November 5, 2007

A Brain of Many Colors

A cluster of multicolored teardrop-shaped cells Neurons in the hippocampus of a Brainbow transgenic mouse.Jean Livet et al.

Using a clever genetic trick to generate dozens of different colors, researchers have for the first time visualized hundreds of cells and their connections to each other in the brain.

Scientists have been using powerful new genetic tools to understand complex genetic networks and the biochemical pathways they encode. However, they still haven't been able to do something similar at the cellular level-to decipher the complex network of interactions between large numbers of cells.

Over the past few years, researchers have developed variations of proteins called fluorescent proteins that can appear in many different colors. A research team at Harvard University led by Dr. Jeff W. Lichtman reasoned that they might be able to use these proteins to generate a range of different colors in cells in the same way that a television or computer monitor can create almost unlimited colors by mixing red, green and blue.

In the November 1, 2007, issue of Nature, the researchers described how they developed DNA constructs, which they called "Brainbows," that randomly rearrange themselves to activate genes for different-colored fluorescent proteins. The first one they made could create red, yellow or blue proteins. The second, Brainbow 1.1, added orange. Brainbow 2.0 could make blue and red. Brainbow 2.1 could create red, blue, green or yellow.

The researchers next made transgenic mice with the constructs and analyzed parts of their brains to see if the technique worked. Some individual nerve cells produced only one of the proteins present in the construct, and so appeared a primary color. However, most cells have more than one copy of the gene construct. Each Brainbow creates a different protein in the end, and so any given individual cell can make multiple colored proteins, resulting in dozens of different hues and color saturation levels.

When the researchers looked at different parts of the same cells, they found the same basic color profile throughout. That enabled them to accurately trace specific cells and their interactions with their neighbors. As a demonstration of the power of their technique, the team reconstructed hundreds of different cells and their connections in a small area of the brain exhibiting almost 90 colors.

This research, which was funded by NIH's National Institute of Neurological Disorders and Stroke (NINDS) and the James S. McDonnell Foundation, is a key step in understanding how the brain and nervous system work. Future researchers will be able to model neural circuits to study both normal and diseased states. In fact, 4 of the mouse lines described in the paper are now available to academic researchers.

— by Harrison Wein, Ph.D.

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