Reprogramming the Outputs of Spinal Circuits

摘要 当周围神经损伤时，肌肉骨骼系统和 脊髓中控制运动的神经回路丧失。轴突在近端残端 被切断的神经可以再生，并可以重新支配周围目标，但肌肉通常 与损伤前相比，由不同的运动神经元重新支配。使用不同的范例， 增强切断的神经中轴突的早期再生加剧了这种地形特异性的丧失。 随着时间的推移，几乎没有证据表明这种神经支配模式的重塑。这种新关系 脊髓回路和肌肉骨骼系统之间的相互作用是导致脊髓功能差的主要原因。 临床观察结果。改善功能恢复的一个潜在策略可能是 诱导脊髓回路自身的适应性变化，使得改善的功能 它们的输出与肌肉骨骼系统的神经再支配模式的关系可能是 办妥了一批在这个项目中，我们将研究诱导这种适应性变化的能力。使用 大鼠坐骨神经切断和手术修复，早期轴突增强和不增强 再生，作为一个模型系统，我们将研究脊髓回路的输出适应能力， 通过分析拮抗肌和踝关节活动的时间， 在不同形式的跑步机运动期间的运动学。此外，还提出了两种创新办法， 将研究修改脊髓电路的输出。首先，我们将研究跑步机的效果 在神经再支配期间的运动对不同的神经再支配肌肉目标的程度 在功能上适当的时候被激活。通过脊髓回路激活运动神经元 在跑步机运动期间，再生运动和感觉轴突正在生长， 重建与肌肉的连接，人们可能会预期， 肌肉可能比没有锻炼时更精确，脊髓回路的输出将 在神经再支配过程中以适应性方式变化，或两者兼而有之。第二，我们会调查 脊髓反射的操作性条件反射是否可以用来改变脊髓回路的输出。 在肌肉被重新神经支配后，脊髓反射将被塑造成功能性地产生 使用这种条件反射的适当反应。这种培训在时间安排上的有效性 将评估在跑步机运动期间的拮抗肌。预计， 这些研究不仅将为改善大面积脑梗死的康复治疗提供科学依据， 周围神经损伤患者人群，以及其他疾病的治疗，其中 脊髓回路和肌肉骨骼系统之间的关系被破坏， 重新建立。

Abstract When a peripheral nerve is injured, the relationship between the musculoskeletal system and the neural circuits in the spinal cord which regulate movement is lost. Axons in the proximal stump of the cut nerve can regenerate and can reinnervate peripheral targets, but muscles are often reinnervated by different motoneurons than before the injury. Using different paradigms which will enhance the early regeneration of axons in cut nerves exacerbates this loss of topographic specificity. Over time, there is little evidence for remodeling of this innervation pattern. This new relationship between spinal circuits and the musculoskeletal system is a major contributor to the poor functional outcomes observed clinically. One potential strategy for improving functional recovery might be to induce adaptive changes in the spinal circuits themselves, such that an improved functional relationship of their outputs to the pattern of reinnervation of the musculoskeletal system might be achieved. In this project, we will investigate the capacity to induce such adaptive changes.. Using transection and surgical repair of the rat sciatic nerve, with and without enhancement of early axon regeneration, as a model system, we will study the capacity of the outputs of spinal circuits to adapt spontaneously over time by analyzing the timing of activity of antagonist muscles and ankle joint kinematics during different forms of treadmill locomotion. In addition, two innovative approaches to modifying the outputs of spinal circuits will be studied. First, we will examine the effect of treadmill exercise during the reinnervation period on the extent to which different reinnervated muscular targets are activated at functionally appropriate times. By activating motoneurons through spinal circuits during treadmill locomotion at a time that regenerating motor and sensory axons are growing and reforming connections with muscles, one might anticipate either that the original reinnervation of muscles might be more precise than found without exercise, that the outputs of the spinal circuits will change in an adaptive manner during the reinnervation process, or both. Second, we will investigate whether operant conditioning of spinal reflexes can be used to modify the outputs of spinal circuits. After muscles have been reinnervated, spinal reflexes will be shaped to produce functionally appropriate responses using such conditioning. The effectiveness of this training on the timing of antagonist muscles during treadmill locomotion will be evaluated. It is anticipated that the results of these studies will provide a science base not only for improved rehabilitation treatment of a large population of patients with peripheral nerve injuries but also the treatment of other disorders in which the relationship between spinal circuits and the musculoskeletal system has been disrupted and then re-established.