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Just five years ago, scientists at Stanford University discovered that neurons injected with a photo-sensitive gene from algae could be turned on or off with the flip of a light switch. This discovery has since turned hundreds of labs onto the young field of optogenetics. Today researchers around the world are using these genetic light switches to control specific neurons in live animals, observing their roles in a growing array of brain functions and diseases, including memory, addiction, depression, Parkinson’s disease, and spinal cord injury.

Now Karl Deisseroth, one of the pioneers of the technique, has added some new tools to the optogenetic repertoire that may advance the study of such diseases, at light speed. A molecular technique that controls whole circuits of neurons rather than a single cell will allow scientists to study the role of specific neural networks in the brain. A new near-infrared technique that reaches brain cells in deep tissue could allow scientists to use these techniques noninvasively–currently, they must implant a fiber-optic cable into an animal’s brain to deliver light activation to such cells. And an improved “off switch” that makes target neurons more sensitive to light allows for tighter neural control. The group published its results in the April 2 edition of the journal Cell.

To date, scientists have mainly concentrated on two light switches, or opsins, to activate or inhibit neurons. The first, channelrhodopsin, is a protein found in the cell membranes of green algae. When exposed to blue light, these proteins open membrane channels, letting in sodium and calcium ions. When genetically engineered into mammalian neurons, these proteins cause similar ion influxes, activating neurons. The second light switch, an ion pump called halorhodopsin, lets in chloride ions in response to yellow light, silencing the neuron.

The halorhodopsin light switch has some drawbacks, however. It doesn’t silence neurons all that effectively, and it can build up and have toxic effects in brain cells. Deisseroth’s team has developed a more effective off switch by taking advantage of a phenomenon called “membrane trafficking.” Instead of keeping halorhodopsin inside the cell, Deisseroth essentially engineered molecular instructions to guide the opsins through the cell, to the outside membrane, where it can more readily respond to light and open ion channels to inhibit neurons.

“Proteins get shipped around a cell and trafficked from spot to spot with incredible complexity,” says Deisseroth. “We had to provide the equivalent of zip codes, bits of DNA on the opsins, to traffic them correctly to the surface of the membrane.” (Ed Boyden, a neuroscientist at MIT and another optogenetics pioneer, has also developed more effective off switches, using proteins from fungi and bacteria.)

The team found that this new off switch is 20 times more responsive to yellow light than previous generations. The researchers also found that, while yellow seems to be the sweet spot along the light spectrum for triggering the off switch, red and near-infrared light can also have an effect. To Deisseroth, these results suggest a tantalizing prospect: it’s well-known that the closer light gets to infrared, the deeper it can pass through tissue. Engineering a light switch that turns neurons on in response to infrared could open the doors to precise control of circuits deep in the brain, potentially enabling noninvasive treatments for diseases like Parkinson’s and depression.

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Credit: Karl Deisseroth

Tagged: Biomedicine, brain, optogenetics, neurons, circuit

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