Our thoughts and actions are the product of large populations of nerve cells, called neurons, working in harmony, often millions at a time. Measuring brain activity during behaviour at detailed resolution in these groups of cells has proved extremely challenging.
Currently, scientists are restricted to measuring their activity in individual brain areas of – for example – moving rats, typically in fewer than a few hundred neurons.
Dr Misha Ahrens, a Sir Henry Wellcome Postdoctoral Fellow based at Harvard University and the University of Cambridge, worked with colleagues to develop a technique that allows neuroscientists to study as many as 2000 neurons simultaneously, anywhere in the brain of a transparent zebrafish. Their work was funded by the Wellcome Trust and the National Institutes of Health.
Dr Ahrens and colleagues created a virtual environment for zebrafish, which allowed them to measure activity in the neurons as the fish ‘moved’. In reality, the zebrafish was paralysed to allow the researchers to image its brain; the fish perceived ‘moving’ through the virtual environment by activating their motor neuron axons, the cells responsible for generating movement.
Zebrafish are often used as a simple organism to study genetics and characteristics of the nervous system that are conserved in humans. They can be genetically modified, and Dr Ahrens and colleagues created a fish in which all neurons contained a protein that increases its fluorescence when the cells are active.
The fish are transparent, so the team was able to use a laser-scanning microscope to see activity in any neuron in the brain of the fish and in up to 2000 neurons simultaneously.
Dr Ahrens explains: “Our behaviour is determined by thousands, possibly millions, of nerve cells working in harmony. The zebrafish performs complex behaviours, with a brain of about 100 000 neurons, almost all of which are accessible to optical recording of neural activity. Our new technique will help us examine how large networks mediate behaviour, while telling us what each individual cell is doing.”
Using the technique, Dr Ahrens and colleagues asked whether zebrafish adapt their behaviour in response to changes in their environment. To do this, they manipulated the virtual environment to simulate the fish suddenly becoming more ‘muscular’. This served as a simplified version of what happens when the brain needs to adapt the way it drives behaviour (e.g. when water temperature changes the efficacy of the muscles or when the fish gets injured).
Dr Ahrens adds: “The paralysed fish in the virtual world do indeed adapt their behaviour, by adjusting the amount of impulses the brain sends to the muscles. They also ‘remember’ this change for a while.
“Imaging the brain everywhere during this behaviour, we identified certain brain regions that were involved, most notably the cerebellum and related structures. This technique opens the possibility that eventually, the behaviour may be used to gain insights into human motor control and motor control deficits.
“Our own motor control is continuously recalibrating itself in a similar way to the fish’s to cope with ever-changing conditions of our body and environment, such as when we injure a leg, or if we’re walking on a slippery floor or carrying a heavy bag.
“The zebrafish’s behaviour is an ultra-simplified version of this, and we have been able to gain some insight into how its brain structures drive behaviour. This might someday help us understand how damage to certain brain regions in humans affects the way in which the brain integrates sensory information to control body movements.”
Understanding the brain is one of the Wellcome Trust’s five strategic challenges.
Image credit: Wellcome Library, London.
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Notes for editors
Ahrens MB et al. Brain-wide neuronal dynamics during motor adaptation in zebrafish. Nature 2012 (epub ahead of print).
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