More and more neuroscientists are using a new tool to shed light–literally–on the brain to uncover its secrets.
The brain is the most complex object in the known universe. It weighs only about 3 pounds but is packed with 100 billion neurons, each of which sends out intertwining processes and forms thousands of connections to other neurons. How to disentangle the brain’s complexity to uncover the specific neurons and patterns of activity that give us memory, fear, self-awareness, and love? What is the ideal approach to identifying the brain circuits that have gone awry in depression and schizophrenia? Nobel laureate Francis Crick addressed these questions in 1979, writing in Scientific American that neuroscientists needed a method by which “all neurons of just one type could be inactivated, leaving the others more or less unaltered.” The answer to Crick’s scientific prayer is called optogenetics–a technology in which lasers and genes converge to enable neuroscientists to turn off neurons–and turn them on–with unprecedented control.
It’s one of those inventions that brings two facets of nature’s ingenuity together in an unnatural way. Green algae microbes make a protein called channelrhodopsin that allows them to detect sunlight. Channelrhodopsin is a channel that opens when activated by sunlight and allows positively-charged ions into the algae. When neurons communicate, they are similarly activated by positively-charged ions. The ions cause the neuron to fire an action potential–the electrical activity that's behind brain function. By inserting algae’s channelrhodopsin gene into neurons, scientists have produced neurons that are activated by light.
Normal neurons fire action potentials on a millisecond timescale. Because the lasers themselves can be flashed at a millisecond timescale, researchers can program the laser to induce the neurons to exhibit activity behavior that is very close to their normal behavior in the brain. Different types of activity that neurons normally exhibit–such as steady, tonic firing or firing in bursts–can be induced and the impact on brain processing can be assessed.
Scientists have been scouring nature for more genes like channelrhodopsin in an effort to expand the optogenetic toolset. Halorhodopsin, a protein found in halobacteria is a channel for, not cations, but negatively-charged anions. When these proteins are activated by light they inhibit the neuron rather than activate it. And it just so happens that these two proteins are activated by different wavelengths of light. Channelrhodopsin is activated by blue light while halorhodopsin is activated by green light, so scientists can inject the two genes into the same group of neurons and turn them on or off at will. The versatility of optogenetics is also strengthened by the ability to insert the genes into specific cell types. Channelrhodopsin has been expressed exclusively in the inhibitory cells of the mouse cortex. The ability to activate specific cell types in different brain regions is a powerful method by which to parse out the different functions of neuronal subtypes in brain circuits.
Before optogenetics, neuroscientists used electricity and drugs to tamper with and study neuronal circuits. But these are comparatively crude probes. Activating neurons by current injection suffers from low spatial resolution, as the current will spread to neurons surrounding the targeted area. Drugs spread too and are often administered systemically. Not only does this reduce spatial resolution and complicate data analysis, it also makes side effects unavoidable. These issues are overcome by the precision of optogenetic’s pinpoint laser.
The video below is a TED Talks seminar in which MIT’s Ed Boyden discusses the latest in optogenetics research. He describes how the technique is being eagerly adopted by labs across the world to advance the study of post-traumatic stress disorder and addiction, and how it might one day be used to treat seizures and macular degeneration. The overactive neurons of a seizure patient could be quieted using inhibitory halorhodopsins. Boyden is himself involved in using optogenetics to treat macular degeneration. In macular degeneration the light-sensitive tissue of the retina die, resulting in vision loss. But the neurons that transmit the visual information from that tissue, however, are still intact. Boyden suggests that the disease might be treated by giving those intact neurons channelrhodopsin and making them responsive to light. He likens it to putting solar panels on a house. He’s already begun testing this idea in mice. In a fascinating demonstration, he shows a blind mouse swimming aimlessly around a pool searching for a platform to stand on. The location of the platform is cued by a light signal that the blind mouse cannot see. After injecting the mouse’s retina with the channelrhodopsin gene it swims right over to the light.
In the manner that polymerase chain reaction (PCR) revolutionized the way we study genes, optogenetics continues the scientific tradition of ingenious new tools leading us to new insights. We owe our debt of gratitude to Karl Deisseroth and his group at Stanford University for bringing us this wonderful tool. Deisseroth was the first to introduce channelrhodopsin into the brains of mice in 2005. Today, thousands of scientists across the world have adopted the technique to study the brain. In 2010 optogenetics was dubbed Method of the Year by the journal Nature Methods. That same year the journal Science listed it among the breakthroughs of the decade. One of the most exciting facets of science is revisiting old problems with new perspectives and new tools. Optogenetics is still in its early days. As more neuroscientists adopt the technique and push it as far as they can, one can only guess what mysteries of brain function and disease will be brought to light.