Chronic corticosterone improves perseverative behavior in mice during sequential reversal learning.

BACKGROUND: Stressful life events can both trigger development of psychiatric disorders and promote positive behavioral changes in response to adversities. The relationship between stress and cognitive flexibility is complex, and conflicting effects of stress manifest in both humans and laboratory animals. OBJECTIVE: To mirror the clinical situation where stressful life events impair mental health or promote behavioral change, we examined the post-exposure effects of stress on cognitive flexibility in mice. METHODS: We tested female C57BL/6JOlaHsd mice in the touchscreen-based sequential reversal learning test. Corticosterone (CORT) was used as a model of stress and was administered in the drinking water for two weeks before reversal learning. Control animals received drinking water without CORT. Behaviors in supplementary tests were included to exclude non-specific confounding effects of CORT and improve interpretation of the results. RESULTS: CORT-treated mice were similar to controls on all touchscreen parameters before reversal. During the low accuracy phase of reversal learning, CORT reduced perseveration index, a measure of perseverative responding, but did not affect acquisition of the new reward contingency. This effect was not related to non-specific deficits in chamber activity. CORT increased anxiety-like behavior in the elevated zero maze test and repetitive digging in the marble burying test, reduced locomotor activity, but did not affect spontaneous alternation behavior. CONCLUSION: CORT improved cognitive flexibility in the reversal learning test by extinguishing prepotent responses that were no longer rewarded, an effect possibly related to a stress-mediated increase in sensitivity to negative feedback that should be confirmed in a larger study.

Sequential reversal learning: a new touchscreen schedule for assessing cognitive flexibility in mice.

RATIONALE: The widespread deficits in cognitive flexibility observed across psychiatric disorders call for improved rodent tests to understand the biology of cognitive flexibility and development of better psychotherapeutics. Current reversal learning paradigms have a forced-choice setup that challenges the interpretation of results. OBJECTIVES: We aimed at developing a free-choice reversal learning test, where images are presented sequentially and animals are free to move, to enable investigation of the cognitive sub-processes that occur during reversal. METHODS: Behavior in female C57BL/6JOlaHsd mice was characterized using chronic fluoxetine as a reference compound. Additional tests were included to support the interpretation of results and exclude confounding pharmacological effects. Behaviors in vehicle-treated mice were furthermore analyzed for relatedness to deepen the understanding of parameters measured. RESULTS: We found that exploitation of the previously rewarded image was independent of exploration and acquisition of the new reward contingency and could be differentially modulated by fluoxetine, supporting recent theories that these processes are not mutually exclusive. Specifically, fluoxetine reduced mistake rate, premature and perseverative responses, and promoted conservative strategies during reversal without affecting hit rate. These effects appeared to be most prominent during the late stage of reversal learning, where accuracy was above chance level. Analysis of behaviors in vehicle-treated mice suggested that exploitation was related to an impulsive-like deficit in response inhibition, while exploration was more related to motivation. CONCLUSIONS: This new schedule was feasible, easy to implement, and can provide a deeper understanding of the cognitive sub-processes during reversal.