Activation of basal forebrain astrocytes induces wakefulness without compensatory changes in sleep drive

Abstract

Mammalian sleep is regulated by a homeostatic process that increases sleep drive and intensity as a function of prior wake time. Sleep homeostasis has traditionally been thought to be a product of neurons, but recent findings demonstrate that this process is also modulated by glial astrocytes. The precise role of astrocytes in the accumulation and discharge of sleep drive is unknown. We investigated this question by selectively activating basal forebrain (BF) astrocytes using designer receptors exclusively activated by designer drugs (DREADDs). Activation of the Gq-protein-coupled pathway in BF astrocytes produced long and continuous periods of wakefulness that paradoxically did not cause the expected homeostatic response to sleep loss (e.g., increases in sleep time or intensity). Further investigations showed that this was not due to indirect effects of the ligand that activated DREADDs. These findings suggest that the need for sleep is not driven by wakefulness per se, but specific neuronal-glial circuits that are differentially activated in wakefulness.