Research prods brain wiring underlying compulsive behavior

Mouse experiments offer insights, potential for new treatment strategies in humans

Two research teams have figured out how to flip a switch in the brain circuits of mice that compels the animals to groom themselves with their paws over and over. The findings may yield new strategies for reducing compulsive behavior such as repetitive hand washing in humans who have obsessive-compulsive disorder  and other diseases marked by the trait such as autism and Tourette syndrome.

In one set of experiments, researchers stimulated a particular neural pathway, generating repetitive, excessive grooming in the mice. A second set of experiments with mutant mice used the same pathway to eliminate the compulsive behavior. The studies are published in the June 7 Science.

“In tandem, this is really a leap forward towards a refined understanding of the circuitry underlying these behaviors,” says psychiatrist Scott Rauch of McLean Hospital in Belmont, Mass.

An uptick in the activity of two brain regions, the orbitofrontal cortex and ventromedial striatum, had previously been identified in brain scanning experiments of people with obsessive-compulsive disorder, which afflicts roughly 1 percent of the population worldwide. People with OCD have obsessive thoughts, such as worrying that they forgot to turn off the stove, and then perform compulsive behaviors in response, such as repeatedly checking the stove’s dials.

While those general brain regions had been implicated, there’s little understanding of the causal relationship between faulty brain wiring and the behaviors. So scientists led by psychiatric neuroscientist Susanne Ahmari of Columbia University targeted the implicated brain regions in living mice by injecting a virus into nerves that run between them, enabling the nerves to respond to light.

After five minutes of laser stimulation per day for about five days, the mice started compulsively grooming. Surprisingly, the repetitive grooming continued for two weeks after the stimulation stopped.

“This is really important,” says Ahmari. “If we can figure out triggers that make the brain more likely to be hyperactive, we may be able to prevent OCD before it starts.” Such triggers might include genetic factors predisposing the nerves to hyperactivity or environmental factors such as traumatic events or stress, she speculates.

Another study led by Eric Burguière and Ann Graybiel at MIT examined the same circuitry in normal mice and in mice genetically engineered to compulsively groom. Both sets of mice were trained to groom when they heard a tone followed by a drop of water on the nose. The water drop isn’t pleasant; the mice soon learned to groom when they just heard the tone. While the normal mice waited to groom until just before the drop hit, the mutant mice groomed right at the tone.

“They get hooked on this external stimulus,” says Graybiel. “It’s compulsive.”

But when the scientists stimulated the designated brain circuit with light, it stopped the compulsive behavior in the mutant mice and they groomed as the normal mice did.

Rauch notes that the two studies not only offer promise for future research and treatments in humans, but they validate that experiments with mice are a legitimate means of investigating compulsive disorders.

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