08 April 2014

Sten Grillner – Motor behaviour and its neurobiological control

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Using various experimental and computational approaches, scientists unravel how our brain selects the actions we make.

Understanding the neurobiology of decision-making is a scientific challenge. The EU-funded project Select-and-Act, completed in 2012, used experimental and modelling approaches to better understand how the brain selects different patterns of motor behaviour. The project focussed on the cellular mechanisms in the brain that control movements. Project coordinator Sten Grillner, director of the Nobel Institute for Neurophysiology at Karolinska Institutet in Stockholm, Sweden, talks to youris.com about the project’s achievements and the challenges of brain research. His long experience as a former member and chair of the Nobel Committee for Physiology or Medicine and of the Nobel Assembly for 20 years, gives him a unique perspective on such scientific challenges.

What were the main goals of your research?
Our main goal was to understand the processes by which the nervous system selects different actions that we make. For example, when we move the hand or start talking. In this context, the basal ganglia, a complex forebrain structure, plays a major role. One part of this structure, the striatum, receives information from the thalamus but also from the cortex. In addition, it receives input from the dopamine system. We asked: how does striatum operate at a cellular and synaptic level, the so-called microcircuitry? We also analysed how learning takes place and how it is modulated by dopamine. Understanding how the basal ganglia operate will also help understanding diseases of the brain, such as Parkinson’s and Huntingdon’s and several psychiatric diseases.

What did the project consortium achieve?
The project has advanced considerably our understanding of how our brain makes decisions at the basal ganglia level. And it also revealed how the brain controls our standard motor repertoire. We found that there are a number of different motor centres in the brain stem, below the basal ganglia, that coordinate movements like eye or locomotor movements. We also found that large parts—nearly 50%—of the input to the striatum is directed from the thalamus, not from the cortex as many had assumed.

Another important finding was that the lamprey, the most primitive vertebrate, has all these different molecular, cellular and synaptic components conserved in great detail. And it has the same design of the nerve cells as humans. The control of behaviour is so important that this decision-making circuitry has been kept, more or less, unchanged through more than 500 million years of vertebrate evolution.

How did you address the scientific challenges of the project?
We applied different approaches. For example, my laboratory worked with the microcircuitry. Others looked at the synaptic input to striatum or recorded from different subtypes of neurons and from multiple cells in the behaving animal. All these experiments are challenging. They require time and persistence. To understand behaviour, you have many different factors that come into play. It is absolutely critical to use a number of different approaches to address the same type of problem.  Because none of these approaches can solve the question by themselves. But if you combine different experimental approaches and modelling, you have a much better chance to understand in a rigorous way.

What is the role of computational modelling?
Modelling is a tool to better understand experimental results. You can build a detailed model of each type of neuron in a network and combine them with synapses that function like normal synapses. This way, you create an artificial network based on what you know from the real striatum. You can test whether the network actually operates and produces the same type of activity as you observe experimentally. Modelling is absolutely indispensable for understanding the brain. But only if it is based on very rigorous and detailed experimentation.

Will the results be useful for other research projects such as the Human Brain Project?
Yes, absolutely. The aim of this project is to model the brain, or at least the forebrain, in a reasonable time perspective. I am responsible for one part that particularly aims at modelling the interaction between cortex, basal ganglia and the brainstem motor command centres. We will be able to model that in much greater detail than we could do before.  Another important part of that project is to develop a neuroinformatics database. There are about fifteen different subdisciplines working on the brain, each with its own methodology, ranging from linguistics and psychiatry to structural biology and genetics. Most specialists know their own area and a little bit around.  But practically nobody can bridge all the different levels. We will be able to facilitate the transfer of knowledge between the different subdisciplines and thereby markedly facilitate research.

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