Stress influences the brain via the immune system

Many stress-related psychiatric illnesses, such as depression, are associated with changes in the immune system; however, the underlying mechanisms behind how these changes affect the brain are still largely unknown. One such mechanism has now been uncovered by an international research team, led by the University of Zurich, the University Hospital of Psychiatry Zurich (PUK) and the Icahn School of Medicine at Mount Sinai.

As detailed in the journal Nature, the researchers used animal models to show that stress increases the migration of white blood cells called monocytes into the vascular system of the brain, particularly into the reward centre regions. These monocytes produce matrix metalloproteinase-8, which is involved in the restructuring and regulation of the net-like frame that surrounds neurons in the brain — the extracellular matrix.

“We were able to show that stress increases the amount of the matrix metalloproteinase-8 (MMP-8), an enzyme in the blood of mice,” said first author Flurin Cathomas, currently based at the Icahn School of Medicine at Mount Sinai. MMP-8 travels from the blood to the brain, where it alters the functioning of certain neurons. In the affected mice, this leads to behavioural changes: they withdraw and avoid social contact.

“If MMP-8 penetrates the brain tissue from the blood, it changes the matrix structure and thus disrupts the functioning of the neurons,” Cathomas said. “Mice who are affected by this process display changes in behaviour that are similar to those seen in humans with depression.”

In order to prove that MMP-8 was really responsible for the behavioural changes, the researchers removed the MMP-8 gene from some of the mice. Compared to the control mice, these animals did not display stress-related negative behavioural changes.

“Blood analyses of patients with depression indicate that the findings from the mouse models are also relevant for humans: both the monocytes and MMP-8 were increased in the blood of people with depression in comparison to healthy participants,” Cathomas said.

According to Cathomas, the findings are novel in two respects.

“Firstly, they indicate a new ‘body–mind mechanism’, which might be relevant not only for stress-related mental illness, but also for other diseases that affect both the immune and nervous systems,” he said. Secondly, identification of the specific MMP-8 protein could be a potential starting point to develop new treatments for depression.

While many more studies are needed before the results can be implemented in clinical practice, Cathomas said the work “demonstrates the importance of the interaction between the immune system and the brain in the development of psychiatric disorders. These insights are already being incorporated into psychiatric treatment today.”

The research team is now planning clinical studies to investigate the extent to which the immune system can be influenced by stimulating certain areas of the brain. They will also look at whether any changes in the immune system cells of depressive patients influence their behaviour.

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