Written by: Catharine Paddock
Medical News Today
19 Oct 2007
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.
"Molecular Adaptations Underlying Susceptibility and Resistance to Social Defeat in Brain Reward Regions."
Vaishnav Krishnan, Ming-Hu Han, Danielle L. Graham, Olivier Berton, William Renthal, Scott J. Russo, Quincey LaPlant, Ami Graham, Michael Lutter, Diane C. Lagace, Subroto Ghose, Robin Reister, Paul Tannous, Thomas A. Green, Rachael L. Neve, Sumana Chakravarty, Arvind Kumar, Amelia J. Eisch, David W. Self, Francis S. Lee, Carol A. Tamminga, Donald C. Cooper, Howard K. Gershenfeld, and Eric J. Nestler.
Cell, Vol 131, 391-404, 19 October 2007.