Weizmann Institute scientists have discovered that certain fish are born with immunity to stressful situations, which accompanies them throughout their lives and is even inherited. The findings may pave new directions for the treatment of post-trauma
Why do some soldiers develop post-traumatic stress disorder, while their brothers in arms leave the horrors of war behind? Why are victims of violence sometimes left scarred for the rest of their lives, while others in similar situations show relative resilience? Over the years, researchers from various fields have been trying to understand the source of the differences in our response to situations of distress and stress. Weizmann Institute of Science scientists recently found some new answers to these questions in a surprising place: in water. According to the findings of the research conducted on zebra fish, resistance to stressful situations may be a trait that is determined at a very early age, remains stable throughout life, and is even inherited. Also, the immune system, and not only the nervous system, apparently plays a major role in mental resilience as well.
"To determine whether resistance to stress - or in the professional language 'stress' - is an acquired or inherited trait, individuals should be studied as young as possible, with as little life experience as possible," explains Dr. Amruta Swaminathan, who led the new research in the laboratory of Prof. Gil Lebkowitz from the departments of molecular cell biology and molecular neurobiology. Zebrafish - small fish common in rivers, lakes and flooded rice fields in Asia and in aquariums in research laboratories around the world - are remarkably suitable for this purpose, since they do not receive the protection and care of their parents, and face stressful challenges alone already in the earliest developmental stage known as larva - A few days after hatching from externally fertilized eggs.
""We clearly showed that Aka affects the immune system which in turn affects brain functions and behavior"
As a social animal that exists in fresh water, zebrafish, also known as zebrafish, are particularly sensitive to stressful situations caused by isolation from their group as well as unexpected contact that may signal an attempt to prey or a change in the level of salinity in their environment. In the new study, the researchers exposed day-old zebrafish to these stress factors and saw that the mobility of the fry decreased and most of them even froze in place. Gradually the fry recovered, but about 10% to 20% recovered faster than others, and it was evident that they had better mechanisms for dealing with stress. These fish were defined as "resistant" (resilient), while the rest were defined as "susceptible".
consistent strain
The researchers raised the susceptible and resistant fish separately and exposed each of the groups to stress at different time points throughout their lives. They saw that the reaction to Aka remained stable in each of the groups - from their days as fingerlings to their adulthood. Moreover, even in the next generation, the findings were decisive: "In general, the descendants of the resistant group tended to cope better with stressful situations, while the descendants of the prone group coped with stress in a lesser way", says Prof. Levkowitz. "From this we concluded that resistance to stress in zebrafish is a trait that is inherited."
After a genetic test conducted by the researchers, considerable differences were found between the genetic programs activated in response to the stress in each of the groups. For example, more comprehensive changes in gene expression were evident in the resistant fry: compared to the susceptible fish, the expression level of 250 genes in the bodies of the resistant ones dropped, while the expression level of 100 genes increased. The extent of the changes indicates that resistance to stress at the behavioral level results from an active molecular process.
A deeper examination of the response revealed surprising findings. The scientists expected to see changes in gene expression mainly in the nervous system, but significant differences were also observed in the cells of the immune system. In fish resistant to stress, various components of the immune system were silenced, in particular proteins of the immune system. These proteins that belong to the innate immune system and are produced in the liver, are responsible for provoking an inflammatory response in the body, and are necessary to deal with infections. However, surprisingly, the findings showed that suppressing these proteins may be beneficial for dealing with stressful situations. To test this assumption, the researchers created, through genetic editing, transgenic fish in which essential components of the complement system were silenced. These fish did tend to show greater resistance to stress than fish with a normal, functioning immune system. "A circumstantial correlation between abnormal activity of the complement system and depression and anxiety in humans has already been found in previous studies, but we still do not know how exactly this system affects stress resistance," says Dr. Swaminathan. "In the current study, we clearly showed that Aka affects the immune system, which in turn affects brain functions and behavior."
like a fish in water
To test the relevance of the study to humans, the scientists compared the new molecular findings in fish to previous findings on stress responses in humans. In particular, they looked at how a short protein molecule known as neuropeptide y, known from previous studies to be associated with stress resistance in humans, affects fish. The researchers found that fish without neuropeptide y were less resistant to stress than fish with neuropeptide y. "These findings give further validity to the fact that the way we test resistance to rabies in fish is also relevant for humans," says Prof. Lebkowitz.
The research findings may advance our understanding of the genetic origin of post-traumatic disorders, as well as open new avenues of research on the interrelationships between dealing with stress and the functioning of the immune system. "With the help of the fish, we discover new insights into the way in which resistance to stress is determined," says Dr. Swaminathan. "In the future, this knowledge may allow us to identify genetic risk factors in humans and perhaps even treat them according to their level of susceptibility to develop a post-traumatic reaction."
Dr. Michael Gliksberg and Savani Anbalgan from the laboratory of Prof. Gil Lebkowitz and Dr. Noa Vigoda from the Life Sciences Research Infrastructure Department of the Weizmann Institute also participated in the study.
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