Reversal learning in C58 mice: Modeling higher order repetitive behavior

Abstract

Restricted, repetitive behaviors are diagnostic for autism and prevalent in other neurodevelopmental disorders. These behaviors cluster as repetitive sensory-motor behaviors and behaviors reflecting resistance to change. The C58 mouse strain is a promising model for these behaviors as it emits high rates of aberrant repetitive sensory-motor behaviors. The purpose of the present study was to extend characterization of the C58 model to resistance to change. This was done by comparing C58 to C57BL/6 mice on a reversal learning task under either a 100% or 80%/20% probabilistic reinforcement schedule. In addition, the effect of environmental enrichment on performance of this task was assessed as this rearing condition markedly reduces repetitive sensory-motor behavior in C58 mice. Little difference was observed between C58 and control mice under a 100% schedule of reinforcement. The 80%/20% probabilistic schedule of reinforcement generated substantial strain differences, however. Importantly, no strain difference was observed in acquisition, but C58 mice were markedly impaired in their ability to reverse their pattern of responding from the previously high density reinforcement side. Environmental enrichment did not impact acquisition under the probabilistic reinforcement schedule, but enriched C58 mice performed significantly better than standard housed C58 mice in reversal learning. Thus, C58 mice exhibit behaviors that reflect both repetitive sensory motor behaviors as well as behavior that reflects resistance to change. Moreover, both clusters of repetitive behavior were attenuated by environmental enrichment. Such findings, along with the reported social deficits in C58 mice, increase the translational value of this mouse model to autism.

Subthalamic nucleus pathology contributes to repetitive behavior expression and is reversed by environmental enrichment

“…These behaviors are expressed at or before weaning, persist throughout development and are readily observed throughout the dark cycle in both the home cage and individual test cages . Moreover, we have shown that C58 mice exhibit a pronounced resistance to change or behavioral inflexibility in a reversal learning task . We have also shown that rearing C58 mice in environmental enrichment (EE) for 6 weeks starting at weaning (postnatal day [PND] 21) dramatically reduced repetitive motor behaviors compared with littermates reared in standard cages and improved reversal learning …”

“…17,19 Moreover, we have shown that C58 mice exhibit a pronounced resistance to change or behavioral inflexibility in a reversal learning task. 20 We have also shown that rearing C58 mice in environmental enrichment (EE) for 6 weeks starting at weaning (postnatal day [PND] 21) dramatically reduced repetitive motor behaviors compared with littermates reared in standard cages 17 and improved reversal learning. 20 Excessive self-grooming behavior is a common repetitive behavior in mouse models of psychiatric and neurodevelopmental disorders.…”

“…20 We have also shown that rearing C58 mice in environmental enrichment (EE) for 6 weeks starting at weaning (postnatal day [PND] 21) dramatically reduced repetitive motor behaviors compared with littermates reared in standard cages 17 and improved reversal learning. 20 Excessive self-grooming behavior is a common repetitive behavior in mouse models of psychiatric and neurodevelopmental disorders. 21 Self-grooming in rodents is sequentially fixed and highly stereotyped.…”

Treatment of resistance to change in children with autism

“…The existing literature demonstrates that response blocking (i.e., extinction; Wolff, Hupp, & Symons, 2013), differential reinforcement of alternative behaviors (DRA) with extinction (Fisher et al, 2013), and functional communication training with extinction (Rispoli et al, 2014) are all effective ways of treating higher-order restricted and repetitive behaviors. Given the well-supported distinction between lower-and higher-order restricted and repetitive behaviors, it is important to more fully evaluate the effects of behavioral interventions with and without extinction on individuals' resistance to change (Whitehouse, Curry-Pochy, Shafer, Rudy, & Lewis, 2017).…”

Environmental Enrichment Intervention in Animal Models of Autism

“…Several studies revealed that C58/J mice displayed increased activity and repetitive behaviors, as well as less social approach in the three-chamber test [48][49][50][51] . Environmental enrichment (rearing in enriched cages) was reported to reduce repetitive behaviors and improve reversal learning in this strain [52,53] .…”