WHY IS STRESS MORE DEVASTATING FOR SOME
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."
The results, published
September 2 in Molecular Psychiatry, point toward potential new
markers to aid the diagnosis of stress-related disorders, such as anxiety and
depression and a promising route to the development of new treatments for these
devastating disorders.
In experiments,
researchers stressed the mice by exposing them to daily, unpredictable bouts of
cage tilting, altered dark-light cycles, confinement in tight spaces and other
conditions mice dislike with the goal of reproducing the sort of stressful experiences
thought to be a primary cause of depression in humans. Afterward, in tests to
see if the mice displayed the rodent equivalent of anxiety and depression
symptoms, they found about 40 percent showed high levels of behaviors that
included a preference for a dark compartment over a brightly lit one, or a loss
of interest in sugar water. The remaining 60 percent coped well with the
stress. This distinction between the susceptible mice and the resilient ones
was so fundamental that it emerged even before the mice were subjected to
stress, with some unstressed mice showing an anxiety-like preference for a dark
compartment over a lighted one.
The researchers found
that the highly stress-susceptible mice had less of an important molecule known
as mGlu2 in a stress-involved region of the brain known as the hippocampus. The
mGlu2 decrease, they determined, resulted from an epigenetic change, which
affects the expression of genes, in this case the gene that codes for mGlu2.
"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."
A reduction in mGlu2
matters because this molecule regulates the neurotransmitter glutamate. While
glutamate plays a crucial role relaying messages between neurons as part of
many important processes, too much can lead to harmful structural changes in
the brain.
"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."
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