Optogenetics Is Opening New Doors

by Guy McKhann, M.D.

June 24, 2010

“Some day we will understand the entire genetic makeup of the brain. But we will still have to ask how the brain works.”
—Max Cowan

A few decades ago, brain researchers began to move in two different directions. The first group responded to the advances in cellular and molecular biology, particularly in the field of genetics. Most of these studies were done on individual cells or groups of cells grown outside the brain. This approach led to an understanding of the receptors on brain nerve cells, the introduction of human genes into animals to produce animal models of human diseases such as Alzheimer’s, and studies of how brain cells move around during development. It also led to studies of how various mechanisms within cells operated.

Another group of brain researchers focused on the intact, whole brain. They sought answers to questions such as: How do nerve cells communicate with one another and respond to the incoming signals derived from touching, vision, or hearing? What approach should be taken to map the brain systems that are involved in language, control of movement, and mood? This line of investigation involved recording of the electrical activity of nerve cells—that is, using implanted electrodes to directly record brain activity in awake animals and in people prior to or during surgery. The limitation of measurements from electrodes is that only a few brain cells can be studied at a time. Thus, it is hard to study whole systems of interacting groups of nerve cells.

In the past decade, the work to define the systems of the brain has been advanced by observing the activity of nerve cells via brain imaging of the entire human brain. These studies depend on the fact that the activity of nerve cells is linked to increases in blood flow. Thus as you move your hand, or listen to music, or read, one can ask, “What parts of your brain are you using?” and look at where the blood is flowing.

Until recently, these two approaches to the brain—the cellular approach and the systems approach—remained quite distinct. The separation was emphasized by the great neuroscientist, Max Cowan, in the quote displayed above. It was inevitable that these two approaches to understanding the brain would come together and complement each other.

An interesting example of this fusion of ideas is the new field of optogenetics. As outlined in “Light Moves,” from the Howard Hughes Medical Institute Bulletin, researchers are using genetic engineering to manipulate receptors on nerve cells so they respond to light at specific wavelengths.

As described in the article, genes from primitive organisms, like algae and fungi, are transplanted into nerve cells. These genes result in light-activated gates that control how particular ions, such as sodium or chloride, enter a nerve cell. For example, if a cell is directed to contain a blue activator, sodium ions enter the cell when exposed to blue light and make that cell respond more easily. A different gene can direct a cell to have a yellow light response, allowing chloride to flow into the cell and making it less likely to respond. The result of all this genetic manipulation is a system in which specific parts of the brain are turned off or turned on in response to blue or yellow light signals.

These two examples are just the beginning. At present, the light is delivered by a very thin optical fiber. In the future, the scientists envision using light sources that can penetrate the skull and directly activate the brain. The genes for the light receptors then could be directed to whole brain circuits, so that light would modify movement, responses to sounds, or even mood.

It is not clear where this field of optogenetics will go, but it is a whole new way to study the brain.