30 Years of Hypocretin/Orexin Research: Sleep–Wake Regulation, Reward, and Motivation

The orexin/hypocretin system, first identified in 1998, is now recognized as a central regulator of energy balance, sleep–wake states, and arousal stability. Orexin-producing neurons in the lateral hypothalamus integrate circadian, metabolic, and environmental signals to promote wakefulness and stabilize sleep–wake transitions. Beyond arousal regulation, orexin signaling plays a key role in hedonic and motivational processes, as these neurons densely innervate limbic and reward-related brain regions. Disruption of this system has been implicated in sleep disorders, including narcolepsy type 1, insomnia, and hypersomnia, as well as substance use disorders. Emerging evidence further links orexin dysfunction to neurodevelopmental, neurodegenerative, and psychiatric conditions.Advances in neuroimaging, electrophysiology, genetics, and pharmacology—particularly the development of orexin receptor agonists and antagonists—have renewed interest in how orexin shapes sleep architecture, motivational drive, and reward-related processes, as well as the bidirectional relationship between sleep disturbance and substance use. A comprehensive examination of orexin function across development, health, and disease is therefore timely.The goal of this Research Topic is to synthesize current knowledge on the role of the orexin/hypocretin system in sleep regulation and sleep-related disorders, as well as reward- and motivation-related processes, including substance use and addictive disorders, reflecting three decades of progress in orexin research. We aim to bring together basic, translational, and clinical studies to elucidate the neural circuitry, molecular mechanisms, and physiological functions of orexin signaling. This collection will also highlight emerging therapeutic approaches targeting orexin receptors and critically evaluate their efficacy, safety, and broader neurobiological effects. By integrating findings across species, developmental stages, and clinical populations, this Topic seeks to identify knowledge gaps, foster interdisciplinary dialogue, and inform future research directions that may improve diagnosis and treatment of sleep and addictive disorders.This Research Topic welcomes original research articles, brief reports, and reviews addressing the orexin/hypocretin system in relation to sleep–wake regulation, reward and motivational processes, and addiction.Topics of interest include, but are not limited to:• Neurobiology and neural circuitry of the orexin/hypocretin system• Interactions between orexin signaling and circadian and homeostatic sleep processes• The role of orexin in sleep–wake regulation and arousal stability• Reward-related and motivational mechanisms involving orexin pathways• Orexin contributions to substance use disorders and addictive behaviors• Developmental and aging-related changes in orexin signaling across the lifespan• Orexin dysfunction in neurological, psychiatric, and neurodevelopmental disorders• Clinical and preclinical studies investigating orexin-targeting therapeutics (e.g., receptor agonists and antagonists)• Multidisciplinary approaches integrating behavioral, physiological, neuroimaging, electrophysiological, genetic, or computational methodsBoth human and animal studies are encouraged. Submissions should clearly articulate their relevance to orexin system research and discuss translational implications where appropriate. All manuscripts must adhere to the journal’s ethical and reporting standards. Topic editors: Lais F Berro, Thomas Kilduff, Cristiane Aparecida Favoretto, Takeshi Sakurai Source: https://www.frontiersin.org/research-topics/78791/30-years-of-hypocretinorexin-research-sleep-wake-regulation-reward-and-motivation