials; Movement; Mus; Muscle; Neurodegenerative Disorders; Neuronal Plasticity; Neurons; Optics; Output; Process; Public Health; Recovery; Recovery Support; Recovery of Function; Rehabilitation therapy; Research; Role; Spinal; Spinal Cord; Spinal cord injury; Stroke; Testing; Therapeutic; Therapeutic Intervention; Traumatic Brain Injury; United States National Institutes of Health; Vertebral column; Work; awake; axon regeneration; axonal sprouting; combinatorial; expectation; functional restoration; human model; in vivo; innovation; motor function recovery; motor learning; motor recovery; new therapeutic target; recruit; response; skills; structural imaging; therapy design

PROJECT SUMMARY: Cortical motor networks are a critical, if often overlooked, mediator of motor recovery after spinal cord injury (SCI). Cortical networks are required for instructing output through the corticofugal projections to the brainstem and spinal cord, and the plasticity of these networks will be indispensable for re- learning how to use the spinal circuits altered by SCI or therapeutic intervention. Rehabilitation is necessary for both the recovery of corticospinal-dependent forelimb function and the commensurate reorganization of disrupted cortical motor maps. It remains unknown what the underlying circuit mechanisms are that support cortical reorganization after SCI, or whether such broad reorganization is necessary to support functional recovery. The long-term goal is to develop therapeutic interventions that take advantage of cortical plasticity to promote recovery from SCI. The overall objective for this proposal is to identify the intracortical circuitry responsible for restoring skilled forelimb function. The central hypothesis is that latent intracortical connections projecting from de-efferented hindlimb to forelimb areas are required for rehabilitation-mediated recovery of skilled forelimb function after cervical SCI. The rationale for the proposed research is that the knowledge of how the motor cortex incorporates circuit changes after SCI will help us to target new therapies for motor recovery. The following three specific aims are proposed: 1) Record the endogenous activity from intracortical neurons during rehabilitation-mediated recovery from SCI; 2) Determine the structural changes in horizontal connections during rehabilitation from SCI; and 3) Identify the contribution of horizontal connections to motor recovery after SCI. For the first aim, the approach will be to record activity from interconnected hindlimb and forelimb motor regions during skilled forelimb behavior in order to determine their response to rehabilitation from SCI. In the second aim, the approach will be to image structural changes of intracortical axons and dendritic spines in vivo longitudinally during rehabilitation from SCI. In the third aim, the approach will be to 1) silence interconnected neurons in awake, behaving mice to determine their contribution to recovery, and 2) stimulate interconnected neurons and measure forelimb motor evoked potentials. The proposed studies are innovative in that they shift the focus of spinal cord injury research from axon regeneration to the intracortical networks required for interpreting the changes in spinal cord circuitry. The proposed studies are significant because they will provide a detailed understanding of the mechanisms of circuit remodeling that influence recovery. The expectation is that completion of the proposed research will determine the extent to which intracortical neuron plasticity underlies cortical motor map reorganization and supports functional recovery after SCI. These findings will establish a foundation upon which to build therapeutic advances and dictate which strategies are most appropriate to pursue for both acute and chronic SCI.

项目摘要：皮质运动网络是运动康复的关键调节因子，但常常被忽视。 脊髓损伤(SCI)。皮质网络是通过皮质神经系统指导输出所必需的。 向脑干和脊髓的投射，以及这些网络的可塑性将是恢复 学习如何使用脊髓损伤或治疗干预改变的脊髓神经回路。康复是必要的 皮质脊髓依赖性前肢功能的恢复和相应的重组 扰乱了大脑皮层的运动地图。目前还不清楚支持什么基本电路机制 脊髓损伤后的皮质重组，或者这种广泛的重组是否为支持功能性的 恢复。长期目标是开发利用皮质可塑性的治疗干预措施 促进从脊髓损伤中恢复。这项建议的总体目标是确定皮质内回路 负责恢复熟练的前肢功能。中心假设是潜在的皮质内联系 康复介导的康复需要从去传出的后肢向前肢的投射 颈椎脊髓损伤后熟练的前肢功能。建议进行这项研究的理由是， 脊髓损伤后运动皮质如何结合电路的变化将帮助我们针对运动的新疗法 恢复。提出了以下三个具体目标：1)记录大脑皮质内的内源性活动 脊髓损伤后康复过程中的神经元；2)确定脊髓水平方向的结构变化 脊髓损伤康复过程中的连接；3)确定水平连接对运动的贡献 脊髓损伤后的康复。对于第一个目标，方法将是记录相互连接的后肢的活动和 在熟练的前肢行为中前肢运动区，以确定他们对康复的反应 来自SCI的。在第二个目标中，方法将是成像皮质内轴突的结构变化和 脊髓损伤康复过程中体内纵向树突棘。在第三个目标中，方法将是1) 静默清醒的小鼠相互连接的神经元，以确定它们对恢复的贡献，以及2) 刺激相互连接的神经元并测量前肢运动诱发电位。建议进行的研究包括 创新之处在于他们将脊髓损伤的研究重点从轴突再生转移到皮质内 解释脊髓回路变化所需的网络。拟议中的研究具有重要意义 因为它们将提供对影响电路重构的机制的详细了解 恢复。预计拟议研究的完成将在多大程度上决定 皮质内神经元的可塑性是皮质运动图重组的基础，并支持术后功能恢复 SCI。这些发现将建立一个基础，在此基础上建立治疗进展，并规定 无论是急性脊髓损伤还是慢性脊髓损伤，策略都是最合适的。

项目成果

Sensory Circuit Remodeling and Movement Recovery After Spinal Cord Injury.

• DOI: 10.3389/fnins.2021.787690
• 发表时间: 2021
• 期刊: Frontiers in neuroscience
• 影响因子: 4.3
• 作者: Moreno-López Y;Hollis ER
• 通讯作者: Hollis ER

Task-specific modulation of corticospinal neuron activity during motor learning in mice.

• DOI: 10.1038/s41467-023-38418-4
• 发表时间: 2023-05-11
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Serradj, Najet;Marino, Francesca;Moreno-Lopez, Yunuen;Bernstein, Amanda;Agger, Sydney;Soliman, Marwa;Sloan, Andrew;Hollis, Edmund
• 通讯作者: Hollis, Edmund