With the flick of a precisely placed light switch, mice can be induced to cower in a corner in fear or bravely explore their environment. The study highlights the power of optogenetics technology—which allows neuroscientists to control genetically engineered neurons with light—to explore the functions of complex neural wiring and to control behavior.
In the study, Karl Deisseroth and collaborators at Stanford University identified a specific circuit in the amygdala, a part of the brain that is central to fear, aggression, and other basic emotions, that appears to regulate anxiety in rodents. They hope the findings, published today in the journal Nature, will shed light on the biological basis for human anxiety disorders and point toward new targets for treatment.
“We want to conceptualize psychiatric disease as real physical entities with physical substrates,” says Deisseroth. “Just like people who have asthma have reactive airways, people with anxiety disorders may have an underactive projection in the amygdala.”
The researchers engineered mice to express light-sensitive proteins in specific cells in the amygdala that send out neural wires, known as axons, to different substructures. Using a specially designed fiber-optic cable implanted in the animal’s brain, researchers found that aiming the light to activate one specific circuit had an immediate and potent effect on the animal’s behavior.
“I’ve never seen anything like it,” says Kay Tye, a postdoctoral researcher in Deisseroth’s lab and lead author on the study. Mice are naturally fearful of exploring open areas, she explains. Under normal circumstances, the animal “will poke its nose out and then scurry into a corner,” says Tye. “But when you turn on the light, the animal begins exploring the platform with no visible signs of anxiety. Then you turn the light off, and it scurries back in to the corner.”
The researchers could induce the opposite effect using a light-sensitive protein that silences the cells instead of activating them.
Shining light on the bodies of the cells, which in turn activates axons in multiple circuits, had no effect on the animals’ behavior, highlighting how important it is to be able to target individual circuits in the brain.
“Our understanding of the more precise circuitry within the amygdala is just now beginning to take off,” says Kerry Ressler, a neuroscientist at Emory University who was not involved in the study. “Optogenetics, where scientist can activate specific cell populations and even parts of cells, is a powerful approach to dissect how the amygdala modulates fear and anxiety.”
Ki Ann Goosens, a neuroscientist at MIT who was not involved in the study, says the research could help explain individual variation in baseline anxiety levels. “The findings tell us that this circuit contributes to an individual set point for anxiety,” she says.
“It may be a theme that some major sources of dysfunction in psychiatric disorders lie in the flow of information between different brain regions,” says Deisseroth. “This is something that optogenetics is uniquely suited to address.”
Researchers hope the discovery will ultimately enable the development of new treatments for anxiety disorders that are free of the side effects of existing drugs. Benzodiazepines, such as valium, are sedating and carry the risk of addiction. Mice given benzodiazepenes become less fearful and more exploratory, but the drug also affects their movement, making them sluggish, says Tye. Activating the circuit with light doesn’t seem to elicit this problem. “These animals are sniffing, grooming, doing everything normally,” she says.
To make more selective anti-anxiety drugs, scientists would need to target only the subset of cells that make up this circuit, which may prove difficult to do chemically. But Deisseroth is already working on another approach, using a noninvasive method of stimulating the brain called transcranial magnetic stimulation (TMS). The technology uses magnetic fields to activate neurons on the surface of the brain, and is approved by the Food and Drug Administration to treat depression. By combining TMS and functional brain imaging, Deisseroth is now examining whether it’s possible to noninvasively stimulate specific circuits in the human brain. His first study, which has just begun, will focus on a circuit that his team has previously linked to Parkinson’s disease.
Tye is working to better understand the role that the circuit identified in the current study plays in fear as opposed to anxiety. While the two terms tend to be interchangeable in everyday usage, neuroscientists define fear as a response to a specific thing—a loud sound, for instance, or oncoming traffic. Anxiety, on the other hand, is chronic, generalized fear. “Fear can be important for survival, but anxiety disorders are maladaptive,” says Tye.