Recruitment of intrasegmental and propriospinal interneuron networks of forelimb motor circuitry in chronic cervical contusion spinal cord injury

Cervical spinal cord injury (SCI) disrupts descending supraspinal input and spinal networks controlling upper extremity motor function, making recovery of arm and hand function a major priority for affected individuals. The vast majority of regenerative strategies have been studied during the acute and sub-acute phases following SCI, while therapeutic testing remains limited for chronic injury, when persistent barriers significantly limit circuit remodeling. We asked whether pharmacologic enhancement of neuronal-intrinsic axon growth capacity through PTEN inhibition could promote forelimb motor recovery and circuit plasticity in a rodent model of chronic cervical SCI. Following C5 hemi-contusion, female rats underwent behavioral testing of forelimb motor function and received PTEN antagonist peptide (PAP) beginning at a chronic time point, and the trans-synaptic tracer, pseudorabies virus (PRV), was injected into ipsilesional triceps to trace forelimb-associated motor circuitry. PAP selectively improved forelimb usage during cylinder paw-preference testing, but not strength, sensorimotor, or gait-related forelimb measures. PAP increased recruitment of PRV-traced local-projecting and propriospinal interneuron networks. In addition, PAP enhanced synaptic input to these recruited propriospinal interneurons, raising the possibility that spared descending pathways may contribute to recovery through spinal relay circuits. Lastly, we mapped the supraspinal connectome providing descending input from brainstem to the lower motor neurons innervating forelimb muscle, and we determined how this connectome was impacted both by SCI and PAP. Together, these findings show that, even in chronic SCI, pharmacological PTEN inhibition can promote forelimb functional recovery and significant circuit remodeling, with spinal interneuron networks emerging as a key site of PAP-induced plasticity.