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Glia underlies brain wide activation and sleep behavior during sickness through adrenergic-glutamatergic axis

ABSTRACT: Sickness induces coordinated changes in physiology and behavior, including increased sleep, and despite specific circuits responsible for some of them have been recently described, 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 follow up experiments uncovered a neuron-glia axis that drives sickness sleep behavior. Specifically, the process requires octopaminergic signaling in ensheathing glia (EG) and it is required for a coupled wave of glial and neuronal activation across the brain. EG gap junction functional coupling facilitates brain wide activation, which ultimately promotes sickness behavior through glutamatergic signaling. Altogether, these findings elevate glia from passive supporters to active coordinators of sickness behavior, opening new avenues for understanding the neuromodulatory basis of behavioral state drifts sleep, fatigue, and malaise.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE333749 | GEO | 2026/06/02

REPOSITORIES: GEO

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Project description:Neuronal injury due to trauma or neurodegeneration is a common feature of aging. The clearance of damaged neurons by glia is thought to be critical for maintenance of proper brain function. Sleep loss has been shown to inhibit the motility and function of glia that clear damaged axons while enhancement of sleep promotes clearance of damaged axons. Despite the potential role of glia in maintenance of brain function and protection against neurodegenerative disease, surprisingly little is known about how sleep loss impacts glial function in aged animals. Axotomy of the Drosophila antennae triggers Wallerian degeneration, where specialized olfactory ensheathing glia engulf damaged neurites. This glial response provides a robust model system to investigate the molecular basis for glial engulfment and neuron-glia communication. Glial engulfment is impaired in aged and sleep-deprived animals, raising the possibility that age-related sleep loss underlies deficits in glial function. To define the relationship between sleep- and age-dependent reductions in glial function, we restored sleep to aged animals and examined the effects on glial clearance of damaged axons. Both pharmacological and genetic induction of sleep restores clearance of damaged neurons in aged flies. Further analysis revealed that sleep restored post-injury induction of the engulfment protein Draper to aged flies, fortifying the notion that loss of sleep contributes to reduced glial-mediated debris clearance in aged animals. To identify age-related changes in the transcriptional response to neuronal injury, we used single-nucleus RNA-seq of the central brains from axotomized young and old flies. We identified broad transcriptional changes within the ensheathing glia of young flies, and the loss of transcriptional induction of autophagy-associated genes. We also identify age-dependent loss of transcriptional induction of 18 transcripts encoding for small and large ribosomal protein subunits following injury in old flies, suggesting dysregulation of ribosomal biogenesis contributes to loss of glial function. Together, these findings demonstrate a functional link between sleep loss, aging and Wallerian degeneration.

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Glia underlies brain wide activation and sleep behavior during sickness through adrenergic-glutamatergic axis

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