But the benefits of this technology for discerning the circuits of the mind go much deeper, because the virus that carries the photoreceptor genes can also carry promoter sequences that express their payload only in neurons with the appropriate molecular address. So rather than exciting all the neurons in a particular neighborhood, it becomes feasible to focus on a subset that synthesize a particular neurotransmitter or that send their outputs to a specific place.
Deisseroth’s group exploited this capability by introducing ChR2 into a subset of neurons located in the lateral hypothalamus, deep inside the mouse brain. Here about 750 cells produce orexin (also known as hypocretin), a hormone that promotes wakefulness. Mutations in the orexin receptors are associated with narcolepsy, a chronic sleep disorder. As a result of the manipulation, almost all the orexin neurons, but none of the other intermingled neurons, carried ChR2 photoreceptors. Furthermore, blue light via an optical fiber precisely and reliably generated waves of spikes in the orexin cells.
What would happen if this experiment were done in a sleeping mouse? In control animals, a couple of hundred blue flashes awakened the rodents after about one minute. When the same light was delivered to animals carrying the ChR2 gene, they woke up in half the time. That is, ghostly blue light that illuminates the catacombs of the brain and causes a tiny subset of neurons with a known identity to produce electrical spikes wakes up the animal. With additional controls, the Stanford group proved that the release of orexin from the lateral hypothalamus was what drove this behavior. This exemplary study established a compelling causal link between electrical activity in a subset of the brain’s neurons and sleep-to-wake transitions.
A string of such beautiful, interventionist mice experiments over the past several years has revealed specific circuit elements involved in a variety of normal and pathological behaviors: depression, behavioral conditioning, Parkinson’s disease and cortical oscillations critical for attention, among others. They have even helped restore sight to mice blinded by degenerating retinas. ChR2 experiments have been carried out successfully in monkeys; experimental human trials for some psychiatric illnesses are being actively considered.
The import of optogenetics for consciousness is that it allows testing of a specific hypothesis about the neural basis of consciousness. For instance, to what extent is feedback from higher cortical regions to lower regions essential? Find out by training an animal in a task that depends on conscious sensation, then inactivate those circuit elements with light and observe the animal’s behavior.
Francis Crick, co-discoverer of the double helical structure of DNA, and I had hypothesized that the claustrum, a mysterious thin structure located below much of cortex, is critical for binding information across sensory modalities and making it accessible to consciousness. The challenge is to find an appropriate behavior that requires mice to combine information dynamically across modalities—say, touch and smell. Then excite or inhibit claustrum neurons while the animals execute the task to study the extent the structure is necessary for this behavior.
A judicious mix of recombinant DNA technology, protein and viral design, genomics, optical fibers, lasers and microinstrumentation will enable scientists to explore strange new theories that close the gap between the objective brain and the subjective mind, to boldly go where no one has gone before.