Monday, February 24, 2014

Immune System May Play a Significant Role in PTSD


New research using a mouse model suggests that the immune system may play a significant role in the development of posttraumatic stress disorder (PTSD). In the study, mice who experienced chronic stress (social defeat) developed a similar stress response when exposed to a single stressor 24 days later, while rats who did not experience the chronic stress had little or no response to the single stressor.

When they removed the spleen from the mice before the second stress experience, the mice did not have the chronic stress response, suggesting that the spleen (part of the immune system) plays a role in the manifestation of PTSD. It appears that "the spleen is used as a reservoir for primed immune cells until they’re activated to response to another stressor."

When the single stressor is introduced, the immune cells from the chronic stress that had been conserved in the spleen are released and travel to the brain where they generate the intense anxiety response associated with the chronic stress.

Re-establishment of Anxiety in Stress-Sensitized Mice Is Caused by Monocyte Trafficking from the Spleen to the Brain

Eric S. Wohleb, Daniel B. McKim, Daniel T. Shea, Nicole D. Powell, Andrew J. Tarra, John F. Sheridana, Jonathan P. Godbout


Persistent anxiety-like symptoms may have an inflammatory-related pathophysiology. Our previous work using repeated social defeat (RSD) in mice showed that recruitment of peripheral myeloid cells to the brain is required for the development of anxiety. Here, we aimed to determine if 1) RSD promotes prolonged anxiety through redistribution of myeloid cells and 2) prior exposure to RSD sensitizes the neuroimmune axis to secondary subthreshold stress.


Mice were subjected to RSD and several immune and behavioral parameters were determined .5, 8, or 24 days later. In follow-up studies, control and RSD mice were subjected to subthreshold stress at 24 days.


Repeated social defeat-induced macrophage recruitment to the brain corresponded with development and maintenance of anxiety-like behavior 8 days after RSD, but neither remained at 24 days. Nonetheless, social avoidance and an elevated neuroinflammatory profile were maintained at 24 days. Subthreshold social defeat in RSD-sensitized mice increased peripheral macrophage trafficking to the brain that promoted re-establishment of anxiety. Moreover, subthreshold social defeat increased social avoidance in RSD-sensitized mice compared with naïve mice. Stress-induced monocyte trafficking was linked to redistribution of myeloid progenitor cells in the spleen. Splenectomy before subthreshold stress attenuated macrophage recruitment to the brain and prevented anxiety-like behavior in RSD-sensitized mice.


These data indicate that monocyte trafficking from the spleen to the brain contributes re-establishment of anxiety in stress-sensitized mice. These findings show that neuroinflammatory mechanisms promote mood disturbances following stress-sensitization and outline novel neuroimmune interactions that underlie recurring anxiety disorders such as posttraumatic stress disorder.

The full article from Biological Psychology (Science Direct) is behind a paywall, of course, so here is a summary of the research from Psych Central, which is based on the Ohio State University press release.

Mouse Study: Is PTSD an Immune Cell Response to Stress?

By Traci Pedersen Associate News Editor
Reviewed by John M. Grohol, Psy.D. on February 22, 2014

Immune cells activated during a state of chronic stress seem to end up on standby in the spleen to be saved for later use, according to a new mouse study by researchers at Ohio State University. This may trigger an exaggerated stress reaction to a single event much later, launching the body back into a state of chronic stress.

The excessive immune response and anxiety later triggered by a brief stressor mimic symptoms of post-traumatic stress disorder.

During the study, researchers found that even after mice had recovered from a state of chronic stress, they quickly returned to that state after experiencing a single stressful event 24 days later. Mice that had not experienced the chronic stress were unaffected by the single stressful event.

Mice without spleens did not experience the same reaction to the single stressor. This suggests that the spleen is used as a reservoir for primed immune cells until they’re activated to response to another stressor.

“No one else has done a study of this length to see what happens to recovered animals if we subject them again to stress,” said Jonathan Godbout, Ph.D, a lead author of the study and associate professor of neuroscience at Ohio State.

“That retriggering is a component of post-traumatic stress. 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.”

In this model of stress, an aggressive male mouse was added to a group of other male mice that had already been given time to establish a hierarchy. For two hours at a time, the aggressive mouse repeatedly defeated the resident mice. After six days, this social defeat led to an inflammatory immune response and anxiety-like behavior.

The researchers then removed the spleens of some of the chronically stressed mice. After spleen removal, the stress-sensitized mice were no longer sensitive to the single stressor and the re-establishment of anxiety.

The scientists also detected no immune cell trafficking to the brain or anxiety-like behavior. This suggests that the spleen is the source of immune cells that respond to the single stressor.

“Our colleagues who study behavior talk about sensitization,” Sheridan said. “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.”

Sheridan added that other researchers are testing blood samples of PTSD patients for biomarkers such as immune cells or pro-inflammatory proteins that could reveal which patients are in a stress-sensitized state.

The research is published online in the journal Biological Psychiatry.

Additional co-authors, all from Ohio State, include Eric Wohleb, Daniel McKim, Daniel Shea, Nicole Powell, and Andrew Tarr.

Source: Ohio State University
Lab technician with research mouse photo by shutterstock.
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