Sex-biased computations underlying differential set shift performance in mice.

Cognitive flexibility can be defined as the ability to adaptively shift between choices or strategies based on environmental feedback and it is disrupted in numerous neuropsychiatric conditions. Individual differences in the computations supporting cognitive flexibility are poised to reveal mechanisms of neuropsychiatric risk and resilience. One critical variable well known to influence individual differences in neuropsychiatric risk is sex. While previous research has identified sex differences in value based decision making in mice, whether sex reflects a major source of variation in cognitive flexibility remains unknown. To directly assess sex-biased individual differences in cognitive flexibility, we developed a novel touchscreen Set Shift task that permits robust and continuous testing in mice. Using this task, we discovered that female mice completed significantly more rule shifts with fewer errors than males. We next employed a suite of computational models that revealed sex-biased individual differences in the computations underlying cognitive flexibility. Overall, our results suggest that following rule shifts, female mice learn the new rule faster and commit to exploiting rule choices sooner compared to males - sometimes because they commit to multiple rules simultaneously. This suggests that increased choice stability in female rodents enhances commitment to a strategy during periods of uncertainty and directly contributes to increased rule shifting. This supports the counterintuitive conclusion that a high degree of stable choice is a strong requirement for enhanced cognitive flexibility in the Set Shift task, one of the gold standard cognitive flexibility tasks.