A new study shows how the immune system’s response to stress causes symptoms of anxiety.

Healthcare professionals, not to mention most people, know that stress goes hand-in-hand with anxiety. The cause seems obvious—if anxiety is fear of the future or the unknown, then the unpredictability of stressors should cause it. But how this connection forms on a cellular level has remained a mystery.

In a new study from Ohio State University, principal investigator Dr. John Sheridan joined colleagues Dr. Jonathan Godbout, Dr. Nicole Powell, and Ph.D candidate Eric Wohleb to unlock the secrets of stress and the brain.

The key, they found, lies in the immune system. When lab mice were under stress, immune cells traveled to the brain and activated the regions associated with anxiety. The greater a mouse’s immune response, the more anxious behavior it displayed.

Stress occurs when a person experiences conditions that are harder than or different from normal in ways that he or she can’t predict or control. Sleep deprivation, starvation, combat, disease, and bullying may not seem to have much in common, but they’re all causes of stress, and they all produce similar responses in the body.

The fight-or-flight system kicks in (in case of enemies), the body begins conserving every calorie it can get (in case of famine), and the immune system gets stronger (in case of injury or infection). In the short term, the person is ready for whatever the world offers up. But in the long run, it’s a different story.

“Chronic, unrelenting stress tends to have an adverse effect on health, in part through its modulation of an individual’s immune response,” explained Sheridan in an interview with Healthline.

The researchers found that there is one type of immune cell, called a monocyte, that bone marrow produces during times of stress. Monocytes cause inflammation as part of the stress response.

“Inflammation is not necessarily damaging,” said Godblut, an associate professor of neuroscience, in an interview with Healthline. “Often times it is beneficial. Think about fever induction—an example of brain inflammation that does not result in tissue damage. This stress-induced brain inflammation represents a form of communication between the immune system and the brain.”

In the rest of the body, the inflammatory monocytes primarily fight infection and heal injured tissue. In the brain, however, they appear to behave differently.

The monocytes flock to the brain regions that send out stress signals: the amygdala and hippocampus, which are involved in processing feelings of fear, and the prefrontal cortex, which is supposed to regulate the fear regions. Once there, monocytes change the way the genes of brain cells behave. When the fear regions of the brain become overactive, the result is anxiety.

“Neuroinflammatory responses due to psychological stress are relatively mild compared to other neurological disease or infectious conditions,” Wohleb told Healthline. “In the case of stress, we believe that neuroinflammation may elicit changes in neurobiology that present as anxiety-like behavior.”

Although the minds of mice hardly approach the complexity of human brains, their stress systems are similar to ours. To make the mouse model as accurate as possible, the team tried to create a stressor that is something humans might experience: bullying.

Several young male mice coexisted peacefully in a single cage. Then, to stress them, the researchers introduced a larger, more aggressive male for two hours. The intruder mouse attacked and bullied the resident mice until their behavior became cowed and submissive. After three such sessions, the resident mice had gone into full-on stress mode.

The mice had two living areas: an open, brightly-lit area to explore and a dark, enclosed area to hide in. Happy and healthy mice will spend more time exploring, while mice that are stressed or scared will spend more time hiding. The more the mice were bullied, the more time they spent in the hiding area, and the more monocytes the researchers found in their brains.

To confirm their findings, the researchers genetically engineered a set of mice so that they didn’t have the genes the monocytes were using to target the brain. When they did this, the bullied mice had the same immune response, but didn’t act more anxious and were happy to explore.

This new finding suggests that either monocytes in the brain or the genes they activate could be targets for new drugs to treat anxiety. However, Sheridan cautions that we shouldn’t assume mice and humans process stress in the same way just yet.

“Extrapolation from the mouse to the human is generally not a good idea,” he said. “However, what we do know is that in an animal model of repeated social stress, there are cells of the immune system that may play a significant role in the development of prolonged anxiety.”

This research was funded by the National Institute of Mental Health (NIMH), the National Institute on Aging, and an NIMH Predoctoral Fellowship.