Christopher Pittenger

My research is aimed towards a better understanding of a particular network of brain structures, called the basal ganglia, and the consequences of dysfunction of this network in various neuropsychiatric diseases. The basal ganglia are involved in motor control, in the formation of behavioral patterns and habits, and in the regulation of reward. Abnormalities in this circuit are implicated in a variety of conditions characterized by maladaptive, inflexible behaviors - habits gone bad. These include obsessive-compulsive disorder, Tourette syndrome, and drug addiction.

Our research in the laboratory has two strands. First, we seek to better understand the mechanisms of normal basal ganglia-dependent habit-like learning, by manipulating this circuit in mice. Second, we seek to better understand how perturbation of the basal ganglia system can lead to symptoms of psychiatric disease. We do this by recapitulating hypothesized causes of diseases such as Tourette syndrome, OCD, and autism, again in mice, and testing the behavioral and neurophysiological consequences.

I also direct the Yale OCD Research Clinic, where our research aims towards the better understanding of the biology of obsessive compulsive disorder and the development of new treatments. We have a number of active research programs. We are investigating abnormalities in the neurotransmitter glutamate in OCD and whether glutamate modulating medications can be of therapeutic benefit. We are probing the network connectivity of the brain in OCD and Tourette syndrome using recent advances in fMRI imaging. We are exploring the phenomenological heterogeneity of OCD, seeking clues to how we might better personalize effective treatments. We are also developing innovative neurofeedback techniques, in which patients actually learn to control the activity of key brain regions, in an effort to develop a new type of nonpharmacological treatment. And we are using noninvasive brain stimulation to modulate the function of cortico-basal ganglia circuits and enhance the mechanisms of psychotherapy.

STUDIES OF BASAL GANGLIA FUNCTION IN MICE. The basal ganglia, consisting of the striatum (caudate-putamen) and related subcortical structures, have historically been considered to have primarily motor functions; but it has become increasingly clear that they are also involved in a variety of cognitive and affective processes. Disruption of normal basal ganglia function is seen in a variety of neuropsychiatric conditions, such as obsessive-compulsive disorder, Tourette syndrome, and drug addiction.

The striatum has been divided into distinct functional regions, though both the anatomical subdivisions and the functions with which they are associated remain approximate and subject to debate. The ventral striatum, consisting of the nucleus accumbens and related structures, has a well-documented role in reward and reward-driven learning, and has been extensively researched in the context of drug addiction. The dorsal striatum (caudate and putamen, in primates) is thought to have a role in the formation of motor and cognitive patterns and in forms of implicit learning, including the formation of habits.

The Pittenger laboratory is focused on better understanding the mechanisms of dorsal striatum-dependent habit-like learning, and of the consequences of its perturbation in various neuropsychiatric conditions. We conduct our researches primarily in mice, which allows us to take advantage of sophisticated reverse genetic techniques to perturb the striatal circuitry in molecularly precise ways and to target specific striatal subregions and neuronal subtypes.

MODELING PSYCHIATRIC DISEASE. We are applying this technology to model neuropsychiatric conditions affecting the striatum, especially Tourette syndrome. This represents a third focus of the laboratory. Modeling psychiatric disease in animals has proven enormously challenging, because etiology is often obscure and symptomatology is often difficult to translate to non-verbal species. We believe that the development of valid models hinges on a sufficient degree of understanding of pathophysiology to ensure validity when translating to animals.

Fortunately, studies at Yale and elsewhere are beginning to produce such understanding in the case of Tourette syndrome. We are using genetic methods to produce putative models of Tourette syndrome based both on post-mortem findings and on genetic insights . These animals are then being tested in a variety of behavioral assays to assess their recapitulation of Tourette syndrome phenomenology, explore secondary and tertiary consequences of the initial manipulations, and investigate the response to both established and novel medications.

A FOCUS ON TRANSLATIONAL RESEARCH: NEW MEDICATIONS FOR OBSESSIVE-COMPULSIVE DISORDER (OCD). The final focus of the Pittenger laboratory is also translational. Dr. Pittenger is Director of the Yale OCD Research Clinic, where he has found glutamate-modulating medications to be of potential benefit in the treatment of patients with obsessive-compulsive disorder (a condition in which basal ganglia dysfunction is implicated). We are examining the behavioral and molecular effects of such glutamate-modulating drugs in animals, to better understand their role in patients with this and related conditions. As new animal models of disorders of the basal ganglia, like OCD, become available, we hope to use this translational approach to advance our understanding both of the normal role of the basal ganglia in behavior and its perturbation in disease, and to develop new generations of therapeutics for the psychiatric population.