Mood is influenced by immune cells called to the brain in response to stress

The findings, in a mouse model, offer a new explanation of how stress can lead to mood disorders and identify a subset of immune cells, called monocytes, that could be targeted by drugs for treatment of mood disorders.

The Ohio State University research also reveals new ways of thinking about the cellular mechanisms behind the effects of stress, identifying two-way communication from the central nervous system to the periphery -- the rest of the body -- and back to the central nervous system that ultimately influences behavior.

Unlike an infection, trauma or other problems that attract immune cells to the site of trouble in the body, this recruitment of monocytes that can promote inflammation doesn't damage the brain's tissue -- but it does lead to symptoms of anxiety.

The research showed that the brain under prolonged stress sends signals out to the bone marrow, calling up monocytes. The cells travel to specific regions of the brain and generate inflammation that causes anxiety-like behavior.

In experiments conducted in mice, the research showed that repeated stress exposure caused the highest concentration of monocytes migrating to the brain. The cells surrounded blood vessels and penetrated brain tissue in several areas linked to fear and anxiety, including the prefrontal cortex, amygdala and hippocampus, and their presence led to anxiety-like behavior in the mice.

"In the absence of tissue damage, we have cells migrating to the brain in response to the region of the brain that is activated by the stressor," said John Sheridan, senior author of the study, professor of oral biology and associate director of Ohio State's Institute for Behavioral Medicine Research (IBMR).

"In this case, the cells are recruited to the brain by signals generated by the animal's interpretation of social defeat as stressful."

The research appears in the Aug. 21, 2013, issue of The Journal of Neuroscience.

Mice in this study were subjected to stress that might resemble a person's response to persistent life stressors. In this model of stress, male mice living together are given time to establish a hierarchy, and then an aggressive male is added to the group for two hours. This elicits a "fight or flight" response in the resident mice as they are repeatedly defeated. The experience of social defeat leads to submissive behaviors and the development of anxiety-like behavior.

Mice subjected to zero, one, three or six cycles of this social defeat were then tested for anxiety symptoms. The more cycles of social defeat, the higher the anxiety symptoms; mice took longer to enter an open space and opted for darkness rather than light when given the choice. Anxiety symptoms corresponded to higher levels of monocytes that had traveled to the animals' brains from the blood.

Additional experiments showed that these cells did not originate in the brain, but traveled there from the bone marrow. In previous studies, this same research group showed that cells in the brain called microglia, the brain's first line of immune defense, are activated by prolonged stress and are partly responsible for the signals that call up monocytes from the bone marrow.

"There are different moving parts from the central and peripheral components, and what's novel is them coming together to influence behavior," said Jonathan Godbout, a senior co-author of the paper and an associate professor of neuroscience at Ohio State.

Exactly what happens at this point in the brain remains unknown, but the research offers clues. The monocytes that travel to the brain don't respond to natural anti-inflammatory steroids in the body and have characteristics signifying they are in a more inflammatory state. These results indicate that inflammatory gene expression occurs in the brain in response to the stressor.

"The monocytes are coming out of the bone marrow and they are not responsive to steroid regulation, so they overproduce proinflammatory signals when they're stimulated. We think this is the key to the prolonged anxiety-like disorders that we see in these animals," Sheridan said.

These findings do not apply to all forms of anxiety, the scientists noted, but they are a game-changer in research on stress-related mood disorders.

"Our data alter the idea of the neurobiology of mood disorders," said Eric Wohleb, first author of the study and a predoctoral fellow in Ohio State's Neuroscience Graduate Studies Program. "These findings indicate that a bidirectional system rather than traditional neurotransmitter pathways may regulate some forms of anxiety responses. We're saying something outside the central nervous system -- something from the immune system -- is having a profound effect on behavior."

This work was supported by the National Institute of Mental Health (NIMH), the National Institute on Aging and an NIMH Predoctoral Fellowship. Nicole Powell of the Division of Oral Biology at Ohio State is an additional co-author of the study. Sheridan and Godbout also are investigators in the IBMR and Center for Brain and Spinal Cord Repair.