Molecule Linked to Stress Susceptibility

Having low levels of a specific molecule could explain why stress is more damaging for some people, a new study suggests.

Researchers at Rockefeller University studied mice and found that rodents that with lower levels of a molecule called mGlu2 in a stress-involved region of the brain known as the hippocampus were more susceptible to stress.

For the study, researchers stressed the mice by exposing them to daily, unpredictable periods of cage tilting, altered dark-light cycles, confinement in tight spaces and other stressful conditions.

Researchers then conducted tests to see if the mice showed signs of anxiety and depression. The study revealed that about 40 percent of mice exhibited higher levels of behaviors like preferring darker spaces or losing interest in sugar water. However, 60 percent of mice coped well with the stress. The study revealed that the difference between stressed and resilient mice were evident even before they were exposed to stress.

Further analysis revealed that highly stress-susceptible mice had less of the mGlu2 molecule in their hippocampus, a brain region involved in regulating stress.  Researchers found that the lower levels of mGlu2 were produced by epigenetic changes that affect the expression of genes.

"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," first author Carla Nasca, postdoc in the lab and a fellow of the American Foundation for Suicide Prevention, said in a news release.

"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."

The findings were published September 2 in the journal Molecular Psychiatry.

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