Unique Genomic Mechanism Discovered by UrFU Scientists

14:24, October 8, 2020

By suppressing this mechanism, you can heal not only mental, but also physical diseases

A group of scientists led by a leading researcher at the Ural Federal University and Professor of St. Petersburg State University Alan Kaluev discovered a unique, genetically determined molecular mechanism in mice that “switches” anxiety to depression. According to scientists, suppressing such mechanisms in humans, it is possible to cure not only mental, but also virtually any disease. The co-authors published an article about the discovery in the journal Progress in Neuro-Psychopharmacology & Biological Psychiatry.

According to the theory put forward in the early 1970s by the eminent American psychogeneticist Irving Gottesman, any mental illness is easier to study and therefore treatable by dividing it into individual symptoms. So, any complex disease-syndrome is more than a simple sum of its components, and this fully applies to diseases as a set of internal symptoms, that is, having a genetic nature - the so-called endophenotypes (a term introduced into scientific circulation by Gottesman).

“The idea of ​​Gottesman turned out to be truly revolutionary and made a revolution in world psychiatry. Our idea is that a disease is not just a set of separate endophenotypes (figuratively speaking, “beads”), but their “necklace”, where the “beads” are connected by a certain thread, behind which there are special molecular processes. For example, one can talk about obsessive-compulsive syndrome only if obsessions - anxious, obsessive thoughts - and compulsive actions are connected with each other and their cycles are regularly repeated, - explains Alan Kaluev. - In other words, a complex, “well-orchestrated” pathology is more dangerous than its constituent symptoms individually, but by breaking the “thread” we dismember the “necklace” of the disease itself, its complex syndrome into disparate “beads” -symptoms, to analyze and suppress which, as Irving Gottesman noted, are much easier. "

However, if the “beads” -endophenotypes are studied in detail by modern genetics, then the “threads” that unite them, although they are an integral element of syndromes, are still outside the scope of attention of big science. For a decade and a half, Alan Kaluyev has consistently proved why it is so important to study the genetics of not only endophenotypes, but also the mechanisms that couple them.

Having received recognition from Gottesman and published joint theoretical works with him, over the past years, Professor Kaluev has been looking for ways to empirically confirm his theory. The problem was solved only recently - thanks to successful cooperation with the Federal Research Center "Institute of Cytology and Genetics" of the Siberian Branch of the Russian Academy of Sciences (Novosibirsk) and the support of the research by a grant from the Russian Foundation for Basic Research (No. 16-04-00851).

In particular, the research team headed by Alan Kaluev used the model of chronic social conflict developed by the head of the sector of neurogenetics of social behavior at the Institute of Cytology and Genetics of the SB RAS, Doctor of Biological Sciences Natalia Kudryavtseva. In laboratory execution, this model, which has received wide worldwide recognition, is a pair of male mice placed in a cage.

“Inside the cage, males immediately converge in a fight for dominance, 15 minutes after the start of the fight, they are separated by a transparent partition with small holes. They see, hear and hate each other, but have no way to attack. The next day, the partition is removed, and for the next 15 minutes the males again “sort things out” in the fight. As a rule, the winner is determined already in the first fights. A chronically losing male “loser” develops anxiety syndrome after 10 days. On the 20th day, instead of anxiety, another experimental pathology is observed - depression, which corresponds to the "classic" clinical picture: after all, in about 70% of patients with mental disorders, anxiety just precedes depression," says Alan Valerievich.

After conducting a complete screening of the expression of genes of experimental mice in the prefrontal cortex (determines social behavior) and the hippocampus (memory and emotions), the scientific group of Professor Kaluev found that the switch of the state of the mice-“loser” from anxiety to depression occurs on the 15th day of the experiment. It is during this period that the brain genes that are responsible for the activity of the cytoskeleton (cellular skeleton) and brain astrocyte cells are specifically "activated".

“Thus, as a result of our research, for the first time it has been empirically confirmed that a unique genomic mechanism is present in the body of mice, which, while not directly related to the anxiety and depression syndromes as such, that is, without causing them on the 10th or 20th day, nevertheless conjugates them on the 15th day of the experiment. If this approach is applied to other diseases, it can be assumed that such unique mechanisms may be involved in the "activation" not only specifically of anxiety and depression, but also any other, and not necessarily mental, diseases, for example, obesity is known to contribute to depression. It is possible that by destroying the “thread” - the mechanism that connects obesity and depression, we will be able to “tear off” one disease from another and thus strengthen the therapy for both of these disorders,” comments Alan Kaluev.

Representatives of the V.A.Almazov National Medical Research Center, the A.M. Granov Russian Scientific Center for Radiology and Surgical Technologies, Research Institute of General Pathology and Pathophysiology, Research Institute of Physiology and Fundamental Medicine of the Siberian Branch of the Russian Academy of Sciences, Moscow Institute of Physics and Technology, Sechenov Moscow State Medical University, Novosibirsk State University, Maastricht University (Netherlands) and Passo-Fundo University (Brazil) also contributed to the research.