Ural Federal University: Zebradanio Fish Showed How to Overcome Chronic Stress

Russian scientists found that immunomodulators, along with their combination with the antidepressant fluoxetine, can help overcome fish anxiety. For this purpose, biologists artificially created conditions of long-term unpredictable stress in zebradanio fish (danio rerio) and then “treated” them with the drugs. In the future, this research will help develop new methods to combat mental disorders caused by chronic stress. The results of the study, which was supported by a grant from the Russian Science Foundation (RSF), were published in the journal Scientific Reports.

In everyday life, people are surrounded by many stressors, such as strenuous work, constant city noise, worry and anxiety, and lack of sleep. If severe stress, such as grueling work, lasts for a long time – months or years – it can lead to serious mental health problems such as depression. Their treatment is difficult because the symptoms can be very different, influenced by many factors: genetic, social, environmental. In addition, stress often increases inflammatory processes that weaken the immune system and may contribute to the development of other diseases. To study in detail the causes and course of stress-induced diseases, scientists use laboratory animals. Zebra fish (zebradanio), or danio rerio, are a good model for such work, because they are easy to breed, unpretentious, and their genome, physiology and brain structure are quite similar to those of humans.

Researchers analyzed the effect of stress on the zebradanio’s behavior and hormonal background. Before the experiment began, the population of several dozen specimens was kept in standard, comfortable conditions for them: a large aquarium with optimal water temperature and lighting. Then half of the fish were transferred to other tanks, where all was not so favorable: the water temperature was higher or lower than usual, a predator swam or the water contained its “smell”, the light was too bright or absent altogether, there was no food or similar stress conditions. A variety of tests were conducted daily for eleven weeks, while biologists monitored the current state of the fish, and after the end of that period, pharmacotherapy for stress was conducted. For this purpose, scientists used fluoxetine, a drug widely used in medicine, as an antidepressant. The novelty of the approach is that the researchers along with him gave the fish more and immunomodulators: lipopolysaccharide – pro-inflammatory polymer from the cell wall of bacteria, which causes an immune response – and eicosapentaenoic acid, which is part of many animal fats and suppresses inflammatory responses in the body.

It turned out that the stressed fish clumped together in dense shoals, also preferring the bottom of the aquarium, indicating that they were more anxious. On the other hand, scientists have noted an increase in their ability to aversive learning – the ability to watch out for danger. Determined this with an interesting test: zebra fish were placed in an aquarium, divided into light and dark halves. By nature, fish prefer low-light places, so in the experiment they tried to spend more time in the dark part of the aquarium. But the researchers periodically applied an electric current to this comfort zone, which caused the fish to swim away. It turned out that under such conditions, individuals who had previously experienced stress, over time began to appear less often in the dark half than “calm” fish, indicating that they quickly learned to avoid the unpleasant factor – the electric current.

After conducting all the experiments, the scientists painlessly sedated the fish and used samples of their nervous tissue to study the hormonal state of the individuals. Treatment of “anxious” zebradanio with antidepressants and immunomodulators showed that fluoxetine, as expected, relieved anxiety and reduced stress-induced levels of noradrenaline in the brain. In addition, it turned out that the combination of fluoxetine and eicosapentaenoic acid had an even stronger effect: together they not only restored calm behavior and stress hormone levels, but also increased levels of dopamine, the hormone of joy. By contrast, when the zebra fish were injected with lipopolysaccharide along with fluoxetine, they became more anxious and gathered in even denser schools than with chronic stress.

“Our research has shown that it is possible to synergistically increase the effectiveness of stress therapy with both antidepressants and their combination with additional substances. For example, the polyunsaturated omega-3 fatty acid, eicosapentaenoic acid, found in many seafoods not only helps fluoxetine combat stress, but also has an anti-inflammatory effect on the body, which is especially important in nervous disorders. In the future, we plan to study the interaction of fluoxetine and immunomodulators eicosapentaenoic acid and lipopolysaccharide between each other to understand the reasons for strengthening or weakening their effectiveness in the fight against stress,” says Alan Kaluev, Head of the project for a grant from the Russian Science Foundation, member of the European Academy, Head of the Laboratory of Biological Psychiatry at St. Petersburg University, leading researcher of the UrFU Research Laboratory of Advanced Studies in Petrochemistry, Chemical Technology and Biotechnology.

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