Hypothalamic Neurons Integrate Male Olfactory Cues And Modulate Inter-male Aggression

Instinctive behaviors are a series of activities to ensure the survival and the reproduction of animals,which are highly conserved in interspecies.The emergence of the behaviors are the animals'appropriate strategies to the external changing world.Therefore,the perception and integration of external sensory information is essential for animals'decision on behavior.As one of the innate behaviors,aggression is critical for male to compete for survival resources in nature.A large number of studies have found that the hypothalamus plays a key role in the regulation of aggression.Moreover,the aggression of male mice extremely depends on the guidance of olfactory cues.However,how the hypothalamic regions receive,integrate and transmit olfactory cues under physiological conditions to trigger aggression remains unclear.In this study,by recording of neuronal activities in behaving mice,we found that neurons expressing dopamine transporter in the ventral premammillary nucleus(PMv^DAT+)of the hypothalamus responded strongly to male urine cues but not to urine of castrated male mice,female mice,newborn mice and rats.Further,we showed that the major urinary proteins elicited the reaction of these neurons.What is more,PMv^DAT+were preferentially activated during the inter-male social interactions and attack,especially in genital sniffing.When PMv^DAT+were inhibited,male mice lost their preference for male urine and showed decreased attack against male invaders.Conversely,activation of these cells promoted aggression as well as urine marking in male mice.Next,in order to explore the source of olfactory information which PMv^DAT+received,we used Trpc2 knockout mice to specifically destroy vomeronasal organ's perception to pheromones.The results showed that the response of PMv^DAT+to male mice urine decreased sharply in the knockout males,indicating that PMv^DAT+integrated olfactory information from vomeronasal organ.Furthermore,using virus tracing,electrophysiological recording,fiber photometry and chemo-genetics,we confirmed that male urine signal was transmitted via the bed nucleus of ventral stria terminalis from the vomeronasal organ to PMv^DAT+.Taken together,these results highlight the specialized function of relaying the conspecific male cues to trigger appropriate behaviors in PMv^DAT+.Our data provide important insights into the neural circuit mechanism underlying sex biased olfactory information processing and regulation of sexually dimorphic social behaviors.