Some cope with stress much better than others, and a new study of mice shows that a naturally occurring mechanism in the brain promotes resilience to psychological stress.

Why is this important? In humans, stress is often associated with the development of some mental health issues such as post-traumatic stress disorder (PTSD) and depression. Results of the study, published online in the journal Cell, show that resistance to stress is not just a passive absence of stress vulnerability mechanisms as had been previously thought, but a biologically active process that results in specific adaptations in the brain’s response to stress.

The results are encouraging because a greater understanding of the brain’s function in regards to stress may help scientists discover how to enhance a naturally occurring mechanism in the brain that promotes resilience to psychological stress.

"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," says Thomas R. Insel, MD, Director of the National Institute of Mental Health (NIMH).

In the study, smaller mice were put in cages with larger and more aggressive mice. Their vulnerability to stress was measured through such behaviors as social withdrawal after these encounters. While most mice adapted and continued social interactions after the stress event, some mice were overwhelmed by the interaction to the point that even after 30 days they were still avoiding social interaction with other mice.

The mice that were more traumatized by the stress showed more impulse firing by the cells that make dopamine, while the mice that were able to adapt maintained normal rates of impulse-firing due to a a protective mechanism—increased activity of channels that allow potassium to flow to the cells, which dampens the firing rate.

The higher firing rates in the traumatized 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 to resistance.

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 genetic experiments on the stress-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 numerous 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 promotes resilience.

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 Eric J. Nestler, MD, PhD, one of the study’s authors.

"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.

The study was published 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, and was funded by the National Institute of Mental Health (NIMH).

Sources:

• National Institutes of Health
• Cell, October 18, 2007