Sleep and wakefulness are regulated to occur at appropriate times that are in accordance with our internal and external environments. Avoiding danger and finding food, which are life-essential activities that are regulated by emotion, reward and energy balance, require vigilance and therefore, by definition, wakefulness. The orexin (hypocretin) system regulates sleep and wakefulness through interactions with systems that regulate emotion, reward and energy homeostasis.

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The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness

Plaguing humans for more than two millennia, manifest on every continent studied, and with more than one billion patients having an attack in any year, migraine stands as the sixth most common cause of disability on the planet. The pathophysiology of migraine has emerged from a historical consideration of the "humors" through mid-20th century distraction of the now defunct Vascular Theory to a clear place as a neurological disorder. It could be said there are three questions: why, how, and when? Why: migraine is largely accepted to be an inherited tendency for the brain to lose control of its inputs. How: the now classical trigeminal durovascular afferent pathway has been explored in laboratory and clinic; interrogated with immunohistochemistry to functional brain imaging to offer a roadmap of the attack. When: migraine attacks emerge due to a disorder of brain sensory processing that itself likely cycles, influenced by genetics and the environment. In the first, premonitory, phase that precedes headache, brain stem and diencephalic systems modulating afferent signals, light-photophobia or sound-phonophobia, begin to dysfunction and eventually to evolve to the pain phase and with time the resolution or postdromal phase. Understanding the biology of migraine through careful bench-based research has led to major classes of therapeutics being identified: triptans, serotonin 5-HT1B/1D receptor agonists; gepants, calcitonin gene-related peptide (CGRP) receptor antagonists; ditans, 5-HT1F receptor agonists, CGRP mechanisms monoclonal antibodies; and glurants, mGlu5 modulators; with the promise of more to come. Investment in understanding migraine has been very successful and leaves us at a new dawn, able to transform its impact on a global scale, as well as understand fundamental aspects of human biology.

Pathophysiology of Migraine: A Disorder of Sensory Processing

▪ Abstract Orexin-A and orexin-B are neuropeptides originally identified as endogenous ligands for two orphan G-protein–coupled receptors. Orexin neuropeptides (also known as hypocretins) are produ...

https://sites.oxy.edu/clint/physio/article/toeatortosleeporexinintheregulationoffeedingandwakefulness.pdf

To eat or to sleep? Orexin in the regulation of feeding and wakefulness.

Orexin A in the VTA is critical for the induction of synaptic plasticity and behavioral sensitization to cocaine.

Food intake and energy expenditure are controlled by complex, redundant, and distributed neural systems that reflect the fundamental biological importance of adequate nutrient supply and energy balance. Much progress has been made in identifying the various hormonal and neural mechanisms by which the brain informs itself about availability of ingested and stored nutrients and, in turn, generates behavioral, autonomic, and endocrine output. While hypothalamus and caudal brainstem play crucial roles in this homeostatic function, areas in the cortex and limbic system are important for processing information regarding prior experience with food, reward, and emotion, as well as social and environmental context. Most vertebrates can store a considerable amount of energy as fat for later use, and this ability has now become one of the major health risks for many human populations. The predisposition to develop obesity can theoretically result from any pathological malfunction or lack of adaptation to changing environments of this highly complex system.

The brain, appetite, and obesity

Orexin-A and -B (hypocretin-1 and -2) have been implicated in the stimulation of feeding. Here we show the effector neurons and signaling mechanisms for the orexigenic action of orexins in rats. Immunohistochemical methods showed that orexin axon terminals contact with neuropeptide Y (NPY)- and proopiomelanocortin (POMC)-positive neurons in the arcuate nucleus (ARC) of the rats. Microinjection of orexins into the ARC markedly increased food intake. Orexins increased cytosolic Ca 2 + concentration ([Ca 2 + ] i ) in the isolated neurons from the ARC, which were subsequently shown to be immunoreactive for NPY. The increases in [Ca 2 + ] i were inhibited by blockers of phospholipase C (PLC), protein kinase C (PKC) and Ca 2 + uptake into endoplasmic reticulum. The stimulation of food intake and increases in [Ca 2 + ] i in NPY neurons were greater with orexin-A than with orexin-B, indicative of involvement of the orexin-1 receptor (OX 1 R). In contrast, orexin-A and -B equipotently attenuated [Ca 2 + ] i oscillations and decreased [Ca 2 + ] i levels in POMC-containing neurons. These effects were counteracted by pertussis toxin, suggesting involvement of the orexin-2 receptor and Gi/Go subtypes of GTP-binding proteins. Orexins also decreased [Ca 2 + ] i levels in glucose-responsive neurons in the ventromedial hypothalamus (VMH), a satiety center. Leptin exerted opposite effects on these three classes of neurons. These results demonstrate that orexins directly regulate NPY, POMC and glucose-responsive neurons in the ARC and VMH, in a manner reciprocal to leptin. Orexin-A evokes Ca 2 + signaling in NPY neurons via OX 1 R-PLC-PKC and IP 3 pathways. These neural pathways and intracellular signaling mechanisms may play key roles in the orexigenic action of orexins.

Orexins (hypocretins) directly interact with neuropeptide Y, POMC and glucose‐responsive neurons to regulate Ca2+ signaling in a reciprocal manner to leptin: orexigenic neuronal pathways in the mediobasal hypothalamus

Orexin receptor type-1 couples exclusively to pertussis toxin-insensitive G-proteins, while orexin receptor type-2 couples to both pertussis toxin-sensitive and -insensitive G-proteins.

Structure, tissue distribution, and pharmacological characterization of xenopus orexins

Orexins (also called hypocretins), which are neuropeptides exclusively expressed by a population of neurons specifically localized in the lateral hypothalamic area, are critically implicated in the regulation of sleep/wake states. Orexin deficiency results in narcoleptic phenotype in rodents, dogs, and humans, suggesting that orexins are important for maintaining consolidated wakefulness states. However, the physiological effect of constitutive increased orexinergic transmission tone, which might be important for understanding the effects of orexin agonists that are promising candidates for therapeutic agents of narcolepsy, has not been fully characterized. We report here the sleep/wakefulness abnormalities in transgenic mice that exhibit widespread overexpression of a rat prepro-orexin transgene driven by a β-actin/cytomegalovirus hybrid promoter (CAG/orexin transgenic mice). CAG/orexin mice exhibit sleep abnormalities with fragmentation of non-rapid eye movement (REM) sleep episode and a reduction in REM sleep. Non-REM sleep was frequently disturbed by short episodes of wakefulness. EEG/EMG studies also reveal incomplete REM sleep atonia with abnormal myoclonic activity during this sleep stage. These results suggest that endogenous orexinergic activity should be appropriately regulated for normal maintenance of sleep states. Orexinergic transmission should be activated during wakefulness, while it should be inactivated or decreased during sleep state to maintain appropriate vigilance states.

Megumi Shibahara

Papers

Orexins (hypocretins) directly interact with neuropeptide Y, POMC and glucose‐responsive neurons to regulate Ca2+ signaling in a reciprocal manner to leptin: orexigenic neuronal pathways in the mediobasal hypothalamus

Orexin receptor type-1 couples exclusively to pertussis toxin-insensitive G-proteins, while orexin receptor type-2 couples to both pertussis toxin-sensitive and -insensitive G-proteins.

Structure, tissue distribution, and pharmacological characterization of xenopus orexins

Ectopic Overexpression of Orexin Alters Sleep/Wakefulness States and Muscle Tone Regulation during REM Sleep in Mice