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Proceedings of the National Academy of... Oct 2023Narcolepsy is a sleep disorder caused by deficiency of orexin signaling. However, the neural mechanisms by which deficient orexin signaling causes the abnormal rapid eye...
Narcolepsy is a sleep disorder caused by deficiency of orexin signaling. However, the neural mechanisms by which deficient orexin signaling causes the abnormal rapid eye movement (REM) sleep characteristics of narcolepsy, such as cataplexy and frequent transitions to REM states, are not fully understood. Here, we determined the activity dynamics of orexin neurons during sleep that suppress the abnormal REM sleep architecture of narcolepsy. Orexin neurons were highly active during wakefulness, showed intermittent synchronous activity during non-REM (NREM) sleep, were quiescent prior to the transition from NREM to REM sleep, and a small subpopulation of these cells was active during REM sleep. Orexin neurons that lacked orexin peptides were less active during REM sleep and were mostly silent during cataplexy. Optogenetic inhibition of orexin neurons established that the activity dynamics of these cells during NREM sleep regulate NREM-REM sleep transitions. Inhibition of orexin neurons during REM sleep increased subsequent REM sleep in "orexin intact" mice and subsequent cataplexy in mice lacking orexin peptides, indicating that the activity of a subpopulation of orexin neurons during the preceding REM sleep suppresses subsequent REM sleep and cataplexy. Thus, these results identify how deficient orexin signaling during sleep results in the abnormal REM sleep architecture characteristic of narcolepsy.
Topics: Animals; Mice; Cataplexy; Narcolepsy; Orexins; Sleep; Sleep, REM; Wakefulness
PubMed: 37796986
DOI: 10.1073/pnas.2301951120 -
Frontiers of Neurology and Neuroscience 2021Orexin receptors (OXRs) are promiscuous G-protein-coupled receptors that signal via several G-proteins and, putatively, via other proteins. On which basis the signal... (Review)
Review
Orexin 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. In the central nervous system neurons, the main acute downstream responses of OXR activation are the inhibition of K+ channels and the activation of the Na+/Ca2+ exchanger and non-selective cation channels of unknown identity. The exact nature of the intracellular signal chain between the OXRs and these downstream targets is yet to be elucidated, but the Gq-phospholipase C (PLC) protein kinase C pathway - which is a significant signaling pathway for OXRs in recombinant cells - may be one of the players in neurons. The Gq-PLC pathway may also, under certain circumstances, take the route to diacylglycerol lipase, which leads to the production of the potent endocannabinoid (eCB), 2-arachidonoyl glycerol, and thereby connects orexins with eCB signaling. In addition, OXRs have been studied in the context of neurodegeneration and cancer cell death. Overall, OXR signaling is complex, and it can change depending on the cell type and environment.
Topics: Humans; Orexin Receptors; Orexins; Signal Transduction
PubMed: 34052812
DOI: 10.1159/000514962 -
Peptides Jul 2023Orexin (also known as hypocretin) is a neuropeptide exclusively synthesized in the neurons of the lateral hypothalamus (LH). Initially orexin was thought to be involved...
Orexin (also known as hypocretin) is a neuropeptide exclusively synthesized in the neurons of the lateral hypothalamus (LH). Initially orexin was thought to be involved in the regulation of feeding behavior. However, it is now known to also be a critical regulator of sleep/wakefulness, especially the maintenance of wakefulness. Although the somas of orexin neurons are exclusively located in the LH, these neurons send axons throughout the brain and spinal cord. Orexin neurons integrate inputs from various brain regions and project to neurons that are involved in the regulation of sleep/wakefulness. Orexin knockout mice have a fragmentation of sleep/wakefulness and cataplexy-like behavior arrest, which is similar to the sleep disorder narcolepsy. Recent progress with manipulation of neural activity of targeted neurons, using experimental tools such as optogenetics and chemogenetics, has emphasized the role of orexin neuron activity on the regulation of sleep/wakefulness. Recording of orexin neuron activity in vivo using electrophysiological and gene-encoded calcium indicator proteins revealed that these cells have specific activity patterns across sleep/wakefulness state changes. Here, we also discuss not only the role of the orexin peptide, but also the role of other co-transmitters that are synthesized and released from orexin neurons and involved in sleep/wakefulness regulation.
