A neuronal population in the bed nucleus of the stria terminalis mediating pup-directed aggression in male mice

Abstract The mammalian brain orchestrates a broad range of social behaviors, including interactions with conspecific young. Sexually inexperienced male mice typically exhibit pup-directed aggression, whereas fathers display caregiving behaviors. Although this behavioral transition provides a valuable framework for understanding life stage-dependent modulation of social behavior, the underlying mechanisms remain unclear. The posterior bed nucleus of the stria terminalis (BST), particularly its principal subdivision (BSTpr), is a critical node regulating pup-directed aggression. Within this region, neurons expressing estrogen receptor 1 ( Esr1 ) promote pup-directed aggression in female mice; however, the specific neuronal subtypes mediating this behavior in males remain unknown. Here, reanalysis of single-cell transcriptomic datasets shows that neurons expressing (+) cocaine- and amphetamine-regulated transcript prepropeptide ( Cartpt ) constitute a subset of Esr1 + neurons within the BST. Exposure to pups selectively increased c-fos expression, a marker of neuronal activation, in BSTpr Cartpt + neurons in infanticidal virgin males. Chemogenetic activation of these neurons enhanced pup-directed aggression, whereas their ablation suppressed infanticide. Anatomical analyses demonstrated that BSTpr Cartpt + neurons received direct inhibitory inputs from the anterior commissure nucleus (ACN), a region associated with parental behavior. Additionally, inhibitory transmission from the ACN to BSTpr Cartpt + neurons was enhanced in fathers. Together, these findings identify BSTpr Cartpt + neurons as key mediators of pup-directed aggression in male mice, suggesting a neural circuit mechanism underlying the transition from aggression to parental care.