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.
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