Sleep increases chromosome dynamics to enable reduction of accumulating DNA damage in single neurons

Nevertheless, the core cellular function of sleep is unknown, and there is no conserved molecular marker to define sleep across phylogeny. Time-lapse imaging of chromosomal markers in single cells of live zebrafish revealed that sleep increases chromosome dynamics in individual neurons but not in two other cell types.

Manipulation of sleep, chromosome dynamics, neuronal activity, and DNA double-strand breaks (DSBs) showed that chromosome dynamics are low and the number of DSBs accumulates during wakefulness. In turn, sleep increases chromosome dynamics, which are necessary to reduce the amount of DSBs. These results establish chromosome dynamics as a potential marker to define single sleeping cells, and propose that the restorative function of sleep is nuclear maintenance.

Sleep is vital to animal life and is found in all studied animals, ranging from jellyfish to worm, fly, zebrafish, rodents, and humans. Prolonged sleep deprivation can be lethal, and sleep disturbances are associated with various deficiencies in brain performance. Sleep is regulated by circadian and homeostatic processes, and is coupled with reduced awareness of the environment and a high risk for survival. Several mechanisms can explain the roles of sleep, ranging from macromolecule biosynthesis, energy conservation, and metabolite clearance, to synaptic plasticity and memory consolidation. However, why sleep has evolved and which fundamental ancestral functions it regulates, remain enigmatic.

In mammals and birds, sleep is defined by behavioral criteria and cycles of electroencephalographic (EEG) patterns, which differentiate between wakefulness and sleep states. In non-mammalian animals, including zebrafish, sleep is solely defined by behavioral criteria, such as periods of immobility associated with a species-specific posture and an increased threshold of arousal to external stimuli. In all animals, including animals with simple neuronal networks, circuits of sleep- and wake-promoting neurons orchestrate the behavioral states. Evidence across multiple animals supports the notion that sleep can occur locally in the brain or perhaps even in a small number of cells. Nevertheless, although sleep significantly contributes to the overall temporal organization of the transcriptome, there are no molecular markers that can be reliably used across phylogeny to define sleep in a single cell.

The nuclear architecture and the dynamic changes in chromatin organization regulate vital cellular processes, including epigenetics, genomic stability, transcription, cell cycle, and DNA replication and repair. Chromatin dynamics, such as chromosome movements and structural genomic arrangements, are regulated by proteins that interact with the nuclear lamina and envelope in dividing cells. In mature and non-dividing neurons, the role of chromatin dynamics is less understood. Accumulating evidence showed that chromatin remodeling is implicated in circadian function. The changes in chromatin organization and epigenetic landscape shape the expression profile of a large number of rhythmic genes. However, the effect of sleep on chromatin dynamics in neurons is unknown.

Recent works showed that sleep can be induced by cellular stress in Caenorhabditis elegans and mammals. Moreover, sleep has been associated with the faster repair of DNA double-strand breaks (DSBs) in mice and fruit flies. The causes of DSBs are diverse and include reactive oxygen species (ROS), ionizing radiation, and inadvertent action of nuclear enzymes. Notably, neuronal activity can also induce DSBs. In specific mouse neurons, DSBs can be generated by physiological brain activity during natural exploration of the environment. Furthermore, activity-induced DSBs facilitate the expression of immediate early genes in mouse and cell cultures, possibly because they resolve topological constraints in the genome.

We hypothesized that sleep has evolved in order to enable single neurons to perform nuclear maintenance. To test which nuclear process favors sleep time, real-time imaging of chromosome dynamics, neuronal activity as well as quantification of DSBs and sleep, were coupled with genetic and pharmacological manipulations in live zebrafish. The findings propose a definition for a single sleeping neuron; i.e., increased chromosome dynamics, and suggest a role for sleep; i.e., nuclear maintenance.

Full article: Nature Communications

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