Revealed: How Male and Female Brain Cells Differ in Gene Activity
By analysing more than a million brain cells, researchers have uncovered widespread differences in patterns of gene activity between male and female brains.
The work, which defined sex on the basis of a person’s combination of sex chromosomes, could help to explain why the risk of developing some brain conditions — such as schizophrenia and Alzheimer’s disease — differs between males and females.
Although the differences were subtle, the team identified more than 100 genes that showed consistent variation in their expression between males and females across several brain regions. The work was published on 16 April in Science1.
“Having these gene-expression signatures provides a molecular handle to understanding the biology of how the brains of men and women might be functioning slightly differently in the context of the different hormonal environments that their bodies produce,” says Jessica Tollkuhn, a neuroscientist and molecular biologist at Cold Spring Harbor Laboratory in New York. She adds that “understanding sex differences in disease susceptibility could lead to better treatments to benefit everyone”.
Subtle differences
Previous studies2,3 have documented sex differences when it comes to a person’s risk of developing various neurological conditions. For example, schizophrenia, attention deficit hyperactivity disorder (ADHD) and Parkinson’s disease are more common in biological males — who typically have XY sex chromosomes. By contrast, Alzheimer’s disease and mood disorders such as depression and anxiety tend to be more common in females, whose sex chromosomes are usually XX.
“What underlies that has been a central question,” says Tollkuhn. Sex differences in the brain tend to be “extremely subtle”, she explains. “Most of the brain doesn’t show sex differences in its day-to-day function.”
However, molecular-level differences in the expression of genes between male and female brain cells could “modulate the impact of disease variants”, says study co-author Alex DeCasien, a computational and evolutionary biologist at the US National Institute of Mental Health in Bethesda, Maryland.
To explore this, DeCasien and her colleagues studied cells from six regions of the brain’s cortex, identifying some 680,000 excitatory neurons and 290,000 inhibitory neurons, as well as 270,000 glial and other cells in tissue samples from 30 people.
In an analysis of more than 4,300 genes, the team reported that sex accounted for less than 1% of variation in gene expression across the brain cells. “This finding fits with what we already know about human variation — there is a lot more variation within a sex than between sexes,” says Donna Maney, a neuroscientist at Emory University in Atlanta, Georgia.
But the study also identified 3,382 genes that showed sex-biased expression in at least one of the six brain regions. A closer look at these genes revealed a set of 133 genes with consistent sex differences in their average expression levels across all cell types and all regions studied. “That’s very much a ground zero for the molecular effects of sex,” says study co-author Armin Raznahan, a child and adolescent psychiatrist also at the National Institute of Mental Health.
Most of the genes they identified are not located on sex chromosomes, but many of them can be activated by sex hormones such as oestrogen and testosterone. “That still leaves open a huge space for those autosomal sex differences in expression to represent environmental factors that we didn’t measure within our study,” notes Raznahan. “And some of those environmental factors have to do with gendered experience of the world.”
Snapshot of gene expression
Maney says that it is still difficult to understand the mechanisms that underlie the effect of sex on gene expression in the brain when it comes to brain disorders. The current study “gives a snapshot of gene expression at one moment in time”, she says. But gene expression can be influenced by various environmental and health factors.
“Given that the brain is remarkably and exquisitely plastic, even large sex differences in gene expression can’t be attributed to an innate developmental program driven only by chromosomes and hormones,” adds Maney.
DeCasien and Raznahan agree. “In humans, sex and gender are profoundly entangled. And that entanglement only elaborates over the lifespan,” says Raznahan. The current work isn’t “the type of study that can unambiguously separate sex as a primary cause for the associated gene-expression differences versus gendered environmental effects”, he says. He adds that further studies in different populations will be needed to confirm the findings.
doi: https://doi.org/10.1038/d41586-026-01227-y
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