Project summary Disruption of supraspinal regulation causes reduced sympathetic and unopposed parasympathetic activity, leading to cardiac and hemodynamic disorders after high-level spinal cord injury (SCI). We recently reported that renewal of serotonergic regulation over hemodynamics could be achieved with transplantation of embryonic raphe nucleus-derived neural progenitors/stem cells (RN-NPCs) in a rat SCI model. It was previously showed that exercise, a viable therapeutic intervention, heightens neuronal activity, axonal regrowth, and production of neurotrophic factors after SCI. Accordingly, we posit that transplanting serotonergic NPCs in the injured spinal cord will reestablish serotonin regulation to improve cardiac function, and combining RN-NPC grafts with exercise will enhance the recovery of cardiac activity, hemodynamics, and autonomic dysreflexia after SCI. In Aim 1, we will determine whether integration of transplanted serotonergic NPCs with spinal cord circuitry will restore sympathetic regulation to improve cardiac electrical conduction following SCI. In Aim 2, we will test whether combining RN-NPC transplants with exercise will further enhance the reconstitution of sympathetic modulation to restore cardiac activity, hemodynamics, and autonomic dysreflexia. Overall, this project will provide novel insight into therapeutic strategy following SCI.