Public Release:  Discovery hints at why stress is more devastating for some

Rockefeller University


IMAGE: Chemical changes to histones, proteins that provide structure for DNA, can alter gene expression. Above, individual spots represent acetylated histones in a brain region called the hippocampus. The researchers found... view more

Credit: Carla Nasca

Some people take stress in stride; others are done in by it. New research at Rockefeller University has identified the molecular mechanisms of this so-called stress gap in mice with very similar genetic backgrounds -- a finding that could lead researchers to better understand the development of psychiatric disorders such as anxiety and depression.

"Like people, each animal has unique experiences as it goes through its life. And we suspect that these life experiences can alter the expression of genes, and as a result, affect an animal's susceptibility to stress," says senior author Bruce McEwen, Alfred E. Mirsky Professor and head of the Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology. "We have taken an important step toward explaining the molecular origins of this stress gap by showing that inbred mice react differently to stress, with some developing behaviors that resemble anxiety and depression, and others remaining resilient."




"If you think of the genetic code as words in a book, the book must be opened in order for you to read it. These epigenetic changes, which affect histone proteins associated with DNA, effectively close the book, so the code for mGlu2 cannot be read," says first author Carla Nasca, postdoc in the lab and a fellow of the American Foundation for Suicide Prevention. Previously, she and colleagues first implicated mGlu2 in depression when they showed that a promising potential treatment known as acetyl carnitine rapidly alleviated depression-like symptoms in rats and mice by reversing these epigenetic changes to mGlu2 and causing its levels to increase.

"Currently, depression is diagnosed only by its symptoms," Nasca says. "But these results put us on track to discover molecular signatures in humans that may have the potential to serve as markers for certain types of depression. Our work could also lead to a new generation of rapidly acting antidepressants, such as acetyl carnitine, which would be particularly important to reduce the risk of suicide."


"The brain is constantly changing. When stressful experiences lead to anxiety and depressive disorders the brain becomes locked in a state it cannot spontaneously escape," McEwen says. "Studies like this one are increasingly focusing on the regulation of glutamate as an underlying mechanism in depression and, we hope, opening promising new avenues for the diagnosis and treatment of this devastating disorder."

