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Understanding Resilience to Stress

Stress can play a major role in the development of several mental illnesses, including post-traumatic stress disorder and depression. Researchers have long wondered why some people are resilient to stress while others aren't. A new mouse study may have brought them a step closer to the answer.

Dr. Eric J. Nestler of the University of Texas Southwestern Medical Center led a research team investigating the vulnerability of mice to stress after social defeat. When mice are put in cages with bigger, more aggressive mice, some still avoid social interactions with other mice even a month later — a sign that the stress has overwhelmed them. Some, however, adapt and continue to interact with others. The differences between these groups gave Nestler and his team the opportunity to examine the biology behind stress resilience. Their research was funded by NIH's ×îÐÂÂ鶹ÊÓƵ Institute of Mental Health (NIMH).

Previous studies found that social defeat raised the activity of a protein called BDNF in 2 of the brain's "reward" areas, which create feelings of enjoyment or pleasure through the chemical messenger dopamine. These regions are known as the VTA (ventral tegmental area) and NAc (nucleus accumbens). In the new study, published online in Cell on October 18, 2007, the researchers found that vulnerable mice had a 90% elevation in BDNF levels in the NAc after social defeat, but resistant mice showed no change.

The researchers next analyzed the differences in gene activity between the 2 groups of mice. In stressful situations, many more genes went into action in the VTA than the NAc of adaptive mice. This wasn't true of vulnerable mice. Among the active VTA genes were 3 for ion channels that allow the mineral potassium to flow into nerve cells.

Potassium channels are known to dampen neuron firing rates, so the researchers decided to test the activity of neurons in the VTA. Vulnerable mice, they found, had a 36% increase in neuron firing rates after social defeat. Adaptive mice, in contrast, maintained normal rates of firing. Susceptibility to social defeat, then, seems to be caused by higher VTA neuron activity, which raises BDNF levels in the NAc. More resilient mice dampen their VTA neuron activity by making more potassium channels.

When the researchers raised the levels of a potassium channel in the VTA of vulnerable mice, their neuron firing rates decreased and the mice became resistant to social defeat. Interfering with potassium channels, in contrast, increased the neuron firing rates and made mice more vulnerable. In another set of experiments, the researchers showed that they could also make vulnerable mice resistant by giving them a variation of the BDNF gene that lowers the protein's production, further supporting their ideas.

To see if these findings might be relevant for humans, the researchers examined the brain tissue of deceased people with a history of depression. They found a 40% increase in levels of BDNF protein in the NAc of depressed people, 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," Nestler said. "The key will be to identify safe ways of enhancing this protective resilience machinery."