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.
Jerry Silver, professor of neuroscience at Case Western University, is particularly excited about this new off switch. Silver is using optogenetics to explore bladder control in spinal cord injury, and has been using light to turn off nerves that relax the bladder. These nerves are located in the lower spine, an especially vulnerable area, and the current generation of halorhodopsins require a high intensity of light to get a measurable effect.
“We were worried that we’d need a lot of light, which creates a lot of heat,” says Silver. “With these new tools that are more sensitive, we might not need as much light, which generates less heat, and the light can invade the tissue much farther, and that’s why I’m so excited about this new generation.”
In addition to engineering a powerful off switch, Deisseroth’s team surmounted another major obstacle in optogenetics–activating a whole neural circuit. While scientists can genetically target light switches to specific types of neurons, it’s more difficult to identify and genetically manipulate the cells downstream or upstream of those neurons. Being able to control whole circuits of neurons at a time, at light speed, could give scientists a better understanding of the neural connections involved in behavioral tasks like learning and memory, and diseases like depression and obsessive compulsive disorder.
To activate a neural circuit, Deisseroth first injected a genetic light switch into a motor neuron of a mouse. He manipulated the switch to only work in the presence of another molecule, CRE. Deisseroth injected CRE, along with a trafficking molecule, into another region of the mouse brain. The trafficking molecule “bodily drags CRE from cell to cell,” tracing a route back to the target neuron, he says. The CRE unlocks the light switch, and in the presence of blue light, the neuron–and the entire circuit–is activated.
“We think that overcomes, or takes a step toward overcoming, the major remaining limitations of optogenetics,” says Deisseroth. “The big challenge is to bring these tools to bear on disease models, and I see patients with autism and depression, and we’ll look [to use these tools], and try to come to a circuit understanding of those diseases.”
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