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.