Polish laboratories with five new discoveries that will help understand the human brain

The brain is the most mysterious and fascinating organ of the human body. While we know a good deal about it, the overall functioning of the brain and its product – the mind – remains a mystery. Solving this puzzle would considerably improve our ability to diagnose and treat brain diseases, including mental and neurodegenerative conditions, as well as addictions. Polish scientists have also made their contributions to advancements in neurobiology. Ahead of the European Brain Day due on 18 March, we took the occasion to present some of the research in this area supported by the Foundation for Polish Science.

The human brain is an about 1.5 kg jelly-like mass in which electrical impulses constantly travel through neurons at a speed of several hundred kilometres per hour. It is 80 percent water, and the rest is composed of proteins, fats, carbohydrates and mineral salts. The brain is made up of nerve cells, or neurons. There are almost 100 billion neurons in the human brain, and each one of them can create thousands of connections with other nerve cells, resulting in an unimaginably complex network of connections. The points at which neurons connect are called synapses. A Nobel Prize was awarded for their discovery in 1906, but what is interesting is that for the next several decades it was believed that synaptic connections were formed only during childhood, and remained unchanged in adults. Today, we know that is not true – the synaptic network is undergoing changes over the entire life. Indeed, the number and location of synapses change when we learn something, have new experiences and meet new people. The ability of the brain to adapt to new conditions and circumstances, and to reorganise its structure in response to these stimuli is called neuroplasticity.

 

Neuroplasticity and brain diseases

Neuroplasticity plays a key role in learning and memorising, as well as in brain regeneration after damage caused by trauma or brain diseases. It helps to mitigate the effects of such diseases as multiple sclerosis, Alzheimer’s disease and Parkinson’s disease. However, weakened or inefficient neuroplasticity can lead to a number of pathological conditions, such as addictions, autism spectrum disorders, schizophrenia, depression and bipolar disorder. This is why a better understanding of the mechanisms underlying neuroplasticity could open up amazing new opportunities to fight basically all brain diseases. BRAINCITY, a centre of excellence established in Warsaw at the Nencki Institute of Experimental Biology of the Polish Academy of Science by prof. dr. hab. Leszek Kaczmarek and dr hab. Ewelina Knapska – both laureates of the Foundation for Polish Science’s International Research Agendas Programme – has taken on just this research challenge.

“The primary aim of our work is to understand the brain and the mind to work out new solutions in order to improve the prevention, diagnostics, monitoring and treatment of diseases and pathologies related to brain neuroplasticity. To achieve this, we will employ advanced methods of molecular biology: genome editing and protein and gene manipulation technologies, high-precision imaging and visualisation of single cells and synapses, as well as of neural network activity throughout the brain, and bioinformatics techniques which allow the analysis of vast sets of data,” said dr hab. Ewelina Knapska.

Another very important part of the research will involve using expert knowledge to collect stem cells from peripheral blood or skin. These cells can be used to grow organoids – miniature structures resembling actual organs. BRAINCITY will grow brain organoids imitating some aspects of the human brain. Among other purposes, these fascinating and innovative research models will be used to investigate how genetic predispositions to neurological or psychiatric diseases actually affect the functioning of neural networks. Also, they will make it possible to test new diagnostic and therapeutic approaches. It is a trail-blazing research approach which resolves all ethical dilemmas inherent to experimentation with human embryo stem cells. In its research BRAINCITY will also use animal-based models: mice and rats will be used as subjects primarily in behavioural studies to investigate how certain molecular changes in the brain influence behaviour. “This interdisciplinary approach, combining various research methods, is essential if you want to study an organ as complex as the brain,” said dr hab. Ewelina Knapska.

The importance of a stable scaffolding

Although the neural network is undergoing changes over the entire life, its “skeleton”, or the scaffolding which holds it together, should be stable and resilient. This scaffolding is formed by a network of so-called dendritic trees. What are they?

“The distinctive feature of neurons is their complex shape attributable to numerous fibres. These fibres are one long and thin axon, which is responsible for passing information to other neurons, and numerous branching dendrites whose role is to receive stimuli and integrate the actions of multiple nerve cells. Dendrites make up millions of dendritic trees, and these form a kind of a brain scaffolding. Changes in the shape of dendritic trees are associated with ageing and neurodegenerative diseases (including Alzheimer’s disease) and mood disorders, including depression. Regulating the stability of dendritic trees is, therefore, fundamentally important for the functioning of the brain, and yet we are still in the dark about the subject”, said prof. dr hab. Jacek Jaworski from the International Institute of Molecular and Cell Biology in Warsaw, a laureate of the Foundation for Polish Science’s TEAM Programme.

Under this grant, Professor Jaworski and his team investigate the mechanisms underlying the regulation of dendritic trees – i.e. how “the scaffolding” of our brain is regulated – using large-scale analysis methods. “By comparing these data with analysed clinical material collected from people with depression, we will be able to establish the link between disorders of dendritic tree stability and the molecular basis of depression, potentially resulting in new therapeutic approaches,” said Professor Jacek Jaworski.

And it is extremely important to develop new depression therapies, as currently available anti-depressants are effective only in about 60% of patients. Meanwhile, the number of people suffering from depression is constantly growing – it has grown by a whopping 50 percent over the last 30 years. In 2019 it was depression and other mental disorders, and not cardiovascular or musculoskeletal diseases, which accounted for the majority of sick leaves among Poles. Depressive disorders affect seniors, middle-aged people, young people, and even children. Also, it is not uncommon for depression to lead to death by suicide.

