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

Abstract

SummarySleep is a complex behavior regulated by a variety of brain cell types. The roles of brain-resident macrophages, such as microglia and CNS-associated macrophages (CAMs), including those derived postnatally, are not well defined. Here, we investigated the reciprocal interaction of brain-resident macrophages and sleep using multimodal high-throughput transcriptional, electrophysiological and metabolomic profiling in mice. We found that sleep deprivation caused profound transcriptional changes in microglia and CAMs, which were intensified by impaired sleep regulation in the absence of the important sleep-regulatory neuropeptide hypocretin/orexin (HCRT). 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.