No Neuron Left Unturned

Practitioners in the nascent field of optogenetics are getting the hang of genetically modifying cells to make them responsive to and controllable by light. They say they are developing what will become a powerful strategy for teasing out the daunting complexity of biological tissues, particularly brain tissue. “You can interrogate every level, up to the entire brain,” says HHMI investigator Massimo Scanziani, a neuroscientist at the University of California, San Diego.

A quick and partial survey of recent and ongoing experiments hints at what Scanziani has in mind.

Pointillist Control. For cells that have been modified to express optogenetic switches all over their membranes, the diffraction limit of light, which dictates how tightly a beam of light can be focused, determines the portion of a neuron's anatomy that researchers can excite or silence. For Scanziani, it means he can optogenetically control neuronal activity all the way down to the minuscule spines on dendrites. These tiny appendages are part of neuron-to-neuron signal relays in the brain, and some brain cells have tens of thousands or more of them. Scanziani believes such optogenetic techniques will help him to probe, monitor, mimic, and control circuit behavior down to a fundamental level of synaptic dynamics.

Beyond Neurons. Even as the neuroscience community embraces optogenetics with ever more enthusiasm, the promise of the technique in other biological tissues beckons. Excitable cells like muscle cells, as well as insulin-producing cells in the pancreas, are particularly amenable to control by light with optogenetic techniques, says neuroscientist and physician Karl Deisseroth. “We have done experiments with heart cells in which we could make them beat by shining light on them,” says Deisseroth, an HHMI early career scientist at Stanford University.

Generating Fear. Some researchers are adapting Deisseroth's technique to make a mouse march by aiming a stream of light on specific motor neuron cells (see main story) and to enter some more tantalizing and somewhat scary arenas, such as probing and manipulating fear and other emotional states of the brain. At a recent neuroscience meeting, for example, researchers from University College London reported that by shining light on a learning-related brain structure, they could replicate fear responses in mice conditioned to associate a tone with an electric shock to the feet. In this case, no more need for the tone to elicit the fear.

Creating Courage. Optogenetics studies could prove useful for erasing fear as well. Researchers from Mount Sinai School of Medicine shined light onto cortical brain cells in mice that were rendered light sensitive with optogenetic techniques. The mice had been badly bullied, but when the light was on, they lost the sensible aversion they had developed to the large, aggressive mouse that had harassed them.

-- Ivan Amato
HHMI Bulletin, May 2010

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