Aggression is controlled by the olfactory system in many animal species. In male mice, territorial and infant-directed aggression are tightly regulated by the vomeronasal organ (VNO), but how diverse subsets of sensory neurons convey pheromonal information to limbic centers is not yet known. Here, we employ genetic strategies to show that mouse vomeronasal sensory neurons expressing the G protein subunit Gαi2 regulate male–male and infant-directed aggression through distinct circuit mechanisms. Conditional ablation of Gαi2 enhances male–male aggression and increases neural activity in the medial amygdala (MeA), bed nucleus of the stria terminalis, and lateral septum. By contrast, conditional Gαi2 ablation causes reduced infant-directed aggression and decreased activity in MeA neurons during male–infant interactions. Strikingly, these mice also display enhanced parental behavior and elevated neural activity in the medial preoptic area, whereas sexual behavior remains normal. These results identify Gαi2 as the primary G protein α-subunit mediating the detection of volatile chemosignals in the apical layer of the VNO, and they show that Gαi2+ VSNs and the brain circuits activated by these neurons play a central role in orchestrating and balancing territorial and infant-directed aggression of male mice through bidirectional activation and inhibition of different targets in the limbic system.

Estradiol derived from neural aromatization of testosterone plays a key role in the organization and activation of neural structures underlying male behaviors. This study evaluated the contribution of the estrogen receptor (ER) β in estradiol-induced modulation of social and mood-related behaviors by using mice lacking the ERβ gene in the nervous system. Mutant males exhibited reduced social interaction with same-sex congeners and impaired aggressive behavior. They also displayed increased locomotor activity, and reduced or unaffected anxiety-state level in three paradigms. However, when mice were exposed to unescapable stress in the forced swim and tail suspension tests, they spent more time immobile and a reduced time in swimming and climbing. These behavioral alterations were associated with unaffected circadian and restraint stress-induced corticosterone levels, and unchanged number of tryptophan hydroxylase 2-immunoreactive neurons in the dorsal raphe. By contrast, reduced mRNA levels of oxytocin and arginine-vasopressin were observed in the bed nucleus of stria terminalis, whereas no changes were detected in the hypothalamic paraventricular nucleus. The neural ERβ is thus involved to different extent levels in social and mood-related behaviors, with a particular action on oxytocin and arginine-vasopressin signaling pathways of the bed nucleus of stria terminalis, yet the involvement of other brain areas cannot be excluded.aggressive behavior of mutant males can be observed in another behavioral test using a neutral testing cage 14 .Furthermore, yet another study on ERβ knockout males showed no impairment of social recognition memory 15 .Concerning mood-related behaviors, few studies have been conducted in male mice and rats. This either resulted in minor effects induced by global ERβ knockout in mice 16 , or significant changes following chronic administration of selective ERβ agonists or androgen metabolites acting at ERβ on the anxiety state level in rats [17][18][19] . By comparison, more studies are available on female behaviors and these all converge on the role of ERβ in mediating estradiol effects 6,16,[20][21][22][23] . This involves at least in part the maintenance of serotonergic neurons and regulation of the expression of tryptophan hydroxylase (TPH), the key enzyme involved in serotonin synthesis in the dorsal raphe 24 .In this context, the present work was undertaken in order to evaluate in the same study the neural role of ERβ in social and mood-related behaviors using male mice lacking the ERβ gene in the whole nervous system, without interference with peripheral effects of this receptor. For this purpose, control and mutant mice were subjected to behavioral tests that measure social interaction, anxiety-related behavior (elevated O-maze, dark-light box and open field), locomotor activity, despair-like behavior (forced swim and tail suspension tests), sucrose preference test, and aggressive behavior (resident-intruder test). Corticosterone levels were measured under basal circadian and induce...