A new study in mice finds that an excessive response provoked in the immune system by chronic stress results in anxiety symptoms resembling post-traumatic stress disorder.
The scientists behind the study, which is published in the journal Biological Psychiatry, had previously found that - in mice with chronic stress - immune system cells traveled to the brain, resulting in anxiety symptoms. The scientists also found that monocytes - a subset of these immune system cells - could be targeted with drugs to treat mood disorders.
In the new study, the researchers would allow a group of male mice living together to establish a hierarchy but would then introduce an aggressive male mouse to the group for 2-hour sessions over 6 days.
The aggressive mouse would dominate the hierarchy, resulting in "social defeat" to the resident mice. This social defeat manifested itself by triggering the sympathetic nervous system and the "fight-or-flight" response.
Over 6 days of exposure to the aggressive mouse, this reaction led to inflamed immune cells in the spleen and anxious behavior in the mice.
At follow-ups of 14 hours and 8 days after achieving the state of chronic stress, the researchers observed high levels - compared with the mice in a control group - of pro-inflammatory proteins in the bloodstream and monocytes accumulating in the brains of the mice.The stressed mice would not return to normal behavioral and physiological levels until 24 days later.
Brief exposure to a stressor resulted in PTSD symptoms
Taking both the stress-sensitized mice and the control group mice, plus a third group of mice new to the experiment, the scientists then exposed all mice to an aggressive mouse for 2 hours.
"That one exposure to an acute stressor produced a similar pattern to what we'd expect to see if they had experienced the chronic stress of repeated social defeat," says study lead author Prof. Jonathan Godbout.
There was no change in the biology or behavior of the unstressed mice, but the mice who had been stress-sensitized returned immediately to their chronically stressed state, exhibiting more anxious behaviors and higher levels of pro-inflammatory proteins. The researchers assumed that these symptoms had been brought on by monocytes traveling to the brain.
"That retriggering is a component of post-traumatic stress," says Prof. Godbout. "The previously stressed mice are living a normal rodent life, and then this acute stress brings everything back. Animals that have never been exposed to stress before were unaffected by that one event - it didn't change behavioral or physiological properties."
Removing the mice's spleens removed their anxiety
The researchers then removed the spleens of the stressed mice. It was the spleen where the immune cells in the mice had been "primed" into a constant state of alert by their chronic stress.
After spleen removal, the stress-sensitized mice no longer re-established anxiety when exposed again to the aggressive mouse. The scientists also noticed that immune cells were no longer traveling to the brain in the stress-sensitized mice.
"Our colleagues who study behavior talk about sensitization," senior author Prof. John Sheridan says. "Clearly, the repeatedly stressed mice were sensitized. What we're adding is that sensitization is associated with a specific cell type that resides in the spleen after the initial sensitization."
"The key is those cells. They originate in the bone marrow but in terms of sensitization, the spleen is a significant organ."
For the next stage of their research, Prof. Godbout and team will compare the immune cells that travel to the brain with those that remain in the spleen during stress response.
Other scientists are looking for PTSD biomarkers in patients by testing blood samples, and Sheridan considers that "this work will validate some of their approaches."
Recently, Medical News Today reported on another trial in mice examining whether a memory-rewriting drug could help treat PTSD.