Reprogramming the Outputs of Spinal Circuits

摘要 当周围神经损伤时，肌肉骨骼系统与 脊髓中调节运动的神经回路丢失。近端残端的轴突 切断的神经可以再生，并可以重新支配周围靶点，但肌肉通常是 与受伤前不同的运动神经元重新支配神经。使用不同的范例，将 促进切断神经中轴突的早期再生会加剧这种地形图特异性的丧失。 随着时间的推移，几乎没有证据表明这种神经支配模式发生了重塑。这种新的关系 脊椎环路和肌肉骨骼系统之间的关系是导致功能低下的主要原因 临床观察结果。改善功能恢复的一个潜在策略可能是 诱导脊髓回路本身的适应性变化，从而改善功能 它们的输出与肌肉骨骼系统的再神经支配模式的关系可能是 已实现。在这个项目中，我们将调查引发这种适应性变化的能力。vbl.使用 大鼠坐骨神经横断修复和早期轴突强化的比较 再生，作为一个模型系统，我们将研究脊髓回路输出的适应能力 通过分析拮抗肌和踝关节的活动时间来自发地随时间推移 不同形式跑步机运动时的运动学。此外，两种创新的方法可以 修改脊椎电路的输出将被研究。首先，我们将检查跑步机的效果 神经再支配期间运动对不同神经支配肌肉靶点的影响 在功能上适当的时候被激活。通过脊髓环路激活运动神经元 在跑步机运动中，再生运动和感觉神经轴突正在生长和 重组与肌肉的连接，人们可能会预料到，原始的神经再支配 肌肉可能比没有运动时发现的更精确，脊椎回路的输出将 在再神经支配过程中以适应性方式改变，或两者兼而有之。第二，我们将调查 脊髓反射的可操作性条件反射是否可以用来改变脊髓回路的输出。 在肌肉重新神经支配后，脊柱反射将被塑造为产生功能性 使用这种条件反射的适当反应。这项培训的有效性在时间上 将评估跑步机运动中的拮抗肌。预计结果将是 这些研究不仅将为改善大型颅脑损伤的康复治疗提供科学基础 人群中的周围神经损伤患者还治疗其他疾病其中 脊椎回路和肌肉骨骼系统之间的关系已经被破坏，然后 重新建立起来。

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.