Oestradiol establishes neural sex differences in many vertebrates1–3 and modulates mood, behaviour and energy balance in adulthood4–8. In the canonical pathway, oestradiol exerts its effects through the transcription factor oestrogen receptor-α (ERα)9. Although ERα has been extensively characterized in breast cancer, the neuronal targets of ERα, and their involvement in brain sex differences, remain largely unknown. Here we generate a comprehensive map of genomic ERα-binding sites in a sexually dimorphic neural circuit that mediates social behaviours. We conclude that ERα 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 oestradiol on brain development, behaviour and disease.

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Women and men differ in disease prevalence, symptoms, and progression rates for many psychiatric and neurological disorders. As more preclinical studies include both sexes in experimental design, an increasing number of sex differences in physiology and behavior have been reported. In the brain, sex‐typical behaviors are thought to result from sex‐specific patterns of neural activity in response to the same sensory stimulus or context. These differential firing patterns likely arise as a consequence of underlying anatomic or molecular sex differences. Accordingly, gene expression in the brains of females and males has been extensively investigated, with the goal of identifying biological pathways that specify or modulate sex differences in brain function. However, there is surprisingly little consensus on sex‐biased genes across studies and only a handful of robust candidates have been pursued in the follow‐up experiments. Furthermore, it is not known how or when sex‐biased gene expression originates, as few studies have been performed in the developing brain. Here we integrate molecular genetic and neural circuit perspectives to provide a conceptual framework of how sex differences in gene expression can arise in the brain. We detail mechanisms of gene regulation by steroid hormones, highlight landmark studies in rodents and humans, identify emerging themes, and offer recommendations for future research. This article is categorized under: Nervous System Development > Vertebrates: General Principles Gene Expression and Transcriptional Hierarchies > Regulatory Mechanisms Gene Expression and Transcriptional Hierarchies > Sex Determination

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Females and males display differences in neural activity patterns, behavioral responses, and incidence of psychiatric and neurological diseases. Sex differences in the brain appear throughout the animal kingdom and are largely a consequence of the physiological requirements necessary for the distinct roles of the two sexes in reproduction. As with the rest of the body, gonadal steroid hormones act to specify and regulate many of these differences. It is thought that transient hormonal signaling during brain development gives rise to persistent sex differences in gene expression via an epigenetic mechanism, leading to divergent neurodevelopmental trajectories that may underlie sex differences in disease susceptibility. However, few genes with a persistent sex difference in expression have been identified, and only a handful of studies have employed genome-wide approaches to assess sex differences in epigenomic modifications. To date, there are no confirmed examples of gene regulatory elements that direct sex differences in gene expression in the brain. Here, we review foundational studies in this field, describe transcriptional mechanisms that could act downstream of hormone receptors in the brain, and suggest future approaches for identification and validation of sex-typical gene programs. We propose that sexual differentiation of the brain involves self-perpetuating transcriptional states that canalize sex-specific development.