Role of the Orbito Frontal Cortex and Midbrain Dopamine Neurons in Associative Learning from Reward Prediction Errors

Grant Type
Grant Year
Institution Location
Institution Organization Name
Investigators Name
Ogawa, Masaaki, MD, PhD

The orbitofrontal cortex (OFC) is central to our understanding of OCD (Obsessive Compulsive Disorder), which is frequently associated with Tourette syndrome (TS). A common feature of OCD and TS is an inability to inhibit unwanted actions that follow premonitory experiences such as thoughts (OCD) and sensations (TS). This similarity indicates a common underlying inability to inhibit inappropriate responses, an ability which has long been linked to the OFC. Consistent with this hypothesis, brain imaging studies have demonstrated changes in OFC function in OCD and TS. For example, patients with OCD show reduced activation of the OFC during reversal learning; a type of associative learning that is exquisitely sensitive to manipulations that disrupt OFC function. However, the precise role that the OFC plays in supporting adaptive behavior in reversal-like settings remains controversial. Inhibitory interneurons defined by the fast-spiking phenotype and expression of the calcium binding protein parvalbumin (PV) are implicated in TS pathophysiology. For example, a strong imbalance between the numbers of PV neurons and projection neurons in basal ganglia in individuals with TS was recently reported. Considering the possibility of a common defect of PV neuron migration during embryogenesis between basal ganglia and cortex, there may be a similar imbalance in the OFC in TS subjects. In this project we will address the role of PV neurons in the OFC for associative learning induced from reward prediction errors. We will use optogenetic technology which enables us to specifically manipulate activities of PV neurons on millisecond order. We will then monitor activity of midbrain dopamine neurons to examine the impact of PV cells in OFC over the dopaminergic neurons. This study may provide a novel insight into the underlying circuit abnormalities in TS and OCD, and ultimately suggest potential therapeutic approaches for these disorders. Masaaki Ogawa, M.D., Ph.D., Ed Boyden, Ph.D. Massachusetts Institute of Technology, Cambridge, MA Award: $40,000 (Fellowship) Commentary: In addition to often being co-associated, Tourette syndrome (TS) and Obsessive Compulsive Disorder (OCD) are similar in that a premonitory urge is followed by an inappropriate and unwanted action. This observation has led scientists to propose that a glitch in normal brain function may be responsible for both disorders. In this study, we will focus on a part of the brain that is involved in decision-making and which is thought to be implicated in both TS and OCD. More specifically, we will attempt to determine whether dysfunction in this part of the brain results in abnormal activity of nerve cells that contain dopamine. Abnormal activity of these dopamine containing nerve cells has long been implicated in the generation of tics. Results from this study may help us understand the neurological basis of TS and OCD. Tourette Association of America Inc. – Research Grant Award 2010-2011