Enhancing Motor Neuron Regeneration Accuracy

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DESCRIPTION (provided by applicant): Preferential motor reinnervation (PMR) refers to the preference of regenerating motor neurons in a mixed peripheral nerve to reinnervate a distal terminal nerve branch to muscle rather than skin. A useful model to study PMR is the rodent femoral nerve. Proximally in the leg, motor axons are dispersed across the entire mixed nerve. Distally, the nerve divides into two approximately equal terminal branches; a motor branch to the quadriceps muscle and a purely sensory branch which continues as the saphenous nerve. Much previous work from several laboratories has shown that following a proximal lesion regenerating motor neurons preferentially, albeit incompletely, reinnervate the terminal quadriceps branch (to muscle) versus the saphenous branch (to skin). During the course of our recent studies on PMR we made a surprising observation: information from the denervated muscle is apparently rapidly conveyed to the proximal nerve lesion site and influences the subsequent accuracy of motor neuron regeneration. We have preliminary data suggesting that the delivery of this information from muscle is dependent upon active retrograde axonal transport which continues in distal denervated nerve for approximately 30 hours, or until the axon undergoes Wallerian degeneration. The experiments in this proposal build upon this unexpected observation, and will clarify the influence in denervated nerve of retrograde transport from muscle as a mechanism that influences PMR. We will use a variety of well characterized surgical models of the rodent femoral nerve to accomplish our specific aims. PUBLIC HEALTH RELEVANCE: Despite regeneration, extensive peripheral nerve injuries can result in the effective paralysis of the entire limb or distal portions of the limb such as the hands. The major key to recovery of function following nerve lesions in the peripheral nervous system is the accurate regeneration of axons to their original target end-organs. The proposed studies utilize the rodent femoral nerve and will assess the accuracy with which motor neurons project back to their original terminal nerve branch.