Project Summary More than half of traumatic spinal cord injuries (SCI) occur at the cervical level, leading to paralysis and respiratory compromise or failure. Approximately 20% of cSCI patients will require ventilator support for which there are very few therapeutic options for recovery. Epidural stimulation has emerged as a strategy to restore a variety of motor, sensory, and autonomic functions in both experimental and clinical conditions after SCI. Though limited underlying mechanisms have been proposed, to date little is known how epidural stimulation elicits motor function at the neuronal level. Even less is known about the capacity for epidural stimulation to promote long-lasting spinal plasticity for true device-independence and to date no studies have explored the potential for eliciting respiratory plasticity. The fundamental hypothesis guiding this proposal is that long-term, closed-loop epidural stimulation elicits functional improvement in diaphragm activity that outlasts the period of stimulation via activity-dependent mechanisms involving BDNF/TrkB signaling in phrenic motor neurons. Preliminary data are promising and indicate at least some short-term plasticity with longer periods of stimulation (4d). We envision that more chronic and targeted stimulation parameters will result in longer persistence of motor recovery. This is the first study to propose chronic epidural stimulation in awake, freely-behaving animals in a defined respiratory neural circuit. Ultimately, data from this project will serve to inform development of future investigations of the mechanistic basis of epidural stimulation efficacy essential for advancing the therapeutic applications to many motor systems but especially to the neural system controlling breathing.