Gene regulation by gonadal hormone receptors defines brain sex differences-[snRNA-Seq]

Estradiol establishes neural sex differences in many vertebrates and modulates mood, behavior, and energy balance in adulthood. In the canonical pathway, estradiol exerts its effects through the transcription factor estrogen receptor a (ERa). While ERa has been extensively characterized in breast cancer, the neuronal targets of ERa, and their involvement in brain sex differences, remain largely unknown. Here we generate a comprehensive map of genomic ERa-binding sites within a sexually dimorphic neural circuit that mediates social behaviors. We conclude that ERa orchestrates sexual differentiation of the mouse brain through two mechanisms: establishing two male-biased neuron types and activating a sustained male-biased gene expression program. Collectively, our findings reveal that sex differences in gene expression are defined by hormonal activation of neuronal steroid receptors. The molecular targets we identify may underlie the effects of estradiol on brain development, behavior, and disease. Overall design: Genomic response to estradiol in mouse brain