A large body of work has demonstrated the therapeutic potential of trophic factors to attenuate neural loss following trauma or disease. Abundant evidence from the clinical and basic literature indicates that physical exercise facilitates functional recovery, but the molecular basis by which activity can promote neural circuit remodeling is poorly understood. Encouraged by our original findings that locomotor activity induces trophic factors in the brain, we propose that locomotion can even have a more critical impact on trophic factor induction in the spinal cord, and that this capacity can be used to improve functional recovery after spinal cord injury (SCI). It is, therefore, a central theme of this proposal to link exercise with neurotrophins, optimizing exercise induced expression of endogenous trophic factors which can boost functional restoration following SCI. A final step in the proposed work will be to test the hypothesis that neurotrophins are an intermediate step in the recovery of locomotor ability after CNS trauma by blocking their actions in SCI rats. Our initial results show that locomotor activity increases the expression of brain-derived growth factor (BDNF) in select regions of the rat CNS. BDNF and neurottrophin-3 (NT-3), improve the viability and functionality of damaged motoneurons. We propose to evaluate conditions under which neuromuscular activity of the upper and lower limbs affects the expression of BDNF, NT- 3, or their receptors in discrete regions of the rodent spinal cord. We then will evaluate the capacity of these interventions to promote specific changes in cellular plasticity of the healthy and injured spinal cord and their effects in functional recovery. It should be noted that most of the approaches to treat SCI have been directed to bridging the gap in the transected spinal cord. In turn, emerging evidence suggests that trophic interactions driven by neural activity mediate processes as diverse as neuronal growth and survival, synaptic function, underlying mechanisms of CNS healing, behavior, and learning/memory. Therefore, an important and novel aspect of our paradigm is that in addition to a possible role in bridging the gap, it can play a significant role in the remodeling of remaining neural circuits below the lesion. Based on recent clinical and basic evidence showing that the injured spinal cord possesses the basic substrates for relearning motor function, success in the proposed investigations can provide additional strategies for the development of new types of treatments to promote functional recovery.