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Evidence for distinct forms of compulsivity in the SAPAP3 mutant-mouse model for obsessive-compulsive disorder

Onderzoeksgroep Willuhn
Publicatiejaar 2020
Gepubliceerd in eNeuro
Auteur(s) I Ehmer, L Crown, W. van Leeuwen, M.G.P. Feenstra, Ingo Willuhn, D. Denys

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 C57BL6 mice as previously reported in rats. Second, we tested the hypothesis that SAPAP3 knockout mice (SAPAP3-/-), prone to exhibit several OCD-like abnormalities including excessive grooming, show enhanced compulsive-like behavior in the SA task compared to their wild-type littermates (WT). 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 a) a general deficit in feedback processing is not related to excessive grooming in SAPAP3-/-, and b) different manifestations of compulsivity may be driven by independent mechanisms.Significance Statement The signal attenuation (SA) task is a well-established behavioral paradigm for rats that promotes compulsivity. First, we demonstrate that the SA task can also be applied to test feedback processing in mice. Second, we investigated if SAPAP3 mutant mice, a highly validated genetic animal model for obsessive-compulsive disorder (OCD), exhibit exacerbated compulsive responding in the SA task. However, we found no enhancement of feedback-induced compulsivity in SAPAP3 mutants. Thus, our results indicate the existence of different types of compulsivity (i.e., behaviorally versus genetically induced compulsivity) that are likely driven by independent mechanisms.

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