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

Abstract

SUMMARYRapid escape against visual threats is critical for survival. Whether it requires a permissive mechanism is unknown. Here, we show that osteocalcin (OCN), a protein produced by bone and persisted in the brain, primes rapid visual escape response by increasing excitability of VTA GABAergic neuron subpopulation via OCN-GPR37-cAMP-THIK-1 (K2P13.1) pathway. Knock-out of OCN or its receptor GPR37, and conditional knock-out of GPR37 in VTA GABAergic or glutamatergic neurons caused delayed escape. Reconstituting OCN-GPR37 signaling specifically in VTA was sufficient to restore normal response. Single-cell transcriptomics combined with electrophysiology showed that OCN decreases potassium currents in a subpopulation of VTA GABAergic neurons via GPR37-induced cAMP reduction and subsequent THIK-1 suppression. This elevation of excitability in VTA neuron subpopulation can be recapitulated by HM4Di, an inhibitory chemogenetic GPCR commonly used to suppress neuronal activity. Our study demonstrated that visual behavior requires a bone-derived protein that tunes electrophysiology of central nervous system neurons.Graph AbstractIn briefThe bone-brain axis regulates visual escape behavior.Osteocalcin (OCN), a small protein secreted by bone, plays a permissive role in rapid visual escape. This is achieved through GPR37 receptor expressed in a subpopulation of VTA GABAergic neurons. OCN-GPR37 signaling increases neuronal excitability by decreasing K+ current via THIK-1 channel suppression.HighlightsThe bone-derived protein osteocalcin and its receptor GPR37 in VTA are required for rapid visual escape response.GPR37 is expressed in a subpopulation of VTA GABAergic neurons and primes rapid visual escape.Osteocalcin-GPR37 signaling increases neuronal excitability by suppressing THIK-1 (K2P13.1) channel via cAMP reduction.Activation of HM4Di increases excitability of subpopulation of VTA GABAergic neurons and enhances rapid visual escape.