Sex differences in reward-based operant conditioning performance and neurotransmitter changes following chronic sleep restriction stress in rats.

Background: Sleep deprivation significantly impairs cognitive function, which disrupts daily life. However, sex differences in these impairments are not well understood, as most preclinical studies primarily use male animals, neglecting potential differences between sexes. This study aims to investigate sex-specific differences in cognitive function under sleep deprivation using reward-based operant conditioning tasks.

Results: Sprague-Dawley rats were pre-trained on a lever-press task and subsequently divided into control and chronic sleep restriction (CSR) groups. The CSR group underwent 14 days of sleep restriction. After CSR modeling, rats were assessed using the open field test, retraining on the lever-pressing task, signal discrimination task, and extinction task to evaluate motor abilities, memory formation, learning, and cognitive flexibility. CSR significantly impaired task performance in both sexes, with rats requiring more time and exhibiting lower accuracy. In the signal discrimination task, male rats showed longer feeding latency and lower accuracy compared to females. CSR also specifically increased the frequency of operant responses in male rats. In the extinction task, CSR enhanced exploration time and frequency in both sexes, with females exhibiting significantly higher exploration frequencies than males. Biochemically, CSR induced sex-specific alterations, including elevated serum MDA and MAO levels in males and increased serotonin, dopamine, and epinephrine in both sexes. Although activation was observed in metabolites of the tryptophan-kynurenine pathway, sex differences were evident in the kynurenic acid metabolism levels in the prefrontal cortex.

Conclusions: CSR impairs cognitive function in both male and female rats, with significant sex differences observed. Male CSR rats exhibited impaired signal discrimination, while CSR impaired extinction learning in female rats. These impairments are accompanied by CSR-induced oxidative stress, neurotransmitter dysregulation, and disturbances in the tryptophan metabolic pathway. These findings underscore the importance of considering sex differences in understanding the effects of sleep deprivation on cognitive function and developing targeted intervention strategies.