From the Lab to the Clinic
During college Christopher Pittenger, MD, PhD, discovered that neurobiology was an ideal way to synthesize his interests in molecular biology and human psychology. “The brain felt like the one place where I could take these two interests I had and study them in the same place,” he said.
While pursuing his PhD under Nobel laureate Eric Kandel, Dr. Pittenger serendipitously embarked on the path that led to his current research. While attempting to alter the hippocampus in mice, he instead accidentally altered the striatum, an area of the brain that plays a critical role in habits and automating routine behavior. When he returned to medical school a few years later, and then went on to residency training in psychiatry at Yale, he was struck by the number of psychiatric conditions that are characterized by patterns of behavior or thoughts that are difficult to control, in much the same way that an ingrained habit is difficult to break. It turns out that many of these conditions, including obsessive compulsive disorder (OCD) and Tourette syndrome, involve pathology of the striatum.
Dr. Pittenger, who directs the Yale OCD Research Clinic, used his Scholar award and an award from the Doris Duke Charitable Foundation to measure levels of the neurotransmitter glutamate in the anterior cingular cortex, which connects to the striatum and is known to be pathologically active in patients with OCD. This research led to an R01 to conduct a study using magnetic resonance spectroscopy, high resolution structural imaging, and cognitive profiles for a large group of patients in order to correlate brain structure, function and connectivity in this disorder.
In 2010, Yale researchers identified a rare mutation in a gene called histidine decarboxylase (or HDC) that causes Tourette syndrome, in a family with nine members who shared both the mutation and the disorder. HDC is required for production of histamine; in the brain, histamine acts as a neurotransmitter and affects the function of a range of brain circuits, including the basal ganglia. Dr. Pittenger received a YCCI pilot award in 2011 to create a mouse model of the disease in order to better understand its cause. His team showed in mice that the HDC mutation disrupts basal ganglia function, increasing signaling by dopamine, a neurotransmitter associated with habit formation, Tourette syndrome, and other psychiatric disorders. “These findings give us a new window into what’s going on in the brains of people with Tourette,” said Dr. Pittenger. “That’s likely to lead us to new treatments.” He has also shown in mice that the tics seen in Tourette may be caused by the loss of specific neurons in the brain.
Dr. Pittenger had always intended doing bench research, but he credits his Scholar award with allowing him to simultaneously pursue clinical research. “It’s not an easy intellectual jump to go back and forth from the lab to the clinic,” he said, noting that it is a collaborative effort that involves such challenges as obtaining separate funding and understanding separate regulatory requirements. “I’ve been able to work in the lab and clinic in parallel thanks to YCCI, along with other funding sources.”