PROJECT ABSTRACT Spinal cord injury (SCI) is a major cause of disability, currently affecting 276,000 individuals in the U.S. alone and millions more worldwide. Cervical SCI (cSCI) accounts for 55% of all SCIs and typically results in impaired upper extremity motor function. The majority of cSCI patients have bilateral damage to the spinal cord. Identifying and developing rehabilitative therapies that promote recovery of upper extremity function after bilateral cSCI is of great clinical importance. We propose to evaluate a novel therapeutic intervention which uses precisely timed stimulation of the vagus nerve paired with rehabilitative training. Pairing vagus nerve stimulation (VNS) with movement engages pro- plasticity neuromodulatory systems and results in highly specific, long-lasting neuroplasticity in rat motor cortex. Based on this enhancement of plasticity, our recent results demonstrate that VNS paired with rehabilitation significantly enhances recovery of forelimb motor function in rat models of ischemic stroke, hemorrhagic stroke, and traumatic brain injury. Moreover, our preliminary results suggest that VNS therapy is effective in a unilateral model of SCI. To test this in a model that more accurately represents the clinical SCI population, we propose to evaluate VNS paired with rehabilitative training in a model of chronic, bilateral cSCI and examine the neuroplasticity in cortical and spinal motor networks that may underlie recovery. In addition, we will define the role of two key neuromodulatory systems, the cholinergic and noradrenergic systems, in recovery after SCI. We hypothesize the VNS paired with rehabilitative training will support functional and anatomical plasticity in descending motor networks to enhance recovery of function after bilateral cSCI. The results of the proposed experiments will clarify the relationship between bilateral cervical spinal damage, neuroplasticity, neuromodulatory function, and upper limb motor recovery. Moreover, this proposal will provide a proof-of-concept evaluation of VNS paired with rehabilitative training to improve recovery of forelimb function after a severe bilateral SCI and elucidate the mechanisms that support recovery.