A marathon runner approaches the finishing line, but suddenly the sweaty athlete collapses to the ground. Everyone probably assumes that this is because he has expended all energy in his muscles. What few people know is that it might also be a braking mechanism in the brain which swings into effect and makes us too tired to continue. What may be occurring is what is referred to as 'central fatigue'.
"Our discovery is helping to shed light on the paradox which has long been the subject of discussion by researchers. We have always known that the neurotransmitter serotonin is released when you exercise, and indeed, it helps us to keep going. However, the answer to what role the substance plays in relation to the fact that we also feel so exhausted we have to stop has been eluding us for years. We can now see it is actually a surplus of serotonin that triggers a braking mechanism in the brain. In other words, serotonin functions as an accelerator but also as a brake when the strain becomes excessive," says Associate Professor Jean-François Perrier from the Department of Neuroscience and Pharmacology, who has spearheaded the new research.
Help in the battle against doping
Jean-François Perrier hopes that mapping the mechanism that prompts central fatigue will be useful in several ways. Central fatigue is a phenomenon which has been known for about 80 years; it is a sort of tiredness which, instead of affecting the muscles, hits the brain and nervous system. By conducting scientific experiments, it is possible to observe and measure that the brain sends insufficient signals to the muscles to keep going, which in turn means that we are unable to keep performing. This makes the mechanism behind central fatigue an interesting area in the battle against doping, and it is for this reason that Anti Doping Danmark has also helped fund the group's research.
"In combating the use of doping, it is crucial to identify which methods athletes can use to prevent central fatigue and thereby continue to perform beyond what is naturally possible. And the best way of doing so is to understand the underlying mechanism," says Jean-François Perrier.
Developing better drugs
The brain communicates with our muscles using so-called motoneurons (see fact box). In several diseases, motoneurons are hyperactive. This is true, for example, of people suffering from spasticity and cerebral palsy, who are unable to control their movements. Jean-François Perrier therefore hopes that, in the long term, this new knowledge can also be used to help develop drugs against these symptoms and to find out more about the effects of antidepressants.
"This new discovery brings us a step closer to finding ways of controlling serotonin. In other words, whether it will have an activating effect or trigger central fatigue. It is all about selectively activating the receptors which serotonin attaches to," explains Jean-François Perrier.
"For selective serotonin re-uptake inhibitor (SSRI) drugs which are used as antidepressants, we can possibly help explain why those who take the drugs often feel more tired and also become slightly clumsier than other people. What we now know can help us develop better drugs," concludes Jean-François Perrier.
The new results have just been published in the renowned scientific journal PNAS. Read the article 'Serotonin spillover onto the axon initial segment of motoneurons induces central fatigue by inhibiting action potential initiation'. DOI: 10.1073 PNAS article #: 201216150.
Associate Professor Jean-François Perrier
Department of Neuroscience and Pharmacology
University of Copenhagen
Telephone: +45 23 81 27 46
Jean-François Perrier will be travelling until March 11. If you cannot reach him by phone, send him an email and he will call you back.
Louise Graa Christensen
Faculty of Health and Medical Sciences
University of Copenhagen
Mobile: +45 24 34 03 22
About the research
In addition to Jean-François Perrier, the research team responsible for mapping the braking mechanism includes Florence Cotel and two researchers from the University of Oxford (Stephanie Cragg and Richard Exley). In order to be able to study the motoneurons, the researchers have studied large American turtles. This is because the adult turtle's spinal marrow, where the motoneurons are found, is accessible to experimentation but also resemble conditions in humans. It is in precisely this respect that that results obtained from cross-sections of the spinal marrow in turtles, help researchers to understand central fatigue in the nervous system of humans.
In the human brain there are about 100 billion nerve cells, or neurons. Each neuron consists of a cell body with dendrites and a nerve fiber called the axon, and they communicate with one another via synapses. Nerve cells use nerve impulses to send signals with the axon from the cell body to the nerve ends, which form synapses with the dendrites of the receiving cell.
A special kind of neuron, the motoneurons, are extremely important as they are responsible for ensuring contact between the brain and the muscles. Every time a motoneuron sends impulses to the muscles, it leads to the contraction of the muscle fibres contacted and thus a movement. In order to control the body's movements, the brain has to be able to control the impulse activity in groups of motoneurons so they are activated in the right sequence and to the right degree. It is here that serotonin plays a role as one of the neurotransmitters which are released from the synapses during the brain's ingenious control of the motoneurons and thereby our patterns of movement.
Serotonin and central fatigue
Serotonin is well known for being involved in many different human functions: Appetite, sleep, sex and motor control. Serotonin is released as soon as you start moving, and the more you move, the more serotonin is released. In other words, serotonin functions as an accelerator for movement and makes the motoneurons more active. However, when large amounts of serotonin are released, it causes a glut at the synapses through which the neurons communicate. This means that the serotonin starts binding with the receptors lying outside the synapses. Some of these receptors sit at the initial part of the axon, i.e. where nerve impulses are formed. And when the serotonin activates these receptors, the nerve impulse is obstructed, the result being that the muscle contraction is weakened and fatigue occurs.