Enhancing supraspinal plasticity to improve functional recovery after SCI

项目摘要 越来越明显的是，治疗引起的脊柱上神经网络内的可塑性 对于脊髓损伤后功能的最佳恢复来说，干预是必要的。我们开发了一部小说 摩托车、5-羟色胺替代疗法和跑步机训练相结合可恢复 完全脊柱横断动物的开阔场地负重踏步(BBB评分9分)。我们的 初步数据表明，脊髓上神经元和神经胶质的可塑性都受到治疗的调节， 它们相互影响。这一建议的中心假设是，治疗与 促进有益的神经/神经胶质可塑性和/或减弱有害可塑性的策略(例如， 星形胶质细胞增多症和炎症)将促进脊柱上重塑和改善功能预后。这一目标 将以两个具体目标来解决。目的1：探讨治疗对患者功能恢复的影响。 脊髓损伤后脊髓上可塑性的神经元和神经胶质细胞变化及其与 功能恢复。目标2：确定是否将NCTherapy与：(A)加强脊柱上的战略相结合 可塑性(例如，通过脑机接口(BMI)训练)和/或(B)抑制反应性胶质增生的方面(例如 调节肿瘤坏死因子活性)在改善脊髓损伤后功能恢复方面比单用NCT治疗更有效。这个 这项工作的结果将有助于恢复意志运动控制的治疗方法的开发。 此外，研究结果还可以用于翻译研究，以开发维持平衡的辅助设备 (例如，外骨骼的皮质控制或功能性电刺激)。神经胶质可塑性被定义为 脊髓损伤后星形胶质细胞和小胶质细胞在脊髓损伤或治疗后数量和/或激活的变化。 神经元可塑性包括感觉运动皮质组织和神经元放电模式的变化 携带有关感觉和运动事件的信息。合并后的贝西娅和莫克森实验室 具有丰富的测量和操作脊髓损伤后神经胶质和神经元可塑性的经验。通过 结合专业知识，我们可以第一次解决这两个系统，神经元和神经胶质是如何相互作用的 促进功能恢复。我们将在动物身上进行一系列9项实验的结果与 对于严重脊柱挫伤的患者，应进行完整的脊柱横断。这些实验将评估 电生理改变(实验1-4)，损伤重组的皮质的影响(实验5) 并追踪这种重组的来源(实验6)。在实验7中，治疗对 将测量穿过病变的备用纤维的差异。最后，蛋白质的差异/ 将对动物大脑中与神经可塑性和炎症相关的基因进行比较 在横断和挫伤动物之间(实验8和9)。

Project Summary It is becoming increasingly evident that plasticity within supraspinal networks, induced by therapeutic interventions, is necessary for optimal recovery of function after spinal cord injury. We have developed a novel combination therapy of motorized bike, 5-HT replacement therapy and treadmill training that can restore open-field weight-supported stepping (BBB score >9) in animals with complete spinal transection. Our preliminary data suggest that both supraspinal neuronal and glial plasticity modulated by therapy and that they influence each other. The central hypothesis of this proposal is that therapy combined with strategies to either promote beneficial neural/glial plasticity and/or attenuate deleterious plasticity (e.g., astrogliosis and inflammation) will enhance supraspinal remodeling and improve functional outcome. This Aim will be addressed with two Specific Aims. Aim 1: Investigate the impact of therapy on functional recovery and supraspinal plasticity after SCI as measured by changes in neurons and glial cells and their relationship to functional recovery. Aim 2: Determine if combining NCTherapy with: (A) strategies to enhance supraspinal plasticity (e.g. via brain-machine interface (BMI) training) and/or (B) inhibiting aspects of reactive gliosis (e.g. modulate TNF activity) is more effective than NCTherapy alone in improving functional recovery after SCI. The results of this work will aid in the development of therapies for recovery of volitional control of movement. Moreover, results could be used for translational research to develop assistive devices to maintain balance (e.g. cortical control of an exoskeleton or functional electrical stimulation). Glial plasticity is defined as a change in the number and or “activation” of astrocytes and microglia in response to SCI or therapy after SCI. Neuronal plasticity includes changes in the organization of sensorimotor cortex and in neuronal firing patterns that carry information about sensory and motor events. The combined Bethea and Moxon labs have extensive experience measuring and manipulating glial and neuronal plasticity after spinal cord injury. By combining expertise, we can address, for the first time, how these two systems, neuronal and glial, interact to promote functional recovery. We will compare results from a series of 9 Experiments in animals with a complete spinal transection to those with a severe spinal contusion. These Experiments will assess electrophysiology changes (Experiments 1-4), the effect of lesioning the reorganized cortex (Experiment 5) and trace the source of this reorganization (Experiment 6). In Experiment 7, the impact of therapy on differences in spared fibers that cross the lesion will be measured. Finally, difference in the proteins/ genes associated with neuroplasticity and inflammation in the brains of animals will be compared between transected and contused animals (Experiments 8 and 9).