As discussed in my book, stress promotes inflammation and immune dysfunction, as well as anxiety. A new and very complete paper from John Sheridan and colleagues at Ohio State University provides evidence that stress also induces an influx of immune cells into the brain, and that this causes anxiety symptoms. They stressed mice by putting an aggressive intruder into their cage for 2 hours each night for 1, 3 or 6 nights. This intruder subdues the residents and makes them subordinate, but does not injure them. Increasing the days of this stress causes and increase in anxiety in the resident mice, as measured in separate assays (not in the presence of an intruder) by their reluctance to enter the center of an open field and their reluctance to go from a dark box into the light. These are some of the standard ways of measuring anxiety in mice. Increasing the days of stress also causes an increase in immune cells called monocytes in the blood. Using a genetic labeling technique, the investigators went on to show that some of the monocytes then entered the brain, where they became macrophages. Moreover, the parts of the brain where these invading cells are found are the areas known to control anxiety behavior.
This entry into the brain is caused by chemokine signals eminating from the brain itself, and if these signals are blocked, the immune cells do not enter the brain and, importantly, the mice do not display anxiety. That is, if mice who cannot do this chemokine signaling are placed in this highly stressful situation, they do not become anxious and their brains do not display the invading immune cells. The suggestion is then that the stressed brain recruits immune cells to do something that leads to anxiety. This ‘something’ could certainly involve cytokines, as stress increases cytokines in the brain, and cytokines can induce anxiety. But why recruiting macrophages is necessary when the brain’s own cells can produce those cytokines is a mystery. Perhaps the recruited immune cells are also carrying out another function that is helpful (or harmful?) in dealing with social stress. What this might be remains mysterious. It is also not clear how long these invaders remain the brain after the stress is over. Creepy?