Topics: Mice; Animals; Orexins; Wakefulness; Sleep; Neuropeptides; Narcolepsy; Neurons; Mice, Knockout; Orexin Receptors
PubMed: 37030519
DOI: 10.1016/j.peptides.2023.171007 -
Digestion 2024Irritable bowel syndrome (IBS) is a functional bowel disorder characterized by chronic abdominal symptoms, but its pathogenesis is not fully understood. (Review)
Review
BACKGROUND
Irritable bowel syndrome (IBS) is a functional bowel disorder characterized by chronic abdominal symptoms, but its pathogenesis is not fully understood.
SUMMARY
We have recently shown in rats that neuropeptides such as orexin, ghrelin, and oxytocin act in the brain to improve the intestinal barrier dysfunction, which is a major pathophysiology of IBS. We have additionally shown that the neuropeptides injected intracisternally induced a visceral antinociceptive action against colonic distension. Since it has been known that intestinal barrier dysfunction causes visceral hypersensitivity, the other main pathophysiology of IBS, the neuropeptides act centrally to reduce leaky gut, followed by improvement of visceral sensation, leading to therapeutic action on IBS. It has been recently reported that there is a bidirectional relationship between neuroinflammation in the brain and the pathophysiology of IBS. For example, activation of microglia in the brain causes visceral hypersensitivity. Accumulating evidence has suggested that orexin, ghrelin, or oxytocin could improve neuroinflammation in the CNS. All these results suggest that neuropeptides such as orexin, ghrelin, and oxytocin act in the brain to improve intestinal barrier function and visceral sensation and also induce a protective action against neuroinflammation in the brain.
KEY MESSAGES
We therefore speculated that orexin, ghrelin, or oxytocin in the brain possess dual actions, improvement of visceral sensation/leaky gut in the gut, and reduction of neuroinflammation in the brain, thereby inducing a therapeutic effect on IBS in a convergent manner.
Topics: Rats; Animals; Irritable Bowel Syndrome; Orexins; Ghrelin; Oxytocin; Neuroinflammatory Diseases; Neuropeptides; Brain
PubMed: 37673052
DOI: 10.1159/000533275 -
Medicine in Drug Discovery Dec 2020Twenty-two years after their discovery, the hypocretins (Hcrts), also known as orexins, are two of the most studied peptidergic systems, involved in myriad physiological...
Twenty-two years after their discovery, the hypocretins (Hcrts), also known as orexins, are two of the most studied peptidergic systems, involved in myriad physiological systems that range from sleep, arousal, motivation, homeostatic regulation, fear, anxiety and learning. A causal relationship between activity of Hcrt and arousal stability was established shortly after their discovery and have led to the development of a new class of drugs to treat insomnia. In this review we discuss the many faces of the Hcrt system and examine recent findings that implicate decreased Hcrt function in the pathogenesis of a number of neuropsychiatric conditions. We also discuss future therapeutic strategies to replace or enhance Hcrt function as a treatment option for these neuropsychiatric conditions.
PubMed: 38738170
DOI: 10.1016/j.medidd.2020.100070 -
BioRxiv : the Preprint Server For... Sep 2023Sleep and circadian rhythm disruption (SCRD) is commonly observed in aging, especially in individuals who experience progressive cognitive decline to mild cognitive...
