How social stress makes your brain vulnerable to depression

Social stress can trigger changes in the brain that open the door to depression. Experiments in human brains and mice suggest that experiences such as bullying make the blood-brain barrier leaky, letting inflammation into the brain and altering mood.

Anything that threatens your sense of worth is a type of social stress – be it bullying, body-image issues, social anxiety or extreme shyness. To see how such stresses might affect mood, Scott Russo of the Icahn School of Medicine at Mount Sinai, New York, and his team exposed 24 small, subordinate mice to larger, dominant mice for 10 minutes every day, for 10 days. Ten of the mice coped well with this, but 14 became socially withdrawn and more timid.

Comparing blood, DNA and tissue samples from the stressed small mice, nine control mice and mice that were more relaxed in the presence of big bruisers suggests that there are three stages in the process of social stress leading to an altered mood. First, the stress kicks off inflammation in the bloodstream. This then weakens the blood-brain barrier, which normally protects the brain, making it leaky and more likely to let substances through into the brain.

This enables large molecules like inflammatory substance interleukin-6 and aggressive white blood cells called monocytes to pass into the brain. Here they seem to disrupt signalling in the nucleus accumbens, a part of the brain that helps evaluate threats and rewards.

Change of mood

This is the first study to link social stress to blood-brain barrier dysfunction and depression-related behaviour, says Russo.

In stressed mice, up to 30 per cent of vessels lining the blood-brain barrier showed signs of breaches in the nucleus accumbens. This seems to be caused by changes in gene activity – in stressed mice, genes in this brain area produced 40 per cent less of a protein called claudin-5, which usually secures the integrity of the blood-brain barrier.

When the team examined post-mortem human brain tissue from 39 people who’d had depression, and 24 people who hadn’t, they found that levels of claudin-5 in the nucleus accumbens of many of the people who had had depression were around 50 per cent lower.

“The study cements the central role of inflammation in the genesis of mood disorders,” says Michael Berk of the University of Melbourne in Australia. “It also explains a critical element of the puzzle –the mechanisms whereby stress can influence the brain via inflammation.”

Russo says the study suggests new avenues for treating depression. One option would be to use an antibody called sirukumab to remove interleukin-6 from the blood, so that it can’t reach the brain. Previous work by Russo’s team has found that people with depression can have as much as 100 times more interleukin-6 in their blood than people who aren’t depressed.

Sirukumab is already being tested in people with depression, but other strategies may work too. One could be to shore-up the blood-brain barrier, making it less likely to let inflammatory molecules through, or reducing the level of monocytes in the blood. If approaches like this could work, they may help protect people in difficult circumstances – such as a hostile work environment or a stressful family situation – from developing depression.

Journal reference: Nature Neuroscience, DOI: 10.1038/s41593-017-0010-3

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