Corticotropin-releasing hormone signaling from prefrontal cortex to lateral septum supports social novelty preference

Abstract Social preference, the decision to interact with one member of the same species over another, is a key feature of optimizing social interactions. In rodents, social preference relies on both extrinsic factors, such as sex, strain and kinship, and intrinsic ones, such as the memory of previous encounters, which favors interactions with novel compared to familiar animals (social novelty preference). At present, it is unclear which neuronal circuits guide social preferences and whether such circuits promote social interactions with the preferred individuals or suppress interactions with the non-preferred ones. Although both the infra-limbic area of the pre-frontal cortex (ILA) and the lateral septum (LS) have been shown to support social novelty preference, the neuronal circuits and molecular mechanisms by which these brain regions interact to regulate social interactions are unknown. Here, we identify a population of inhibitory neurons in ILA that express the neuropeptide corticotropin releasing hormone (CRH) and project to the rostro-dorsal region of LS (rdLS). Release of CRH from ILA in rdLS during interactions with familiar mice disinhibits rdLS neurons, thereby suppressing interactions with familiar mice and contributing to social novelty preference. We further demonstrate how the maturation of CRH expression 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.