Thousands of people a year receive a spinal cord injury (SCI) and there are hundreds of thousands of individuals living with long-term SCI-related deficits in the United States alone. Frustratingly, there are very few successful interventions, particularly for people who are months to years out from their injury. The SCI field has largely focused on the immediate lesion area in terms of both understanding SCI and developing therapeutic targets. It is, however, “spared” tissue distant from the immediate site of injury that is most often targeted with current interventions such as epidural stimulation and treadmill-based rehabilitation. While previous studies have explored changes in neurons and axons within these distal regions, the glial response has largely been overlooked. Therefore, this study will interrogate oligodendrocyte progenitor cells (OPCs) and new myelin formation in distal regions after SCI. OPCs are a large pool of proliferative glia within the adult central nervous system, and are known to respond to insults by proliferating and differentiating into myelinating oligodendrocytes. New myelin formation is also emerging as an important factor in circuit modulation in the adult brain. Furthermore, the long-term regenerative capacity of these cells makes them an ideal target for intervention long after the initial SCI. It is known that SCI increases in OPC proliferation and differentiation, as well as new myelin formation near the lesion area. How these processes unfold in distal tissue, where circuit reorganization is occurring, is hereto unexplored. This proposal intends to build a far more complete picture of glial involvement in circuit modulation after SCI. Furthermore, we will interrogate these changes in both mid-thoracic and cervical injuries, allowing us to make comparisons between clinically relevant models of SCI. The first goal of this proposal is to interrogate to what extent oligodendrocyte genesis and myelin formation are altered in these distal tissues, including spared spinal cord regions rostral and caudal to the lesion as well as the brain. This will also be explored from early through late time points after SCI to determine the extent to which new myelin formation contributes to long-term changes in distal tissues. The second goal is to specifically characterize OPC-neuronal interactions. These interactions have been previously unexplored in the spinal cord, let alone in the context of SCI. This experiment would build a core understanding of how spinal cord OPC-neuronal interactions are modulated by injury. The final goal is to use the therapeutically relevant intervention of voluntary exercise to explore the roles new myelin formation and OPC-neuron interactions play in current rehabilitation strategies. Overall, this application aims to contribute to the fundamental understanding of SCI, particularly the modulation of distal tissues over time. These studies could further underscore the importance of new myelin form...