Sleep and circadian rhythm disruption (SCRD) is commonly observed in aging, especially in individuals who experience progressive cognitive decline to mild cognitive impairment (MCI) and Alzheimer's disease (AD). However, precise molecular mechanisms underlying the association between SCRD and aging are not fully understood. Orexin A is a well-characterized "sleep neuropeptide" that is expressed in hypothalamic neurons and evokes wake behavior. The importance of Orexin is exemplified in narcolepsy where it is profoundly down-regulated. Interestingly, the synaptic immediate early gene NPTX2 is co-expressed in Orexin neurons and is similarly reduced in narcolepsy. NPTX2 is also down-regulated in CSF of some cognitively normal older individuals and predicts the time of transition from normal cognition to MCI. The association between Orexin and NPTX2 is further evinced here where we observe that Orexin A and NPTX2 are highly correlated in CSF of cognitively normal aged individuals and raises the question of whether SCRD that are typically attributed to Orexin A loss of function may be modified by concomitant NPTX2 down-regulation. Is NPTX2 an effector of sleep or simply a reporter of orexin-dependent SCRD? To address this question, we examined NPTX2 KO mice and found they retain Orexin expression in the brain and so provide an opportunity to examine the specific contribution of NPTX2 to SCRD. Our results reveal that NPTX2 KO mice exhibit a disrupted circadian onset time, coupled with increased activity during the sleep phase, suggesting difficulties in maintaining states. Sleep EEG indicates distinct temporal allocation shifts across vigilance states, characterized by reduced wake and increased NREM time. Evident sleep fragmentation manifests through alterations of event occurrences during Wake and NREM, notably during light transition periods, in conjunction with an increased frequency of sleep transitions in NPTX2 KO mice, particularly between Wake and NREM. EEG spectral analysis indicated significant shifts in power across various frequency bands in the wake, NREM, and REM states, suggestive of disrupted neuronal synchronicity. An intriguing observation is the diminished occurrence of sleep spindles, one of the earliest measures of human sleep disruption, in NPTX2 KO mice. These findings highlight the effector role of NPTX2 loss of function as an instigator of SCRD and a potential mediator of sleep disruption in aging.
PubMed: 37808783
DOI: 10.1101/2023.09.26.559408 -
Neurology India 2021While understanding the pathophysiology of migraine has led to CGRP-based treatments, other potential targets have also been implicated in migraine. (Review)
Review
BACKGROUND
While understanding the pathophysiology of migraine has led to CGRP-based treatments, other potential targets have also been implicated in migraine.
OBJECTIVES
To catalog new promising targets for the treatment of migraine.
METHODS
We completed a literature review focusing on 5HT, PACAP, melatonin, and orexins.
RESULTS
The 5HT receptor agonist lasmiditan, following two positive randomized placebo-controlled trials, was FDA-approved for the acute treatment of migraine. PACAP-38 has shown analogous evidence to what was obtained for CGRP with its localization in key structures, provocation tests, and positive studies when antagonizing its receptor in animal models, although a PAC-1 receptor monoclonal antibody study was negative. Melatonin has undergone several randomized controlled trials showing a positive trend. Filorexant is the only dual orexin receptor antagonist, which was tested in humans with negative results.
CONCLUSIONS
Further and ongoing studies will determine the utility of these new therapies with lasmiditan and melatonin having demonstrated efficacy for the treatment of migraine.
Topics: Animals; Humans; Migraine Disorders
PubMed: 34003154
DOI: 10.4103/0028-3886.315989 -
Annual Review of Pharmacology and... Jan 2024Sleep is essential for human well-being, yet the quality and quantity of sleep reduce as age advances. Older persons (>65 years old) are more at risk of disorders... (Review)
Review
Sleep is essential for human well-being, yet the quality and quantity of sleep reduce as age advances. Older persons (>65 years old) are more at risk of disorders accompanied and/or exacerbated by poor sleep. Furthermore, evidence supports a bidirectional relationship between disrupted sleep and Alzheimer's disease (AD) or related dementias. Orexin/hypocretin neuropeptides stabilize wakefulness, and several orexin receptor antagonists (ORAs) are approved for the treatment of insomnia in adults. Dysregulation of the orexin system occurs in aging and AD, positioning ORAs as advantageous for these populations. Indeed, several clinical studies indicate that ORAs are efficacious hypnotics in older persons and dementia patients and, as in adults, are generally well tolerated. ORAs are likely to be more effective when administered early in sleep/wake dysregulation to reestablish good sleep/wake-related behaviors and reduce the accumulation of dementia-associated proteinopathic substrates. Improving sleep in aging and dementia represents a tremendous opportunity to benefit patients, caregivers, and health systems.
