A single vomeronasal receptor promotes intermale aggression through dedicated hypothalamic neurons

The pheromonal information received by the vomeronasal system plays a crucial role in regulating social behaviors such as aggression in mice. Despite accumulating knowledge of the brain regions involved in aggression, the specific vomeronasal receptors and the exact neural circuits responsible for pheromone-mediated aggression remain unknown. Here, we identified one murine vomeronasal receptor, Vmn2r53, that is activated by urine from males of various strains and is responsible for evoking intermale aggression. We prepared a purified pheromonal fraction and Vmn2r53 knockout mice and applied genetic tools for neuronal activity recording, manipulation, and circuit tracing to decipher the neural mechanisms underlying Vmn2r53-mediated aggression. We found that Vmn2r53-mediated aggression is regulated by specific neuronal populations in the ventral premammillary nucleus and the ventromedial hypothalamic nucleus. Together, our results shed light on the hypothalamic regulation of male aggression mediated by a single vomeronasal receptor. [Display omitted] •Vmn2r53 is activated by male urinary pheromones from various mouse strains•Sensory input from Vmn2r53 is necessary and sufficient to promote male aggression•Social experience alters the VMHvl response to Vmn2r53-mediated signaling•PMv relays Vmn2r53-mediated signaling to VMHvl Pheromonal information is known to be crucial for regulating intermale aggression, but how do pheromones trigger aggression? Itakura and Murata et al. identify one specific murine vomeronasal receptor, Vmn2r53, that receives male urinary pheromone. Sensory input from Vmn2r53 activates the hypothalamic circuit with a social-experience-dependent modulation, resulting in aggression enhancement.