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

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.