The multi-stage plasticity in the aggression circuit underlying the winner effect.

Winning increases the readiness to attack and the probability of winning, a widespread phenomenon known as the "winner effect". Here, we reveal a transition from target-specific to generalized aggression enhancement over 10 days of winning in male mice, which is supported by three stages of plasticity in the ventrolateral part of the ventromedial hypothalamus (VMHvl), a critical node for aggression. Over 10-day winning, VMHvl cells experience monotonic potentiation of long-range excitatory inputs, a transient local connectivity strengthening, and a delayed excitability increase. These plasticity events are causally linked. Optogenetically coactivating the posterior amygdala (PA) terminals and VMHvl cells potentiates the PA-VMHvl pathway and triggers the cascade of plasticity events as those during repeated winning. Optogenetically blocking PA-VMHvl synaptic potentiation eliminates all winning-induced plasticity. These results reveal the complex Hebbian synaptic and excitability plasticity in the aggression circuit during winning that ultimately leads to an increase in "aggressiveness" in repeated winners.

A hypothalamic pathway that suppresses aggression toward superior opponents.

Aggression is costly and requires tight regulation. Here we identify the projection from estrogen receptor alpha-expressing cells in the caudal part of the medial preoptic area (cMPOAEsr1) to the ventrolateral part of the ventromedial hypothalamus (VMHvl) as an essential pathway for modulating aggression in male mice. cMPOAEsr1 cells increase activity mainly during male-male interaction, which differs from the female-biased response pattern of rostral MPOAEsr1 (rMPOAEsr1) cells. Notably, cMPOAEsr1 cell responses to male opponents correlated with the opponents' fighting capability, which mice could estimate based on physical traits or learn through physical combats. Inactivating the cMPOAEsr1-VMHvl pathway increased aggression, whereas activating the pathway suppressed natural intermale aggression. Thus, cMPOAEsr1 is a key population for encoding opponents' fighting capability-information that could be used to prevent animals from engaging in disadvantageous conflicts with superior opponents by suppressing the activity of VMHvl cells essential for attack behaviors.