Topics: Humans; Aged; Aged, 80 and over; Orexins; Orexin Receptor Antagonists; Orexin Receptors; Sleep; Alzheimer Disease
PubMed: 37708433
DOI: 10.1146/annurev-pharmtox-040323-031929 -
Molecular Brain Mar 2022It is unclear why orexin-deficient animals, but not wild-type mice, show cataplexy. The current hypothesis predicts simultaneous excitation of cataplexy-inhibiting...
It is unclear why orexin-deficient animals, but not wild-type mice, show cataplexy. The current hypothesis predicts simultaneous excitation of cataplexy-inhibiting orexin neurons and cataplexy-inducing amygdala neurons. To test this hypothesis, we measured the activity of putative orexin neurons in orexin-knockout mice during cataplexy episodes using fiber photometry. We created two animal models of orexin-knockout mice with a GCaMP6 fluorescent indicator expressed in putative orexin neurons. We first prepared orexin-knockout mice crossed with transgenic mice carrying a tetracycline-controlled transactivator transgene under the control of the orexin promoter. TetO-GCaMP6 was then introduced into mice via an adeno-associated virus injection or natural crossing. The resulting two models showed restricted expression of GCaMP6 in the hypothalamus, where orexin neurons should be located, and showed excitation to an intruder stress that was similar to that observed in orexin-intact mice in our previous study. The activity of these putative orexin neurons increased immediately before the onset of cataplexy-like behavior but decreased (approximately - 20% of the baseline) during the cataplexy-like episode. We propose that the activity of orexin neurons during cataplexy is moderately inhibited by an unknown mechanism. The absence of cataplexy in wild-type mice may be explained by basal or residual activity-induced orexin release, and emotional stimulus-induced counter activation of orexin neurons may not be necessary. This study will serve as a basis for better treatment of cataplexy in narcolepsy patients.
Topics: Animals; Cataplexy; Humans; Mice; Mice, Knockout; Mice, Transgenic; Narcolepsy; Neurons; Orexins
PubMed: 35246205
DOI: 10.1186/s13041-022-00907-w -
Pharmacological Reviews Jun 2024The orexin system consists of the peptide transmitters orexin-A and -B and the G protein-coupled orexin receptors OX and OX Orexin receptors are capable of coupling to...
The orexin system consists of the peptide transmitters orexin-A and -B and the G protein-coupled orexin receptors OX and OX Orexin receptors are capable of coupling to all four families of heterotrimeric G proteins, and there are also other complex features of the orexin receptor signaling. The system was discovered 25 years ago and was immediately identified as a central regulator of sleep and wakefulness; this is exemplified by the symptomatology of the disorder narcolepsy with cataplexy, in which orexinergic neurons degenerate. Subsequent translation of these findings into drug discovery and development has resulted to date in three clinically used orexin receptor antagonists to treat insomnia. In addition to sleep and wakefulness, the orexin system appears to be a central player at least in addiction and reward, and has a role in depression, anxiety and pain gating. Additional antagonists and agonists are in development to treat, for instance, insomnia, narcolepsy with or without cataplexy and other disorders with excessive daytime sleepiness, depression with insomnia, anxiety, schizophrenia, as well as eating and substance use disorders. The orexin system has thus proved an important regulator of numerous neural functions and a valuable drug target. Orexin prepro-peptide and orexin receptors are also expressed outside the central nervous system, but their potential physiological role there remains unknown. The orexin system was discovered 25 years ago and immediately emerged as an essential sleep-wakefulness regulator. This discovery has tremendously increased the understanding of these processes and has thus far resulted in the market approval of three orexin receptor antagonists, which promote more physiological sleep than previous hypnotics. Further, orexin receptor agonists and antagonists with different pharmacodynamic properties are in development since research has revealed additional potential therapeutic indications. Orexin receptor signaling is complex and may represent novel features.
PubMed: 38902035
DOI: 10.1124/pharmrev.123.000953