Glia mediate brain-wide activity and sleep behavior during sickness through an adrenergic-glutamatergic axis

Sickness induces coordinated changes in physiology and behavior, but despite the identification of circuits that underlie specific aspects of sickness, how the brain orchestrates this global state shift remains unclear. Whole-brain-single-cell RNA sequencing in a Drosophila model of sickness revealed that glia, rather than neurons, undergo the most extensive transcriptional remodeling and signal to neurons to drive sickness sleep behavior. Specifically, the process requires octopaminergic signaling and gap junctional coupling across a network of ensheathing glia (EG). EG modulate extracellular glutamate that is perceived by neurons via ionotropic glutamate receptors, producing a wave of neuronal activation that follows the EG calcium increase across the brain. Altogether, these findings elevate glia from passive supporters to active coordinators of sickness behavior, opening new avenues for understanding the neuromodulatory basis of sleep in the context of fatigue and malaise.