|Stress: Brain Yields Clues About Why Some Succumb
While Others Prevail
Discovery of resistance mechanisms in mouse brain may lead to
help for stress-related mental illness in humans
Results of a new study may one day help scientists learn how to
enhance a naturally occurring mechanism in the brain that promotes
resilience to psychological stress. Researchers funded by the National
Institutes of Health's National Institute of Mental Health (NIMH)
found that, in a mouse model, the ability to adapt to stress is
driven by a distinctly different molecular mechanism than is the
tendency to be overwhelmed by stress. The researchers mapped out
the mechanisms — components of which also are present in
the human brain — that govern both kinds of responses.
In humans, stress can play a major role in the development of
several mental illnesses, including post-traumatic stress disorder
and depression. A key question in mental health research is: Why
are some people resilient to stress, while others are not? This
research indicates that resistance is not simply a passive absence
of vulnerability mechanisms, as was previously thought; it is a
biologically active process that results in specific adaptations
in the brain's response to stress.
Results of the study were published online in Cell, on October
18, by Vaishnav Krishnan, Ming-Hu Han, PhD, Eric J. Nestler, MD,
PhD, and colleagues from the University of Texas Southwestern Medical
Center, Harvard University, and Cornell University.
Vulnerability was measured through behaviors such as social withdrawal
after stress was induced in mice by putting them in cages with
bigger, more aggressive mice. Even a month after the encounter,
some mice were still avoiding social interactions with other mice — an
indication that stress had overwhelmed them — but most adapted
and continued to interact, giving researchers the opportunity to
examine the biological underpinnings of the protective adaptations.
"We now know that the mammalian brain can launch molecular
machinery that promotes resilience to stress, and we know what
several major components are. This is an excellent indicator that
there are similar mechanisms in the human brain," said NIMH
Director Thomas R. Insel, MD.
Looking at a specific part of the brain, the researchers found
differences in the rate of impulse-firing by cells that make the
chemical messenger dopamine. Vulnerable mice had excessive rates
of impulse-firing during stressful situations. But adaptive mice
maintained normal rates of firing because of a protective mechanism — a
boost in activity of channels that allow the mineral potassium
to flow into the cells, dampening their firing rates.
Higher rates of impulse-firing in the vulnerable mice led to more
activity of a protein called BDNF, which had been linked to vulnerability
in previous studies by the same researchers. With their comparatively
lower rates of impulse-firing, the resistant mice did not have
this increase in BDNF activity, another factor that contributed
The scientists found that these mechanisms occurred in the reward
area of the brain, which promotes repetition of acts that ensure
survival. The areas involved were the VTA (ventral tegmental area)
and the NAc (nucleus accumbens).
In a series of experiments, the scientists extended their findings
to provide a progressively larger picture of the vulnerability
and resistance mechanisms. They used a variety of approaches to
test the findings, strengthening their validity.
"The extensiveness and thoroughness of their research enabled
these investigators to make a very strong case for their hypothesis," Insel
For example, the researchers showed that the excess BDNF protein
in vulnerable mice originated in the VTA, rather than in the NAc.
Chemical signals the protein sent from the VTA to the NAc played
an essential role in making the mice vulnerable. Blocking the signals
with experimental compounds turned vulnerable mice into resistant
The scientists also conducted a genetic experiment which showed
that, in resistant mice, many more genes in the VTA than in the
NAc went into action in stressful situations, compared with vulnerable
mice. Gene activity governs a host of biochemical events in the
brain, and the results of this experiment suggest that genes in
the VTA of resilient mice are working hard to offset mechanisms
that promote vulnerability.
Another component of the study revealed that mice with a naturally
occurring variation in part of the gene that produces the BDNF
protein are resistant to stress. The variation results in lower
production of BDNF, consistent with the finding that low BDNF activity
The scientists also examined brain tissue of deceased people with
a history of depression, and compared it with brain tissue of mice
that showed vulnerability to stress. In both cases, the researchers
found higher-than-average BDNF protein in the brain's reward areas,
offering a potential biological explanation of the link between
stress and depression.
"The fact that we could increase these animals' ability to
adapt to stress by blocking BDNF and its signals means that it
may be possible to develop compounds that improve resilience. This
is a great opportunity to explore potential ways of increasing
stress-resistance in people faced with situations that might otherwise
result in post-traumatic stress disorder, for example," said
"But it doesn't happen in a vacuum. Blocking BDNF at certain
stages in the process could perturb other systems in negative ways.
The key is to identify safe ways of enhancing this protective resilience
machinery," Nestler added.
For more information about posttraumatic stress disorder and depression,
visit the NIMH web site at:
The National Institute of Mental Health (NIMH) mission is to reduce
the burden of mental and behavioral disorders through research
on mind, brain, and behavior. More information is available at
the NIMH web site: http://www.nimh.nih.gov/.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.