Recovery of walking after paralysis by regenerating characterized neurons to their natural target region

Axon regeneration can be induced across anatomically complete spinal cord injury (SCI), but robust functional restoration has been elusive. Whether restoring neurological functions requires directed regeneration of axons from specific neuronal subpopulations to their natural target regions remains unclear. To address this question, we applied projection-specific and comparative single-nucleus RNA sequencing to identify neuronal subpopulations that restore walking after incomplete SCI. We show that chemoattracting and guiding the transected axons of these neurons to their natural target region led to substantial recovery of walking after complete SCI in mice, whereas regeneration of axons simply across the lesion had no effect. Thus, reestablishing the natural projections of characterized neurons forms an essential part of axon regeneration strategies aimed at restoring lost neurological functions. , Editor’s summary Although several experimental approaches have shown positive results in axonal regeneration after spinal cord injury (SCI), complete recovery of motor functions remains an elusive target. Squair et al . hypothesized that restoration of complete axonal projection of a selected neuronal population to their natural target could promote better functional recovery. After using single-cell RNA sequencing to identify the most promising neuronal population, the authors showed that promoting axonal growth and path guidance to their natural target in this population restored walking in mice after complete SCI. By contrast, broad axonal restoration across the lesion had no effect, suggesting that a more targeted approach is necessary for functional recovery after SCI. —Mattia Maroso , Restoring axonal projections of selected neurons to their target is critical for functional recovery after spinal cord injury in mice.