Swammerdam Institute for Life Sciences
Focus on research: neurobiologist Marian Joëls
Have you ever had to give an unprepared speech to a grudging audience? Your heart starts to beat faster, you begin to perspire and perhaps you even experience a total black-out. All a result of stress, something Professor Marian Joëls knows everything about. Not that she gets stressed easily herself, but because she studies the effects of short-term and long-term stress on the brain.
In order to clarify what she does, Professor Joëls tells us some more about stress. There are two different types of stress: short-term and long-term. You experience short-term stress when, for instance, you are late for an appointment. The effect is temporarily unpleasant, but most people are able to cope with it. Short-term stress can even save your life. Suppose there is a lion at large and you suddenly need to run away. You immediately become stressed: your body produces the stress hormones adrenaline and cortisol. Your muscles and brain require more energy, so more sugar circulates in your blood, and your heart beats faster to cope with your need for extra oxygen. These are all effects of the stress hormones that ensure that you can escape quickly. Or, in the case of an examination, that you can think clearly.
But what happens if you are constantly stressed and unable to influence this? For example, if you work for an unpleasant boss you can’t complain about. In such circumstances stress hormones make your body continue to react for days on end. Your body, including your brain, will fail under the stressful situation. Your body is continuously exposed to sugars so that, in the long term, it will become less sensitive to this source of energy and even shield itself against it. And so you might develop type 2 diabetes as a result of stress. In addition, because your heart is constantly beating faster than normal, you are prone to all sorts of heart complaints. Furthermore, stress also affects the brain, and this is the main area where Professor Joëls and her group work.
The brain reacts to stress, and long-term exposure to stress can damage it. We are born with about 100 billion brain cells and during our lifetime practically no new brain cells are produced, except in a few small areas of the brain. When you experience long-term stress, these areas produce fewer new cells. Moreover, certain brain structures shrink while others become larger, and the shape of some brain cells is altered. This can result in an increased risk of depression. You also become less adept at storing new information. ‘These effects are probably reversible’, says Joëls reassuringly.
Learning behaviour
Marian Joëls studies the brain at cell level, and tries to describe the effects of stress on the shape of brain cells and on how they function. She is especially interested in studying the effects of short-term stress on learning behaviour, i.e. how our learning potential and memory are influenced by stress.
‘When I started research into the function of cells, this was a completely new field. No-one had thought to investigate the effect of stress on the electrical activity of brain cells. And so my first article was published in Science, which was a nice start!’, laughs Professor Joëls. ‘Now, eighteen years on, we are among the world’s leading experts in the field of physiology of brain cells. As my group grew, I began to link that physiology to the molecular mechanism, i.e. to what really happens at the molecular level, and to look at the effects on behaviour.’
Positive stress
Although stress often has a negative connotation, it can – when it’s the short-term variant – be extremely positive. Short-term stress has little effect on the shape of cells and on the ‘birth' of new cells, but it does have a marked effect on how cells function. For short-term stress, two phases can be distinguished during which the brain is affected. The first, fast effect increases brain activity; this is especially true for those areas of the brain involved in attention, in assessing a situation, in making comparisons with previous experience and storing information on what you experience.
The second phase is slower, since it requires gene transcription. In this process, genes are transcribed and need to be translated into proteins, which takes some time. When, during a stressful situation, you produce a hormone that works via gene transcription, you will only notice the effects after an hour or so. ‘This second phase has two functions: it ensures a reduction in the extra brain activity – you can’t remain charged for hours on end after a stressful experience’, says Professor Joëls. ‘Moreover, thanks to this phase, you store information about the situation well, so that you will be able to cope with it better if you experience it again in the future.’
Expression
In order to find out exactly what takes place in the brain during stress, you need to be able to examine it very precisely, since the size of a single brain cell is only about 10 microns. Because current MRI-scanners are still unable to work on this scale, laboratory animals are used, mainly rats and mice.
Tiny pieces of brain tissue are removed and kept alive artificially so that they remain functional. ‘We can add all sorts of matter to such a piece of tissue; corticosteron, for example, which has the same effect on rats as the stress hormone cortisol has on humans. Or we can remove something from the tissue, which we then measure very precisely. We can also make changes to the receptors, molecules with which a neurotransmitter or hormone combines and which subsequently bring about an effect in the cell. We investigate whether this change influences how the cell functions and, if so, in what manner, thus learning more about the underlying mechanism. Another possibility is to inhibit expression of receptors in certain areas of the brain. One of the things we learned from this experiment is that stress hormones play an important role in memory.’
New discovery
Professor Joëls no longer carries out research in the laboratory, but fortunately there are plenty of enthusiastic people in her group who work in the lab every day. She herself is usually too busy supervising the fifteen or more researchers in her group and lecturing. However, she still sees all data, participates in data-interpretation and carries out some of the analyses.
The experiments Professor Joëls supervises are very diverse, but all of them concern stress. One of the projects at the institute concerns how stressful experiences during youth affect the rest of your life. ‘One way to cause stress is maternal deprivation: a rat pup is taken away from its mother for some time. In another experiment we study how the amount of time and attention a rat pup receives from its mother affects the way it functions in later life. It turns out that the amount of time and attention has an effect on the expression of genes. The genetic code is, thus, changed by experiences in early life. We call this epigenetics.’
At the institute, research is also carried out on the effects of stress hormones on that part of the brain involved in emotions.
Last year, Professor Joëls’ research group made a spectacular discovery. ‘Henk Karst demonstrated that some receptors are able to exist without gene transcription. This means that these receptors do not necessarily first need to bind to the DNA in the cell nucleus, but can go directly to the outside of the cell. Gene transcription normally takes about an hour. If this is not necessary, the whole process takes place much faster than was always assumed, perhaps even within minutes. This was a totally new discovery’, says Professor Joëls enthusiastically.
Professor Joëls doesn’t use her scientific knowledge of stress much in everyday life. ‘I am quick to recognize the signs of the bad type of stress, also in myself’, she adds, laughing. ‘But anybody with some knowledge of occupational psychology is able to do so too.’
Meta level
‘I think that my strong point is that I am good at thinking up new concepts, I do research at a meta level. Original ideas aren’t coupled to money or exclusive to whoever has the best facilities. Despite the fact that we have less funding than American scientists we are, thanks to our originality, able to play an important role in the field.’
Professor Joëls gives programme information to secondary school scholars and co-initiated the new successful Psychobiology study which started in 2003. Although the number of students in most science studies is declining, the number of first-year students enrolled for Psychobiology has increased to 120 in three years. However, the neurobiologist wonders whether this enormous growth is advantageous to lecturers and students. Professor Joëls will address this question at some length in her speech ‘More science students?’, to be held on 29th March during the foundation day of the Faculty of Science.
‘Doing research is like a holiday to me. If I had six months sabbatical leave, I would like to investigate human imaging: letting people learn a task while observing them in an MRI scanner. That is, in fact, neuropsychology - a completely new field to me. I think it would be really exciting to see whether the ideas we have obtained on the basis of laboratory animal models also hold true for humans. However, if I had started out on this type of research, I think I would have moved on to my present work, as I find this truly satisfying. I like working mechanistically since, in the long run, I want to find out how things really work!’