Researchers have for years tried to discover what determines “resilience to stress,” a term describing the ability to adapt to difficult situations and to overcome adversity. Is it acquired through experience, or is there a tendency to easily recover from stress possibly ingrained in us from a very early age or even from birth?
A new study lead by Prof. Gil Levkowitz of the molecular cell biology and molecular neuroscience departments at the Weizmann Institute of Science in Rehovot has revealed an important piece of this puzzle. The study examined zebrafish – small, black-and-white-striped, transparent fish whose natural habitat spans rivers, ponds and rice paddies in Pakistan, Myanmar, Nepal and India.
Using advanced behavioral and molecular analysis and gene editing in successive generations of fish, the researchers found that much of stress resilience is a heritable trait that is determined early on and remains constant throughout the fish’s life.
Is stress resilience a heritable trait?
Writing in the peer-reviewed Journal of Molecular Cell Biology under the title 1.2023, Levkowitz was especially interested in answering the question why some combat soldiers exhibit post-traumatic stress disorder, while their comrades faced with the same situations do not.
“Stress-resilient fish are born that way; their immune system reveals why,” he wrote.
Dr. Amrutha Swaminathan, who led experiments for the new study in Levkowitz’s lab, said: “From a very early age, you need to study very young subjects with as little life experience as possible. Zebrafish are exceptionally suitable subjects for exploring such research questions, since they already show clear responses to stress as larvae mere hours after hatching from eggs that are fertilized externally.”
“From a very early age, you need to study very young subjects with as little life experience as possible. Zebrafish are exceptionally suitable subjects for exploring such research questions, since they already show clear responses to stress as larvae mere hours after hatching from eggs that are fertilized externally.” Amrutha Swaminathan
Zebrafish’s early response to stressful situations is essential for their survival; the parents don’t provide care for their young, which are independent and agile. Therefore, the behavior that scientists observe in their test subjects cannot be the result of nurture – that is, it’s not something they picked up from observing their parents.
“By and large, offspring of the selected resilient parents tended to cope with stressful situations better than the average population, and the contrary was observed in offspring of susceptible parents, so we’re talking about a heritable trait,” Swaminathan said.
When the scientists temporarily exposed six-day-old larvae to one of such stress factors, the fish displayed clear stress responses as defense mechanisms, including diminished movement and freezing (playing dead). Their behavior normalized eventually, but a significant minority of 10% to 20% rebounded much faster than others, and they were soon behaving as though they had a superior stress-coping ability. The researchers defined the fast rebounders as stress resilient and the others as susceptible.
The identified resilient and susceptible groups of young fish were reared separately. The researchers exposed them to stress again days and even months later and found that both resilient and susceptible individuals remained that way throughout their lives, from the larval stage into adulthood.
The study then went deeper in an attempt to characterize the mechanisms that determine resilience in zebrafish. The researchers compared the genetic program activated throughout the bodies of fish in both groups, resilient and susceptible, in response to stress. This program was more extensive in the stress-resilient larvae: Their expression levels of about 250 genes decreased and those of about 100 increased, suggesting that resilience to stress is an active process.
When the scientists looked at the specific genes involved in the stress responses, they were surprised. They had expected to see the main changes in gene expression occurring in the brain, but they found that resilient and susceptible larvae also displayed differences in their immune systems.
In resilient larvae, parts of the immune system were suppressed – particularly, proteins that are produced in the liver and that belong to the part of the innate immunity known as the complement system, which tags harmful microorganisms in our bodies and induces inflammatory responses that help fight infections.
“We had been mainly oriented towards the brain, but it turns out that the liver is very much involved in regulating the response to stress,” Levkowitz said.
The study’s findings could lead to a better understanding of the role of genetics in determining how we cope with stress, and they open new avenues of research into the interplay between stress and immunity in human beings. They may also promote the search for biomarkers that could help identify susceptible individuals, enabling future generations to better treat or prepare for stress in an orderly way.
