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The human brain presents surprises

Svetlana Belyaeva, "Search"

For a long time it was believed that the nerve cells of the brain do not recover, and there were numerous experimental confirmations of this. However, it turned out that it was premature to put an end to this issue: today scientists' opinions on this matter differ. In April, an article was published in the authoritative journal of cell biology, which claims that new neurons are produced throughout a person's life, until old age, which contradicts the results of another recent study, the authors of which concluded that neurogenesis ceases with the end of childhood. The correspondent of "Search" tried to understand this in a conversation with a Russian-American neuroscientist, professor at Stony Brook University and the famous Cold Spring Harbor laboratory (to which he was invited by James Watson, who headed it for a long time), head of the brain stem cell laboratory at the Faculty of nano-, bio-, information and Cognitive Technologies of MIPT (created by according to the megagrant of the Russian Federation) by Grigory Enikolopov.

Photo by Nikolay Stepanenkov

– Grigory Nikolaevich, why is it important to understand the mechanism of the birth of new neurons – neurogenesis – what does this give researchers?

– New neurons appear from stem cells in the embryonic state or, as was recently discovered, in the adult brain. The latter is in great contradiction with what we have always been taught: brain cells do not regenerate, and almost everything we inherited at birth is the set of neurons with which we have to live our whole life. It turned out that there are several areas in the human and animal brains whose stem cells produce neurons throughout life. Although this process fades with age, but the main thing is that it continues after birth. One of these areas that scientists are most interested in is the hippocampus.

– Why exactly does it arouse interest?

– It is very closely related to memory, learning, emotions, response to stress, etc. It has long been known that if the hippocampus is damaged, then a person cannot form a new memory. This can be seen in Alzheimer's disease or in patients after strokes: if the hippocampus was seriously damaged, much of the behavior of these people may remain unchanged, but they cannot remember the events that occurred half an hour ago. So when there was evidence that new neurons could appear in the hippocampus in adulthood, it was easy to imagine that, perhaps, the formation of new memories was somehow connected with them. It turned out that the situation is more subtle. It's not just about memorization, but about the ability to distinguish between similar, but not identical objects. Here is an example: in an office building there are several rooms in front of you, the entrances to them are similar, but you remember which one you need to enter, because you remember some small signs that distinguish one from the other. We rarely think about it, but in reality our brain constantly makes such comparisons and calculations, and this ability to distinguish closely related objects often weakens with certain neurodegenerative diseases. It is known, for example, that patients with Alzheimer's can get lost in the city because it is difficult for them to distinguish some very similar places. It is for this process, apparently, that new neurons are responsible.

– Does this mean that Alzheimer's can be reversible?

– Unfortunately, we don't know how to achieve this yet. Hippocampal neurons are particularly sensitive, therefore, in Alzheimer's, they first begin to degrade, and the general decline in memory in patients is most likely due to this. Some of the manifestations of the disease may indeed be associated with a decrease in neurogenesis. But we must remember that with this disease, many other changes occur in the brain.

However, new neurons are important not only for the ability to distinguish closely related situations, but also for responding to stress or taking antidepressants; there are many different behavioral reactions that are apparently related to neurogenesis.

– Is it possible to say that the more new neurons are born in the adult brain, the better?

– Almost everything that benefits a person – stress reduction, exercise, antidepressants – correlates (occurs in parallel) with an increase in the number of new neurons. And vice versa: depression, chronic stress, chemotherapy, radiotherapy lead to a slowdown in the process of the appearance of new neurons. This does not prove that good mood depends on neurogenesis, but there are a lot of examples of such a relationship, when an increase in neurogenesis correlates with some positive stimuli, and its decrease with negative events.

– Is it possible with the help of some drugs to "rock", strengthen the process of neurogenesis?

– It's not for nothing that I talked about a large number of examples when an increase in neurogenesis correlates with an improvement in cognitive abilities, memory, mood. And although it is not shown every time and not for every case that one depends on the other, and not just goes hand in hand, several large companies are making great efforts today to try to find drugs or some approaches to increase neurogenesis in the hippocampus. But a similar result can be achieved both through physical exercise and through an enriched living environment. In other words, everything that we used to associate with healthy lifestyle (physical education, busy life, new impressions and sensations) increases, at least in animals, the appearance of new neurons.

– A few months ago, Search reported on an article whose authors claim that human neurogenesis fades after 15 years and in adults it is very low. And a couple of weeks later, an article by another group of scientists appeared, which states the exact opposite: hippocampal neurogenesis continues almost unchanged until old age. Who should I believe?

