So much of what we do, we do on autopilot—whether tying our shoes or driving the same route to work. Functioning on autopilot frees our attention for other things, but it can also entrap us in inflexible and uncontrollable behaviors that assume lives of their own, said Christopher Pittenger, M.D., Ph.D., associate professor of psychiatry and in the Child Study Center and assistant professor of psychology, who studies how the brain’s cortical-basal ganglia circuits help to automate routine behaviors.
In his clinical work and as director of the Yale OCD Research Clinic, Pittenger realized that many psychiatric disorders ranging from obsessive-compulsive disorder (OCD) and Tourette syndrome to drug addiction entail habits turned into compulsions. These disorders are also all associated with abnormalities in the basal ganglia, a brain region critical to motor control and procedural learning. To discover what is out of balance in a specific circuit, how it got that way, and how to fix it, Pittenger studies affected patients; looks for genetic variations that may contribute to their condition; and observes the effect of those variations in mice to learn something new—with the ultimate aim of exploring the broader relevance of those findings in patients.
But discovering such genetic variants is tricky. Tourette syndrome, for example, is 50 percent genetic, but it may involve perhaps hundreds of mutations that individually have a minuscule effect; thus, geneticists often search for rare genes with large effects to gain new insights about a disorder.
In 2010, researchers at the School of Medicine found such a gene for Tourette, a syndrome characterized by involuntary repetitive movements and vocalizations called tics. A father and his eight children share this syndrome—and a mutation not found anywhere else in a gene called HDC. HDC normally codes for an enzyme that helps produce histamine, a signaling molecule associated with allergies. Histamine also relays messages between neurons; it was the loss of this neurotransmitter function that seemed to cause Tourette in this family.
Pittenger’s team reported in the January 2014 issue of Neuron that the HDC deficiency in mice disrupts the basal ganglia, which increases signaling by dopamine, a neurotransmitter associated with habit formation, Tourette, and other psychiatric disorders. Mice with the mutation twitched their noses, sniffed, and groomed in a “rapid, repetitive and purposeless way, paralleling human behaviors.” But the tic-like behaviors disappeared when the mice received haloperidol, a drug that can lessen Tourette symptoms by blocking some effects of dopamine. When researchers infused histamine into a mouse’s brain in another experiment, the infusion reversed the symptoms.
“That proved that the HDC mutation caused the disorder in these mice,” Pittenger said. “The mutation is so rare that it cannot be the cause of Tourette in most people, but it’s a foot in the door for learning more about the disorder.” For example, HDC deficiency in mice causes abnormalities in the levels of dopamine receptors. When Pittenger went back to the family with the rare HDC mutation, PET brain imaging showed a similar irregularity in dopamine receptors. Now he is asking whether this irregularity occurs in other Tourette patients and if so, what causes it.
“We’re optimistic that using this method again and again, we’ll find previously unknown characteristics of Tourette that we can target with new treatments. We’re not there yet, but it’s an exciting first step.”