Woe from wit
Epigenetics of learning and mutagenesis of neurons
Varvara Diakonova, Post-science
Scientists have long learned that most of our genome is active specifically in the nervous system or brain. In recent decades, new opportunities and methods have emerged that have made it possible to study what happens to the activity of the genome in individual neurons. This approach has brought a lot of new information.
Firstly, neurons differ greatly from each other in transcriptome – this is a matrix or informational RNA that exists in individual neurons. The ideas about the diversity of nerve cells that arose on the basis of their transmitter differences, electrical activity, and morphology were underestimated, because the diversity of cells that are obtained using their transcriptomes turns out to be orders of magnitude higher.
In addition, in recent years, neuroscientists have learned that neurons constantly turn to their genome and are able to change the expression of their own genes. They do this depending on past experience and, as we like to think, depending on the forecasts that appear in relation to the expected future.
Different neurons change the activity of different genes, and this suggests several important conclusions. On the one hand, an advanced apparatus for controlling the activity of its own genome has been formed in the nervous system. On the other hand, it has long been known that when the genome has to be accessed frequently, often to change the state of chromatin, to change the availability of the genome for expression and regulation, the genome is in danger. The higher the activity of genes, the higher their availability for some regulatory influences, the more they are exposed to the effects of a variety of mutagens. These can also be mobile elements, for example, pieces of DNA that can jump over and embed themselves in various parts of the genome, disrupting the work of normal genes.
Payment for plasticity
Neurons have high plasticity, which is associated with the plasticity of the genome, with changes in the state of chromatin and chromosomes.
Chromatin is the packaging of DNA. It is known that DNA is not just in our chromosomes, but is packaged in a certain way. There are histone proteins in chromosomes that are responsible for DNA packaging. When everything is condensed, DNA is packed tightly, and genome activity is low, genes are not expressed. It is difficult to regulate genes in this position, although it is possible to change the state of histones and stretch chromatin in this area. Then it will be possible to activate a specific section of the genome. Scientists have suggested that the price for the high plasticity of neurons associated with the high plasticity of their genome is their high susceptibility to mutations. To confirm or refute this assumption, it is advisable to look at the genome of individual neurons – not at the RNA and not at the transcriptome, but at the DNA molecule itself.
Prior to this assumption, scientists did not see much point in studying a single DNA molecule, because it was known that the genome is the same throughout the body. Comparison of the genome of individual nerve cells was necessary to see what happens to mutations in the genome of individual neurons. It turned out that mutations in neurons accumulate a lot. Now there is already data on the genome of individual human and mouse neurons. The authors of the studies say that there are about a hundred mutations per nerve cell.
This number of mutations looks large only in comparison with other cells of the body. Scientists continued to study how and when neurons mutate, and found out a few more interesting facts.
It turned out that most of the mutations accumulate not during the period when neurons are still being formed, but already during their adult life. This means that mutations are associated with the work and adult life of neurons. This is an important difference between neurons and those cells that are not nervous, and accumulate most mutations during division. In addition, neuron mutations were found in functional regions of the genome. They were not distributed randomly, but were found in genes that were most often expressed by neurons.
A new feature of mutations in neurons has given rise to a new difference, because other cells are able to protect exactly the genes that they most often use, and neurons either do not know how or cannot protect such genes. What is the reason for this is still unknown. There is an assumption that this is due to high plasticity. Due to the fact that neurons often change the expression of their genes, they cannot protect them. The very presence of a large number of mutations in neurons suggests that the repair system cannot cope with the level of mutagenesis that occurs in living nerve cells.
The danger of mutations
It is important to understand the danger of these mutations. This is a difficult question, because mutations are not a good thing, but they can be neutral. It all depends on where the mutation gets to, because it's a chaotic process. Sometimes a mutation may not lead to any changes at all. In another situation, if it hits a weak spot, it will lead to significant disruptions of the functioning of the gene and the cell. In one study, scientists replaced the mouse genome with a genome from a mutated neuron to see if a normal organism would turn out from such a genome with mutations. The animal turned out to be viable and even capable of reproduction. This means that there were no serious consequences in this random combination of mutations that turned out to be in the isolated nerve cells.
Such studies form an interesting conclusion, from which we understand that cognitive functions have to pay not only energetically. The conclusion that cognitive functions are an expensive thing in terms of energy has always been known. We know that the brain consumes glucose the most, it is terribly sensitive to a decrease in oxygen, and so on. But the fact that we can pay for cognitive abilities with the loss of genetic information, the accumulation of mutations, is a completely new idea that neuroscientists have not yet had time to fully study. Perhaps in the future, the causes of many neurodegenerative diseases will be sought in the accumulation and modification of the functioning of the genome of nerve cells.
What do animals sacrifice for the sake of the mind
In one type of behavioral experiments, scientists selected those males and females who were better at solving a problem, and then paired them together. Then they repeated this procedure again, hoping to get smarter rats and see what had changed in these animals and why they were getting smarter. But scientists faced an unexpected problem: it turned out that pathological problems were growing faster in animals than cognitive abilities. The rats turned out to be neurotic, so there was no way to put such an animal in the experimental conditions.
Another group of scientists used a different method. They selected animals based on their ability to learn. It turned out that as a result of this selection, rats were indeed able to learn faster than more "stupid" animals, but they were unhappy on a number of other indicators. Firstly, they lost in fights to more "stupid" males. Secondly, their metabolic system, the use of glucose and other components differed unfavorably. Thirdly, they had a predisposition to alcoholism, which was higher than in rats specially selected for predisposition to alcohol.
Similar behavioral experiments were carried out on fruit flies. They also tried to select them according to their learning abilities. As a result, scientists faced the same thing: it turned out that the larvae of "smart" flies could not compete with the larvae of ordinary flies with a decrease in the amount of food substrate and died faster. The fertility and life expectancy of such flies decreased.
These data are not directly related to whether the plasticity of the brain increases and whether the neurons of intelligent animals accumulate mutations more. The results do not give a direct answer to this question, but these phenomena may be related. The information that can be found in individual cells and behavioral experiments that have been conducted before show about the same thing: high plasticity and cognitive abilities have to be paid very dearly.
Perhaps this is the reason why cognitive evolution is developing so slowly. As soon as the factors that require cognitive enhancement disappear in the natural environment, these abilities quickly deteriorate in animals, because biologically being smart is wasteful and dangerous. Although cognitive abilities give great advantages, which have long been known. We have always known about the advantages that intelligent animals have, and we began to learn about what the nervous system pays for it relatively recently.
About the author: Varvara Diakonova – Doctor of Biological Sciences, N. K. Koltsov Institute of Developmental Biology of the Russian Academy of Sciences.
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