They are recovering
How did the "revolutionary" neuroscientists refute the dogma that nerve cells do not regenerate
Alexey Rzheshevsky, "The Attic"
In June 2013, the scientific journal Cell published the work of a large international group of researchers from Sweden, France, Germany and the USA. In it, scientists provided evidence of neurogenesis – the birth of new nerve cells – in the adult brain.
The researchers applied a method based on radiocarbon analysis, which allowed them to retrospectively study brain cells of deceased people. They measured the levels of a radioactive carbon isotope, carbon-14, in the brain cells of people who lived in 1955-1963. Why exactly during this period? At that time, the USSR and the USA were actively testing nuclear weapons, and as a result of these tests, the amount of radioactive carbon-14 in the atmosphere increased dramatically. At first, this isotope was accumulated by plants and animals that ate these plants, and then, along with food, it got into the human body. And then it was embedded in the DNA of newly emerging cells, becoming a kind of label by which it was possible to determine the time of embedding. When scientists examined brain cells of people who lived in 1955-1963, the concentration of carbon-14 in them directly showed that these cells were formed already in adulthood. Thus, another confirmation of neurogenesis was obtained. But this, one might say, is almost the very end of the story.
And it all started at the turn of the XIX and XX centuries, when neurobiology was just emerging. Then the Nobel laureate Santiago Ramon y Cajal formulated a well-known dogma, the echo of which we hear to this day: nerve cells in the adult brain do not recover. In 1913 he wrote: "The centers of the adult brain are something established, complete and unchangeable. Everything can die, nothing can be restored. The vocation of the science of the future is to change this harsh sentence, if possible." It took many years and considerable efforts of enthusiastic researchers who risked their scientific reputation to break the firmly rooted stereotype and demonstrate that Ramon y Cajal could not hope for the future, but just look more closely - nature had already solved his problem.
The first person who was able to partially shake the opinion about the impossibility of updating nerve cells was the American biologist Joseph Altman. In 1962 , in the journal Science , he published the first of his pioneering works. Altman injected rats with a tritium-labeled nucleotide, thymidine. In the body of rats, thymidine, due to its properties, was embedded in synthesized DNA. After Altman examined the brains of rats and found out that it was in the DNA of brain cells that radioactive tritium was detected, which was labeled thymidine. And since this nucleotide could only be embedded in new DNA formed during cell division, the researcher was forced to make a sensational conclusion: new nerve cells appear in the adult brain! Having received a tangible blow, the central dogma of neuroscience was shaken, but it did not give up so quickly.
As is often the case when breaking stereotypes, fellow scientists took Altman's results with hostility, writing off the data he received for technical errors. Because of this attitude, the scientist had to curtail his research, as sponsors deprived him of funding. Following Altman, another enthusiast, American biologist Michael Kaplan, took up nerve cells at his own risk. In 1977, he published the results of his research on rat brain neurons. Like Altman, he was able to detect radioactively labeled thymidine in the DNA of brain cells. But in addition, Kaplan was able to see through an electron microscope the characteristic signs of newborn neurons – synaptic contacts with other neurons in the brain. After these works, the scientist conducted another series of studies, already with the brains of macaques, but he was never able to achieve the recognition of colleagues, although his work was published by the most authoritative scientific publications. The dogma of neuroscience was bursting at the seams, but the power of faith continued to hold.
It took another two decades before these works received new confirmation. And it was obtained at Rockefeller University in a rather unexpected way. Fernando Nottebohm, a professor at this university, has been studying the biology of songbirds for a long time. Interested in what exactly happens to the canaries of Serinus canaria when they learn new songs, Nottebohm suggested that there are no changes in the brain of birds here. And he was right: he found that in the spring, during the mating period in the brain of male canaries, namely in its structures responsible for singing and learning (the so-called vocal center), the number of neurons increased! "It was a real shock, because we were taught that the adult brain retains the same size, the same cells forever. This was an indisputable fact about the brain. How could it get bigger? It contradicted everything I've ever studied," the scientist later recalled.
