Activity of spinal RORβ neurons is related to functional improvements following combination treatment after complete SCI

Abstract

SUMMARYVarious strategies targeting spinal locomotor circuitry have been associated with functional improvements after spinal cord injury (SCI). However, the neuronal populations mediating beneficial effects remain largely unknown. In a mouse model of complete SCI, virally-delivered BDNF (AAV-BDNF) activates hindlimb stepping and causes hyperreflexia, whereas sub-motor threshold epidural stimulation (ES) reduced BDNF-induced hyperreflexia. Given their role in gating proprioceptive afferents and potential convergence point of BDNF and ES, we hypothesized that an enhanced excitability of inhibitory RORβ neurons would be associated with locomotor improvements. Ex vivo spinal slice recordings revealed that the excitability of RORβ neurons was decreased in mice with poor locomotor function after SCI, but was similar between the uninjured and ‘best stepping’ SCI groups. Further, chemogenetic excitation of RORβ neurons reduced BDNF-induced hyperreflexia and improved stepping, similar to ES. Our findings identify inhibitory RORβ neurons as a target population to limit hyperreflexia and enhance locomotor function after SCI.