Essential Role of the Anterior Piriform Cortex in Mediating Social Novelty Output via a Top–Down Circuit

Abstract Social novelty is indispensable for a wide range of social behaviors. The medial prefrontal cortex (mPFC), along with other social information hubs, composes the foundational circuitry of social novelty. However, the precise circuit mechanisms that govern social novelty processing remain elusive. The piriform cortex, as the largest olfactory cortex, receives extensive innervation from top‐down centers that dictate social behavior. Here, it is shown that the anterior piriform cortex (APC) exhibited an increase in gamma event incidence during social engagement in male mice. In vivo electrophysiology and fiber photometry reveal that APC pyramidal neurons respond more intensely to novel mice than familiar ones. Intriguingly, silencing APC neurons selectively impairs social novelty processing, yet leaves the basic olfactory discrimination capabilities intact. Moreover, the APC inherits social cues from the mPFC and sends feedback projections to the olfactory bulb (OB) to modulate social novelty. These findings unveil the APC's role as extending well beyond olfaction, encompassing a specialized function in social novelty recognition in male mice.