Embryo-derived brain-resident macrophages sustain sleep-wake circuits

Sleep is a complex behavior regulated by various brain cell types. However, the roles of brain-resident macrophages, including microglia and CNS-associated macrophages (CAMs), particularly those derived postnatally, in sleep regulation remain poorly understood. Here, we investigated the effects of natural (embryo-derived) and repopulated (postnatally derived) brain-resident macrophages on the regulation of vigilance states. We found that depletion in embryonically-derived brain macrophages caused increased sleep in the active period, but reduced its quality, reflected in reduced power of brain sleep oscillations. This was observed both for the Non-REM and REM sleep stages. Subsequent repopulation by postnatal brain macrophages unexpectedly failed to reestablish normal sleep-wake patterns and additionally induced sleep fragmentation. Furthermore, brain macrophage depletion caused excitatory-inhibitory synaptic imbalance, which was resistant to repopulation, and led to increased inhibitory synapses. At the metabolite level, the distinct metabolite profile induced by brain macrophage depletion largely returned to normal after repopulation. Our findings suggest a so far largely unknown interaction between brain-resident macrophages and sleep and emphasizes striking functional differences between embryonic and postnatally-derived brain macrophages, paving the way to future exploration of the role of brain macrophages of different origin in sleep disorders and synaptic connectivity.