PROJECT SUMMARY/ABSTRACT Spinal cord Injury (SCI) produces a devastating syndrome characterized by motor dysfunction, hyper-reflexia, spasticity, and neurogenic pain. The long-term goal of SCI therapy is to promote adaptive plasticity for restoration of function while limiting maladaptive plasticity that results in hyper-reflexia, spasticity and intractable pain. Recent research has indicated that both adaptive and maladaptive CNS plasticity can occur at the level of the spinal cord to dictate recovery of function. However, the specific conditions that promote adaptive versus maladaptive spinal plasticity in SCI are not well-understood. The central hypothesis of this R01 is that spinal cord plasticity is shaped by aberrant peripheral stimulation in the acute phase of SCI that tips plasticity toward a maladaptive form. This hypothesis has strong clinical/translational relevance, as epidemiological studies indicate that peripheral injuries and early limb disuse are prevalent comorbidities in human SCI. Up to 85% of SCI individuals presenting to level I trauma centers have peripheral injuries in addition to CNS damage. Preliminary data demonstrate that peripheral nociceptive stimulation delivered caudal to a complete SCI lesion produces maladaptive spinal plasticity that manifests as tactile hyper-reflexia and spasticity. Similar effects are observed with peripheral nerve injury or forced hindlimb disuse below SCI, and in both transection SCI and contusion SCI models. Our findings link these effects to specific alterations in glutamate receptor-mediated synaptic plasticity in the spinal ventral horn, providing a novel therapeutic target for restoration of function after SCI. The Aims of this R01 expand on the preliminary data to: 1) test mechanistic underpinnings of aberrant nociceptive stimulation below SCI (Aim 1), 2) evaluate whether similar effects occur with aberrant proprioceptive stimulation driving spinal cord central neuronal hyper- reflexia/spasticity (Aim 2), and 3) test new targets for combating maladaptive plasticity to promote adaptive recovery in SCI using transcriptomic and transgenic technologies (Aim 3). The proposed project has implications for shaping acute neuronal activity in polytraumatic SCI—a prevalent clinical presentation where CNS lesions are accompanied with peripheral injuries and protracted bedrest.