Integrating Reproductive States and Social Cues in the control of Sociosexual Behaviors

Female sociosexual behaviors, essential for survival and reproduction, are adaptively modulated by ovarian hormones and triggered in the context of appropriate external social cues. Here we identify primary estrous-sensitive Cacna1h-expressing medial prefrontal (mPFCCacna1h+) neurons that integrate hormonal states with recognition of potential mates to orchestrate these complex cognitive behaviors. Bidirectional manipulation of mPFCCacna1h+ neurons drives opposite-sex-directed behavioral shifts between estrus and diestrus females via anterior hypothalamic outputs. In males, these neurons serve opposite functions compared to estrus females. Miniscope imaging reveals mixed-representation of self-estrous states and social target sex in distinct mPFCCacna1h+ 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 mPFCCacna1h+ 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. For pathway-specific TRAP-seq, retrograde viruses rAAV2-EGFP-Rpl10a were injected into the AHNc of wild type mice. The mPFC regions from male and female mice with AHNc virus injection were used for independent TRAP replicates. For cell type-specific TRAPseq, three male and eight female Cacna1h-Cre::EGFP-Rpl10a mice of four distinct estrous cycles were used for independent TRAP replicates. NOTE: Additional sample records (GSM9014308-GSM9014343) have been included; both raw and processed data have been replaced for GSM8661153, GSM8661154 records on May 29, 2025.