Enhancing supraspinal plasticity to improve functional recovery after SCI

项目摘要 越来越明显的是，由治疗诱导的脊髓上网络的可塑性 脊髓损伤后的功能恢复是必要的。我们已经开发出一种新颖 摩托车、5-HT替代疗法和跑步机训练的联合治疗可以恢复 在具有完全脊髓横断的动物中的开放场重量支撑的步行（BBB评分>9）。我们 初步数据表明，脊髓上神经元和神经胶质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， 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， 星形胶质细胞增生和炎症）将增强脊髓上重塑并改善功能结果。这一目标 将有两个具体目标。目的1：研究治疗对功能恢复的影响， 脊髓损伤后脊髓可塑性的变化，神经元和胶质细胞的变化及其与脊髓损伤的关系 功能恢复目的2：确定是否将NC疗法与以下策略相结合：（A）增强脊髓上的 可塑性（例如，通过脑-机接口（BMI）训练）和/或（B）抑制反应性神经胶质增生的方面（例如， 调节TNF活性）在改善SCI后的功能恢复方面比单独的NC疗法更有效。的 这项工作的结果将有助于开发恢复运动意志控制的疗法。 此外，研究结果可用于转化研究，以开发维持平衡的辅助设备 (e.g.外骨骼的皮质控制或功能性电刺激）。胶质可塑性被定义为 星形胶质细胞和小胶质细胞的数量和/或“活化”对SCI或SCI后治疗的响应的变化。 神经元的可塑性包括感觉运动皮层的组织和神经元放电模式的变化 携带着关于感觉和运动的信息。Bethea和Moxon联合实验室 在脊髓损伤后测量和操纵神经胶质和神经元可塑性方面具有丰富的经验。通过 结合专业知识，我们可以解决，第一次，这两个系统，神经元和胶质细胞，如何相互作用， 促进功能恢复。我们将比较一系列9个动物实验的结果， 完全脊髓横断到严重脊髓挫伤。这些实验将评估 电生理学变化（实验1-4），损伤重组皮层的影响（实验5） 并追踪这种重组的来源（实验6）。在实验7中，治疗对 将测量穿过损伤的备用纤维的差异。最后，蛋白质/ 与动物大脑中的神经可塑性和炎症相关的基因将被比较 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).