Neurogenomics: on the way to the perfect antidepressant
The cure for suicide
The Institute of Cytology and Genetics SB RAS creates a fail-safe antidepressantPeter Malkov, NGS.
It is thanks to such projects that new medicines, new equipment and new materials usually appear. Everything that changes our lives – from frost-resistant shoe insoles to quantum processors. NGS.The NEWS will try to tell about the most interesting things that are being studied and created in Siberia today, in a small special project called the NGS.the science. We decided to start with a story about a comprehensive study of the mechanism of depression and the influence of the human immune system on it.
Nina Popova, head of the Behavioral Neurogenomics Laboratory at the Institute of Cytology and Genetics, told about the project, which in the future may make it possible to create trouble-free antidepressants.
What is the novelty of your interdisciplinary project, considering how many years they have been studying depression and how many psychotherapeutic schemes and medications are already being used?Depression, as a very serious problem for the whole world, has really been studied for a long time and intensively.
However, it is precisely the complexity of the problem – since the key to it is the work of the brain, and the brain is the most complex thing that is generally known to man – that leaves a lot of unexplored aspects.
In particular, we are engaged in the creation and study of experimental models of genetic predisposition to depression. Obviously, the tools for studying depression on a living person are very limited. We have created a line of laboratory mice showing clear depressive behavior. They are inherently predisposed to it. And this is very important. Although external factors, such as chronic stress, are usually put in the first place in the occurrence of depression, however, genetics is still at the heart.
Why do some people experience difficult circumstances, while others – when much less serious problems appear – commit suicide? Undoubtedly, this is a genetic disposition that manifests itself in the work of neurotransmitters – substances involved in the transmission of nerve impulses in the brain.
One of these neurotransmitters is serotonin. In the brains of animals and humans there are neurons in which it is synthesized. A malfunction in this system, leading to a violation of serotonin synthesis, affects behavior, aggressiveness, emotionality, predisposition to depression. And our mice show all these symptoms. If you remember, after the colossal work was completed – the decoding of the human and mouse genomes and their closeness was shown, it greatly inspired geneticists – including the creation of various "mouse" models. On these mice, you can study the effect of fundamentally new antidepressants, their effectiveness, and so on – everything that cannot be studied on humans.
However, why did cytokines come to the fore in your study – molecules that are believed to be responsible for the coordinated defense of the body against infections, and not for the work of the brain?Indeed, cytokines are usually dealt with by immunologists.
However, relatively recently there has been evidence that cytokines also work in the brain.
It turned out that some cytokines, for example the so-called interleukin-6, with which we will work, act on the body in the same way as chronic stress causing depression. They suppress neurogenesis, that is, they act directly opposite to antidepressants, which cause an increase in serotonin levels in synapses.
We, in turn, have contacts with the Institute of Organic Chemistry. They synthesized a large group of new drugs that supposedly have an antidepressant effect.
Then the question arises: why do we need new antidepressants, given how many of them have already been created – including those that stimulate the production of serotonin?There are a lot of antidepressants.
But there is a big problem with them: a certain percentage of patients with deep depression – according to various estimates from 20 to 40 percent – are insensitive to antidepressants.
Of course, here we need to keep in mind that we are not talking about everyday "ah, I fell into depression", but about a deep state from which a person will not come out without medical help. And now we have this insensitivity. What is the reason? Now we have this genetic model, and chemists have these new drugs that we will study.
The second alliance is with the Institute of Automation and Electrometry. They develop computer-processed programs to register the behavior of experimental animals. For example, the so-called open field test, that is, an "open area" when the motor and research activity of a mouse is studied. Previously, an experimenter sat there, registered behavioral features and counted the squares that the mouse crossed. Now everything happens automatically, the video camera captures, and the program outputs ready-made numbers.
Another participant is the Design and Technology Institute of Computer Engineering. They record the electrical activity of brain regions, compare the brain activity of normal mice and those that are predisposed to depression, as well as the results of the action of drugs on both. And finally, the Institute of Chemical Biology and Fundamental Medicine is developing methods for detecting point mutations in genes – specific genes that control the serotonin system, which will allow analyzing their role.
Where is depression formed? Which parts of the brain are responsible for its appearance?This is a difficult question.
Undoubtedly, depression is associated with an emotional mood, for which the so–called limbic system is responsible - the hypothalamus, the amygdala complex, as well as the frontal cortex, which is responsible for the subjective assessment of what is happening: how terrible everything is and whether it is worth living on. This is exactly what models are needed for – in humans, based only on measuring the electrical activity of their brain, it is impossible to accurately describe this mechanism.
In general, it remains to be amazed how balanced everything is in a normal brain, how complicated and fantastically coordinated everything is there! After all, if anything is surprising, it's how few people go crazy.
It is amazing how the brain itself turns on compensatory mechanisms that protect it: one system is violated – the spare one automatically turns on. And a person copes with tragedies, with chronic stress.
If we dot the "I" – the ineffectiveness of antidepressants is due precisely to the fact that they do not take into account the effect of cytokines on the brain caused by heredity?Elucidating the interaction of the cytokine and serotonin systems of the brain can provide a key to understanding the hereditary predisposition to depression – that is, to solve a fundamental problem.
On the other hand, it can really help solve the issue of insensitivity to antidepressants. Another thing is that there are depressions caused not by problems with serotonin, but, for example, by a hormonal disorder. However, serotonin and, as we now think, cytokine systems still usually play a key role.
Is there any statistics on how often severe forms of depression are provoked by heredity?There are such studies, and the genetic component has been established reliably.
There are families among whose relatives there are many suicides. There are studies on twins – they also clearly show the role of heredity.
Are there whole nations predisposed to depression?Apparently, yes.
For example, the number of suicides in Sweden is abnormally high. Moreover, the discrepancy between the financial well-being of its residents and this situation is especially striking.
In general, according to the World Health Organization, women suffer from depression more often – more than 20% of women and about 13% of men are susceptible to them.
It is often necessary to meet mentions that during depression the immune system seriously suffers. In your opinion, here again we can talk about the "wrong" work of cytokines, which, as we remember, are usually associated with the immune system? Or does depression just reduce the tone of the body, opening it up to infections?Good question!
Most likely – the first option. I didn't have time to mention that our depressed mice have reduced immunity indicators. And we believe that cytokine disorders are primary here. And the fact that
Portal "Eternal youth" www.vechnayamolodost.ru03.02.2009