Getting sick is definitely a bummer. But besides feeling icky and being stuck in bed, viral infections may cause us to actually be depressed. While scientists have been clued into this connection for a while, there was little data on how everyday viral infections, like the flu, might mess with our moods.

Now, data from a new mouse study shows that common viruses may spur sadness by causing the cells that line the blood-brain barrier to release signals that hush the chatter between neurons in the area of the brain responsible for mood. The findings, published this week in the journal Immunity, may finally explain the link between infections and mental health problems, and it could point researchers towards new strategies for treating depression and other mood disorders.

Researchers have been collecting hints of the connection between mental health and infections for years. Though it was first dismissed as people simply being blue about getting sick, doctors now accept that there is a condition called “sickness behavior.” This condition is marked by cognitive deficits, drowsiness, general malaise, and other depression-like symptoms in those with an infection. Moreover, in a 2013 Danish study, researchers found that people who had been treated for a severe infection were 62 percent more likely to suffer from mood disorders. Perhaps related, those that had an autoimmune disease were 45 percent more likely to have such a mental health issue.

Researchers began suspecting that infections might be causing the immune system to run amok in the brain. Specifically, researchers hypothesized that sickness behavior might be triggered by immune signals, called cytokines, that somehow made their way to the brain and altered the activity of neurons. However, researchers didn’t know what those signals and the cells that emit them were.

Researchers in Germany, led by Marco Prinz at the University of Freiburg, began to unravel the mystery by noting a similarity between sickness behavior and depressive-like symptoms of people taking cytokines called type I interferons (IFNs) as part of a cancer treatment. Viruses, the researchers realized, also trigger the release of type I IFNs.

To test the hypothesis that these cytokines may spark mood problems, the researcher started experimenting with mice, looking to see if they could induce then alter signs of depression in the rodents. The tested for depression using a standard swim test method, which basically works by dropping the rodents into a container of water and measuring how long they frantically splash around to try to get out. Depressed mice give up more quickly.

Infecting normal mice with a common, mild virus made the mice depressed, the researchers found. Next, the researchers tried the swim test with genetically engineered mice whose brain cells couldn’t respond to type I IFNs. Still, the mice got depressed.

Going back to the drawing board, the researchers hypothesized that perhaps the cytokine didn’t actually get into the brain, but instead it could relay signals through the blood brain barrier. They next tried the depression test using mice engineered so that the cells that line their brains’ surfaces and blood vessels couldn’t respond to type I IFNs. When those mice were infected with the virus, they didn’t get depressed.

Tracking the activity of those blood brain barrier cells in normal mice, the researchers found that the cells were activated by type I IFNs and released another cytokine called CXCL10 directly into the brain. In the brain's hippocampus (the area that’s responsible for controlling mood), CXCL10 hampered neuron firing, quieting electrical pulses in that area of the brain.

While more work needs to be done to validate the results and determine if they're relevant to human health, the authors are hopeful that finding ways to block CXCL10 could lead to a treatment for certain mood disorders.

Immunity, 2016. DOI: 10.1016/j.immuni.2016.04.005 (About DOIs).