The ingrained opinion about the stability of nerve cells began to crumble. In the late 90s, after experiments with rodents, birds and monkeys, the birth of new neurons was confirmed in the human brain. The dogma was finally defeated in 1998 by Swedish neuroscientists from the Institute of Neurology in Gothenburg. Professor Peter Eriksson and his colleagues examined the postmortem brain tissues of patients who agreed to take a synthetic analogue of thymidine, bromdeoxyuridine, for the sake of science. This nucleotide, as well as thymidine, is able to integrate into the DNA of newly formed cells. Swedish researchers were able to see that new neurons reliably appeared in the dentate gyrus of the hippocampus. From this it followed that the human hippocampus retains its ability to generate neurons throughout life. Neurogenesis in the human brain has been definitively proven. So, almost a century after Ramon y Cajal formulated his dogmatic "prohibition" on the restoration of nerve cells, the epic battle between "revolutionaries" and "conservatives" ended with the victory of the former.
Now it was necessary to find out all the details of the still open phenomenon. What are the scales of neurogenesis in the adult mammalian brain and in which parts of the brain does it occur? What is its physiological function? And one of the most important questions facing biologists could be of great practical importance: whether external factors affect the processes of neurogenesis and whether it can be enhanced. Today we can more or less reliably answer all these questions.
The main function of neurogenesis in the body is to replenish brain neurons that have been lost naturally (during aging) or due to diseases and injuries. It also turned out that neurogenesis plays an important role in learning and memory formation. The appearance of new cells in the brain occurs in several stages. Initially, there is a phase of expansion, division of neuronal stem cells of the brain: a stem cell divides into two, of which one turns into a progenitor cell (a dividing nerve precursor), also capable of division. This is the shortest phase: its time is just over a day. The next stage takes about 10 days: the progenitor cells divide and the cells formed from them migrate to their final "place of residence". And at the final stage, the migrated cell, having reached its destination, turns into a new neuron or into a cell for its provision – an astrocyte and an oligodendrocyte.
Confocal micrography of GFP-positive nerve progenitor cells (green) of the mouse olfactory bulb. Photo: Oleg Tsupykov, Wikimedia commons
But this is not the end. In order for the newly formed nerve cell to survive, it must connect synaptic contacts with other cells, that is, organically integrate into the structure of the brain, join the cellular collective. And new connections between neurons appear when a person assimilates any information - that's why it is so important for the process of neurogenesis that the brain is actively working. Cells that have not created such connections with neighboring ones become superfluous and die. The whole cycle of neurogenesis from beginning to end takes about seven weeks. It is considered established that about 700 new neurons are born in the human hippocampus per day.
It should be noted here that scientists are still not completely clear about the number and renewal of brain stem cells themselves. In 2011, two groups of researchers from the Cold Spring Harbor Laboratory and Johns Hopkins University presented to the scientific community two directly opposite hypotheses on this score. The first scientists, whom the German neuroscientist Gerd Kempermann called "pessimists", voiced a model according to which the number of stem cells in the brain is laid in the womb and then they are not renewed during life, but only exhausted. In this state of affairs, attempts by scientists and doctors to artificially stimulate neurogenesis (in elderly or unhealthy people) can turn into an unexpected side and bring harm instead of benefit. Artificially stimulated stem cells will run out ahead of time, and a person will be left defenseless without their necessary supply.
According to the more optimistic scenario described Michael Wheeler and his colleagues from Johns Hopkins University, in the adult brain, the set of stem cells is constantly being updated and the stimulation of neurogenesis benefits health. After dividing, the stem cell turns into two, one of which (the daughter) will become a new neuron, and the second will remain a stem cell, giving new neurons many more times. I want to believe that the "optimists" are right. It would seem that we can see the confirmation of their words with our own eyes every day: cheerful, successful and engaged in sports people, as a rule, live longer and have better health. And physical education and positive emotions, as is already reliably known, directly stimulate neurogenesis. But about this – a little below.
It is considered established that neurogenesis in mammals takes place mainly in two areas of the brain: in the olfactory bulb and the dentate gyrus of the hippocampus. From time to time, reports appear in the press about the discovery of new nerve cells in other brain structures, but after checks, they all turn out to be insufficiently convincing and are rejected by most scientists so far. But what we are sure of today is not so little.
