The PGE₂-Driven Arousal Circuit: A Testable Model of Functional Decoupling in the "Tired but Wired" Phenotype

The “Tired but Wired” phenotype—characterized by persistent wakefulness accompanied by profound cognitive fatigue—remains a central challenge in sleep medicine, particularly in chronic insomnia, post-viral syndromes, and ME/CFS. We propose a mechanistic and testable model based on functional decoupling between hypothalamic and brainstem arousal systems. Systemic inflammation induces PGE₂ synthesis in brain endothelial cells, acting as a proximal neuroimmune transducer. PGE₂ exerts spatially divergent effects: potentiating posterior hypothalamic arousal hubs(orexinergic and histaminergic systems) while inhibiting the locus coeruleus (LC) via EP3 receptors, producing a noradrenergic deficit and cognitive impairment. This dissociation explains how clinical wakefulness can coexist with impaired concentration. By reframing insomnia as a disorder of neuroimmune signal translation rather than global hyperarousal, we provide a framework bridging systemic inflammation and paradoxical insomnia, along with testable experimental and therapeutic predictions.