The researchers say that mice's ability or inability to cope with stress is linked to specific differences in the way brain cells communicate with each other. They believe that understanding these mechanisms may eventually help scientists develop methods to boost resilience to stress and depression in humans.
"One of the major insights provided by this work is that resilience to stress is an active process. This means that chronic stress, depression, post-traumatic stress disorder and similar disorders might be treated by promoting the mechanisms that underlie resilience," said Dr. Eric Nestler, chairman of psychiatry and senior author of the study, which appears in the journal Cell.
A previous study by the same research team has already shown that mice that repeatedly go through "social defeat" are a good model for human depression.
In the current study, Dr. Nestler's team stressed the rodents by placing them in the territory of a larger, aggressive mouse and recorded the impact of this stress on their ability to interact socially.
While some of the genetically identical mice interacted with the bigger mouse, others avoided it and showed submissive behaviour. The researchers also found that some mice showed a long-lasting social withdrawal, while others continued to interact normally with other mice.
It was also observed that the mice that coped less effectively with the stress were more attracted to cocaine and less to sugar, in comparison with the rodents that coped well. The finding attains significance as it suggests between their vulnerability to stress and substance abuse.
Thereafter, the researchers examined two areas of the brain that are associated with pleasure and reward, called the ventral tegmental area (VTA) and the nucleus accumbens (NAc).
They found that mice that were more susceptible to social defeat showed increased levels of a growth factor known as brain-derived neurotrophic factor (BDNF) in the two brain regions, while rodents who coped better with the stress did not show the same chemical rise.
When the researchers genetically blocked BDNF in the more timid mice, they became resistant to stress.
"Preventing BDNF signaling to the nucleus accumbens may be a key mechanism of resistance to stress and depression," Dr. Nestler said.
The researchers also found that better-coping mice had far more genes turned on and off in the VTA and NAc than vulnerable mice, indicating that successful coping with stress is an active process that involves the regulation of many genes, not just the lack of responses seen in poorly coping animals.
With an eye on exploring how these results might apply to humans, the researchers obtained brain samples from depressed and non-depressed humans. The depressed people showed a 40 per cent increase in BDNF levels in the nucleus accumbens, compared to controls.
They concluded that preventing BDNF release into the nucleus accumbens might be a way to increase coping ability to stress or depression.
"It may be possible to develop compounds that improve one's ability to cope with stress. But blocking BDNF might also affect other systems, so we must find a way to focus on this single pathway," Dr. Nestler said.
"The study yields significant insights into molecular mechanisms that may underlie individual differences of people in reacting to stressful life events," added Vaishnav Krishnan, an M.D./Ph.D. student in the Medical Scientist Training Program and lead author of the paper.