A circuit linking dentate gyrus and retrosplenial granular cortex regulates fracture healing in male mice

Traumatic brain injury often accelerates fracture repair, but the neural circuits linking brain state to bone healing remain unclear. Here we show that, in male mice, a hippocampal–cortical circuit linking the dentate gyrus (DG) and the retrosplenial granular cortex (RSGc) regulates repair after bone injury. Skeletal injury increased activity–associated labeling in both regions. Inhibiting excitatory neurons in the DG or RSGc, or suppressing neuronal populations associated with the DG–RSGc pathway, accelerated repair, whereas activating DG or RSGc excitatory neurons delayed healing. RSGc activation counteracted the pro–healing effect of DG inhibition, supporting DG–RSGc circuit dependence under the tested conditions. Inhibitory circuit manipulations were associated with increased circulating neuropeptide Y, macrophage IDO1 induction at the repair site, and elevated L–kynurenine, which promoted osteogenic differentiation. Pharmacological blockade and rescue experiments support an NPY–IDO1–kynurenine effector arm linking central circuit state to peripheral bone repair. This study identifies a brain circuit that influences bone repair in male mice by engaging immune cells and metabolism, suggesting new ways to understand why brain injury can accelerate fracture healing.