Glial Control of Insomnia: Astrocyte–Microglia Interactions in Stress, Hyperarousal and Sleep Dysregulation

ABSTRACT

Insomnia is a highly prevalent and burdensome sleep disorder whose pathophysiology remains incompletely understood. While traditional models have emphasized neuronal hyperarousal, accumulating evidence indicates that glial cells—particularly astrocytes and microglia—play central and complementary roles in the regulation of sleep–wake dynamics and the persistence of chronic insomnia. This review synthesizes clinical, experimental and translational evidence supporting a dual regulatory framework in which astrocytes and microglia act as key integrators of stress signalling, neuroinflammation, synaptic plasticity and sleep homeostasis. Astrocytes emerge as primary modulators of metabolic and neuro‐modulatory coupling within sleep–wake circuits, linking hypothalamic–pituitary–adrenal axis activation to dysregulated adenosine signalling, excitatory–inhibitory imbalance, impaired glymphatic clearance and circadian misalignment. In parallel, microglia function as immune and synaptic sculptors, with chronic sleep disturbance biasing them toward maladaptive activation states characterized by altered cytokine release, disrupted synaptic pruning and stress hormone‐dependent signalling cascades. Although direct glia‐resolved evidence in human insomnia remains limited, convergent findings from neuroimaging, animal models and sleep–immune research support a coordinated stress–glia–insomnia axis. We further highlight mechanisms of astrocyte–microglia crosstalk, including purinergic signalling, inflammatory feedback loops and calcium‐dependent network synchronization, which may stabilize pathological hyperarousal states. Finally, we discuss emerging glia‐targeted therapeutic strategies and key translational challenges, emphasizing the need for cell‐type‐specific biomarkers, spatiotemporally precise interventions and personalized treatment frameworks.