): This project represents a multidisciplinary approach to a long-term objective of developing a therapeutic strategy for functionally repairing the dorsal column-dorsal column nuclei sensory pathway in both acute and chronic cervical spinal cord injury (SCI). To improve upper and lower extremity function in humans with cervical SCI, it is hypothesized that injured axons need to regenerate, reinnervate their target sites, and make functional synapses with their target neurons. To test this hypothesis, we are using an adult rat model of mid-cervical SCI and are focusing on ascending primary afferent axons of forelimb dorsal root ganglia (DRG) neurons within the dorsal columns. Our preliminary anatomical and electrophysiological data suggests that some acutely injured forelimb primary afferent axons regenerate through extraspinal peripheral sciatic nerve grafts, reinnervate the brainstem, and make functional synapses with dorsal column nuclei neurons. For the Specific Aims, we will I ) use anatomical techniques to identify strategies for increasing axonal regeneration by acutely injured adult forelimb DRG neurons within sciatic nerve grafts, 2) use anatomical techniques to develop effective strategies for promoting forelimb primary afferent axonal outgrowth from sciatic nerve grafts into their target brainstem dorsal column nuclei, 3) use in vivo and in vitro electrophysiological techniques to evaluate functional synapse formation between regenerating forelimb primary afferent axons and their target dorsal column nuclei neurons as well as conditioned behavioral testing techniques to assess the effects of reconstructing the dorsal column-dorsal column nuclei sensory pathway on forelimb sensorimotor function, and 4) use the best strategies from Aims l and 2, anatomical techniques, electrophysiological techniques, and behavioral testing techniques to examine whether chronically injured forelimb primary afferent axons regenerate and form functional synapses with their target dorsal column nuclei neurons. The significance of this project is that it will delineate a novel treatment strategy for sensory dysfunction in rats with cervical SCI that, if implemented clinically, could lead to enhancement in the quality of life for persons with cervical SCI.
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