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A novel multichoice touchscreen paradigm for assessing cognitive flexibility in mice.

ABSTRACT: Cognitive flexibility refers to various processes which enable behaviors to be modified on the basis of a change in the contingencies between stimuli or responses and their associated outcomes. Reversal learning is a form of cognitive flexibility which measures the ability to adjust responding based on a switch in the stimulus-outcome contingencies of, typically two, perceptually distinct stimuli. Reversal tasks have provided valuable insight into the neural basis of cognitive flexibility, implicating brain regions including the lateral orbitofrontal cortex (lOFC) and dorsomedial prefrontal cortex (dmPFC). However, with two-stimulus reversal, it is difficult to determine whether response errors are due excessive perseveration, deficient learning, or other problems with updating. To address this limitation, we developed a mouse three-choice touchscreen-based visual reversal task, in which the contingencies of two stimuli were switched on reversal but a third, simultaneously presented, stimulus was never reinforced. We found that, in male C57BL/6J mice, responding at the previously rewarded stimulus predominated over the newly and never-reinforced stimuli during early reversal. Next, we showed that acute pharmacological inhibition of lOFC, but not dmPFC, impaired early reversal performance, relative to noninactivated controls. Interestingly, however, lOFC inactivation deficits were characterized by increased choice of the never-reinforced stimulus and a decrease in (perseverative-like) responding at the previously rewarded stimulus. These effects are inconsistent with the historical notion of lOFC mediating response inhibition and closer to recent views of the lOFC's role in response/outcome tracking. Overall, these findings provide initial support the utility of this novel paradigm for studying cognitive flexibility and its underlying neural substrates.

SUBMITTER: Piantadosi PT

PROVIDER: S-EPMC6298539 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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A novel multichoice touchscreen paradigm for assessing cognitive flexibility in mice.

Piantadosi Patrick T PT Lieberman Abby G AG Pickens Charles L CL Bergstrom Hadley C HC Holmes Andrew A

Learning & memory (Cold Spring Harbor, N.Y.) 20181217 1

Cognitive flexibility refers to various processes which enable behaviors to be modified on the basis of a change in the contingencies between stimuli or responses and their associated outcomes. Reversal learning is a form of cognitive flexibility which measures the ability to adjust responding based on a switch in the stimulus-outcome contingencies of, typically two, perceptually distinct stimuli. Reversal tasks have provided valuable insight into the neural basis of cognitive flexibility, impli ...[more]

PMID: 30559117

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Project description:A decline in working memory (WM) capacity is suggested to be one of the earliest symptoms observed in Alzheimer's disease (AD). Although WM capacity is widely studied in healthy subjects and neuropsychiatric patients, few tasks are developed to measure this variation in rodents. The present study describes a novel olfactory working memory capacity (OWMC) task, which assesses the ability of mice to remember multiple odours. The task was divided into five phases: context adaptation, digging training, rule-learning for non-matching to a single-sample odour (NMSS), rule-learning for non-matching to multiple sample odours (NMMS) and capacity testing. During the capacity-testing phase, the WM capacity (number of odours that the mice could remember) remained stable (average capacity ranged from 6.11 to 7.00) across different testing sessions in C57 mice. As the memory load increased, the average errors of each capacity level increased and the percent correct gradually declined to chance level, which suggested a limited OWMC in C57 mice. Then, we assessed the OWMC of 5 × FAD transgenic mice, an animal model of AD. We found that the performance displayed no significant differences between young adult (3-month-old) 5 × FAD mice and wild-type (WT) mice during the NMSS phase and NMMS phase; however, during the capacity test with increasing load, we found that the OWMC of young adult 5 × FAD mice was significantly decreased compared with WT mice, and the average error was significantly increased while the percent correct was significantly reduced, which indicated an impairment of WM capacity at the early stage of AD in the 5 × FAD mice model. Finally, we found that FOS protein levels in the medial prefrontal cortex and entorhinal cortex after the capacity test were significantly lower in 5 × FAD than WT mice. In conclusion, we developed a novel paradigm to assess the capacity of olfactory WM in mice, and we found that OWMC was impaired in the early stage of AD.

Dataset Information

A novel multichoice touchscreen paradigm for assessing cognitive flexibility in mice.

Publications

A novel multichoice touchscreen paradigm for assessing cognitive flexibility in mice.

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