The Ultimate Intra-/Extra-Dimensional Attentional Set-Shifting Task for Mice

Abstract

Alterations in executive control and cognitive flexibility, such as attentional set-shifting abilities, are core features of several neuropsychiatric diseases. The most widely used neuropsychological tests for the evaluation of attentional set shifting in humans are the Wisconsin Card Sorting Test and the Cambridge Neuropsychological Test Automated Battery Intra-/Extra-Dimensional set-shift task (ID/ED). These tasks have proven clinical relevance and have been successfully adapted for monkeys. However, similar tasks currently available for rodents are limited, mainly because of their manual-based testing procedures. The current limitations of rodent attentional set-shifting tasks are hampering translational advances in psychiatric medicine. To closely mimic the Cambridge Neuropsychological Test Automated Battery ID/ED task in primates, we present the development of a novel operant-based two-chamber ID/ED "Operon" task for mice. We show the ability of this novel task to measure attentional set shifting in mice and the effects of genetic and pharmacologic manipulations of dopamine and glutamate. In genetically modified mice with reduced catechol-O-methyltransferase activity there was selective improvement on extradimensional shift abilities and impairment of serial reversal learning. Chronic administration of phencyclidine produced a selective impairment of extradimensional shift while producing a generalized decrease in latency to respond. We demonstrate that this novel ID/ED Operon task may be an effective preclinical tool for drug testing and large genetic screening relevant to the study of executive dysfunctions and cognitive symptoms of psychiatric disorders. These findings may help elucidate the biological validity of similar findings in humans.