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

项目总结/摘要 皮质脊髓通路是人类自主运动控制的关键介质， 脊髓损伤后皮质脊髓运动功能仍然是面临的最实质性挑战之一， 转化和临床神经科学。无论采取何种办法来缓解对 皮质脊髓轴突，功能恢复将依赖于皮质运动网络的可塑性，以纳入 改造或更换电路。创造新的治疗干预措施，以恢复功能后， 损伤将必须与对支持皮层神经元功能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。长期目标是开发新的治疗干预措施 脊髓损伤后的功能恢复，通过了解细胞和亚细胞 驱动神经回路重塑的机制本提案的总体目标是确定 运动地图可塑性的神经调节机制与熟练运动功能的恢复相关， 目的：探讨颈髓损伤后皮质神经网络改变与皮质脊髓回路重塑的关系。 脊髓损伤中心假设是，胆碱能输入直接向皮质脊髓运动神经元， 脊髓后皮质脊髓回路变化功能整合到从头运动网络所需 损伤这项研究的基本原理是，一旦胆碱能活性在术后康复中的作用被证实， 脊髓损伤的定义，它可能提供新的机会，药理学调制和配对 通过增强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遗传学/化学遗传学控制以调节已知的运动调节因子 学习，同时使用双光子显微镜来评估受损皮质脊髓的功能整合 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测量神经元。的 第二种方法将是确定信号事件的分子机制和细胞定位， 是运动学习和运动康复的基础。拟议的研究是创新的，因为它们改变了 脊髓康复的重点是皮层网络可塑性的电路机制，将有很大的- 在将急性和慢性损伤的治疗转化为运动网络方面发挥重要作用。的 提出的研究是重要的，因为他们将阐明电路重塑的机制， 影响恢复，这将对转化急性和慢性疾病的治疗具有深远的重要性。 皮层运动网络的损伤预计完成拟议的研究将产生 增强皮质脊髓轴突的药理学调节和组合治疗的新机会 再生，同时介导皮质运动网络重组。

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.