October 25, 2010
Chronic stress may cause long-lasting changes
Long-term exposure to a common stress hormone may leave a lasting mark on the genome and influence how genes that control mood and behavior are expressed, a mouse study led by Johns Hopkins researchers suggests.
The finding, published in the September issue of Endocrinology, could eventually lead to new ways to explain and treat depression, bipolar disorder and other mental illnesses.
Scientists and physicians have long been interested in the cause of depression, a sometimes debilitating disorder that affects about 16 percent of people at least once over the course of a lifetime. While studies have shown that many other mental illnesses are strongly heritable, the risk of depression has been shown to be only about 40 percent genetic. Consequently, environmental factors are thought to play a major role in causing this disease.
Unsurprisingly, previous research has shown that stressful life events can increase the risk of depression. But how these life events play into the biology of this disease is unknown.
James Potash, an associate professor at the Johns Hopkins University School of Medicine, and colleagues suspected that epigenetic factors might be at work in the disease. Epigenetic, or “above the genome,” factors are so-named because they affect how genes are expressed without changing the genetic sequence. One of the most prevalent epigenetic changes, or “marks,” are methyl chemical groups that clip onto DNA, often shutting off the gene to which they attach.
To see if stress might influence epigenetic marks on genes involved in depression, Potash and his Johns Hopkins colleagues, including study co-leader Gary Wand, a professor in the Division of Endocrinology; Kellie Tamashiro, an assistant professor in Psychiatry and Behavioral Sciences; and Richard Lee, a postdoctoral fellow in Psychiatry and Behavioral Sciences, gave some mice corticosterone in their drinking water for four weeks. Corticosterone is the mouse version of cortisol, a hormone produced by the human body during stressful situations. Other mice drank water without this hormone.
At the end of the four-week period, the mice who received corticosterone displayed anxious characteristics in behavioral tests. Gene expression tests on these animals showed a marked increase in protein produced by a gene called Fkbp5, which in its human form has been linked to mood disorders, including depression and bipolar disease.
When the researchers examined the rodents’ DNA for epigenetic marks on Fkbp5, they found substantially fewer methyl groups attached to this gene in mice that received corticosterone compared with those that didn’t. These differences in epigenetic marks persisted for weeks after the mice stopped receiving the hormone, suggesting long-lasting change.
“This gets at the mechanism through which we think epigenetics is important,” said Potash, who directs research programs at Johns Hopkins’ Mood Disorders Center. He explains that epigenetic marks that are added through life experience may prepare an animal for future events. “If you think of the stress system as preparing you for fight or flight, you might imagine that these epigenetic changes might prepare you to fight harder or flee faster the next time you encounter something stressful.”
Although these behaviors were probably advantageous earlier in evolution, they aren’t as useful today, with modern stressors that we can’t fight or flee, such as work deadlines, Potash added. Consequently, he said, chronic stress might instead lead to depression or other mood disorders triggered by epigenetic changes.
Potash, who holds the Arlene and Robert Kogod Professorship in Mood Disorders, notes that, eventually, doctors may be able to look for these epigenetic changes in DNA isolated from a patient’s blood to predict or diagnose psychiatric illnesses. Ultimately, researchers may someday be able to target these epigenetic marks with drugs to treat depression and other diseases.
Mood Disorders Center at Johns Hopkins
Psychiatry and Behavioral Sciences Department at Johns Hopkins