Sex differences in brain in response to midlife stress linke
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Men and women whose mothers experienced stressful events during pregnancy regulate stress differently in the brain 45 years later, results of a long-term study demonstrate.

In a unique sample of 40 men and 40 women followed from the womb into their mid-forties, the brain imaging study showed that exposure during fetal development to inflammation-promoting natural substances called cytokines, produced by mothers under negative stress, results in sex-associated differences in how the adult brain responds to negative stressful situations more than 45 years after birth.

The researchers found that abnormal levels of pro-inflammatory cytokines produced in mothers during pregnancy and the balance between pro-inflammatory and anti-inflammatory cytokines affect brain development differences by sex in their offspring that continue throughout life.

Researchers used functional MRI, which measures brain activity by showing differences in blood flow within and between different areas of the brain. The researchers found that exposure to pro-inflammatory cytokines in the womb was associated with sex differences in how areas of the brain are activated and communicate with one another under negative stressful conditions in midlife.

--For example, they found that in both sexes, lower maternal levels of TNF? a pro-inflammatory cytokine, were significantly associated with higher activity in the hypothalamus, a region of the brain that, among other functions, coordinates brain activity that regulates the release of stress hormones, like cortisol.

--In contrast, lower levels of TNF? were also associated with more active communication between the hypothalamus and the anterior cingulate in men only. The anterior cingulate is an area of the brain associated with impulse control and emotion.

--In women only, higher prenatal exposure to IL-6 was associated with higher levels of activity in the hippocampus, a brain region important for inhibitory control of arousal.

--Lastly, they found that the ratio between TNF? and the anti-inflammatory cytokine IL-10 was associated with sex-dependent effects on activity in the hypothalamus and its communication with the hippocampus, which provides inhibitory control of arousal in the hypothalamus under stress.

"Given that these psychiatric disorders are developing differently in the male and female brain, we should be thinking about sex-dependent targets for early therapeutic intervention and prevention," says the author.

Proceedings of the National Academy of Sciences
Source: https://doi.org/10.1073/pnas.2014464118
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