Bridging the gap in translational psychiatry

Study in mice and humans reveals a mechanistic role for a microRNA molecule in regulating the ability to cope with chronic stress

November 29, 2016

Scientists at Max Planck Institute of Psychiatry have brought together their basic and translational research skills to discover the mechanism behind how the body copes with stress. The findings of this successful collaboration were published recently in Cell Reports.

Volk et al. reveal an important role for microRNA-15a in coping with chronic stress, with amygdala-specific manipulation affecting behavioral responses to stressful challenge. Individuals exposed to childhood trauma exhibit increased levels of miR-15a in their peripheral blood, suggesting a target for the treatment of stress-related psychopathologies.

MicroRNAs (miRNAs) are tiny molecules that regulate gene expression. In this study, the scientists concentrated on the miRNAs found in the amygdala, an area of the brain frequently associated with the emotional stress response.

First author, Naama Volk describes what they did: “We used a mouse model to look at what happens to miRNAs in the amygdala after chronic stress. The molecule miRNA-15a immediately stood out from the rest”. They found that following chronic stress, the levels of this particular molecule are increased.

The scientists went on to look at what this increase might be doing at the molecular level. They found that the increase in miRNA-15a caused a decrease in the FK506 binding protein 51 (FKBP51). This protein is a well-known regulator of stress-related receptors in the brain. It interacts with the so-called glucocorticoid receptor, thus influencing the stress hormone axis and stress physiology in general. The reverse was also true, when they lowered levels of miRNA-15a in the amygdala, FKBP51 levels increased.

They then went on to look at how these changes affected the behaviour of mice. Stress Neurobiology scientist and director of the Institute, Alon Chen states “interestingly, we found that when we manipulated levels of miRNA-15a to be lower specifically in the amygdala, the mice displayed exaggerated anxiety-like behaviour following chronic stress”. Chen went on to explain “anxiety-like behaviour can be measured in mice by tracking them to see how much time and how often the mice go into open, well-lit areas. Knowing that anxious mice avoid open areas”.

To complement the work done in the animal model, they also looked at levels of miRNA-15a in humans. The ability to translate basic research findings to see if it is mirrored in humans exemplifies the real strength of the Max Planck Institute of Psychiatry: the successful collaboration between the Stress Neurobiology Research Department and the Translational Research in Psychiatry Department.

Researchers collected blood samples from healthy participants, before and after the participants had been given dexamethasone. Dexamethasone is a glucocorticoid receptor agonist, which can be given to stimulate the stress-response pathway. Elisabeth Binder, director and Translational Research in Psychiatry Department Head, explains “we found that the microRNA miR-15a is also elevated in human blood following the dexamethasone challenge, so indeed, what was found in mice brains is mirrored in human blood”.

The scientists then took the project one step further, hypothesizing that individuals who were exposed to childhood trauma might have increased levels of miR-15a. “Our hypothesis was confirmed, levels of miR-15a were 32% higher in the blood of individuals who were exposed to childhood trauma compared to those who were not exposed” states Binder.

These data reveal a new essential role for miRNA-15a in regulating the behavioural response to stress. As such, miRNA-15a becomes an important target to explore in the prevention and treatment of stress-related illnesses, such as anxiety and posttraumatic stress disorder.

JK

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