A hypothalamic dynorphin-KOR pathway that orchestrates male sexual behavior under sexual competition

Abstract

In nature, males often attack rivals before mating, yet how aggression shapes mating strategies remains unclear. Using a laboratory sexual competition model with optogenetics, calcium imaging, and pharmacology, we found that aggressive male mice attack competitors before mating, whereas social males mate promptly. This delay is mediated by Gi-coupled kappa-opioid receptor-expressing GABAergic interneurons in the medial preoptic area (MPOAKOR), recruited by estrogen receptor 1-expressing neurons in the ventrolateral subdivision of the ventromedial hypothalamus (VMHvlEsr1), which inhibit MPOAEsr1 mating neurons. VMHvlEsr1 neurons activate MPOAKOR neurons through direct glutamatergic transmission and indirect disinhibition by suppressing dynorphin release from prodynorphin-expressing arcuate nucleus terminals (ArcPdyn). During rival encounters, aggressive males show a greater MPOA dynorphin decline and stronger MPOAKOR activity than social males. Thus, a VMHvlEsr1/ArcPdyn[->]MPOAKOR[->]MPOAEsr1 circuit gates mating according to prior aggressive experience, explaining how social competition shapes reproductive strategies.