Using Light and Genes to Probe the Brain

Optogenetics emerges as a potent tool to study the brain's inner workings

Courtesy of John Carnett, Viviana Gradinaru, Murtaza Mogru and Karl Deisseroth Stanford University

In 1979 Francis Crick, famed co-discoverer of DNA’s structure, published an article in Scientific American that set out a wish list of techniques needed to fundamentally improve understanding of the way the brain processes information. High on his wish list was a method of gaining control over specific classes of neurons while, he wrote, “leaving the others more or less unaltered.”

Over the past few years Crick’s vision for targeting neurons has begun to materialize thanks to a sophisticated combination of fiber optics and genetic engineering. The advent of what is known as optogenetics has even captured popular attention because of its ability to alter animal behavior—one research group demonstrated how light piped into a mouse’s brain can drive it to turn endlessly in circles. Such feats have inspired much public comment, including a joke made by comedian Jay Leno in 2006 about the prospect for an optogenetically controlled fly pestering George W. Bush.

Controlling a subordinate or a spouse with a souped-up laser pointer may be essential for science-fiction dystopia and late-night humor, but in reality optogenetics has emerged as the most important new technology for providing insight into the numbingly complex circuitry of the mammalian brain. It has already furnished clues as to how neural miswiring underlies neurological and mental disorders, including Parkinson’s disease and schizophrenia.

A seminal event that sparked widespread neuroscience interest came in 2005, when Karl Deisseroth and his colleagues at Stanford University and at the Max Planck Institute for Biophysics in Frankfurt demonstrated how a virus could be used to deliver a light-sensitive gene called channelrhodopsin-2 into specific sets of mammalian neurons. Once equipped with the gene (taken from pond algae), the neurons fired when exposed to light pulses. A box on Crick’s list could be checked off: this experiment and ones that were soon to follow showed how it would be possible to trigger or extinguish selected neurons, and not their neighbors, in just a few milliseconds, the speed at which they normally fire. Hundreds of laboratories worldwide have since adopted Deisseroth’s technique.

A 38-year-old psychiatrist by training who still sees patients once a week, Deisseroth entered the field of bioengineering because of his frustration over the inadequate tools available to research and treat mental illness and neurodegenerative disorders. “I have conducted many brain-stimulation treatments in psychiatry that suffered greatly from a lack of precision. You can stimulate certain cells that you want to target, but you also stimulate all of the wrong cells as well,” he says. Instead of just observing the effects from a drug or an implanted electrode, optogenetics brings researchers closer to the fundamental causes of a behavior.

Since 2005 Deisseroth’s laboratory—at times in collaboration with leading neuroscience groups—has assembled a powerful tool kit based on channelrhodopsin-2 and other so-called opsins. By adjusting the opening or closing of channels in cell membranes, opsins can switch neurons on or turn them off. Molecular legerdemain can also manipulate just a subset of one type of neuron or control a circuit between groups of selected neurons in, say, the limbic system and others in the cortex. Deisseroth has also refined methods for delivering the opsin genes, typically by inserting into a virus both opsin genes and DNA to turn on those genes.

To activate the opsins, Deisseroth’s lab has attached laser diodes to tiny fiber-optic cables that reach the brain’s innermost structures. Along with the optical fibers, electrodes are implanted that record when neurons fire. “In the past year what’s happened is that these techniques have gone from being something interesting and useful in limited applications to something generalizable to any cell or question in biology,” Deisseroth says.

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