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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