A molecularly defined mPFC-BLA circuit specifically regulates social novelty preference

Social novelty preference is an important aspect of social interaction for evaluating new threats and opportunities for survival, but the underlying neuronal mechanism remains unclear. Here, we identify a molecularly defined medial prefrontal cortex (mPFC) excitatory neuron subtype, located in layer 5 expressing <i>Il1rapl2</i>, which is highly associated with social deficit disorders in genome-wide association studies and might be responsible for regulating social novelty preference. Using an <i>Il1rapl2</i>-Cre mouse line, we show that chemogenetic activation of the mPFC <i>Il1rapl2</i>-expressing neurons impairs social novelty preference but with little effect on sociability. In addition, fiber photometry recording indicates that this neuron subtype is inhibited when mice interact with novel but not with familiar mice. Furthermore, viral tracing and terminal manipulation reveal that basolateral amygdala (BLA)-projecting <i>Il1rapl2</i>⁺ neurons mediate the social novelty preference. Thus, our study uncovers a molecularly defined mPFC-BLA circuit that specifically regulates social novelty preference, highlighting that specific neuron subtypes and circuits could modulate distinct aspects of social behaviors.