Behavioral flexibility in a mouse model for obsessive‐compulsive disorder: 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 (WT) littermates were trained in a Pavlovian conditioning task pairing visual cues with the delivery 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 shows that SAPAP3^?/? are capable of Pavlovian learning, but lack flexibility to adapt associated conditioned approach behavior. Thus, SAPAP3^?/? not only display compulsive‐like behavior and anxiety, but also cognitive deficits, confirming and extending the validity of SAPAP3^?/? as a suitable model for the study of 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 the treatment of OCD.