Physiological roles of reactive oxygen species in sleep homeostasis

Sleep is essential for brain health, and its loss is linked to oxidative stress and inflammation, with acute sleep deprivation triggering reversible redox responses and chronic loss leading to neural damage and dysfunction. Reactive oxygen species (ROS), particularly hydrogen peroxide (H₂O₂), are not merely harmful byproducts but also act as signaling molecules that regulate neurodevelopment, synaptic plasticity, and behavior. Advances in genetically encoded sensors and manipulating tools now enable real-time, cell-specific measurement and perturbation of ROS in vivo, revealing that redox dynamics encode sleep drive across species. In Drosophila, sleep deprivation induces mitochondrial oxidative stress in sleep-promoting neurons, driving sleep initiation. Similarly, in mice, cytosolic H₂O₂ in midbrain sleep circuits tracks the duration of wakefulness and gates sleep initiation. These findings support a conserved mechanism where sleep circuits sense redox-mediated sleep pressure. Quantitative ROS manipulation also reveals an inverted-U response, with eustress levels stabilizing sleep, while distress levels induce fragmentation. These insights motivate circuit-specific redox tuning, restoring eustress rather than globally suppressing ROS, as a promising therapeutic strategy for sleep disorders.