Variations in Brain Glutamate and Glutamine Levels Throughout the Sleep-Wake Cycle

Abstract

Background: Glutamatergic signaling is essential for modulating synaptic plasticity and cognition. However, the dynamics of glutamatergic activity over the 24-hour sleep-wake cycle, particularly in relation to sleep, remain poorly understood. In this study, we aimed to investigate diurnal variations in brain Glx levels—representing the combined concentrations of glutamate and glutamine—in humans and to explore their implications for cognitive performance and sleep pressure. Methods: We conducted 2 independent experiments to measure Glx levels across the sleep-wake cycle using proton magnetic resonance spectroscopy. In experiment 1, 14 participants underwent 13 hours of Glx measurements during a typical sleep-wake cycle. Experiment 2 extended these measurements to an around-the-clock observation over a 6-day period. This period included 2 days of normal sleep-wake cycles, 24 hours of enforced wakefulness, and a 3-day recovery phase. Seven participants took part in experiment 2. Results: The study observed that brain Glx levels increased during wakefulness and decreased during sleep. Notably, Glx levels were lower during enforced wakefulness than during normal wakefulness. Reduced Glx levels were associated with diminished cognitive performance, while greater Glx exposure over the preceding 24 hours correlated with increased sleep pressure. Conclusions: These findings suggest that Glx accumulation may contribute to increased sleep pressure, while its reduction appears to support wakefulness. These observations, together with the diurnal variations in Glx levels, underscore the dynamic nature of glutamatergic activity across the daily cycle. Further research is warranted to explore the potential role of sleep in regulating glutamatergic homeostasis. © 2025 Elsevier B.V., All rights reserved.