Reprogramming the Outputs of Spinal Circuits

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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.