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Researchers, Using Light to Activate Neurons, Make Mice Obsessive, or Not

Mind-control optogenetics experiments in mice give new clarity to the neural circuitry that underlines repetitive behaviors.

Two teams of researchers have pinpointed some of the neural circuitry that underlies compulsive grooming behaviors. The discoveries, reported in Science on Thursday, could guide new treatments for people with obsessive-compulsive disorder, autism, and other conditions that exhibit symptoms of repetitive and compulsive actions.

contact sheet photos of rats
Extreme preen: A series of images shows the grooming behavior of a mouse that can become compulsive after repeated stimulations in a particular neural circuit.

Using so-called optogenetics techniques, which precisely control neuron activity with light, one of the groups induced repetitive grooming behaviors by stimulating a neural circuit known to be overactive in OCD patients. The obsessive grooming behaviors persisted even after the light stimulation stopped. The other team used optogenetics to alleviate repetitive, compulsive grooming in a strain of mutant mice born with the behavior defect.

The neural circuits studied by each team are both part of the larger neural network implicated in repetitive behaviors in people. More broadly, understanding the structure and activity of neural circuitry could be key to understanding a variety of mental illnesses, say scientists. The U.S. government is funding a large research effort (see “Why Obama’s Brain Mapping Project Matters”) into the workings of the brain that could also bring a greater understanding to these issues.

To figure out if the circuit disruptions observed in OCD patients are a cause or effect of the disorder, Susanne Ahmari, a neuroscientist and psychiatrist at Columbia University, and colleagues used optogenetics to stimulate in mice a neural circuit known to be hyperactivated in OCD patients. They expected to see repetitive behavior in the mouse as soon as they stimulated the circuit, but they didn’t. “This was a surprise to us,” says Ahmari. “The direct activation did not lead to repetitive behaviors in the mice.” But when they repeatedly stimulated the neural circuits, the mice developed obsessive behaviors.

The stimulation lasted for only five minutes each day, but by the fifth day, that stimulation was enough to change the circuits, says Ahmari. She and her coauthors demonstrated that the repeated stimulations led to increased firing of the circuit; they suggest that the repetitions prime the circuit so that it is more likely to fire, perhaps stimulating even more circuits downstream. The repetitive grooming behavior persisted for up to two weeks after the researchers stopped the daily stimulation.

In a separate study, MIT researchers looked into the brains of a strain of mice that exhibit repetitive behaviors to find out which circuits are abnormal in the brain during compulsive disorders. The team found that when the mutant mice groomed their faces in a compulsive manner, a particular brain circuit—one related to the circuit studied by Ahmari— exhibited less neural activity. Using optogenetics, the investigators were able to boost the activity of the diminished circuit in the mutant mice. This blocked the animals’ compulsive behaviors, even in the midst of a bout of excessive grooming.

This could have implications for next-generation therapies, says senior author Ann Graybiel, a neuroscientist at MIT. In patients with hard-to-treat cases of OCD, some doctors have turned to implanted electronic devices that emit electrical pulses to reset malfunctioning neural circuitry (see “Brain Implants Can Reset Misfiring Circuits”). These devices deliver their electrical stimulation on a preprogrammed cycle throughout the day. The mouse optogenetic experiment points to a healthier option. “[That result] suggests that treatments such as deep-brain stimulators for OCD patients may not always have to be on. Maybe you can just turn it on when you feel a compulsion coming on,” she says. 

The pair of “cutting-edge and insightful” studies “illuminates the neurocircuitry of compulsive behavior with unprecedented clarity,” write Harvard Medical School psychiatrist Scott Rauch and neuroscientist William Carlezon in an editorial in Science. “Although there is still far to go, these discoveries represent a major leap forward toward eventual methods for ‘flipping the off-switch’ on pathological behaviors.”

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