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Sleep Problems in Narcolepsy and the Role of Hypocretin/Orexin Deficiency
Front Neurol Neurosci. 2021;45:103-116. doi: 10.1159/000514959. Epub 2021 May 28.ABSTRACTSince its description in the 19th century, narcolepsy type 1 (NT1) has been considered as a model sleep disorder, and after the discovery of rapid eye movement (REM) sleep onset in the disorder, a gateway to understanding REM sleep. The discovery that NT1 is caused by hypocretin/orexin deficiency, together with neurochemical studies of this system, has helped to establish how this neuropeptide regulates the organization of sleep and wake in humans. Current analyses suggest that the main functions of the hypocretin/orexin system are (1)...
Source: Frontiers of Neurology and Neuroscience - May 30, 2021 Category: Neuroscience Authors: Emmanuel Mignot Jamie Zeitzer Fabio Pizza Giuseppe Plazzi Source Type: research

Sleep, Orexin and Cognition
Front Neurol Neurosci. 2021;45:38-51. doi: 10.1159/000514960. Epub 2021 May 28.ABSTRACTOrexins regulate a wide variety of biological functions, most notably the sleep-wake cycle, reward and stress processing, alertness, vigilance, and cognitive functioning. Alterations of central and peripheral orexin levels are linked to conditions such as narcolepsy, anorexia nervosa, age-related cognitive decline, and neurodegenerative disease. Preliminary studies suggest that orexin mimetics can safely promote the wake signal via orexin agonism during the day and that orexin receptor antagonists can promote the sleep signal during the ...
Source: Frontiers of Neurology and Neuroscience - May 30, 2021 Category: Neuroscience Authors: Balmeet Toor Laura B Ray Alyssa Pozzobon Stuart M Fogel Source Type: research

Twenty-Three Years of Hypocretins: The "Rosetta Stone" of Sleep/Arousal Circuits
Front Neurol Neurosci. 2021;45:1-10. doi: 10.1159/000514961. Epub 2021 May 28.ABSTRACTThe discovery of the hypocretins/orexins (HCRTs) has revolutionized sleep science in the last two decades. A combination of anatomical tracing methods, optogenetics, and pharmacology is delineating a blueprint of functional inputs and outputs of the HCRT system. Here, we discuss several models of HCRT action that involve the integration between physiological variables, circadian output, and sleep homeostasis. Generation of activity maps during the sleep-wake cycle at the cellular level will allow investigators to decipher computational fr...
Source: Frontiers of Neurology and Neuroscience - May 30, 2021 Category: Neuroscience Authors: Luis de Lecea Source Type: research

Cellular Signaling Mechanisms of Hypocretin/Orexin
Front Neurol Neurosci. 2021;45:91-102. doi: 10.1159/000514962. Epub 2021 May 28.ABSTRACTOrexin receptors (OXRs) are promiscuous G-protein-coupled receptors that signal via several G-proteins and, putatively, via other proteins. On which basis the signal pathways are selected and orchestrated is largely unknown. We also have an insufficient understanding of the kind of signaling that is important for specific types of cellular responses. OXRs are able to form complexes with several other G-protein-coupled receptors in vitro, and one possibility is that the complexing partners regulate the use of certain signal transducers. ...
Source: Frontiers of Neurology and Neuroscience - May 30, 2021 Category: Neuroscience Authors: Jyrki P Kukkonen Pauli M Turunen Source Type: research

Hypocretin/Orexin Receptor Pharmacology and Sleep Phases
Front Neurol Neurosci. 2021;45:22-37. doi: 10.1159/000514963. Epub 2021 May 28.ABSTRACTThe hypocretins/orexins are two excitatory neuropeptides, alternately called HCRT1 or orexin-A and HCRT2 or orexin-B, that are the endogenous ligands for two G-protein-coupled receptors, HCRTR1/OX1R and HCRTR2/OX2R. Shortly after the discovery of this system, degeneration of hypocretin/orexin-producing neurons was implicated in the etiology of the sleep disorder narcolepsy. The involvement of this system in a disorder characterized by the loss of control over arousal state boundaries also suggested its role as a critical component of end...
Source: Frontiers of Neurology and Neuroscience - May 30, 2021 Category: Neuroscience Authors: Yu Sun Ryan K Tisdale Thomas S Kilduff Source Type: research

Heterogeneity of Hypocretin/Orexin Neurons
Front Neurol Neurosci. 2021;45:61-74. doi: 10.1159/000514964. Epub 2021 May 28.ABSTRACTThe multifunctional, hypothalamic hypocretin/orexin (HCRT)-producing neurons regulate an array of physiological and behavioral states including arousal, sleep, feeding, emotions, stress, and reward. How a presumably uniform HCRT neuron population regulates such a diverse set of functions is not clear. The role of the HCRT neuropeptides may vary depending on the timing and localization of secretion and neuronal activity. Moreover, HCRT neuropeptides may not mediate all functions ascribed to HCRT neurons. Some could be orchestrated by addi...
Source: Frontiers of Neurology and Neuroscience - May 30, 2021 Category: Neuroscience Authors: Dana Sagi Luis de Lecea Lior Appelbaum Source Type: research

