CREDIT: FENG ZHANG AND KARL DEISSEROTH
by Greg Miller
Optogenetics continues to be a hot topic. This emerging set of research tools combines genetic engineering and sophisticated optics to image or stimulate neural activity. The neural circuits that mediate things like mood, memory, and behavior are assembled from different types of cells--and optogenetics gives researchers a way to manipulate one cell type at a time to figure out what role it plays in the circuit.
Three posters presented this afternoon at the Society for Neuroscience meeting in Chicago illustrate how researchers interested in a wide range of questions are putting these methods to use. All three used the same basic strategy: injecting a virus into the brain region of interest to introduce a gene encoding a light-activated ion channel called channelrhodopsin-2 (ChR2). When neurons express ChR2, pulses of laser light delivered by an optical fiber open the channels and stimulate the neurons to fire.
Antoine Adamantidis of Stanford University in Palo Alto, California, has been using this approach to investigate neurons in the hypothalamus that influence the sleep-wake cycle. In previous work, he and colleagues used methods borrowed from genetic engineering to target ChR2 to only hypothalamic neurons that express the neuropeptide hypocretin. In a 2007 Nature paper, they reported that stimulating these hypocretin cells with laser pulses promoted wakefulness in mice. At the meeting, Adamantidis reported that stimulating a different type of hypothalamic neuron seems to have the opposite effect. When he and co-workers stimulated neurons that express melanin-concentrating hormone, a neuropeptide only recently linked to sleep regulation, mice slept more. The findings suggest that the two cell types have a push-pull effect on the sleep-wake cycle, Adamantidis says. But because they are such close neighbors in the hypothalamus, he says, it would have been impossible to tease them apart using conventional methods.
Meanwhile, Herbert Covington and colleagues at Mount Sinai School of Medicine in New York City have been using optogenetic methods to study a mouse model of depression. Mice that spend time with an aggressive bully (mouse) become withdrawn and avoid social contact even with friendly mice--an effect that's reversed by antidepressant drugs. Covington and colleagues used ChR2 to confer light sensitivity on neurons in the medial prefrontal cortex (mPFC), a brain region that's underactive in humans with depression, and then used laser pulses to stimulate neural activity. "Depressed" mice that got this treatment were less socially withdrawn, judging by the amount of time they spent interacting with a nonhostile stranger. In this case, Covington says the advantage of using optogenetics was the fast time resolution of the laser, which allowed the researchers to recreate patterns of neural activity that closely mimic those seen in the mPFC of presumably nondepressed mice freely exploring their enclosure.
Finally, Mary Kay Lobo of Mount Sinai presented findings suggesting that stimulation of different subtypes of cells in the nucleus accumbens, a key node in the brain's reward circuitry, can enhance or inhibit the rewarding effects of cocaine in mice. These cells express different versions of the receptor for the neurotransmitter dopamine and have different connections to other brain regions. Lobo has more experiments planned to investigate how they might be involved in drug use and addiction.
Although the findings are all preliminary, these studies (and others, such as this recent paper on memory) seem to suggest that these flashy methods are beginning to live up to their promise.