Hydrogen peroxide in midbrain sleep neurons regulates sleep homeostasis

Sleep could protect animals from oxidative damage, yet the dynamic interplay between the redox state and sleep homeostasis remains unclear. Here, we show that acute sleep deprivation (SD) in mice caused a general increase in brain oxidation, particularly in sleep-promoting regions. In vivo imaging of intracellular hydrogen peroxide (H₂O₂) real-time dynamics revealed that in nigra sleep neurons, the increase in cytosolic but not mitochondrial H₂O₂ reflects sleep debt and tracks spontaneous wakefulness by positively correlating with wake duration. By controllably manipulating intraneuronal H₂O₂, we discovered that H₂O₂ elevation is required for compensatory sleep and causally promotes sleep initiation, at least partly dependent on transient receptor potential melastatin 2 (TRPM2) channel. However, excessive H₂O₂ induced brain inflammation and sleep fragmentation. Together, our study demonstrates intraneuronal H₂O₂ as a crucial signaling molecule that translates brain redox imbalance into sleep drive and underscores the significance of oxidative eustress in sleep homeostasis.