Published online 31 October 2007 | Nature | doi:10.1038/news.2007.209

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Colours light up brain structure

Neuronal circuits can now be seen in a multicolour 'brainbow'.

A mix of 5 colours can produce about 90 distinct shades.Courtesy of the researchers

It's not often that research results look this good. An elegant new way to visualize individual brain cells not only provides a major boost to scientists trying to understand how the brain works, but has also won one of its developers a major prize in science photography.

The method — described by neuroscientists at Harvard University in Cambridge, Massachusetts, in today’s Nature1 — allows researchers to see more clearly how individual neurons connect with each other by colouring each one from a palette of about 90 shades. In this way they will be able to build up a detailed diagram of the brain's wiring, which will help to study how it computes.

More than a century ago, neuroscientists developed the first method of staining individual neurons — with silver chromate. Work with this technique was the basis of the Nobel Prize in Physiology or Medicine in 1906. But this could only stain neurons with one colour.

Only in the last decade have scientists improved on this technique, using genetic engineering to transfer genes for fluorescent proteins into mice such that they are expressed in neurons. But until now they could transfer no more than two florescent-protein genes at a time, lighting up the brain with two colours. “It was clear that two colours were not enough to map connections efficiently in the brain’s complex tangle of neurons,” says Joshua Sanes, one of the paper’s senior scientists.

All the colours of the rainbow

Colours show how cells intertwine.Courtesy of the researchers

Jeff Lichtman, Sanes and colleagues found a way for transgenic mice to express various mixtures of four colours of fluorescent proteins in their neurons: yellow, red, cyan, and either orange or green.

They did this by introducing a string of four colour-producing genes, controlled by a genetic system called Cre/ lox. They organized the elements of this system such that it would randomly promote the activity of just one of the colour-producing genes in vivo. Then they introduced multiple copies of the gene string into the genome of mouse embryonic stem cells, from which they developed transgenic mice.

Each neuron of the transgenic mice switched on a random number of these colour genes. The result was some 90 shades that could be seen by a researcher looking at the cells.

One neuron, for example, might switch on just red and cyan, so it would glow a pleasant mauve; a neighbour might switch on a lot of red and a bit of green and blue glow a shocking pink. They call their system the Brainbow.

This colour mixing is similar to that used by television sets, says Sanes, which produce only red, green or blue pixels but mix them to make any colour needed.

You light up my brain

Brain researchers say that they are amazed that the Harvard scientists managed to pull off such a technically difficult stunt while making it so easy to use in practice. The transgenic mice and necessary research tools are now available for other scientists to use.

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"It will give those of us trying to work out how the brain computes different insights," says Karel Svoboda, a neuroscientist at the Howard Hughes Medical Institute’s Janelia Farm laboratories, in Loudoun County, Virginia. “Brainbow will allow you to trace neuronal circuits over long distances — maybe across centimetres of tissue," says Svoboda. "You can see how different neuronal circuits relate to each other in the same animal."

It’s also "very aesthetic", he says. Which is why Jean Livet — the postdoc credited with having the idea for the Cre/ lox tricks, and the paper’s first author — has just won the 2007 Olympus BioScapes Digital Imaging competition, says Sanes. 

  • References

    1. Livet, J. et al. Nature 450, 56-61 (2007). | Article |
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