For decades a causal role for orbitofrontal cortex (OFC) and striatal dysfunction in obsessive compulsive disorder (OCD) has been hypothesized. Structural as well as functional MRI studies have implicated these regions and their interconnections in OCD pathogenesis, though their precise roles in encoding obsessive or compulsive symptoms are still an area of active investigation. Several lingering questions therefore remain. First, what are the molecular adaptations in the OFC and striatum that give rise to these structural and functional deficits in OCD? Second, how do activity patterns in these regions give rise to compulsive behavior, and how do treatments that reduce compulsive behavior affect these activity patterns? Using a translational approach, we have investigated each of these questions for the first time.
In Chapter 1, we have performed the first post-mortem analysis of OCD tissue looking at gene expression in the OFC and striatum. Targeting our analysis only to genes implicated in previous clinical and preclinical studies, we found that many genes critical for excitatory synapse function were reduced in the OFC of individuals with OCD. Several transcripts were also reduced across OFC and striatal brain regions, including DLGAP3 (also known as SAPAP3), which has been previously linked to OCD via preclinical studies showing that Sapap3-knockout mice display a compulsive behavioral phenotype and cortico-striatal alterations. In Chapter 2, we examine the functional consequences of reduced cortico-striatal Sapap3 expression on activity patterns of large groups of neurons in the OFC and central striatum using Sapap3-knockout (KO) mice and in vivo calcium imaging. Finally, in Chapter 3 we examine the role of genetically distinct striatal cell types in producing compulsive behavior. These data directly test several long-standing hypotheses regarding OCD pathogenesis and shed new light on how compulsive behavior may be generated in the brain
