Histone deacetylase inhibitor treatment induces postpartum-like maternal behavior and immediate early gene expression in the maternal neural pathway in virgin mice

The peripartum period is associated with the onset of behaviors that shelter, feed and protect young offspring from harm. The neural pathway that regulates caregiving behaviors has been mapped in female rats and is conserved in mice. However, rats rely on late gestational hormones to shift their perception of infant cues from aversive to attractive, whereas laboratory mice are "spontaneously" maternal, but their level of responding depends on experience. For example, pup-naive virgin female mice readily care for pups in the home cage, but avoid pups in a novel environment. In contrast, pup-experienced virgin mice care for pups in both contexts. Thus, virgin mice rely on experience to shift their perception of infant cues from aversive to attractive in a novel context. We hypothesize that alterations in immediate early gene activation may underlie the experience-driven shift in which neural pathways (fear/avoidance versus maternal/approach) are activated by pups to modulate context-dependent changes in maternal responding. Here we report that the effects of sodium butyrate, a drug that allows for an amplification of experience-induced histone acetylation and gene expression in virgins, are comparable to the natural onset of caregiving behaviors in postpartum mice and induce postpartum-like patterns of immediate early gene expression across brain regions. These data suggest that pups can activate a fear/defensive circuit in mice and experience-driven improvements in caregiving behavior could be regulated in part through decreased activation of this pathway.