Cortical astrocyte histamine-1-receptors regulate intracellular calcium and extracellular adenosine dynamics across sleep and wake

Astrocytes in mammalian cortex express particularly high levels of the wake-promoting histamine-1-receptor (H1R), yet little is known about how astrocytic H1R contributes to arousal regulation. To address this gap, we test how astrocyte-specific H1R signaling in murine cortex affects local astrocyte calcium (Ca2+), sleep/wake dynamics, and extracellular adenosine—an astrocytic output that regulates cortical arousal. Using ex vivo two-photon Ca2+ imaging in acute cortical slices, we show that H1R mediates cell-autonomous astrocyte Ca2+ responses to histamine and attenuates responses to norepinephrine. Next, using freely moving fiber photometry and electroencephalogram/electromyogram recordings, we show that astrocyte-specific H1R deletion in cortex promotes wakefulness, reduces REM sleep, and alters astrocyte Ca2+ signals during wake and extracellular adenosine dynamics around REM transitions. Our data indicate that H1R activity not only mediates histamine responses in astrocytes but also modulates their responses to non-histaminergic inputs, potentially through lasting changes in astrocyte physiology that influence adenosine release and REM sleep.