Key Concepts

• Neuroscientists have traditionally studied the function of the brain by stimulating and recording the activity of single nerve cells with elec­trodes. But this method is indirect, making analyses of specific neurons very difficult.
• The emerging field of optogenetics, which combines genetic engineering with light to observe and control groups of neurons, is allowing researchers to scrutinize individual neural circuits—an approach that will revolutionize the study of brain function.

 In 1937 the great neuroscientist Sir Charles Scott Sherrington of the University of Oxford laid out what would become a classic description of the brain at work. He imagined points of light signaling the activity of nerve cells and their connections. During deep sleep, he proposed, only a few remote parts of the brain would twinkle, giving the organ the appearance of a starry night sky. But at awakening, “it is as if the Milky Way entered upon some cosmic dance,” Sherrington reflected. “Swiftly the head-mass becomes an enchanted loom where millions of flashing shuttles weave a dissolving pattern, always a meaningful pattern though never an abiding one; a shifting harmony of subpatterns.”

Although Sherrington probably did not realize it at the time, his poetic metaphor contained an important scientific idea: that of the brain revealing its inner workings optically. Understanding how neurons work together to generate thoughts and behavior remains one of the most difficult open problems in all of biology, largely because scientists generally cannot see whole neural circuits in action. The standard approach of probing one or two neurons with electrodes reveals only tiny fragments of a much bigger puzzle, with too many pieces missing to guess the full picture. But if one could watch neurons communicate, one might be able to deduce how brain circuits are laid out and how they function. This alluring notion has inspired neuroscientists to attempt to realize Sherrington’s vision.

Their efforts have given rise to a nascent field called optogenetics, which combines genetic engineering with optics to study specific cell types. Already investigators have succeeded in visualizing the functions of various groups of neurons. Furthermore, the approach has enabled them to actually control the neurons remotely—simply by toggling a light switch. These achievements raise the prospect that optogenetics might one day lay open the brain’s circuitry to neuroscientists and perhaps even help physicians to treat certain medical disorders.

Enchanting the Loom
Attempts to turn Sherrington’s vision into reality began in earnest in the 1970s. Like digital computers, nervous systems run on electricity; neurons encode information in electrical signals, or action potentials. These impulses, which typically involve voltages less than a tenth of those of a single AA battery, induce a nerve cell to release neurotransmitter molecules that then activate or inhibit connected cells in a circuit. In an effort to make these electrical signals visible, Lawrence B. Cohen of Yale University tested a large number of fluorescent dyes for their ability to respond to voltage changes with changes in color or intensity. He found that some dyes indeed had voltage-sensitive optical properties. By staining neurons with these dyes, Cohen could observe their activity under a microscope.

Dyes can also reveal neural firing by reacting not to voltage changes but to the flow of specific charged atoms, or ions. When a neuron generates an action potential, membrane channels open and admit calcium ions into the cell. This calcium influx stimulates the release of neurotransmitters. In 1980 Roger Y. Tsien, now at the University of California, San Diego, began to synthesize dyes that could indicate shifts in calcium concentration by changing how brightly they fluoresced. These optical reporters have proved extraordinarily valuable, opening new windows on information processing in single neurons and small networks.

Synthetic dyes suffer from a serious drawback, however. Neural tissue is composed of many different cell types. Estimates suggest that the brain of a mouse, for example, houses many hundreds of types of neurons plus numerous kinds of support cells. Because interactions between specific types of neurons form the basis of neural information processing, someone who wants to understand how a particular circuit works must be able to identify and monitor the individual players and pinpoint when they turn on (fire an action potential) and off. But because synthetic dyes stain all cell types indiscriminately, it is generally impossible to trace the optical signals back to specific types of cells.