The science of stress resilience

Is resilience to stress a skill we acquire with life experience, or can it be ingrained from a very early age, or even birth? Understanding what makes a person more resilient may enableus to better help people according to their susceptibility to stress at various stages of their lives. In a study recently published in Cell Reports, Prof. Gil Levkowitz and his group showed that for zebrafish, some are born great at adapting to and overcoming adversity.

Employing advanced behavioral and molecular analysis and gene editing in successive generations of fish, the Levkowitz team—based in two departments: Molecular Cell Biology and Molecular Neuroscience—found that much of stress resilience is a heritable trait that is determined early on and remains constant throughout life.

Zebrafish show clear responses to stress as larvae, mere days after hatching, making them ideal models of early stress resilience. Such resilience is essential to their survival as parent fish don’t provide care for their independent, agile young. Therefore, their resilience results not from nurture, but rather nature. What sorts of stressors do baby zebrafish encounter? These freshwater fish are particularly sensitive to increased salinity, isolation, and physical contact (e.g., with a potential predator). When the scientists exposed newborn larvae to one such stressful condition, the fish responded with clear defense mechanisms, including diminished movement and freezing. Their behavior normalized eventually, but a significant minority rebounded much faster than others, displaying a superior stress-coping ability.

The researchers reared the resilient and susceptible subgroups of young zebrafish separately, then exposed them again to stress days and even months later. Both resilient and susceptible fish remained that way throughout their lives, from the larval stage into adulthood. The researchers even found that the offspring from both groups mimicked their respective parents, unambiguously showing that superior resilience is a heritable trait.

What is being inherited in this case? The scientists compared the genetic program activated throughout the bodies of fish in both groups—resilient and susceptible— in response to stress. This program was found to be more extensive in the stress-resilient larvae: The activity of about 250 genes decreased and those of about 100 increased, suggesting that resilience to stress is an active process.

What truly surprised the scientists, however, was that the fish with more resilience-inducing gene variants also had suppressed immune systems. That is, following a stressful encounter, resilient larvae suppressed certain factors that are part of the innate immune response of the body’s “complement system.” While normal functioning of this complementary system is crucial in fighting infections, these findings suggest that inhibiting an exaggerated complement response is beneficial when coping with adversity. Further DNA analysis confirmed that zebrafish with mutations in their complement system genes were significantly more resilient than fish with functional complement systems.

In humans, abnormal complement-system activation has previously been associated with depression and anxiety. To explore the similarities between the stress responses of fish and humans, the Levkowitz group checked for molecules previously linked to stress resilience in people.

They also examined the effects of neuropeptide Y—a chemical messenger in the brain that has been linked to resilience in humans—on mthe zebrafish. They found that fish lacking neuropeptide Y were less likely to be resilient than those with normal levels. “This gives us greater confidence that the way we test resilience in fish is relevant tohumans,” Prof. Levkowitz says.

The findings may 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 betweenstress and immunity in human beings.

Gil Levkowitz is supported by:
- Hedda, Alberto and David Milman Baron Center for Research on the Development of Neural Networks
- Sagol Institute for Longevity Research
- Elias Sourasky Professorial Chair