Orexin Hypocretin System

The orexin system, discovered in 1998, has emerged as a crucial player in regulating the sleep and wake balance inside our brain. This discovery has sparked a burst of novel and dynamic research on the physiology and pathology of sleep. The Orexin System: Basic Science and Role in Sleep Pathology honors this research and the authors share their ideas and perspectives on the novel developments within the field. The book examines the intricate role of the orexin system in regulating sleep and wake, and its interaction with other wake-regulating systems. The orexin system is dissected at the cellular and molecular level to explore the diversity of the orexin-producing neurons, their projections, and their signaling pathways. Additionally, the book discusses the diseases which are associated with a dysfunctional orexin system, such as narcolepsy, insomnia, substance abuse, and Alzheimer’s disease, and explores the new potential therapeutic applications derived from the burst of research around this fascinating system. This publication is essential reading for neurobiologists, neurologists, psychopharmacologists, sleep researchers, and other researchers and clinical scientists interested in sleep, sleep research, insomnia, and medicine in general.

The Orexins/Hypocretins System: Functional Roles and Therapeutic Potential summarizes research on both the physiological functioning of orexins, their impact on homeostatic processes, and related disorders. The book encompasses the effects on appetite, sleep, substance abuse, cognition, and anxiety. Additionally, it examines new therapeutic approaches utilizing orexins, including utilization of orexin receptors for drug development. It is essential reading for neuroscience researchers interested in brain-behavior relationships, as well as psychiatrists, endocrinologists and pharmacologists. Provides an overview of new research on orexins/hypocretins Includes an overview of intracellular signaling and orexin physiology Discusses the effects on arousal, appetite, cognition, addiction and anxiety Examines orexin based therapies and their potential use in disorders Explores orexin receptors for drug development

The first report that rapid eye movements occur in sleep in humans was published in 1953. The research journey from this point to the realization that sleep consists of two entirely independent states of being (eventually labeled REM sleep and non-REM sleep) was convoluted, but by 1960 the fundamental duality of sleep was well established including the description of REM sleep in cats associated with “wide awake” EEG patterns and EMG suppression. The first report linking REM sleep to a pathology occurred in 1961 and a clear association of sleep onset REM periods, cataplexy, hypnagogic hallucinations and sleep paralysis was fully established by 1966. When a naïve individual happens to observe a full-blown cataplexy attack, it is both dramatic and unnerving. Usually the observer assumes that the loss of muscle tone represents syncope or seizure. In order to educate health professionals and the general public, Christian Guilleminault and I made movies of full-blown cataplectic episodes (not an easy task). We showed these movies of cataplexy attacks to a number of professional audiences, and were eventually rewarded with the report of a similar abrupt loss of muscle tone in a dog. We were able to bring the dog to Stanford University and with this as the trigger, we were able to develop the Stanford Canine Narcolepsy Colony. Breeding studies revealed the genetic determinants of canine narcolepsy, an autosomal recessive gene we termed canarc1. Emmanuel Mignot took over the colony in 1986 and began sequencing DNA, finally isolating canarc1 in 1999.

Impairment of orexin/hypocretin signaling causes narcolepsy-cataplexy in animals and humans. Most human narcolepsy-cataplexy cases are associated with orexin/hypocretin ligand deficiency, which can be detected clinically using cerebrospinal orexin/hypocretin measures and may lead to future treatments with orexin/hypocretin replacement therapy. In The Orexin/Hypocretin System: Physiology and Pathophysiology, leading researchers and clinicians review these exciting developments to set the stage for further research on the loss of orexin/hypocretin neurons in humans, regulation of sleep and wakefulness by the orexin/hypocretin system, and the role of the orexin/hypocretin system in many other physiological processes, including feeding, autonomic regulation, and neuroendocrine regulation. Topics of interest include an assessment of the functions and the physiology of orexin/hypocretin, its pathophysiology in human narcolepsy-cataplexy, and possible pharmacological treatments. The authors also introduce several experimental methods for orexin/hypocretin research, and, using multidisciplinary approaches, explain their uses and limitations. Authoritative and state-of-the-art, The Orexin/Hypocretin System: Physiology and Pathophysiology will aid scientists in the search for novel bioactive peptides and their receptors, as well as novel physiological insights and opportunities for the clinical treatment of not only narcolepsy, but also a broad range of diseases associated with endocrine, feeding, and body weight regulation.

Leading authors review the state-of-the-art in their field of investigation, and provide their views and perspectives for future research. Chapters are extensively referenced to provide readers with a comprehensive list of resources on the topics covered. All chapters include comprehensive background information and are written in a clear form that is also accessible to the non-specialist. Leading authors review the state-of-the-art in their field of investigation, and provide their views and perspectives for future research Chapters are extensively referenced to provide readers with a comprehensive list of resources on the topics covered All chapters include comprehensive background information and are written in a clear form that is also accessible to the non-specialist

This issue of Current Topics in Behavioral Neuroscience focuses on the neuropeptide orexin (hypocretin) and brings together scientists from around the world who will provide a timely discussion of how this peptide regulates behavior. This is a fast-moving field, and with the incorporation of novel technologies, new breakthroughs are likely to continue. For example, the use of optogenetic approaches has enabled the identification of the role of orexin-containing neurons in arousal states, critical for higher order functioning. From a clinical perspective, genetic polymorphisms in hypocretin/orexin and orexin receptors are implicated in a number of psychiatric disorders. In addition, advanced clinical trials are currently underway for orexin receptor antagonists in the treatment of insomnia and sleep disorders. We aim to capture a broad audience of basic scientists and clinicians.

Narcolepsy serves as a prototype of how the interaction of high quality clinical research and groundbreaking basic science can collaborate to defne the cause of a disease and change forever how we evaluate and treat it. There is scarcely a topic in this book that would have been covered in the same way 10 years ago as it is d- cussed today. We are also fortunate that many of the players in this dramatic tu- around have contributed to this volume, so that the result is a tapestry of the events that have transformed the feld over the last decade that is both authentic and detailed. The frst section of the book provides much of the basic science background. As described in the frst two chapters, the dramatic convergence of lines of evidence from two different laboratories frst demonstrated in 1999 that narcolepsy is a disease of loss of neurotransmission by lateral hypothalamic neurons making the peptides that have been called orexins or hypocretins. These fndings did much to clarify and unify a feld that had puzzled for decades over the fundamental nature of this puzzling disease, as refected in the chapters that review its epidemiology and neuroanatomical and imaging fndings.

The diagnosis of mental illness is frequently accompanied by sleep problems; conversely, people experiencing sleep problems may subsequently develop mental illness. Sleep and Mental Illness looks at this close correlation and considers the implications of research findings that have emerged in the last few years. Additionally, it surveys the essential concepts and practical tools required to deal with sleep and co-morbid psychiatric problems. The volume is divided into three main sections: basic science, neuroendocrinology, and clinical science. Included are over 30 chapters on topics such as neuropharmacology, insomnia, depression, dementia, autism, and schizophrenia. Relevant questionnaires for the assessment of sleep disorders, including quality-of-life measurement tools, are provided. There is also a summary table of drugs for treating sleep disorders. This interdisciplinary text will be of interest to clinicians working in psychiatry, behavioral sleep medicine, neurology, pulmonary and critical care medicine.