Neurobehavioral Sensitization to Sleep Deprivation is Associated with Re-organization of Circadian Metabolic Rhythm

Sleep deprivation (SD) produces a wide range of acute and chronic physiological effects. Acute SD impairs multiple neurobehavioral functions, including attention and cognition, which can substantially reduce quality of life and may even become life-threatening in situations requiring sustained vigilance, such as long-distance driving. Notably, the neurobehavioral response to SD varies markedly across individuals: while some remain relatively resistant to sleep loss, others exhibit pronounced vulnerability. The molecular mechanisms underlying this inter-individual variability remain poorly understood.

We hypothesized that differences in the dynamic regulation of metabolic rhythms may contribute to these distinct neurobehavioral phenotypes. To test this, we compared the temporal metabolic profiles of 20 age-, sex-, and BMI-matched individuals classified as either SD-resistant (n=10) or SD-vulnerable (n=10). Plasma samples were collected at 4-hour intervals during a baseline day and during 36 hours of total SD and analyzed using UPLC-MS/MS-based metabolomics. We examined metabolite dynamics associated with both homeostatic sleep pressure and circadian rhythmicity.

Metabolic signatures associated with increasing sleep pressure were largely similar between groups, suggesting that the homeostatic metabolic response to sleep loss is largely phenotype-independent. In contrast, circadian analysis revealed substantial phenotype-specific differences following SD. Vulnerable individuals exhibited pronounced reorganization of circadian metabolic rhythms, characterized by increased cycling within one-carbon metabolism and loss of rhythmicity in amino acid and redox pathways. In contrast, resistant individuals showed loss of rhythmicity primarily in purine metabolism.

Together, these findings suggest that resistance to sleep deprivation may involve greater metabolic re-organization in adapting circadian metabolic programs to prolonged wakefulness, whereas vulnerability may reflect a more rigid metabolic organization. These results highlight circadian metabolic regulation as a potential mechanism underlying individual differences in neurobehavioral responses to sleep loss.