Elsevier

Biological Psychiatry

Volume 75, Issue 8, 15 April 2014, Pages 660-670
Biological Psychiatry

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

https://doi.org/10.1016/j.biopsych.2013.05.021Get rights and content

Background

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.

Methods

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.

Results

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.

Conclusions

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.

Section snippets

Subjects

Testing was conducted in male mice, 3 to 7 months old, C57BL/6J or COMT null mutant (COMT−/−), and their heterozygous (COMT+/−) and wild-type (COMT+/+) littermates (16). Distinct cohorts of naive mice were used for each experiment. See Supplement 1 for detailed descriptions on animal housing, apparatuses, statistics, food restriction, and testing procedures.

Novel Two-Chamber Operon ID/ED Task

See Figure 1 for details on the apparatus.

“Stuck-in-Set” ID/ED Paradigm. For habituation to the apparatus, in the first two days, mice were

The Novel Two-Chamber ID/ED Operon Task Consistently Measures “Stuck-in-Set” Attentional Set Shifting

To overcome the limitations of the current available attentional set-shifting tasks for rodents and to closely mimic the WCST and ID/ED tasks used in human and nonhuman primates, we generated a novel two-chamber ID/ED apparatus for mice (Figure 1). We first tested C57BL/6J adult mice using an ID/ED stuck-in-set paradigm 14, 16 (Table 1). This refined procedure is able to distinguish different components of set shifting and is a more selective measure of frontal lobe functioning in humans 7, 23.

Discussion

In this study, we present the development of a novel two-chamber ID/ED Operon task for rodents that overcomes the major limitations of the previous manual versions and of the first versions that attempted its automation. This paradigm is analogous to the WCST and ID/ED tasks commonly used in human and nonhuman primates. The Operon paradigm can reliably measure reversal learning, attentional set formation, and shifting, providing an effective new tool in the study of animal cognitive models for

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