Behavioral flexibility in an OCD mouse model: Impaired Pavlovian reversal learning in SAPAP3 mutants

Obsessive-compulsive disorder (OCD) is characterized by obsessive thinking, compulsive behavior, and anxiety, and is often accompanied by cognitive deficits. The neuropathology of OCD involves dysregulation of cortical-striatal circuits. Similar to OCD patients, SAPAP3 knockout mice 3 (SAPAP3 -/- ) exhibit compulsive behavior (grooming), anxiety, and dysregulated cortical-striatal function. However, it is unknown whether SAPAP3 -/- display cognitive deficits and how these different behavioral traits relate to one another. SAPAP3 -/- and wild-type littermates (WT) were trained in a Pavlovian conditioning task pairing the delivery of visual cues with that of sucrose solution. After mice learned to discriminate between a reward-predicting conditioned stimulus (CS+) and a non-reward stimulus (CS-), contingencies were reversed (CS+ became CS- and vice versa). Additionally, we assessed grooming, anxiety, and general activity. SAPAP3 -/- acquired Pavlovian approach behavior similarly to WT, albeit less vigorously and with a different strategy. However, unlike WT, SAPAP3 -/- were unable to adapt their behavior after contingency reversal, exemplified by a lack of re-establishing CS+ approach behavior (sign tracking). Surprisingly, such behavioral inflexibility, decreased vigor, compulsive grooming, and anxiety were unrelated. This study demonstrates that SAPAP3 -/- are capable of Pavlovian learning, but lack flexibility to adapt associated conditioned approach behavior. Thus, SAPAP3 -/- do not only display compulsive-like behavior and anxiety, but also cognitive deficits, confirming and extending the validity of SAPAP3 -/- as a suitable model for OCD. The observation that compulsive-like behavior, anxiety, and behavioral inflexibility were unrelated suggests a non-causal relationship between these traits and may be of clinical relevance for OCD patients.