Part I. Historyn n History and Overview of Orexin/Hypocretin Research: From Orphan GPCR to Integrative Physiologyn Michihiro Mieda and Takeshi Sakurain n Part II. Overview of the Orexin/Hypocretin Neuronal Systemn n Orexin and Orexin Receptorsn Takeshi Sakurain n Orexin Projections and Localization of Orexin Receptorsn Jacob N. Marcus and Joel K. Elmquistn n Neuronal Responses to Hypocretin/Orexinn Anthony N. van den Pol and Claudio Acuna-Goycolean n Afferent System of Orexin Neuronsn Akihiro Yamanakan n Part III. Assessment of Orexin/Hypocretin Functions in Tissue and Biological Fluidsn n Hypocretin Measurements in the CSF, and Blood and Brain Tissue: Basic and Clinical Applicationsn Seiji Nishinon n Hypocretin Receptor-Activated G Proteins Revealed by [35S]GTPgS Autoradiographyn René Bernard, Ralph Lydic, and Helen A. Baghdoyann n Part IV. Physiologyn n A. Orexin/Hypocretin System and Hypothalamic Functionn n Orexin System and Feeding Behaviorn Takeshi Sakurain n Orexins and the Autonomic Nervous Systemn Tetsuro Shirasaka and Masamitsu Nakazaton n Neuroendocrine Role of the Orexins (Hypocretins)n Shahrad Taherin n The Orexin/Hypocretin System and Stress and Emotionn Yoichi Ueta and Hiroaki Fujiharan n B. Orexins/Hypocretins and Sleep Regulationn n Hypocretin as a Wakefulness Regulatory Peptiden Luis de Lecea and J. Gregor Sutcliffen n Hypocretin/Orexin Tonus and Vigilance Controln Yasushi Yoshida and Seiji Nishinon n Hypocretin System and Aminergic and Cholinergic Systems in the Control of Vigilancen Krister S. Eriksson and Helmut L. Haasn n Orexin and Hypothalamic Control of Sleep and Wakingn Rodrigo A. España and Thomas E. Scammelln n Hypocretin/Orexin and Motor Functionn Jerome M. Siegeln n Part V. Pathophysiology:Narcolepsy and Orexin/Hypocretin Deficiencyn n A. Orexin/Hypocretin Deficiency and Narcolepsyn n Overview of Human Narcolepsyn Scott Fromherz and Emmanuel Mignotn n Canine Models of Narcolepsyn Seiji Nishinon n Rodent Models of Human Narcolepsy-Cataplexyn Michihiro Mieda and Masashi Yanagisawan n B. Orexin/Hypocretin Deficiency in Human Narcolepsy and Other Conditionsn n Hypocretin Deficiency in Human Narcolepsy: Mutation Screening, Neuropathology, and CSF Hypocretin-1 Leveln Patrice Bourgin, Jamie M. Zeitzer, and Emmanuel Mignotn n Hypocretin Status in Neurological Disorders in Relation to Excessive Sleepiness and Cataplexyn Takashi Kanbayashi, Junko Arii, Hideaki Kondo, Tetsuo Shimizu, and Seiji Nishinon n Hypocretin Measures in Psychiatric Disordersn Ronald M. Salomonn n Neuroendocrinology of Human Narcolepsyn Gert Jan Lammers, Sebastiaan Overeem, and Hanno Pijln n Narcolepsy and Autoimmunityn Shahrad Taheri, Jose Paterno, Ling Lin, and Emmauel Mignotn n C. Treatment/Pharmacologyn n Pharmacology of Orexin/Hypocretin Peptides and Small Moleculesn Stephen J. Perry, David A. Schwarz, and Richard A. Makin n Rescue of Narcoleptic Orexin Neuron-Ablated Mice by Ectopic Overexpression of Orexin Peptidesn Michihiro Mieda, Jon T. Willie, and Takeshi Sakurain n Hypocretin/Orexin Replacement Therapy in Hypocretin/Orexin-Deficient Narcolepsy: An Overviewn Nobuhiro Fujiki and Seiji Nishinon n Index
Orexin/hypocretin research began in 1998, as a result of the discovery of a new hypothalamic neuropeptide. In 1999, it was found that mutations in the orexin/ hypocretin-related genes caused a sleep disorder (narcolepsy) in dogs and mice. These findings were soon followed by the discoveries of orexin/hypocretin ligand deficiency in human narcolepsy. The finding of the major pathophysiological mechanisms of human narcolepsy resulted in its reclassification as a neurological, not a psychiatric, disorder. The - portance of early diagnosis and initiation of treatment for human narcolepsy has been repeatedly emphasized because the disease typically starts around puberty (when social and school influences become important). Orexin/hypocretin de- ciency in narcolepsy subjects can be detected clinically in cerebrospinal fluid (CSF) orexin/hypocretin measures (low CSF orexin/hypocretin levels are strongly asso- ated with narcolepsy-cataplexy among various neurologic and sleep disorders). Thus, the CSF orexin/hypocretin measurements are expected to be included as a diagnostic test for narcolepsy-cataplexy in the second revision of international di- nostic criteria (ICSD). This positive diagnostic test is very useful for establishing an early diagnosis for narcolepsy-cataplexy, and many patients will likely receive im- diate benefits. Cerebrospinal orexin/hypocretin measurements are also informative for the nosological classification of hypersomnia. Because orexin/hypocretin de- ciency is observed in most human narcolepsy-cataplexy, orexin/hypocretin repla- ment therapy is now a promising new choice for the treatment of human narcolepsy, and research in this area is actively in progress.
The Orexin/Hypocretin System provides an overview of all the recent exciting discoveries in the field as well as new findings such as ligand replacement and gene therapies in the animal models of narcolepsy. Several contributions cover sleep and the multiple systems involved in its regulation.