Mouse hippocampus. The blue zone is the border between the dentate gyrus and the CA3 zone. Photo: Raunak Basu, University of Utah, Salt Lake City
For the olfactory bulb of the human brain, the appearance of new cells is uncharacteristic, and if it occurs, then in very small quantities. This is due to our peculiarity of weakly using our sense of smell. In many animals, on the contrary, a good sense of smell is sometimes in the first place of all available senses. For technical reasons, neurogenesis in general and in the olfactory bulb in particular is best studied in experimental rodents. It is already known that new neurons appear in rats in this zone during mating and during pregnancy: rats look for partners by smell and then recognize their young. Experiments were conducted when mice were plugged in their nasal passages, making it impossible for the sense of smell to work. The mouse brain immediately reacted to such "tricks" by a sharp decrease in the volume of olfactory bulbs – the number of neurons in them fell. And when the sense of smell was restored, these areas of the mice's brain quickly regained their former shape.
It is also known that the environment has an exceptional effect on the renewal of nerve cells. New experiences, comfortable and comfortable living conditions stimulate neurogenesis. The earliest works that made it possible to detect this phenomenon were carried out in the late 90s of the last century. Professor Fred Gage and his colleagues conducted experiments with rodents, which were divided into two groups. A group of "happy" mice lived in a miniature town consisting of many labyrinths. Good feeding, constant movement and search for exits from the maze led to the fact that scientists were able to record increased neurogenetic activity in the hippocampus of mice. In the second group of rodents, who were constantly kept in the vivarium and lived a boring, monotonous life, no new neurons were found. Subsequently, these experiments were repeatedly confirmed, and today the influence of the "enriched environment" on neurogenesis is considered firmly established.
Last but not least, the birth of new neurons under the influence of a comfortable "enriched environment" is associated with the "hormones of happiness" – dopamine and serotonin. It has already been proven that these two hormones have a very important and positive effect on the renewal of nerve cells. That's why a positive attitude is so important for the brain to work. Thus, it was found that when serotonin levels drop in the brain during depression, neurogenesis immediately slows down. Since memory function is also deteriorating at the same time, it can be assumed that there is some kind of protective mechanism that helps a person forget past troubles that caused depression. Taking antidepressants aimed at increasing serotonin in the brain simultaneously increases neurogenesis.
Stress hormones, glucocorticoids, which firmly and surely block the birth of nerve cells, have the opposite effect to serotonin. Therefore, stress and good brain function are poorly compatible. Also, almost all the harmful habits of modern man turned out to be poorly compatible with neurogenesis: smoking, alcohol consumption, as well as sedentary and gluttony. A very recent study showed that alcohol has a very negative and purposeful effect on neuronal stem cells. Moreover, the female body was more vulnerable to the harmful effects of alcohol than the male.
Lovers of hamburgers, soda and sweet buns also did not accidentally fall into the risk group for neurogenesis. It turned out that excess weight can have a very negative effect on the renewal of neurons. Fat around the waist, accumulating in large quantities, stimulates inflammation in the body, releasing inflammatory substances, cytokines into the blood. And these cytokines, having reached the brain, will interfere with the birth of new cells. In addition, excess fat deposits cause oxidative stress in the body, as a result of which the nuclear transcription factor NF-kB is activated, which also blocks neurogenesis. That's why diet plays such a big role in brain function.
In general, as scientists have found out, neurogenesis turned out to be extremely "skittish", and almost any deviation in the body suppresses the birth of nerve cells. But along with this there is also good news! A person who follows a diet and does sports has every chance to maintain normal brain function until old age. Numerous experiments of neuroscientists have clearly demonstrated how physical activity has a beneficial effect on the work of the brain and the renewal of its cells. For example, under the influence of prolonged running, the level of two substances that stimulate neurogenesis – BDNF and VGF - significantly increases. So we can confidently say that running, swimming and pedaling, a person strengthens not only his muscles and circulatory system, but also the brain.
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