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Brain Mapping Goes Viral

Most neuroscientists believe that understanding how the human brain works requires understanding how it is put together. But that is no small task considering that the brain contains billions of neurons, with hundreds of trillions of connections between them.

Several state-of-the-art projects focus on mapping the brain’s circuitry. Three-dimensional maps of gene expression are under construction for the human brain, as well as the mouse and rhesus monkey brain. It is possible to see remarkable details of brain anatomy in maps such as these. However, researchers are limited in their ability to reconstruct the connections between neurons, which – aside from their daunting numbers –can take long, circuitous paths.

Lynn Enquist, Ph.D., a molecular biologist at Princeton University in New Jersey, aims to visually dissect this jumble of connections by combining two existing brain mapping techniques. One technique, called Brainbow, involves marking individual brain cells with distinct, randomly generated colors. The other technique involves tracing the path of a virus as it hops from one cell to other connected cells.

“Dr. Enquist’s research will give us a way to see how brain cells are wired together, which is a fundamental step in understanding how the brain works and how it responds to injury and disease,” said Edmund Talley, Ph.D., a program director at the National Institute of Neurological Disorders and Stroke (NINDS). The project is supported by a grant from NINDS funded through the American Recovery and Reinvestment Act (ARRA).
Dr. Lynn Enquist
Dr. Lynn Enquist

Brainbow was developed by a team led by Jeff Lichtman, M.D., Ph.D., at Harvard University in Cambridge, Mass. In its current form, the technique requires creating genetically engineered mice. The mice are bred to carry a synthetic gene capable of producing several fluorescent proteins, each with its own unique color. As the animals’ brains develop, these colorful proteins are activated, but their level of activity varies randomly cell by cell. In the same way that a television can generate almost limitless colors by mixing red, blue and green, the Brainbow technique produces a mosaic of brain cells marked by different colors.

Meanwhile, Dr. Enquist and his team at Princeton have pioneered the use of viruses to map brain connections. For most studies, the team uses a type of herpes virus called the pseudorabies virus (which has no relation to rabies). These viruses infect neurons and can jump to neighboring, connected neurons – a property that Dr. Enquist and his team have exploited in order to turn the pseudorabies virus into an anatomical tracer.

First, the virus is weakened so that it is still infective, but does not cause full-blown illness. Then, it is loaded with a ‘marker’ gene that will be recognized and turned on by infected neurons. With the virus and the marker moving from one neuron to another, the technique can label long, convoluted chains of neurons.

Cells glow brightly 18 hours after being infected with a genetically engineered virus that directs them to produce fluorescent proteins. Courtesy of Dr. Enquist.
Cells glow brightly 18 hours after being infected with a genetically engineered virus that directs them to produce fluorescent proteins. Courtesy of Dr. Enquist.
Dr. Enquist’s innovative method involves inserting a Brainbow gene into the pseudorabies virus. Like other viral tracing techniques, the combined approach will reveal chains of connected neurons. But researchers will have the added benefit of being able to distinguish each neuron based on the unique color it produces.

Also, because the approach relies on viral infection rather than genetic engineering to introduce the Brainbow system into brain tissue, researchers will be able to use it in animals other than transgenic mice. For example, it could be applied to rats, which are used more often than mice to study links between brain anatomy and behavior.

In addition to improvements in brain mapping, the research is expected to yield insights into how herpes viruses spread within the nervous system and how to better control this process.

For more information, see the Princeton web story, Virus 'explorers' probe inner workings of the brain.

- By Daniel Stimson, Ph.D.

Last updated June 24, 2011