Ventral Epidural Stimulation Restores Forelimb Function and Reduces Microglial Activation after Subacute Cervical Spinal Cord Injury

Neuromodulation has recently garnered attention as a potent approach to improve sensorimotor function following neural injury. After spinal cord injury, electrical stimulation targets sensorimotor circuitry to enhance volitional movement; however, motor neurons are located in the ventral gray matter. Previously, we developed a versatile wireless stimulation system and surgical approach to selectively activate motor neurons caudal to a cervical spinal cord injury. Here, we empirically tested if ventral epidural stimulation is sufficient to promote lasting recovery of skilled motor function. Ventrally stimulated animals exhibited significantly improved forelimb function associated with electrically stimulated motor pathways. Further, stimulation produced increases in neuronal Nr4a1 expression, a subacute reduction in microglia Nr4a1 expression, and a shift from activated toward ramified microglial morphologies in the stimulated ventral gray matter. This study reports the first successful application of ventral spinal stimulation to improve function in an animal model and the first sustained improvement in skilled forelimb reaching when behavioral testing was decoupled from the stimulation.