Chronic stress has far-reaching effects on our bodies. Many stress-related psychiatric illnesses, including depression, are related to abnormalities of the immune system. However, the basic mechanisms governing how these alterations influence the brain remain unclear.
Enzyme from immune cells in blood affects nerves in the brain
An international research team led by the University of Zurich (UZH), the Zurich University Hospital of Psychiatry (PUK) and the Icahn School of Medicine at Mount Sinai, New York, has discovered a novel mechanism. “We were able to show that stress increases the amount of matrix metalloproteinase-8 (MMP-8), an enzyme in the blood of mice. The same changes were found in patients with depression,” says first author Flurin Cathomas. MMP-8 travels from the blood to the brain, where it alters the functioning of certain neurons. In affected mice, this causes behavioral changes: they withdraw and avoid social contact.
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Potential for new treatments for depression
According to Cathomas, the findings are novel in two respects: “First, they indicate a new ‘mind-body mechanism’, which could be relevant not only for stress-related mental illnesses, but also for other diseases that affect both the immune system as well as the nervous systems.” And secondly, says the psychiatrist, the identification of the specific MMP-8 protein could be a possible starting point for developing new treatments for depression.
Changes in the extracellular matrix of the brain.
The researchers were able to use animal models to show that stress increases the migration of a specific type of white blood cells called monocytes into the brain’s vascular system, particularly into reward center regions. These monocytes produce MMP-8. MMP-8 is involved in restructuring and regulating the network-like framework surrounding neurons in the brain, called the extracellular matrix. “When MMP-8 penetrates from the blood into brain tissue, it changes the structure of the matrix and, therefore, alters the functioning of neurons. Mice affected by this process show behavioral changes similar to those observed in humans with depression”. says Flurin Cathomas.
To show that MMP-8 was indeed responsible for the behavioral changes, the researchers deleted the MMP-8 gene from some of the mice. Compared to control mice, these animals did not show negative stress-related behavioral changes. “Blood analyzes from patients with depression indicate that the results from the mouse models are also relevant to humans: both monocytes and MMP-8 increased in the blood of people with depression compared to healthy participants.”
Clinical studies with planned patients.
Many more studies are needed before the results can be implemented in clinical practice. However, says Cathomas, “our work demonstrates once again the importance of the interaction between the immune system and the brain in the development of psychiatric disorders. This knowledge is already being incorporated into current psychiatric treatment.” In the PUK’s special comprehensive care ward, led by Cathomas, doctors treat their patients with a holistic mind-body approach based on the latest scientific discoveries.
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 observe whether any changes in the immune system cells of depressed patients influence their behavior.
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