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.

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Restricted, repetitive behavior (RRB) is diagnostic for autism spectrum disorder (ASD) and characteristic of a number of neurodevelopmental, psychiatric, and neurological disorders. RRB seen in ASD includes repetitive motor behavior and behaviors reflecting resistance to change and insistence on sameness. C58 mice provide a robust model of repetitive motor behavior and have shown resistance to change in a reversal learning task. We further characterized resistance to change in this model by inducing habitual responding and testing for differences in the ability to suppress habitual behavior and shift to goal-directed responding. We found no differences between C58 and control (C57BL/6) mice in the acquisition of operant tasks, habit formation, and expression of habitual responding. Habitual responding, however, induced significant reversal learning and contingency reversal performance deficits in C58 mice compared with C57BL/6 mice. Decreased dendritic spine density of the dorsomedial striatum in C58 mice was related to higher repetitive motor behavior, whereas dendritic spine density in the subthalamic nucleus was significantly positively correlated with improved contingency reversal performance in both C58 and C57BL/6 mice. Our results demonstrate that induction of habitual responding markedly impaired the ability of C58 mice to shift to goal-directed behavior. Such impairment may have resulted from the effects of the induction of habitual responding on already compromised basal ganglia circuitry mediating repetitive motor behavior. These findings provide additional evidence for the translational value of the C58 model in modeling RRB in neurodevelopmental disorders.