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Project Success Stories - Probing an ancient part of the brain

European scientists are studying motor control and cognitive function to gain a better understanding of the basic mechanisms used to control movements. Their work will throw light on what causes chronic brain conditions like Parkinson's, ADHD and many others.

Health

The EU-funded scientists are focusing their efforts on an important and somewhat enigmatic portion of the brain called the basal ganglia, which is responsible for motor control and cognitive aspects of behaviour. The basal ganglia are a group of structures in vertebrate brains that act as a cohesive functional unit. If one imagines the human brain as a bowler hat, perched at an angle on a hat stand, then the basal ganglia is in the centre, about three centimetres from the bottom. Now European researchers at the Select-and-Act project are probing the area using a variety of advanced tools to understand exactly how it works. The research is important both for the basic science it will explain, and for the new light it will shine on central nervous system diseases like Parkinson's, Huntington's and even attention deficit hyperactivity disorder (ADHD). 'The basal ganglia is associated with a variety of functions, including voluntary motor control, procedural learning relating to routine behaviours or habits, eye movements, and cognitive and emotional functions,' explains Sten Grillner, coordinator of the Select-and-Act and professor at Sweden's prestigious Karolinska Institute. The focus of Select-and-Act's research is a key structure within the basal ganglia, called the striatum. The striatum plays a critical role serving as a filter for signals coming from the cortex and thalamus. Mr Grillner explains that sensitivity of the striatum is set by dopamine, and it is important for Parkinson's disease. Too little dopamine, and the circuits in the striatum do not activate. Too much and they cause involuntary movements, called hyperkinesias, with obvious relevance. Similarly, 5-HT and histamine have other impacts. The cerebral cortex is a key area for memory, attention, perceptual awareness, thought, language, and consciousness, while the thalamus relays sensation, spatial sense and motor signals to the cerebral cortex and the basal ganglia. The cerebral cortex and thalamus work in close interaction with the basal ganglia. What the striatum did next The cortex and thalamus acquire data about what needs to be done next, and the striatum receives that information and uses it to help determine which actions should be performed at a given instant, playing an obvious and important role in motor control and coordination. 'The focus of our research is on the striatum because that is the structure in the brain that is largely responsible for the selection of behaviour,' says Mr Grillner. 'So if you need to turn left or right you have separate circuits in the brainstem to do that. But you need another structure to decide which circuit should be activated at a given moment, and that is a primary role of the striatum.' The Select-and-Act team consists of five research groups, with complementary expertise, which have been systematically studying the striatum in a matrix of related and relevant ways. The Grillner laboratory is exploring the operation of the microcircuits in striatum at the molecular, cellular and synaptic level by recording from several nerve cells at the same time using the striatum from both rodents and a primitive vertebrate, the lamprey. Meanwhile the Bolam laboratory in Oxford is looking at the fine structure of specific types of synapses in the striatum and how different modulators like dopamine, 5-HT and histamine affect the microcircuits of the striatum using different physiological techniques. At the Royal Institute of Technology in Stockholm the Lansner/Hellgren laboratory is making computer models of the striatum and its interaction with the cortex and different motor centres. The models are based on the detailed biological and morphological findings of the Grillner and Bolam laboratories. 'The models allow us to test whether our biological results can account for the operation of the different circuits.' An in vivo study is taking place at the Graybiel laboratory at MIT in Cambridge, USA. There, researchers are studying striatum activity using rodent models, recording simultaneously a number of nerve cells in the microcircuits of the striatum when the rat is running. The rats are also trained to turn left or right according to where they expect to find food and the team can see how these actions are engaged by the striatum. 'So one can learn when the different circuits come into action,' says Mr Grillner. Finally, the Bergman laboratory of the Hebrew University, Jerusalem is studying the activity of neurons in the striatum, together with dopamine cells that signal reward in the behaving monkey. The monkey is trained to detect and interpret different cues indicating rewards or simply air puffs. The test situation allows for an analysis of the function of the striatum under more complex conditions. 'By combining the approach of the five laboratories we get to understand the mode of microcircuit operation in the striatum and how these microcircuits are operating during simpler tasks in rodents and more complex tasks in primates,' says Mr Grillner, adding that the combination of research techniques makes Select-and-Act unique. The team got a big surprise when they discovered how long the striatum has existed. 'We compared the circuits in mammals with the circuits in one of the first type of vertebrates to occur in evolution, which is the lamprey,' he says. The lamprey is very old, evolving 560 million years ago when it diverged from the main vertebrate line. It is one of the most primitive vertebrates still available for study. 'But it surprised us to learn that already 560 million years ago the basic design and the properties and the connectivity of these nerve cells had evolved. Mammals only developed 130 million years ago and humans appeared just 200,000 years ago. So the entire control structure of the striatum was ready very early on in vertebrate evolution and has not been changed much since then,' Mr Grillner notes. Research will continue for another year. 'The end point for this project will see us develop an understanding of striatum microcircuits and how they are modified by different modulators like dopamine, 5-HT and histamine,' Mr Grillner explains. While the team has achieved a lot so far, the scientist says work remains on the project itself, although important new insights have been gained. 'This kind of research needs, however, to continue for a long time in order to understand the intricate mechanism that underlies the complex function of the brain,' concludes Mr Grillner. The Select-and-Act project received funding from the Health initiative of the Seventh Framework Programme (FP7) for research.