A functional cellular framework for sex and estrous cycle-dependent gene expression and behavior.

Sex hormones exert a profound influence on gendered behaviors. How individual sex hormone-responsive neuronal populations regulate diverse sex-typical behaviors is unclear. We performed orthogonal, genetically targeted sequencing of four estrogen receptor 1-expressing (Esr1) populations and identified 1,415 genes expressed differentially between sexes or estrous states. Unique subsets of these genes were distributed across all 137 transcriptomically defined Esr1 cell types, including estrous stage-specific ones, that comprise the four populations. We used differentially expressed genes labeling single Esr1 cell types as entry points to functionally characterize two such cell types, BNSTpr and VMHvl. We observed that these two cell types, but not the other Esr1 cell types in these populations, are essential for sex recognition in males and mating in females, respectively. Furthermore, VMHvl cell type projections are distinct from those of other VMHvl cell types. Together, projection and functional specialization of dimorphic cell types enables sex hormone-responsive populations to regulate diverse social behaviors.