Persistent stress—leading to elevated cortisol levels and, subsequently, epigenetic change—is implicated in psychiatric disorders such as depression, bipolar disorder, and post-traumatic stress disorder. In describing this vicious chain of events at the molecular level, scientists have relied on a crucial assumption: Epigenetic changes detectable in peripheral tissues correlate with disease-relevant, cellular alterations that occur in the brain.
In studies with humans, this assumption is necessary because the brain is largely inaccessible and difficult to test. Instead, human studies that explore epigenetic links in the chain of stress-induced psychiatric disease rely on blood samples. Easily accessible, blood samples are examined for molecular substrates of neuropsychiatric disorders. Among these substrates, the most prominent is FKBP5, which has been identified as a stress-response gene.
In fact, FKBP5 is something of a celebrity in psychobiology circles. It helps regulate cortisol levels in the brain and body. In particular, it influences the hypothalamic-pituitary-adrenal axis, the body’s prime stress-response system. If a researcher wanted to test any correlation between epigenetic changes detectable in blood, and those detectable in the brain, the FKBP5 gene would be a good place to start. At least that’s what researchers at Johns Hopkins University concluded.
A team of Johns Hopkins researchers led by Richard S. Lee, Ph.D., an instructor in the department of psychiatry and behavioral sciences, used a mouse model of Cushing’s disease and asked whether epigenetic changes induced by glucocorticoids could be correlated between blood and brain.
For four weeks, the mice were given different doses of stress hormones in their drinking water to assess epigenetic changes to FKBP5. The researchers took blood samples weekly to measure the changes and then dissected the brains at the end of the month to study what changes were occurring in the hippocampus as a result of glucocorticoid exposure. The hippocampus, in both mice and humans, is vital to memory formation, information storage, and organizational abilities.
The results of these investigations were summarized in an article published online ahead of print in Psychoneuroendocrinology. The article, which will be printed in June, is entitled “Alterations in DNA methylation of Fkbp5 as a determinant of blood–brain correlation of glucocorticoid exposure.”
“Significant linear relationships were observed between DNA methylation and four-week mean plasma corticosterone levels for both blood and brain,” the authors wrote. “Further, degree of methylation change in blood correlated significantly with both methylation and expression changes in hippocampus, with the notable observation that methylation changes occurred at different intronic regions between blood and brain tissues.”
“This research on mice,” commented Dr. Lee, “suggests that the blood can legitimately tell us what is going on in the brain, which is something we were just assuming before, and could lead us to better detection and treatment of mental disorders and for a more empirical way to test whether medications are working.”
While the article focused epigenetic changes to the FKBP5 gene, the researchers say that they have discovered the same blood and brain matches in dozens more genes, which regulate many important processes in the brain. At the same time, however, the researchers struck a cautious note in their conclusions: “For such correlation analyses to be effective, tissue-specific locations of these epigenetic changes may need to be considered when investigating brain-relevant changes in peripheral tissues.”
While the study showed that the higher the levels of stress hormone, the greater the epigenetic changes in the blood and brain tissue, it also revealed that in the brain, the epigenetic changes occurred in a different part of the gene than expected. “This was what made finding the blood-brain connection very challenging,” Dr. Lee said.
