Gpr158 deficiency alleviates co-occurring motor and anxiety-like deficits after spinal cord injury in a partially dissociable manner.

Spinal cord injury (SCI) is traditionally viewed as a neurological disorder characterized predominantly by motor dysfunction, yet anxiety-like and social behavioral abnormalities frequently co-occur and substantially impair functional outcomes. Whether motor and anxiety-like behavioral impairments are mechanistically coupled or regulated through partially independent pathways remains unclear. Here, we demonstrate that SCI induces a robust co-occurrence of motor deficits and anxiety-like/social behavioral abnormalities in mice - a phenotype we conceptually term 'motor-emotional comorbidity' to highlight its clinical relevance. Using G protein-coupled receptor 158 (Gpr158) knockout mice, we showed that loss of Gpr158 markedly ameliorated anxiety-like and social behavioral abnormalities following SCI, while exerting a more modest effect on motor recovery. Multidimensional behavioral analyses and mediation effect models revealed that improvements in anxiety-like and social behaviors were only partially explained by motor recovery, supporting a model of partially dissociable regulation. Together, these findings suggest that SCI in mice involves co-occurring motor and anxiety-like deficits and identify Gpr158 as a molecule that affects both motor and anxiety-like outcomes.