Estrus-Tracking Cortical Neurons Integrate Social cues and Reproductive states to Adaptively Control Sexually Dimorphic Sociosexual Behaviors

SUMMARY Female sociosexual behaviors, essential for survival and reproduction, are adaptively modulated by ovarian hormones. However, the neural mechanisms integrating internal hormonal states with external social cues to guide these behaviors remain poorly understood. Here we identified primary estrous-sensitive Cacna1h -expressing medial prefrontal (mPFC Cacna1h+ ) neurons that orchestrate adaptive sociosexual behaviors. Bidirectional manipulation of mPFC Cacna1h+ neurons drives opposite-sex-directed behavioral shifts between estrus and diestrus females. In males, these neurons serve opposite functions compared to estrus females, mediating sexually dimorphic effects via anterior hypothalamic outputs. Miniscope imaging reveals mixed-representation of self-estrous states and social target sex in distinct mPFC Cacna1h+ subpopulations, with biased-encoding of opposite-sex social cues in estrus females and males. Mechanistically, ovarian hormone-driven upregulation of Cacna1h -encoded T-type calcium channels underlies estrus-specific activity changes and sexual-dimorphic function of mPFC Cacna1h+ neurons. These findings uncover a prefrontal circuit that integrates internal hormonal states and target-sex information to exert sexually bivalent top-down control over adaptive social behaviors.