Sex differences in brain gene activity could explain why some disorders affect men and women differently

The physical differences between men and women are all too obvious, but the biological divide goes right down to the cellular level in the brain, according to a new study published in the journal Science.

While we have known for a long time that men and women face different risks for brain disorders such as depression and Alzheimer’s, we haven’t always known why. Although this latest research doesn’t directly answer this, it could help us better understand the underlying biology.

Most previous research has focused on broad sections of brain tissue, but in this study, a team of researchers analyzed more than one million nuclei from six different cortical regions from 30 donors.

Decoding brain differences

Previous MRI scans of these brain regions had shown physical differences in size or volume between the sexes. The scientists wanted to see if gene activity matched the physical differences seen on the scans.

The technique they used was single-nucleus RNA sequencing, which allows researchers to examine the genetic instructions within individual cells. Specifically, the focus was on how gene expression varies across different cell types and regions.

The study identified more than 3,000 genes that differ in expression between males and females. These differences included how genes are turned on or off and how active genes are in producing RNA messages that guide protein production. What’s more, they aren’t spread evenly across the brain, as the team explains, “Broader effects of sex on autosomal expression are captured in 13 core signatures with varying cell type versus region specificity.”

For example, the differences were much stronger (a higher number of genes were behaving differently) in certain areas like the fusiform cortex, which is a part of the brain involved in face recognition and complex visual processing.

Some of the strongest variations were seen in glial cells, which insulate neurons, but perhaps not surprisingly, the biggest differences were in the sex chromosome genes (X and Y). However, hundreds of genes across the entire genome are also influenced by sex.

Disease risk

When it comes to disease risk, the study found that some of the genes showing sex differences are the same ones linked to brain conditions that affect men and women differently, such as autism, ADHD, Alzheimer’s disease and mood disorders. “This study substantially advances the breadth, depth, and granularity of knowledge on sex differences in the human brain,” added the team.

The researchers explain that while their study has provided a massive amount of data, it is just the beginning. Future research could focus on when the changes appear and how they are influenced by the environment.

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