– This is a complex issue, and it is still difficult to make a definite verdict. Both laboratories are very high-level, and they used the same approach. But we must remember that the evidence that neurogenesis is supported in an adult is very different and they are obtained not by one method, but by three or four completely non-overlapping methods. And all these methods say the same thing, that if the production of neurons in adults is falling, then they still have a fairly high level of neurogenesis. And this is probably a huge resource to rely on. Of course, in adulthood, neurogenesis is less than in children. The question, rather, is whether it really falls to some insignificant values, as stated in some works, or whether an adult continues to have hundreds, if not thousands, of new neurons every day, as reported in others.

– Maybe it's because research on the human brain is technically very difficult?

- of course. We can say something with very high accuracy so far only about animals. We recently published an article in which we describe methods that allow us to characterize extremely accurately different populations of stem cells and, for example, break down a long cascade of transformations and transition from stem cells to new neurons into separate stages. But none of these methods is suitable for humans, because in animals we can study a living brain. With a person, almost all studies involve working with the material of the deceased. And here a huge number of technical difficulties accumulate, many factors matter, for example, how quickly samples were taken for research after death, how the tissue was prepared, how its analysis was carried out, and so on. Perhaps the discrepancies in the conclusions of the articles are precisely related to these small details. It's easier with mice. We are now working a lot with teenage rodents, and these are quite adequate models.

– In the physics laboratory, which you run, the effect of low doses of radiation on the brain is being studied. What is attractive about this topic?

– There are several reasons. One of them is that radiation very easily kills dividing stem cells, which will then turn into neurons. Radiotherapy of tumors is actually based on the destruction of dividing cells. It has long been shown that with strong radiation, progenitor cells (or stem cells) die, new neurons become fewer and this leads to a drop, at least in animals, their cognitive abilities, memory, etc.

– How can this manifest itself in humans?

– There is more and more evidence that, for example, children who, due to leukemia or some other cancers, have to be repeatedly exposed to radiotherapy, accumulate some lag in intellectual development. It can be compensated later, but, nevertheless, the question of whether there is some connection with suppressed neurogenesis and whether it is impossible to protect brain stem cells during radiotherapy is being raised more and more often. However, this applies to fairly large doses of radiation.

A more rare and even exotic example is space flights. On Earth, we are protected from a large number of radioactive particles by the magnetic field of our planet. But as soon as a person crosses this belt and flies, for example, to Mars, this problem will become quite real. There the astronauts will meet with a type of radiation that we are not used to on Earth and which, as shown in our experiments, has a very strong effect on neurogenesis. These are not huge doses, so it is unlikely that they will provoke cancer in astronauts, but what will happen to the brain is not very clear. A long–term space flight is an extremely complex and responsible mission. And although the most prepared people are sent into space, whose intellectual abilities are at the highest level and allow them to make adequate decisions in a dangerous situation, there are still possible brain changes in a person who flies to Mars for a whole year and then back (and at this time, memory deterioration or depression begins due to the effects of cosmic radiation), become critical both for the astronaut himself and for the mission.

And there is a completely different problem, and this is closer to what we are doing: small doses of radiation. We meet with them all the time, going through, for example, various medical procedures that are associated with radiation in very small doses. These doses are harmless in the usual sense. Whether they can influence neurogenesis and stem cell division is still an open question. Speaking about low doses of radiation, it should be understood that it is not very clear what they can lead to. For example, could it be that at the same time there is some kind of stimulation of stem cell division and the brain becomes even better? So far we have no data to believe that low doses of radiation are necessarily bad. In order to find out, our laboratory was founded at the Faculty of nano-, bio-, information and Cognitive Technologies of Phystech, which operates on the basis of the Kurchatov Institute, where, by the way, scientists are also interested in similar issues. Our megagrant, as well as several other grants from the Russian National Fund and the Russian Foundation for Basic Research, were directed to this. The topic is very big and is a kind of "cap" for our research, which is focused not only on the study of the effects of radiation, but also on the development of new approaches to how to study neurogenesis, on the creation of new models of neurogenesis, new methods for studying stem cell division.

– It's nice to hear that such serious and relevant research is being conducted under your leadership in Russia.

– When I received the megagrant, the main idea was that Russian researchers would go to my American laboratory, learn from experience and come back, ensuring close interaction between the two scientific structures. Indeed, all the employees who studied at the American laboratory have returned and are working in Russia, but thanks to these internships, a very intense connection has now been created between scientists: now the same experiment that is being done in Russia or America is being discussed by all participants. Based on this synergy, we have managed to create an extremely strong scientific group, and I hope we will be able to keep it active.

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