June 17, 2013

Brain Circuits Involved in Compulsive Behaviors

Woman washing her hands vigorously.

Researchers used optogenetics to identify the brain circuits responsible for compulsive behaviors in mice. The findings could lead to new approaches for treating obsessive-compulsive disorder (OCD) and other conditions that include compulsive behavior.

People with OCD have persistent intrusive thoughts — like an obsession with germs or a need to check something repeatedly — or perform repetitive routines and rituals such as compulsive hand-washing. The thoughts and rituals associated with OCD cause distress and get in the way of daily life. The disorder affects about 2.2 million adults nationwide.

OCD can be treated with psychotherapy, medication or both. By learning more about fear and anxiety in the brain, scientists hope to develop better treatments. Brain imaging studies suggest that hyperactivity in the orbitofrontal cortex and ventromedial striatum are associated with OCD. However, imaging data from people isn’t precise enough to pinpoint the specific neurocircuitry involved. Two recent studies in mice, published together in Science on June 7, 2013, shed new light on the problem.

A team led by Dr. Susanne Ahmari at Columbia University tested whether stimulating the glutamatergic neurons that bridge the orbitofrontal cortex and ventromedial striatum can lead to OCD-like excessive grooming in mice. The scientists used genetically engineered viruses to add light-sensitive proteins to glutamatergic neurons in the brains of living mice. The neurons were then activated with light shone via optical fibers.

Stimulation of this circuit didn’t directly invoke excess grooming. However, repeated activation over multiple days caused a progressive increase in grooming. The excess grooming lasted up to 2 weeks after the stimulation ended. Both the increased grooming and evoked circuit activity were reversed with fluoxetine, a medication used to treat OCD.

A team led by Drs. Eric Burguière and Ann Graybiel at the Massachusetts Institute of Technology focused on Sapap3 mutant mice, which have compulsive facial grooming and anxiety. The mice were trained to associate a tone with a water drop to the forehead, which provokes grooming. Normal mice learn to adapt their response to the tone so that they groom when the water drops. The mutant mice never adapted; they just immediately started grooming as soon as they heard the tone. This showed that they lacked normal behavior inhibition.

By recording neuron activity, the researchers linked specific neurons in the centromedial striatum, called medium spiny neurons, with the excessive grooming. Activity in these neurons decreased during training in normal mice but not in the mutant mice. The scientists hypothesized that the compulsive behavior might be caused by a defect in inhibition of these neurons.

Fast-spiking striatal interneurons are known to be involved in inhibiting medium spiny neurons. The researchers thus used optogenetics to synchronize fast-spiking striatal interneuron activity in the mutant mice. They found that optogenetic stimulation of these neurons stopped the excessive medium spiny neuron activity. It also restored normal grooming behavior.

“Through the activation of this pathway, we could elicit behavior inhibition, which appears to be dysfunctional in our animals,” Burguière says.

These findings on brain circuits and excessive grooming in mice may lead to insights into the neurobiology of OCD in people. Such understanding could suggest novel ways to diagnose, prevent and treat this serious disorder.

— by Harrison Wein, Ph.D.

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References: Science. 2013 Jun 7;340(6137):1234-9. doi: 10.1126/science.1234733. PMID: 23744948. Science. 2013 Jun 7;340(6137):1243-6. doi: 10.1126/science.1232380. PMID: 23744950.

Funding: NIH’s National Institute of Mental Health (NIMH) and Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); the Simons Foundation; the Louis V. Gerstner, Jr., Scholars Program; the Irving Institute for Clinical and Translational Research; the Gray Matters Foundation; the Leon Levy Foundation; the Brain and Behavior Research Foundation; the Sackler Institute; the Howard Hughes Medical Institute; the Defense Advanced Research Projects Agency; the Hope for Depression Research Foundation; and the International Mental Health Research Organization.