For years, scientists have probed the complex interplay of billions of neurons that make up the human brain—exploring how their rapidly exchanged signals give rise to thoughts and emotions, how things can go wrong in disease, and how such diseases can be fixed.
To do all this, they needed the right tools. Neuroscientists originally relied on rudimentary technology such as dissection and the microscope to analyze the brain and nervous system. The field blossomed over the years, as scientists invented a variety of new tools such as electrodes that can initiate or record activity in a single neuron, and fMRI scanners that reveal the activity transpiring in large groups of neurons responsible for psychological phenomena ranging from humor to decision-making.
One of the most recent game-changing innovations is optogenetics — a technology that has given scientists unprecedented control over neurons in living animals. In 2005, Karl Deisseroth, a professor of bioengineering at Stanford University, and his colleagues devised a way to artificially tweak cellular genetics in order to turn neurons on or off by shedding light on them. The method allowed the researchers to precisely target and modify cells' activity, even in freely-moving animals.
Image: Orange light turns neurons off. Credit: Ed Boyden and McGovern Institute for Brain Research at MIT.
"In classical neuroscience, you had a good ability to look at the activity of a small number of neurons at a time, but you did it blindly. From the recorded activity, you could guess what type of cell it was based on its distinctive firing pattern," says Ehud Isacoff, a professor of neurobiology at University of California Berkeley who was one of the researchers involved in the initial development of the technology. Optogenetics, he explains, has a unique advantage over all previous technologies in that it allows scientists to directly control and monitor specific cell types in defined areas of the brain with precise timing.
Scientists can now ask far more detailed questions about the role an individual neuron plays in a larger circuit— the inputs it receives, the outputs it makes, what transmitters it uses, and how the individual cell contributes to a particular behavior. "It is such a huge step forward just in terms of how you analyze how a circuit works," says Isacoff.
How optogenetics works
Biologists have identified proteins in microorganisms, such as algae, that, in response to visible light, can suppress or excite electrical activity within individual cells. These proteins (part of a gene family called "opsins") enable microorganisms to identify the presence of light in their environment.
Image: the one-celled green algae Chlamydomonas. It lives in lakes and ponds, and contains a light-sensitive protein.
By isolating the genes coding for light-sensitive proteins and inserting them into a specific neuron, scientists are able to create cells that can be excited or inhibited by different colored light. Various methods are utilized to insert the gene, such as using a virus as a delivery vehicle, or electroporation, in which a foreign gene is integrated into a cell after an electrical pulse is delivered. A fiber-optic cable is then placed directly above the engineered neuron, delivering light to the targeted cell and controlling its activity.
Ed Boyden, an associate professor of biological engineering at MIT, explains optogenetics and how it is used in neurological research.
Although optogenetics is still in its infant stage, there has already been an explosion of studies leveraging this new technology which have produced a number of truly brain-altering experiments, albeit in animals, ranging from restoring auditory activity in deaf mice to crafting memories. "It has made a huge impact," says Isacoff. "Initially, it was so exciting to be able to do this at all that almost anything was jaw dropping."
In 2013, for example, a group of researchers at MIT applied optogenetics technology to artificially implant false memories in mice. In the experiment, the researchers placed the animals in a small chamber, and using a molecular trick, tracked which neurons became activated while the mice registered a memory of that place. These cells, which were now holding a memory, were then genetically altered to become sensitive to light.
The mice were then placed in a second chamber where the team applied light to turn on the genetically altered neurons— provoking the mice to recall the initial chamber. At the same time, the mice also received a painful electric shock to their foot, which made them link the memory of the first chamber with the foot shock, creating a false fearful memory. When the mice were placed back in the first chamber again, they froze out of fear. These results provided unique insight into how memories are contained in the distributed activation of particular neurons and how these initial memories can be subject to change each time we recall them.
A fiber optic inside mouse hippocampus, via Tonegawa lab
Another example is the research done by a group of scientists at University of California, Irvine, who have been using optogenetics to arrest seizures early in their tracks. Epileptic seizures occur as a result of abnormal activity of large populations of neurons in the brain. So in theory, it should be possible to control a seizure by inhibiting the neurons before they become dangerously active. After artificially inducing epilepsy in mice, the scientists used an algorithm to quickly identify the first groups of cells that start building up a seizure, and then used light to suppress those neurons. Thus, the researchers were able to reliably detect and swiftly stop seizures before they fully developed.
These studies are merely the foundation for a deeper and more nuanced understanding of the brain. Scientists are currently working to diversify the field of optogenetics to include more cells and receptors, while continuing to expand the applications of this technology to a multitude of human diseases. "Many of the really interesting things are going to emerge over the next few years," says Isacoff. "This is only just the beginning."