Evidence for Distinct Forms of Compulsivity in the SAPAP3 Mutant-Mouse Model for Obsessive-Compulsive Disorder.

The specific mechanisms underlying compulsive behavior in obsessive-compulsive disorder (OCD) are unknown. It has been suggested that such compulsivity may have its origin in cognitive dysfunction such as impaired processing of feedback information, received after the completion of goal-directed actions. The signal attenuation (SA) task models such a processing deficit in animals by attenuating the association strength between food reward and audiovisual feedback (signal) presented after performance of an operant response. The compulsive-like responding resulting from SA is well characterized in rats, but was so far not established in mice, a species for which powerful genetic OCD models exist. Thus, first, we demonstrate that the SA task can be implemented in mice and show that attenuation of reward-associated response feedback produces similar behavior in C57BL/6 mice as previously reported in rats. Second, we tested the hypothesis that SAPAP3 knock-out mice (SAPAP3-/-), prone to exhibit several OCD-like abnormalities including excessive grooming, show enhanced compulsive-like behavior in the SA task compared with their wild-type (WT) littermates. However, task-related compulsivity measures in SAPAP3-/- and WT did not yield significant differences, neither following SA nor during "regular" extinction of operant behavior. Thus, compulsive-like instrumental behavior following feedback distortion was not potentiated in compulsively grooming mice, implicating specifically that (1) a general deficit in feedback processing is not related to excessive grooming in SAPAP3-/- and (2) different manifestations of compulsivity may be driven by independent mechanisms.

Instrumental learning in a mouse model for obsessive-compulsive disorder: Impaired habit formation in Sapap3 mutants.

It has been hypothesized that maladaptive habit formation contributes to compulsivity in psychiatric disorders such as obsessive-compulsive disorder (OCD). Here, we used an established animal model of OCD, Sapap3 knockout mice (SAPAP3-/-), to investigate the balance of goal-directed and habitual behavior in compulsive individuals and if altered habit formation is associated with compulsive-like behavior. We subjected 24 SAPAP3-/- and 24 wildtype littermates (WT) to two different schedules of reinforcement in a within-subjects design: a random-ratio (RR) schedule to promote goal-directedness, and a random-interval (RI) schedule, known to facilitate habitual responding. SAPAP3-/- acquired responding under both schedules, but showed lower response rates and fewer attempts to collect food pellets than WT, indicative of altered reward processing. As expected, WT were sensitive to sensory-specific satiety (outcome devaluation) following RR training, but not RI training, demonstrating schedule-specific acquisition of goal-directed and habitual responding, respectively. In contrast, SAPAP3-/- were sensitive to outcome devaluation after both RR and RI training, suggesting decreased engagement of a habitual response strategy. No linear relation was observed between increased grooming and behavior during the outcome devaluation test in SAPAP3-/-. Together, our findings demonstrate altered reward processing and impaired habit learning in SAPAP3-/-. We report a diminished propensity to form habits in these mice, which albeit inconsistent with the predominant idea of excessive habit formation in OCD, nonetheless points at dysregulation of behavioral automation in the context of compulsivity. Thus, the habit hypothesis of compulsivity should be updated to state that an imbalance of habitual and goal-directed responding in either direction can contribute to the development of compulsive behavior.