Acute stress impairs reversal learning in mice via neurochemical and transcriptional mechanisms in the orbitofrontal cortex.

The effects of acute stress on cognitive flexibility are significant but inconsistent across studies. To address this inconsistency, we investigated how varying durations of acute restraint stress affect reversal learning in mice with different innate cognitive flexibility, across tasks of varying difficulty. Results revealed that 1-hour acute restraint stress impaired reversal learning in a 4-choice task but not in a 2-choice task. In the 2-choice task, 2-hour stress led to reversal learning deficits in mice with low baseline cognitive flexibility but not in those with high baseline cognitive flexibility. Though 1-hour and 2-hour stress similarly caused upregulation of corticosterone and dopamine, 3-methoxytyramine, 5-hydroxyindoleacetic acid, and norepinephrine, 2-hour restraint stress additionally caused the elevated levels of phenylalanine, γ-aminobutyric acid, aspartate, and glycine. Transcriptomic analysis of the orbitofrontal cortex in mice with stress-induced reversal learning deficit revealed associations with synaptic plasticity, the MAPK signaling pathway, and neuroendocrine modulation. Therefore, our findings establish a hierarchical model where stress effects on reversal learning are dependent on stress intensity, task difficulty, and baseline cognitive flexibility. We identified neurochemical and transcriptional changes associated with this specific vulnerability, providing a potential framework for understanding how stress affects cognitive flexibility.