Adenosine-independent regulation of the sleep–wake cycle by astrocyte activity

Abstract Astrocytes play a crucial role in regulating sleep–wake behavior, and adenosine signaling is generally thought to be involved. Here we show multiple lines of evidence supporting that modulation of the sleep–wake behavior by astrocyte Ca2+ activity could occur without adenosine signaling. In the basal forebrain and the brainstem, two brain regions that are known to be essential for sleep–wake regulation, chemogenetically-induced astrocyte Ca2+ elevation significantly modulated the sleep–wake cycle. Although astrocyte Ca2+ level positively correlated with the amount of extracellular adenosine, as revealed by a genetically encoded adenosine sensor, we found no detectable change in adenosine level after suppressing astrocyte Ca2+ elevation, and transgenic mice lacking one of the major extracellular ATP-adenosine conversion enzymes showed similar extracellular adenosine level and astrocyte Ca2+-induced sleep modulation. Furthermore, astrocyte Ca2+ is dependent primarily on local neuronal activity, causing brain region-specific regulation of the sleep–wake cycle. Thus, neural activity-dependent astrocyte activity could regulate the sleep–wake behavior independent of adenosine signaling.