A novel approach to treating depression

One of the reasons for the low effectiveness of depression therapies is that its underlying neurobiological mechanisms are still poorly understood. Most existing therapies focus on signal transduction, which was described many years ago. The pathogenesis of depression is, however, much more complex. Hence, we need a completely new approach to this problem, like the one presented by dr Monika Bijata from the the Nencki Institute of Experimental Biology at the Polish Academy of Sciences in Warsaw.

“It seems that one of the neurobiological causes of depression is the excessive activity of the MMP-9 enzyme, which is secreted at synapses and involved in protein digestion. Why so? Well, patients experiencing an episode of depression exhibit increased levels of MMP-9,” said dr Bijata. Under the Foundation for Polish Science’s HOMING grant, she will study how serotonin and serotonin receptors modulate MMP-9 secretion, and whether reducing this secretion could become a new approach in the treatment of depression.

 

Electrical stimulation for memory disorders

While understanding the neurobiological mechanisms of mood disorders is very important from the clinical point of view, an equally intriguing puzzle to solve is how the electric activity of the brain generates our mind, thoughts and memory, all of which form our identity. Investigating the electrophysiological basis of thoughts and memory is the objective pursued by the Brain and Mind Electrophysiology Lab at the Faculty of Electronics, Telecommunications and Informatics of the Gdansk University of Technology. Led by dr Michał Tomasz Kucewicz, a group of neurobiologists, physicists, biomedical engineers and physicians at the Lab is trying to answer the questions of what memory actually is, where it is located in the brain and how it can be treated in such conditions as Alzheimer’s and Parkinson’s diseases, and many others involving memory disorders, Indeed, memory and cognitive deficits are some of the key health concerns in our ageing society. They are increasingly common and have a major impact on the quality of life and healthcare costs.

“We use the latest brainwave measurement and electrical stimulation technology to study the mechanisms of memory. Such measurement and stimulation during memory processes in people is technically very challenging due to the microscopic size of neurons and limited access to the brain. To bypass this difficulty, we make use of the rare cases of patients with epilepsy or locomotor system diseases in whom electrodes have been implanted. These patients are asked to perform tasks displayed on a screen – for instance, to memorise words. When they are performing these tasks, we are measuring electrical activity in specific regions of their brains while also using a technology to track pupillary movements. Next-generation electrodes implanted directly in the brain provide us with the cleanest and most reliable data. We are also looking at how to improve memory and cognitive performance among patients by sending electrical impulses to specific regions of the brain,” said dr Kucewicz.

These studies have the potential to not only provide new insights into the mechanisms of memory and cognitive processes in people, but also contribute to the development of a new brain-computer interface used to treat brain diseases. The end product will be an invention – a brain stimulation system for patients with memory diseases. The system will be patented for commercialisation. There is a chance that it will be useful not only in memory deficit treatment, but also in attention and mood disorders. The project is co-financed by the Foundation for Polish Science as part of the FIRST TEAM Programme.

Smog is harmful to the brain

An entirely different line of research, albeit also in the field of neurobiology, has been conducted by the Institute of Psychology at the Jagiellonian University in Kraków. An interdisciplinary research project called “Neurosmog” has been launched there to answer the question of how smog affects the developing brains in children.

Smog is a mixture of dust particles suspended in air and containing toxic substances such as heavy metals and dioxins. These particles vary in size – the largest ones are about 100 times bigger than sand grains and easily enter the lungs, while the smallest have no difficulties with penetrating into the circulatory system, making their way to all organs, and crossing the blood-brain barrier. This makes smog a potential cause of inflammatory conditions and damages in all tissues and organs, not only in the respiratory tract, as previously believed. Research shows that the babies of women who are exposed to polluted air during pregnancy have a lower birth weight and – most likely – are more prone to neurodevelopmental disorders, such as ADHD. Polish researchers are planning to prove the hypothesis about the link between exposure to pollution among pregnant women and their babies, and the future disorders of self-control and a propensity for impulsive behaviour. The findings will be much stronger as evidence, one reason being that they will involve pollution concentrations far exceeding those described in previous studies.  „Our air is not only more polluted, but also potentially more toxic due to coal combustion products,”  said dr hab. Marcin Szwed from the Jagiellonian University, who leads the NeuroSmog project. “Previous studies on the impact of smog on brain development failed to provide any conclusive results. Some employed superficial approaches by using psychological tests – regular questionnaires completed by parents. In others the samples were too small and hence had low statistical power. The majority of them used the most basic brain imaging methods. Actually, they were not interdisciplinary studies. By contrast, as part of our NeuroSmog project, we are putting together an actual interdisciplinary consortium comprising four teams: air pollution modelling, child psychology, neuroimaging and epidemiology teams.”

What the researchers involved in the project are trying to do is not only to prove that smog can affect the development of ADHD, but also to understand the mechanisms underlying this phenomenon and find out specifically which neural pathways, or which parts of the developing brain, are damaged by air pollution. Studies will be carried out among 800 children aged 10-13, including both children diagnosed with ADHD and children without any manifest neuropsychological issues. In addition to advanced brain imaging tests, all study participants will be administered detailed psychological tests to make sure their psychological assessment is as reliable as possible. “We expect the project to deliver robust and reliable data on how children’s brains are affected by smog given its concentrations in Poland. If the effects of smog turn out as bad as we think, we hope our discoveries will prompt European and Polish authorities responsible for air quality to take action,” stressed dr hab. Marcin Szwed.

The NeuroSmog project can be implemented thanks to the Foundation for Polish Science’s TEAM-NET grant.

The MAB, FIRST TEAM, HOMING, TEAM and TEAM-NET Programmes are implemented by the Foundation for Polish Science using Smart Growth Operational Programme funds.