Targeted neuromodulation of spinal interneurons enhances breathing in chronic spinal cord injury

Respiratory dysfunction is a debilitating consequence of cervical spinal cord injury (cSCI) with few available treatment options. Restoring function in the chronic phase is challenging due to the limited regenerative capacity of the adult central nervous system. This study investigates the targeted neuromodulation of cervical excitatory interneurons (eINs) to improve functional respiratory recovery in chronic cSCI. Cervical eINs, crucial for acute injury recovery, showed no reduction in numbers at 8- and 12-weeks post injury, highlighting their potential as neuromodulatory targets in the chronic phase. Targeted chemogenetic activation of these cervical eINs significantly improved breathing at 6- and 12-weeks post-cSCI. Repeated stimulation induced dendritic plasticity in respiratory spinal neurons without altering soma size. Notably, stimulation-mediated recovery at 12 weeks was comparable to that observed at 6 weeks underscoring the sustained efficacy of this approach. These findings highlight the potential of targeted neuromodulation of spinal interneurons to improve breathing in the chronic phase of SCI. TEASER: Targeted stimulation of spinal neurons improves breathing long after cervical spinal cord injury, offering new hope for treatments.