Obsessive-compulsive disorder (OCD), a psychiatric condition characterized by obsessive thoughts and compulsive behaviors, greatly contributes to illness-related disability worldwide. While first line treatments for OCD such as cognitive behavioral therapy (CBT) and selective serotonin reuptake inhibitors (SSRIs) have proven effective in mitigating OCD symptoms, many patients with OCD remain resistant to these available treatment options. Thus, it is imperative to develop novel therapeutic strategies through gaining a deeper mechanistic understanding of the disorder. Research in model organisms, through its ability to control for confounding variables and manipulate individual parameters to make causal assertions, provides an ideal platform through which to gain this mechanistic understanding. However, since it is unfeasible to model a psychiatric condition such as OCD in its entirety in model organisms, instead research focuses on understanding discrete behavioral processes with high relevance to the disorder that are easily tractable in model organisms. For OCD, some of these behavioral processes include fear, reward, goal-directed learning, habitual learning, negative reinforcement, and compulsivity. In this work, we seek to further our understanding of OCD through behavioral, circuit, and molecular characterization of behavioral processes relevant to OCD in mouse models. In Chapter 2, we begin by characterizing the behavioral processes of fear, reward, goal-directed learning, and habitual learning in a mouse model of compulsive behavior, the SAPAP3 knockout (KO) mouse model. Through this work, we find that SAPAP3 KO mice, which have a compulsive grooming phenotype, also show evidence of enhanced fear learning, impaired fear extinction, impaired reward learning, and impaired goal-directed learning. We additionally find similar behavioral trends in OCD patients, who showed evidence of heightened negative valence processing and impaired positive valence processing. In Chapter 3, we next characterize the behavioral process of negative reinforcement on the circuit level through studying the contributions of the dorsomedial prefrontal cortex (dmPFC) as well as its projections to the dorsomedial striatum (dmPFC-DMS) and the basolateral amygdala (dmPFC-BLA) to active avoidance learning in wild-type (WT) mice using fiber photometry and calcium imaging. We find that the dmPFC as well as the dmPFC-DMS and dmPFC-BLA projections show learning-related activity during active avoidance learning. We also find that the dmPFC shows opposing patterns of activity during active avoidance and cued freezing behavior. Finally, we find that the dmPFC-DMS and dmPFC-BLA projections divergently encode active avoidance behavior. In Chapter 4, we molecularly characterize the behavioral process of compulsivity and determine the contributions of frontal and striatal networks to this process by performing RNA-sequencing on medial prefrontal and dorsal striatal samples from SAPAP3 WT and KO mice. We find differential gene expression in the medial prefrontal cortex and dorsal striatum between SAPAP3 WT and KO mice including in neuropeptides and neurotransmitters. We additionally show that two genes, Trnp1 and Plekhf1, are differentially expressed between SAPAP3 KO mice that are resilient or susceptible to the compulsive grooming phenotype. Overall, this work takes important strides in further characterizing behavioral processes relevant for OCD on behavioral, circuit, and molecular levels which helps to provide a foundation for future research aimed at developing novel therapeutic strategies for this debilitating disorder.
