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Psychiatry Newsletter - Turning Off Stress at the Spigot

Hopkins BrainWise Fall 2010

Turning Off Stress at the Spigot

Date: November 29, 2010

Dr. James PotashJimmy Potash sees stress effects with an epigeneticist's eye.

Stress is such a common denominator in depression. Look at any large study of those who had it that aims to uncover a cause for the disease: Whatever the age, race or socioeconomic status of the group under study, chronic stress is there with its persistent little companion, the molecule cortisol, bathing vulnerable parts of the brain. 

While no one doubts that genes can raise the chance of depression—some 40 percent of risk is genetic—we think that “most vulnerability to depression isn’t accounted for by genetic inheritance,” says Jimmy Potash, who directs research for Hopkins’ Mood Disorders Center. “And a large body of evidence figures stress into the remaining 60 percent. Stress and genetic vulnerability somehow interact to promote depression.”

It’s the “somehow” that Potash, Richard Lee and their team want to define.

In a study recently published in Endocrinlogy, they focused on the HPA axis, the trio of hypothalamus, pituitary and adrenal glands that together manage the body’s stress response. Specifically, the researchers analyzed the structure and workings of five genes known to affect the HPA axis. All five have some tie to the hormone cortisol, an HPA by-product.

Cortisol is typically secreted much as a good mother spoons out cough syrup—sparingly and only when needed. Then it’s useful and crucial in mobilizing the body for fight or flight. But chronic, high levels of the steroid deliver unwanted effects, including anxiety, depression, irritability and insomnia. And the research’s results suggest how.

In the study, test mice drank the rodent-equivalent of cortisol in their drinking water for a month, then recovered for another. The researchers observed the animals for behavioral and physiological changes. But equally important, Potash analyzed DNA in the five test genes, sampling them from the animals’ white blood cells as well as select brain regions, including the hypothalamus. He’d hoped to see epigenetic changes in the DNA. And in one of the genes, he found them.

Epigenetic changes can decide whether a gene gets expressed or not. As the name implies, they’re “above”  genetics; they come about through a cell’s environment. The most common such change bonds methyl chemical groups—or marks—onto DNA. The effect is like using the Tab key in a Word document: Marked parts of the DNA are passed over when a gene’s code is translated into cell action.

Potash made two important finds. First, he found fewer marks than usual in the Fkpb5 gene of the mice with the “spiked” water. Tampering with Fkpb5 would likely increase cortisol levels even more.

Moreover, the marks persisted weeks after the mice stopped getting the added hormone, suggesting the changes might last. “This gets at a role that epigenetics could play in psychiatric disease,” Potash says.

Epigenetic marks added through life experience, he explains, may ready animals for future events. “They might prepare you to fight harder or flee faster the next time you’re up against something stressful.” But helpful as those behaviors were in earlier times, they aren’t that way today. “You can’t fight or flee modern stressors like work deadlines. Consequently,” he says, “the chronic cortisol release that epigenetic changes trigger might lead to depression or other mood disorders.”

The idea, though, is that possibly in the near future, doctors will be able to profile epigenetic changes in a patient’s blood cell DNA and then use drugs to add or subtract marks as needed. It’d be tailoring cures from within. 

For information: 443-287-4135.

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