Spinal cord injury results in the loss of neuropil at the injury site and disruption of ascending and descending fibers that pass through the lesioned area. Our preliminary data suggests that intrathecal administration of exogenous BDNF after a mid-thoracic contusion injury stimulates the synaptic activity of spinal circuits in the lumbar cord. In contrast, transplants of fetal spinal cord tissue and genetically engineered fibroblasts can be used to repair the anatomical deficit at the lesion cavity and promote axonal growth. We propose that the direct effects of BDNF infusion are complementary to the tropic and trophic effects of fetal grafts or neurotrophin producing fibroblast grafts. Together, the combination of infusion and transplantation will (1) enhance elongation or sprouting of descending fibers beyond the lesion or transplantation site and (2) improve the functional activity of systems important for descending control of motor function. The proposed plan will first maximize tissue penetration and dosage of BDNF. We will then test the effects of the individual and combined strategies on axonal sprouting using immunohistochemical and tract tracing methods. Physiological indices of functional recovery will be assessed by using a unique operant conditioning paradigm to test the ability of descending systems to modulate hindlimb H-reflex amplitude. Finally, the roll of anatomical and physiological changes on behavioral recovery will be determined using operationally defined behavioral outcome measures of segmental, propriospinal, and descending control of hindlimb motor activity. These experiments provide a multidisciplinary approach to developing a unique strategy for functional recovery after spinal cord injury.
