A hypothalamic dynorphin-KOR pathway that orchestrates male sexual behavior under sexual competition
Year: 2026
Type: preprint
Abstract: SUMMARY 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 (MPOA KOR ), recruited by estrogen receptor 1-expressing neurons in the ventrolateral subdivision of the ventromedial hypothalamus (VMHvl Esr1 ), which inhibit MPOA Esr1 mating neurons. VMHvl Esr1 neurons activate MPOA KOR neurons through direct glutamatergic transmission and indirect disinhibition by suppressing dynorphin release from prodynorphin-expressing arcuate nucleus terminals (Arc Pdyn ). During rival encounters, aggressive males show a greater MPOA dynorphin decline and stronger MPOA KOR activity than social males. Thus, a VMHvl Esr1 /Arc Pdyn →MPOA KOR →MPOA Esr1 circuit gates mating according to prior aggressive experience, explaining how social competition shapes reproductive strategies. HIGHLIGHTS Males with distinct aggression levels exhibit divergent reproductive strategies: aggressive males compete before mating; non-aggressive social males mate promptly. MPOA KOR interneurons act as the long-sought relay, mediating inhibition from VMHvl Esr1 to MPOA Esr1 neurons to delay mating. VMHvl glutamatergic excitation and Arc dynorphin disinhibition collectively activate MPOA KOR neurons. Aggressive males sustain competitor-induced MPOA dynorphin suppression to maintain MPOA KOR in high activity during aggression training.
Authors: Quanchi Lyu, Yang Zheng, Xun Ma, Luping Yin
Institution: Westlake University
Language: English
Subfield: Endocrine and Autonomic Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7211867899