While the environment of the adult spinal cord limits regeneration, studies using peripheral or embryonic grafts have demonstrated that adult spinal cord axons retain the ability to regenerate in the absence of inhibitory cues. The axon guidance receptor EphA4 acts to limit axon growth as the spinal cord matures and is implicated in restricting regeneration after spinal cord injury. EphA4 signaling is an attractive target for both acute and chronic spinal cord injury as it is a growth restrictive pathway that is present throughout life in the spinal cord. The objective of this proposal is to determine how inhibitory EphA4 signaling limits recovery of the motor circuit after spinal cord injury. The hypothesis is that eliminating EphA4 from motor axons will increase regeneration after spinal cord injury, creating a new circuit to support motor recovery. State-ofthe-art tools will be used to determine the effects of removing EphA4 on not only structural changes in motor axons, but also in the ability of the brain to incorporate changes to the spinal cord architecture. The expectation is that identification of a role for EphA4 in limiting motor recovery after spinal cord injury will provide an avenue for the subsequent development of therapeutic interventions for acute and chronic spinal cord injury.