Following transection of a muscle nerve, axons of motoneurons will regenerate and reinnervate the muscular targets of that nerve. Even so, attaining favorable motor outcomes after reinnervation remains a significant clinical problem. Motor axons regenerate at different rates and some of those arriving early in the process innervate different muscles than before the lesion, some axons reinnervating more than one target. As progressively more motor axons regenerate, this profuse early innervation is changed by a process known as axonal pruning, and muscle-, and even compartment-based innervation is restored. Pruning could be considered adaptive if it is associated with the restoration of the pre-lesion interaction of spinal circuits and the musculoskeletal system. In this project, we will evaluate the extent to which early regenerating motor5 axons make inappropriate synaptic connections and the degree to which the process of axonal pruning restores the pre-lesion innervation of skeletal muscle fibers. We will examine rats in which the tibial branch of the sciatic nerve is cut and surgically repaired and compare the results of two different interventional methods aimed at enhancing axonal regeneration: electrical stimulation and immunosuppressant therapy. We will also evaluate the effects of activate blockade with botulinum toxin; a paradigm designed to influence the outcome of axonal pruning. In addition, we will examine the functional consequences of altered interactions of spinal circuits and their output elements that follows reinnervation of cat muscles and how these functional measures change in response to enhancements of axonal regeneration of manipulation of the outcomes of motor axon pruning. These results provide a strengthening of the science base for rehabilitationists treating patients with peripheral nerve injuries, and they will provide a test of potential rehabilitation interventions that might promote more favorable motor outcomes in these patients.
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