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Vulnerability to Stress Linked to Brain Molecule

THURSDAY Oct. 18, 2007 -- Researchers have identified molecular mechanisms in the brain that may explain why some people are less vulnerable to the stress caused by difficult situations.

While the research was done with mice, the findings could eventually lead to better treatments for chronic stress, depression and the post-traumatic stress disorder suffered by troops in Iraq and other battlefields, said study co-author Dr. Eric Nestler, chairman of psychiatry at the University of Texas Southwestern Medical Center at Dallas.

"One important lesson we have shown even in previous papers is that a series of genetically identical animals respond differently to chronic stress," Nestler said. "Thirty to 40 percent seemed to be resilient and did not develop bad symptoms. The clinical implications are that the ability to identify mechanisms of resistance can help provide new and novel approaches to stress."

The key lies in a pair of molecules used by some brain cells to communicate with one another, said Vaishnav Krishnan, lead author of the report and a student in a University of Texas Southwestern Medical Center program that leads to simultaneous M.D. and Ph.D. degrees.

"Under stress, vulnerable mice increase the frequency of nerve activity using the neurotransmitter dopamine," Krishnan said. "That subsequently causes release of a nerve growth factor called brain-derived neurotrophic factor [BDNF]. Resilient mice overcome these changes by increasing the expression of molecules that prevent the release of dopamine."

A neurotransmitter is a molecule that sends signals from one nerve cell to another.

Mice in the experiments were so inbred that they were genetically identical. Then they were put under stress by being placed in the territory of larger, more aggressive mice. Some of the test mice adjusted well to the stress of the situation, while others avoided contact and showed submissive behavior.

The researchers then made detailed studies of two brain regions -- the ventral tegmental area (VTA) and the nucleus accumbens (NAcc), which are part of the brain's reward area that promotes acts that aid in survival. They found that the excess BNDF production in vulnerable mice occurred in the VTA but not the NAcc region. Chemical signals sent by the protein from the VTA to the NAcc made the mice vulnerable to stress. Experimental compounds that blocked those signals turned vulnerable mice into resistant mice.

The findings, published online Oct. 18 in the journal Cell, raise the possibility of "tools to develop things in the brain that encourage resilience, to help people with stress," Nestler said.

"We have always tried to understand the changes in the brain that lead to such things as the symptoms of post-traumatic stress disorder," Krishnan added. "This study shows we can increase our understanding and development of new therapeutic measures to overcome those changes."

But new therapies might not be easy to develop, Nestler said, since a decrease of dopamine or BDNF activity might be helpful in one part of the brain but harmful in another area.

Dr. Thomas R. Insel, director of the U.S. National Institute of Mental Health, which funded the research, said the findings are "part of a large body of work coming out of Dr. Nestler's laboratory trying to understand what this important neurotrophic molecule, BDNF, does."

"What's exciting here is that it is important for resilience, being able to recover from a traumatic event," Insel added. "One of the great values of this work is to help us understand how mammals, including humans, might be able to recover from the traumas inherent in human existence."

More information

Learn more about the role of stress in sickness and health from the American Institute of Stress.

Posted: October 2007


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