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

Abstract

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 thatSAPAP3knock-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.

A novel automated approach for improving standardization of the marble burying test enables quantification of burying bouts and activity characteristics

“…4). These results indicate that compulsivity is not a unitary construct (Ehmer, Crown, et al, 2020) and that burying behavior, although it is often ascribed to repetitive behaviors (Thomas et al, 2009), captures a distinctly different behavioral aspect than self-grooming. Grooming is an innate behavior that is maintained in the absence of sensory feedback and when it is no longer serving its regular maintenance function (Spruijt et al, 1992).…”

A Novel Automated Approach for Improving Standardization of the Marble Burying Test Enables Quantification of Burying Bouts and Activity Characteristics

“…4 ). These results indicate that repetitive behavior is not a unitary construct ( Ehmer et al, 2020a ) and that burying behavior, although it is often ascribed to repetitive behaviors ( Thomas et al, 2009 ), captures a distinct behavioral aspect.…”

SAPAP Scaffold Proteins: From Synaptic Function to Neuropsychiatric Disorders

“…Owing to the promising association between SAPAP3 and OCD, much more attention has been given to Sapap3 -mutant mice—a well-established OCD-relevant murine model displaying repetitive self-grooming behavior, augmented anxiety, cognitive inflexibility, imbalances between goal-directed and habitual behavior, selective deficits in behavioral response inhibition, insensitivity to reward devaluation, altered valence processing, hypolocomotion, disrupted sleep patterns, normal preference motivation for sucrose, and Pavlovian learning [ 13 , 102 , 104 , 106 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 ]. Convergent evidence from structural, biochemical, electrophysiological, and neural circuitry studies of Sapap3 -mutant mice demonstrates and emphasizes the crucial role of SAPAP3 in corticostriatal synapses and striatum-based circuitry in OCD-like phenotypes.…”

“…Convergent evidence from structural, biochemical, electrophysiological, and neural circuitry studies of Sapap3 -mutant mice demonstrates and emphasizes the crucial role of SAPAP3 in corticostriatal synapses and striatum-based circuitry in OCD-like phenotypes. Surprisingly, neither cognitive inflexibility, augmented anxiety, nor aberrant habit formation are correlated with compulsive, repetitive behavior, implying that these different OCD-like behaviors in Sapap3 -mutant mice probably involve complex or independent etiologies [ 157 , 159 , 160 , 162 , 163 ]. For example, the compromised PFC–striatal synaptic and circuitry function observed in Sapap3 -mutant mice have been thought to be involved in their excessive compulsive and repetitive behavior [ 13 , 82 , 102 ].…”