The Insomnia-Addiction Positive Feedback Loop: Role of the Orexin System
Front Neurol Neurosci. 2021;45:117-127. doi: 10.1159/000514965. Epub 2021 May 28.ABSTRACTSignificant sleep impairments often accompany substance use disorders (SUDs). Sleep disturbances in SUD patients are associated with poor clinical outcomes and treatment adherence, emphasizing the importance of normalizing sleep when treating SUDs. Orexins (hypocretins) are neuropeptides exclusively produced by neurons in the posterior hypothalamus that regulate various behavioral and physiological processes, including sleep-wakefulness and motivated drug taking. Given its dual role in sleep and addiction, the orexin system represents ...
Source: Frontiers of Neurology and Neuroscience - May 30, 2021 Category: Neuroscience Authors: Jennifer E Fragale Morgan H James Jorge A Avila Andrea M Spaeth R Nisha Aurora Daniel Langleben Gary Aston-Jones Source Type: research

Sleep and Metabolism: Implication of Lateral Hypothalamic Neurons
Front Neurol Neurosci. 2021;45:75-90. doi: 10.1159/000514966. Epub 2021 May 28.ABSTRACTDuring the last decade, optogenetic-based circuit mapping has become one of the most common approaches to systems neuroscience, and amassing studies have expanded our understanding of brain structures causally involved in the regulation of sleep-wake cycles. Recent imaging technologies enable the functional mapping of cellular activity, from population down to single-cell resolution, across a broad repertoire of behaviors and physiological processes, including sleep-wake states. This chapter summarizes experimental evidence implicating h...
Source: Frontiers of Neurology and Neuroscience - May 30, 2021 Category: Neuroscience Authors: Lukas T Oesch Antoine R Adamantidis Source Type: research

Hypocretin/Orexin, Sleep and Alzheimer's Disease
Front Neurol Neurosci. 2021;45:139-149. doi: 10.1159/000514967. Epub 2021 May 28.ABSTRACTAdvances in translational research provide key opportunities to explore the physiological and pathological effects of sleep in different neurodegenerative diseases. Recent findings suggest that sleep-wakefulness dysfunctions may predispose to neurodegenerative disorders such as Alzheimer's disease (AD), and vice versa. New theories on the link between sleep and β-amyloid and tau secretion, accumulation and clearance, and its interaction with hypocretins/orexins (key neuropeptides regulating wakefulness) suggest mechanistic ways to bet...
Source: Frontiers of Neurology and Neuroscience - May 30, 2021 Category: Neuroscience Authors: Yves Dauvilliers Source Type: research

Preface
Front Neurol Neurosci. 2021;45:IX-X. doi: 10.1159/000514968. Epub 2021 May 28.NO ABSTRACTPMID:34052818 | DOI:10.1159/000514968 (Source: Frontiers of Neurology and Neuroscience)
Source: Frontiers of Neurology and Neuroscience - May 30, 2021 Category: Neuroscience Authors: Michel A Steiner Masashi Yanagisawa Martine Clozel Source Type: research

Prelims
Front Neurol Neurosci. 2021;45:I-VIII. doi: 10.1159/000514976. Epub 2021 May 28.NO ABSTRACTPMID:34052819 | DOI:10.1159/000514976 (Source: Frontiers of Neurology and Neuroscience)
Source: Frontiers of Neurology and Neuroscience - May 30, 2021 Category: Neuroscience Source Type: research

Interaction between Orexin Neurons and Monoaminergic Systems
Front Neurol Neurosci. 2021;45:11-21. doi: 10.1159/000514955. Epub 2021 May 28.ABSTRACTOrexins have received a lot of attention as potent endogenous arousal-promoting peptides, and orexin receptor antagonists have shown clinical efficacy for the treatment of insomnia. Orexin neurons are thought to act primarily on monoaminergic neurons to maintain arousal and vigilance. In this chapter, we discuss the functional interaction between monoaminergic systems, including noradrenaline, serotonin and histamine, and orexin neurons, as well as interactions between the acetylcholine system and the orexin neurons, focusing, in particu...
Source: Frontiers of Neurology and Neuroscience - May 30, 2021 Category: Neuroscience Authors: Takeshi Sakurai Yuki C Saito Masashi Yanagisawa Source Type: research

Causes and Consequences of Chronic Sleep Deficiency and the Role of Orexin
Front Neurol Neurosci. 2021;45:128-138. doi: 10.1159/000514956. Epub 2021 May 28.ABSTRACTSleep is one of the pillars of health. Experimental models of acute sleep loss, of chronic partial sleep deprivation, and of sleep fragmentation in healthy sleepers are helpful models of sleep deficiency produced by insufficient sleep duration, sleep timing, and sleep disorders. Sleep deficiency is associated with changes in markers associated with risk for disease. These include metabolic, inflammatory, and autonomic markers of risk. In addition, sleep disruption and sleep deficits lead to mood instability, lack of positive outlook, a...
Source: Frontiers of Neurology and Neuroscience - May 30, 2021 Category: Neuroscience Authors: Janet M Mullington Tony J Cunningham Monika Haack Huan Yang Source Type: research

Subsecond Ensemble Dynamics of Orexin Neurons Link Sensation and Action
Front Neurol Neurosci. 2021;45:52-60. doi: 10.1159/000514957. Epub 2021 May 28.ABSTRACTHypothalamic hypocretin/orexin neurons have been initially conceptualized as slow, modulatory controllers of behavior. Furthermore, their behavioral effects have been assumed to be a secondary consequence of their impact on arousal. However, cellular-resolution calcium imaging and optogenetic studies show that orexin neurons regulate self-generated and sensory-evoked movement on rapid, subsecond timescales. Orexin cell activity rapidly and transiently peaks before and during movements. Optogenetic prevention of this activation reduces th...
Source: Frontiers of Neurology and Neuroscience - May 30, 2021 Category: Neuroscience Authors: Denis Burdakov Source Type: research