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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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Credit: Karl Deisseroth

Tagged: Biomedicine, brain, optogenetics, neurons, circuit

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