Modulation of cortical networks, a new approach to spinal cord injury rehabilitation

项目摘要/摘要 皮质脊髓通路是人类自主运动控制和恢复的关键媒介 脊髓损伤后皮质脊髓运动功能仍然是面临的最大挑战之一 今天的翻译和临床神经科学。不管采取什么方法来缓解中断 皮质脊髓轴突的功能恢复将依赖于皮质运动网络的可塑性来整合 已改装或更换电路。为术后功能恢复创造新的治疗干预措施 损伤必须与对支持大脑皮层的细胞和亚细胞机制的理解相结合。 运动网络重塑和受损神经元的整合。直到最近才有必要的工具来 回答这些关键问题已经被开发出来。长期目标是开发新的治疗干预措施。 通过对细胞和亚细胞的了解，促进脊髓损伤后功能的恢复 驱动神经回路重塑的机制。这项提案的总体目标是确定 运动地图可塑性与熟练运动功能和功能恢复相关的神经调节机制 颈椎损伤后皮质网络改变与皮质脊髓环路重塑的关系 脊髓损伤。中心假设是直接传入皮质脊髓运动神经元的胆碱能是 脊髓后皮质脊髓回路改变为新生运动网络的功能整合所需 受伤。这项拟议研究的基本原理是，一旦胆碱能活动在康复中的作用 脊髓损伤的定义，很可能为药物调节和配对提供新的机会 通过促进皮质脊髓轴突再生的治疗。第一种方法是使用细胞毒性损伤。 以及相关皮质下回路的光发生/化学发生控制，以调节已知的运动介体 在使用双光子显微镜评估受损皮质脊髓的功能整合时的学习 通过测量清醒的行为动物在康复过程中的活动和结构变化来确定神经元。这个 第二种方法是定义信号事件的分子机制和细胞位置， 运动学习和可能的运动康复都是基础。拟议的研究具有创新性，因为它们将 脊髓康复的重点是皮质网络可塑性的回路机制，并将产生深远的影响。 在将急性和慢性损伤的治疗方法转化为运动网络方面具有重要意义。这个 拟议的研究具有重要意义，因为它们将阐明电路重塑的机制 影响康复，这将对急性和慢性治疗方法的转换具有深远的重要性 大脑皮层运动神经损伤。预计拟议研究的完成将产生 增强皮质脊髓轴突的药物调节和联合治疗的新机遇 再生的同时调节皮质运动网络的重组。

Project Summary/Abstract The corticospinal pathway is a pivotal mediator of voluntary motor control in humans and restoring corticospinal motor function after spinal cord injury remains one of the most substantial challenges facing translational and clinical neuroscience today. Regardless of the approach taken to alleviate the interruption of corticospinal axons, functional recovery will rely on the plasticity of the cortical motor network to incorporate the remodeled or replaced circuit. The creation of novel therapeutic interventions for the recovery of function after injury will have to be coupled to an understanding of the cellular and subcellular mechanisms that support cortical motor network remodeling and incorporation of injured neurons. Only recently have the tools necessary to answer these critical questions been developed. The long-term goal is to develop novel therapeutic interventions for the recovery of function after spinal cord injury through an understanding of the cellular and subcellular mechanisms that drive neural circuit remodeling. The overall objective for this proposal is to identify neuromodulatory mechanisms of motor map plasticity that correlate with recovery of skilled motor function and to determine the relationship between cortical network changes and corticospinal circuit remodeling after cervical spinal cord injury. The central hypothesis is that cholinergic input directly to corticospinal motor neurons is required for functional integration of corticospinal circuit changes into de novo motor networks after spinal cord injury. The rationale for the proposed research is that once the role of cholinergic activity in rehabilitation after spinal cord injury is defined, it is likely to provide new opportunities for pharmacological modulation and pairing with treatments that enhance corticospinal axon regeneration. The first approach will be to use cytotoxic lesions and optogenetic/chemogenetic control of relevant subcortical circuitry to modulate known mediators of motor learning while using two-photon microscopy to assess the functional incorporation of injured corticospinal neurons by measuring activity and structural changes during rehabilitation in awake, behaving animals. The second approach will be to define the molecular mechanisms and the cellular location of signaling events that underlie motor learning, and likely motor rehabilitation. The proposed studies are innovative in that they shift the focus of spinal cord rehabilitation onto the circuit mechanisms of cortical network plasticity and will have far- reaching importance in translating treatments for both acute and chronic injuries to motor networks. The proposed studies are significant because they will elucidate the mechanisms by which circuit remodeling influences recovery, which will have far-reaching importance in translating treatments for both acute and chronic injuries to cortical motor networks. The expectation is that completion of the proposed research will generate new opportunities for pharmacological modulation and combinatorial treatments that enhance corticospinal axon regeneration while mediating cortical motor network reorganization.