"Brainbows" Illuminate the Mind's Wiring

Genetically engineered mice furnished with fluorescent proteins are providing the most detailed pictures yet of the brain's intricate circuitry.
The innovation offers an intimate peek into the development and inner workings of the nervous system at the level of individual neurons, researchers say.

"Imagine the brain as a radio for which we never had a good wiring diagram," said Jeff Lichtman, a neurobiologist at Harvard University and a co-author of the study.

"The aim of this work is to tag the individual wires with their own color" to get a better idea of their connections, he added.

If every cell in the brain were imaged using a single color, Lichtman explained, numerous wires bunched together would be indistinguishable.

But the various fluorescent proteins used in the new research make the multitudes of strands that comprise the complex tissue of the nervous system stand out from each other.

In their effort to tease out the details of connections in the nervous system, Lichtman and his colleagues developed about 30 lines of mice.

The team incorporated a chain of three different fluorescent protein genes—which they call a brainbow—into these mice.

The researchers then crossed the genetically engineered mice with mice that expressed an Cre, an enzyme in their brains.

In the offspring of this cross, Cre randomly snipped off or rearranged the brainbow sequence. This process caused just one of the brainbow colors to turn on at any given point.

Since each cell contains multiple copies of the brainbow, the end result is a unique mixture of red, green, and blue colors in each cell—and a random riot of color in the brain overall.

"It is like a television monitor where three basic colors—red, blue, and green—mix together and form various other colors," said Lichtman, whose findings will appear tomorrow in the journal Nature.

Shape Matters

Ed Lein is director of neuroscience at the Allen Institute for Brain Science in Seattle, Washington.

The Harvard researchers, he said, have essentially developed a novel technique that allows one to look at the shape of many different neurons simultaneously.

"The shape of the neuron is a pretty powerful piece of information. It allows you to infer, and in some cases demonstrate, who that cell is connected to," Lein said. " It lets you look at detailed microcircuitry in the brain."

The technique, he explained, will help researchers look at the shape of cells during embryo development and postnatal development in real time—and perhaps understand the progression of disease.

"It is too difficult to trace the 'wires' of the brain, because they are so thin and it is easy to make mistakes," said Sebastian Seung, a computational neuroscientist at MIT.

"The brainbow technique makes it easier to trace them."