LAUSR

Significance Heightened intruder-directed aggressive behavior in female mice is displayed during lactation to enable a mother to protect her offspring. Although recent work has identified that the ventromedial nucleus of the hypothalamus plays an important role in governing aggressive behavior, it is unknown how the changing hormones of pregnancy and lactation might regulate this behavior during specific reproductive states. Here, we show that prolactin-responsive neurons are activated during aggression and project to multiple brain regions with known roles in regulating behavior. Through neuron-specific and region-specific deletion of the prolactin receptor, our data reveal that prolactin is an important modulator of maternal aggression. By acting on glutamatergic neurons in the ventromedial nucleus, prolactin restrains maternal aggression, specifically in lactating female mice. Aggressive behavior is rarely observed in virgin female mice but is specifically triggered in lactation where it facilitates protection of offspring. Recent studies demonstrated that the hypothalamic ventromedial nucleus (VMN) plays an important role in facilitating aggressive behavior in both sexes. Here, we demonstrate a role for the pituitary hormone, prolactin, acting through the prolactin receptor in the VMN to control the intensity of aggressive behavior exclusively during lactation. Prolactin receptor deletion from glutamatergic neurons or specifically from the VMN resulted in hyperaggressive lactating females, with a marked shift from intruder-directed investigative behavior to very high levels of aggressive behavior. Prolactin-sensitive neurons in the VMN project to a wide range of other hypothalamic and extrahypothalamic regions, including the medial preoptic area, paraventricular nucleus, and bed nucleus of the stria terminalis, all regions known to be part of a complex neuronal network controlling maternal behavior. Within this network, prolactin acts in the VMN to specifically restrain male-directed aggressive behavior in lactating females. This action in the VMN may complement the role of prolactin in other brain regions, by shifting the balance of maternal behaviors from defense-related activities to more pup-directed behaviors necessary for nurturing offspring.