Narcolepsy: immunity, neural circuitry, and brain network reconfiguration.

Introduction: Narcolepsy is a rare sleep disorder characterized by cataplexy and excessive daytime sleepiness. The hallmark neuropathological feature is the selective loss of hypothalamic hypocretin (HCRT) neurons. This review systematically summarizes the roles of neuroimmune dysregulation, HCRT neuron loss, and neural circuit remodeling in the pathogenesis of narcolepsy. Methods: We searched PubMed, Web of Science, and Scopus from 1990 through April 2026. Search terms included narcolepsy, hypocretin/orexin, autoimmunity, HLA, T cell, neural circuit, brain network, and functional connectivity. Articles were included if they were in English, peer-reviewed, and provided mechanistic insights. In addition, key references identified in the search articles were included.We organized the review according to a conceptual framework linking immune dysregulation, hypocretin neuron loss, sleep-wake circuit imbalance, and large-scale brain network reconfiguration. Results: Genetic susceptibility and environmental triggers collectively promote an immune-mediated attack, causing irreversible loss of lateral hypothalamic HCRT neurons. This disruption impairs sleep-wake circuit homeostasis and upsets the balance between REM-off and REM-on neurons. Consequently, brain network remodeling and functional instability ensue, manifesting as excessive daytime sleepiness, cataplexy, and cognitive impairment. Discussion: This review provides a theoretical framework integrating immunity, neural circuitry, and brain network reconfiguration in narcolepsy pathophysiology. Understanding these mechanisms may identify potential diagnostic biomarkers and therapeutic targets for narcolepsy, particularly for type 1 narcolepsy.