Corticotropin-releasing hormone signaling from prefrontal cortex to lateral septum suppresses interaction with familiar mice

Social preference, the decision to interact with one member of the same species over another, is a key feature of optimizing social interactions. Thus, adult rodents favor interacting with novel conspecifics over familiar ones but whether this preference for social novelty stems from neural circuits facilitating interactions with novel conspecifics or suppressing interactions with familiar ones remains unknown. Here, we identify neurons in the infra-limbic area (ILA) of the mouse prefrontal cortex that express the neuropeptide corticotropin-releasing hormone (CRH) and project to the dorsal region of the rostral lateral septum (rLS). We show how release of CRH during familiar encounters disinhibits rLS neurons, thereby suppressing social interactions with familiar mice and contributing to social novelty preference. We further demonstrate how the maturation of CRH expression in ILA during the first two post-natal weeks enables the developmental shift from a preference for littermates in juveniles to a preference for novel mice in adults. Taken together, our findings suggest that the developmental maturation of CRH in ILA and its later release onto rLS is critical for controlling the preference for socially novel encounters exhibited by adult mice.