News Release 

A putative mechanism that switches brain pathology from anxiety to depression discovered

In the long term, this discovery could make it possible to create new, more effective drugs for mental disorders in humans

St. Petersburg State University

Research News

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IMAGE: Сhronic social defeat stress model in C57BL/6 J male mice view more 

Credit: Prof. N.N.Kudryavtseva's laboratory, Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia

The study was based on the authors' original hypothesis that a specific novel mechanism responsible for linking distinct symptoms into a single disease may exist in the brain. 'A disease is more complex than a collection of symptoms. For example, while decreased appetite or blues can occur in many people, only together these symptoms form a disease - depression. We suggested that there must be some kind of molecular "link", likely mediated by specific brain genes, that "bring together" diseases by combining their symptoms, but not causing symptoms per se,' explained Professor Alan Kaluev, study's Principal Investigator and head of the Laboratory of Biological Psychiatry at the Institute of Translational Biomedicine at St Petersburg University.

When studying mental disorders, researchers try to understand which gene in the brain is responsible for a particular symptom. The C57BL/6?J mice in a chronic social stress model are often used as an experimental model. This animal model, created in the 1980s in Novosibirsk, is generated by placing two male mice in the same cage, where they begin to fight, after which they are separated by a transparent partition with holes through which they can feel each other, but cannot contact. They are left separated in the same cage for the whole day, and then the manipulations are repeated daily for 3 weeks. As a result, the 'winners' and the 'losers' reveal themselves clearly, and the state of 'losers' is of particular interest for studying anxiety and depression.

'In the classical model of chronic social stress, if the defeated losers are stressed for about 10 days, they develop anxiety-like state, but do not show 'depression' yet. However, if you continue to stress them, then after 20 days these animals develop a pronounced depressive-like state, but no longer have anxiety. Simply put - it takes 10 days of fights to cause "mouse" anxiety - one brain pathology. And by 20 days they already have depression. Thus, the question we asked in the present study concerned what happens in the middle of this interval - for example, on day 15? Hypothetically, this is the point where one pathology (anxiety) begins to turn into another (depression). If you imagine a train at a junction: it can go left or right - then the track switches, and the switch (relay) is the 15th day. This "relay" itself does not cause anxiety or depression. However, this switch in the brain may involve its own set of unique genes,' explained Professor Kaluev.

As he noted, these 'switch' genes cannot be detected by classical methods of genetics, because they are not responsible for any symptom: neither for anxiety, nor for depression. They only hypothetically 'switch' from one pathology to another. To experimentally prove their hypothesis, the researchers performed a genome-wide screening of mice brain gene activity in two key areas - the prefrontal cortex (responsible for long-term planning and social behaviour) and the hippocampus (responsible for memory).

'Our present discovery can be briefly summarized as follows: we found that on Day 15 during the transition from experimental anxiety- to depression-like state in mice, neither genes associated with neurotransmitters (as during the anxiety-like state) nor with the inflammation (as with depression-like state) are involved. Rather, these 'transitional' mechanisms are associated with the cytoskeleton and astrocytes - the glial cells in the brain that are increasingly associated with mental illness. Overall, we showed that when in mice one brain pathology progresses into another, unique cellular mechanisms are activated. In fact, they may act as a unique molecular "switch" that can send the vector of pathogenesis either in one direction (anxiety) or in another (depression),' explained Dr. Kaluev.

The scientist also noted that with continued stress, in about 70% of people with chronic anxiety it can turn into depression. At the same time, traditional antidepressants do not always work effectively. According to study director, only about 30-40% of people respond to therapy, and the majority either does not respond at all, or reacts in a weak form. He stressed that, at the same time, the number of detected cases is growing every year, and fundamentally new drugs for depression have not appeared over the past half century.

'It therefore seems that stopping depression is a key unmet biomedical task. And since existing antidepressants are not always effective, the question arises: how can we stop this 'rushing train' of brain affective pathology? If it is already on the path to depression, can we slow it down? Or, alternatively, we can target the "switch" of the track instead, to present depression progression? As such, the putative mechanisms we have discovered can become a new target for creating fundamentally new classes of psychotropic drugs,' added the professor.

He also emphasised that our mouse data are highly consistent with recent clinical evidence where astrocytes and cytoskeletal mechanisms are increasingly implicated in human affective pathogenesis. The research team plans to test their hypothesis in humans, in the long term aiming to understand how exactly to influence the 'switch' and stop depressive disorder at its very beginning.

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In addition to staff of the Institute of Translational Biomedicine at St Petersburg University, the international team of scientists contributing to this study included researchers from, Institute of Cytology and Genetics, Ural Federal University, Almazov National Medical Research Centre, Moscow Institute of Physics and Technology, I M Sechenov First Moscow State Medical University, Institute of General Pathology and Pathophysiology, Granov Scientific Research Centre of Radiology and Surgical Technologies, Scientific Research Institute of Physiology and Basic Medicine, Institute of Medicine and Psychology at Novosibirsk State University, the University of Passo Fundo (Brazil) and Maastricht University (the Netherlands).

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