Abstract
Inadequate sleep is a prevalent problem within our society that can result in cognitive dysfunction. Elevations in kynurenic acid (KYNA), a metabolite of the kynurenine pathway (KP) of tryptophan degradation known to impact cognition, in the brain may constitute a molecular link between sleep loss and cognitive impairment. To test this hypothesis, we investigated the impact of 6 hours of sleep deprivation on memory and KP metabolism (brain and plasma) in male and female rats. Sleep-deprived males were impaired in a contextual memory paradigm, and both sexes were impaired in a recognition memory paradigm. After sleep deprivation, hippocampal KYNA levels increased significantly only in males. The response in hippocampal KYNA levels to sleep loss was suppressed in gonadectomized males, delineating a role of circulating gonadal hormones. Circulating corticosterone, which has previously been linked to KP metabolism, correlated negatively with hippocampal KYNA in sleep-deprived females, however the relationship was not significant in male animals. Taken together, our study introduces striking sex differences in brain KYNA formation and circulating corticosterone in response to sleep deprivation. Relating these findings to sex differences in cognitive outcomes after sleep deprivation may further advance the development of novel therapeutic agents to overcome sleep loss-induced cognitive dysfunction.
Highlights
The kynurenine pathway (KP) has remained relatively unexplored in sleep studies, an association between sleep disturbances, excessive levels of kynurenic acid (KYNA), and cognitive impairments has been recently bolstered by studies in rats
Sleep deprivation by gentle handling from zeitgeber time (ZT) 0 to ZT 6 resulted in 95% elimination of NREM and 100% elimination of rapid eye movement (REM) sleep in male and female animals (Fig. 2)
While female animals did not present significantly elevated brain KYNA, we report a female-specific elevation in circulating corticosterone, demonstrating a differential response in HPA reactivity after acute sleep loss
Summary
The KP has remained relatively unexplored in sleep studies, an association between sleep disturbances, excessive levels of KYNA, and cognitive impairments has been recently bolstered by studies in rats. To further investigate the hypothesized relationship between sleep and KYNA7–9, in designing our present studies we considered several important biological variables, including the impact of i) biological sex and circulating gonadal hormones and ii) sleep loss-induced stress. As elevations in corticosterone may impact tryptophan metabolism via the KP16, we assess the relationship between KP activation and circulating corticosterone after sleep deprivation. We determine a conspicuous sex difference in response to sleep deprivation in hippocampal-dependent contextual memory, but not recognition memory, which relies on the perirhinal cortex. To explore the mechanisms underlying the sex differences, the gonads were removed from adult male and female rats and biochemical assessments after sleep deprivation experiments were repeated. Taken together our data introduce a sex-dependent interplay between circulating gonadal hormones, the HPA axis activation, and KP metabolism in response to sleep deprivation
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