A bone-derived hormone permits rapid visual escape via GPR37 receptor in a subpopulation of VTA GABAergic neurons

Rapid escape from visual threats is essential for survival, yet the mechanisms establishing its “permissive state” remain poorly understood. Here, we demonstrate that osteocalcin (OCN), a bone-derived hormone, permits rapid visual escape by enhancing the excitability of a ventral tegmental area (VTA) GABAergic neuron subpopulation through the OCN-G Protein-Coupled Receptor 37 (GPR37)-cAMP-TWIK-related halothane-inhibited potassium channel (THIK-1) pathway. Loss of OCN, loss of its receptor GPR37, or conditional deletion of GPR37 in VTA GABAergic or glutamatergic neurons delays escape responses, while reconstituting OCN-GPR37 signaling in the VTA restores normal behavior. Single-cell transcriptomics and electrophysiology reveal that OCN suppresses THIK-1 potassium currents via GPR37-mediated cyclic AMP (cAMP) reduction, thereby increasing neuronal excitability. These findings reveal a novel mechanism through which a bone-derived hormone modulates the excitability of co-releasing neurons to facilitate rapid escape, offering new insights into the regulation of survival behaviors by the bone-brain metabolic axis.