Why feeling sick and sad go hand in hand


Got the sniffles and the grumps? New research with mice shows how the immune system affects emotions. Phil Ritchie reports.


A cross-sectional view of a brain's blood vessel with cell nuclei shown in blue. Some endothelial cells at the inside vessel wall are activated by type I interferons (purple) following a viral infection. Blood cells are in yellow. – Thomas Blank

Feeling a bit low seems to go hand in hand with being under the weather. But your brain might be wired to get sad when sick, according to a new study.

Researchers from the University of Freiburg in Germany traced a virus-triggered cascade which affects cells in the hippocampus, a brain structure associated with learning and emotion. The next step, they say, is to break that chain.

The work was published in Immunity.

Along with familiar symptoms such as headaches or fatigue, viral infections such as the ‘flu have also been linked to depression-like emotional states – as have patients undergoing antiviral therapies using molecules called type I interferons.

Type I interferons are naturally released by white blood cells in response to a viral invader. They act by dampening virus replication and are used therapeutically to treat, for instance, certain cancers, hepatitis C and multiple sclerosis.

But the mechanisms responsible for their depressive symptoms had not been identified, until now.

Thomas Blank and colleagues infected mice with the vesicular stomatitis virus – a strain known to cause ‘flu-like symptoms in humans.

The animals’ mood was measured using the forced swimming test, sometimes called the behavioural despair test. It simply involves placing a mouse in a tank of water with no way out. Eventually, the mouse will give up swimming and float motionless.

A mouse in a depressive state gives up sooner than a normal mouse. And sure enough, they found virus-infected mice did, indeed, stop swimming sooner than their healthy counterparts, signalling that they were feeling more despondent.

The researchers then traced the molecular mechanisms behind that emotional change.

They found higher levels of blood interferons, boosted by the immune system's response to the viral infection, activated the interferon receptor chain 1, a protein embedded in endothelial and epithelial cells that line the inside of blood vessels and caverns in the brain called ventricles.

In turn, those cells released a protein called CXCL10 which bound to yet another, CXCR3, but inside hippocampus cells.

When the two proteins hooked up, synaptic plasticity in the hippocampus was reduced. In other words, the part of the brain responsible for learning and emotion was less able to create new links between neurons, so couldn't work as effectively.

This provides a handy target for therapeutics, Blank says: “Our findings suggest that preventing the release of CXCL10 or blocking its receptors at an early phase should eliminate at least the initial stages of sickness behaviour seen in response to viral infection or type I interferon therapy.”

  1. http://www.cell.com/immunity/fulltext/S1074-7613
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