Integrating reproductive states and social cues in the control of sociosexual behaviors

  • Cell. 2025 Jun 26;188(13):3530-3549.e24. doi: 10.1016/j.cell.2025.04.035.
Yuping Wang  1 ,  Xinli Song  1 ,  Xiangmao Chen  2 ,  Ying Zhou  1 ,  Jihao Ma  1 ,  Fang Zhang  1 ,  Liqiang Wei  1 ,  Guoxu Qi  1 ,  Nakul Yadav  3 ,  Benjie Miao  1 ,  Yiming Yan  1 ,  Guohua Yuan  1 ,  Da Mi  1 ,  Priyamvada Rajasethupathy  3 ,  Ines Ibañez-Tallon  3 ,  Xiaoxuan Jia  1 ,  Nathaniel Heintz  4 ,  Kun Li  5
Affiliations
  • 1. IDG/McGovern Institute for Brain Research at Tsinghua, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
  • 2. Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China.
  • 3. The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
  • 4. The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA. Electronic address: [email protected].
  • 5. IDG/McGovern Institute for Brain Research at Tsinghua, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China. Electronic address: [email protected].
PMID: 40398420 DOI: 10.1016/j.cell.2025.04.035
Abstract

Female sociosexual behaviors, essential for survival and reproduction, are modulated by ovarian Hormones and triggered in the context of appropriate social cues. Here, we identify primary estrous-sensitive Cacna1h-expressing medial prefrontal cortex (mPFCCacna1h+) neurons that integrate hormonal states with recognition of potential mates to orchestrate these complex cognitive behaviors. Bidirectional manipulation of mPFCCacna1h+ neurons shifts opposite-sex-directed social behaviors between estrus and diestrus females via anterior hypothalamic outputs. In males, these neurons serve opposite functions compared with 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 cues in estrus females and males. Mechanistically, ovarian-hormone-induced Cacna1h upregulation enhances T-type rebound excitation after oxytocin inhibition, driving estrus-specific activity changes and the sexually 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.

Keywords
Cacna1h; T-type calcium channels; anterior hypothalamic nucleus; estrous states; mPFC; mixed selectivity; oxytocin; prefrontal cortex; sex differences; sociosexual behavior.
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