Differences In Brain Chemistry

A new US study on mice has suggested that differences in the chemistry of reward circuits in the brain may explain why some people are more susceptible than others to post traumatic stress, depression and other mental and emotional disorders when faced with adversity. It is hoped the findings will lead to new types of drugs and treatments for people who are victims of or working in high stress situations such as combat zones and disasters.

The study is published in the 19th October issue of the journal Cell and is the work of researchers at The University of Texas Southwestern Medical Center (UTSWMC) in Dallas and colleagues from Harvard University, Cambridge, Massachusetts, and Weill Medical College of Cornell University, New York.

The researchers found that mice that coped less well with "social defeat" had higher levels of BDNF (brain-derived neurotrophic factor) in a part of the brain that is important for controlling behaviours related to reward and emotions. The mice that coped well showed lower levels of BDNF when exposed to the same stressor.

BDNF promotes brain plasticity by helping to make new connections between neurons, an important function for memory and learning, said the researchers.

Eric Nestler (UTSWMC), corresponding author of the study suggested that:

"The increase in BDNF may have an adaptive role normally, allowing an animal to learn that a situation is bad and avoid it in the future."

"But under conditions of extreme social stress, susceptible animals may be 'over-learning' this principle and generalizing it to other situations. They avoid their aggressors, but they also avoid all mice and even other fun things like sugar or sex," explained Nestler.

All the mice in the experiment were virtually genetically identical and were raised in the same carefully controlled enviroment, said Nestler. The researchers said it was possible that environment and social factors (eg the dominance hierarchy in a litter) could explain the differences in the reactions of the mice, or even random events during their development.

A person's response to stress is thought to be due to a complex interplay of genetic and environmental factors, said the researchers, paying witness to a large body of literature on the effects of acute and chronic stress on physiology and behaviour. But much less is known about the biological differences of different stress reactions, they said.

The experiment comprised forcing large mice to be aggressive toward smaller mice. An earlier experiment had shown that after experiencing 10 defeats in 10 days, the small mice tended to avoid social interaction for a long time afterwards.

But this latest experiment demonstrated a range of responses within that reaction. While all the small mice showed signs of anxiety, only some of them showed symptoms similar to post traumatic stress and depression. The more susceptible mice lost weight and became less interested in sugar, symptoms consistent with depressive states. These mice also had greater sensitivity to low doses of cocaine.

When the researchers examined the brains of the more susceptible mice they found they had 90 per cent higher levels of BDNF in the "mesolimbic dopamine" reward circuit compared to the other, more resilient, mice. The BDNF levels in the brains of the resilient mice had not changed.

When they did genetic tests on the brains of the two groups of mice the researchers found that the more resilient mice had more activity in the genes that stop neurons becoming over-excited. They also found that the more vulnerable mice had dopamine neurons that fired at a faster rate than those of the resilient mice. It appeared that resilience to social stress was linked to having a less active type of BDNF.

The researchers also said that when they carried out post mortem tests on the brain tissue of human patients that had been depressed, they found their levels of BDNF were 40 per cent higher than in patients who had not been depressed.

Genetic testing allows the genetic diagnosis of vulnerabilities to inherited diseases, and can also be used to determine a person's ancestry. Every person carries two copies of every gene, one inherited from their mother, one inherited from their father. The human genome is believed to contain around 25,000 - 35,000 genes. In addition to studying chromosomes to the level of individual genes, genetic testing in a broader sense includes biochemical tests for the possible presence of genetic diseases, or mutant forms of genes associated with increased risk of developing genetic disorders. Genetic testing identifies changes in chromosomes, genes, or proteins. Most of the time, testing is used to find changes that are associated with inherited disorders. The results of a genetic test can confirm or rule out a suspected genetic condition or help determine a person's chance of developing or passing on a genetic disorder. Several hundred genetic tests are currently in use, and more are being developed.

About Researcher:

Eric J. Nestler, Ph.D.

Professor and

Chairman, Department of Psychiatry

Lou and Ellen McGinley Distinguished Chair in Psychiatric Research

Cell

Regulation

Neuroscience

Office: 214-648-1111

FAX: 214-648-4947

Email: eric.nestler@utsouthwestern.edu

About UT Southwestern

Part of The University of Texas System, UT Southwestern is governed by the UT Board of Regents. President Dr. Kern Wildenthal leads the medical center which includes three degree-granting institutions: UT Southwestern Medical School, UT Southwestern Graduate School of Biomedical Sciences, and UT Southwestern Allied Health Sciences School. These three schools train more than 4,200 medical, graduate and allied health students, residents and postdoctoral fellows each year.

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