Sleep is vital for survival and all animals with a nervous system, ranging from jellyfish, worms to zebrafish and humans sleep. Although sleep clearly improves brain performance, even invertebrates with simple nerve nets sleep, and the core cellular function of sleep is unclear. The zebrafish enables the study of the physiology of defined single cells in the context of an intact nervous system in a live animal. We combined imaging of single chromosomes and repair proteins, 3D particle motion analysis, optogenetics stimulation, as well as calcium imaging to study the interaction between sleep, neuronal activity, DNA damage and repair. We found that neuronal DNA damage is accumulated during wakefulness, and that sleep upregulates nuclear maintenance in neurons. Using inducible CRISPR/Cas9- mediated system, we study the effect of tissue-specific DNA damage on sleep pressure.