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Hormone Surge Unlocks Sex-Biased Genes

Written by Bethany Hoernfeldt, Science Writer

Researchers have found that a neonatal hormone surge triggers a lasting male-biased gene expression programme in the developing brain.

Gonadal steroid hormones, such as oestrogen, greatly influence sex differences in neural activity and behaviour. However, the intricacies of this process, and their effect on brain development early in life, have long been shrouded in mystery. While focussing on a brain region involved in the regulation of mammalian sex-typical behaviours, scientists found that sex differences in gene expression and brain development are heavily driven by oestradiol – an oestrogen steroid hormone. These findings, published in Nature, detail the genes involved in this process, and may also offer important insights into the impact of oestrogen on brain development, behaviour, and disease.

Physical differences during development

Sex hormones regulate sex differences in neural activity and behaviour in mammals. During critical periods of development, these hormones rewire neural circuitry and influence our innate social behaviour in adulthood. The hormone oestrogen regulates hundreds of genes by binding to oestrogen receptor-α (ERα) – a transcription factor that sets in motion sex-specific changes in gene expression and cell number. However, little is known about the precise genomic and genetic mechanisms at play.

A neonatal hormone surge

Researchers compared the brains of adult mice to the developing brains of young pups, with special focus on the posterior bed nucleus of the stria terminalis (BNSTp). The BNSTp is a brain area vital to the regulation of sex-typical behaviours, such as mating and territorial behaviour. In male rodents and humans, the area is 1.5-2 times larger than that of females. In mice, this is linked to a spike in testosterone at birth. The hormone is then converted into oestradiol, which promotes neuron survival and subsequently causes those areas of the brain to become larger. Improved connectivity in those regions is then likely to influence differences in behaviour relative to females.

A transient surge with long-lasting effects on development

Furthermore, the scientists found that changes in neural activity emerged over the course of 2 weeks following birth, despite neural oestrogen being degraded far quicker. This suggests that either temporary or permanent epigenomic modifications are caused during the neonatal hormone surge. The researchers also suggested that the male-specific gene expression programme, resulting from the spike, establishes neuronal connectivity that differs from that of females. This potentially means that ERα activation during puberty or other critical periods of development would evoke a very different response from what is observed in the female brain.

Lastly, and perhaps most importantly, the scientists identified 358 genes that are regulated by oestrogen. Together, these observations further demystify sex differences in neural activity and behaviour, and may direct ground-breaking research into the impact of oestrogen on brain development, behaviour, and disease.

Image Credit: Canva