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Nature Neuroscience Jul 2023Brain orexin (hypocretin) neurons are implicated in sleep-wake switching and reward-seeking but their roles in rapid arousal dynamics and reward perception are unclear....
Brain orexin (hypocretin) neurons are implicated in sleep-wake switching and reward-seeking but their roles in rapid arousal dynamics and reward perception are unclear. Here, cell-specific stimulation, deletion and in vivo recordings revealed strong correlative and causal links between pupil dilation-a quantitative arousal marker-and orexin cell activity. Coding of arousal and reward was distributed across orexin cells, indicating that they specialize in rapid, multiplexed communication of momentary arousal and reward states.
Topics: Orexins; Neuropeptides; Pupil; Intracellular Signaling Peptides and Proteins; Neurons
PubMed: 37336973
DOI: 10.1038/s41593-023-01365-w -
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 -
Biological Psychiatry Dec 2022In 2014, we proposed that orexin signaling transformed motivationally relevant states into adaptive behavior directed toward exploiting an opportunity or managing a... (Review)
Review
In 2014, we proposed that orexin signaling transformed motivationally relevant states into adaptive behavior directed toward exploiting an opportunity or managing a threat, a process we referred to as motivational activation. Advancements in animal models since then have permitted higher-resolution measurements of motivational states; in particular, the behavioral economics approach for studying drug demand characterizes conditions that lead to the enhanced motivation that underlies addiction. This motivational plasticity is paralleled by persistently increased orexin expression in a topographically specific manner-a finding confirmed across species, including in humans. Normalization of orexin levels also reduces drug motivation in addiction models. These new advancements lead us to update our proposed framework for the orexin function. We now propose that the capacity of orexin neurons to exhibit dynamic shifts in peptide production contributes to their role in adaptive motivational regulation and that this is achieved via a pool of reserve orexin neurons. This reserve is normally bidirectionally recruited to permit motivational plasticity that promotes flexible, adaptive behavior. In pathological states such as addiction, however, we propose that the orexin system loses capacity to adaptively adjust peptide production, resulting in focused hypermotivation for drug, driven by aberrantly and persistently high expression in the orexin reserve pool. This mechanistic framework has implications for the understanding and treatment of several psychiatric disorders beyond addiction, particularly those characterized by motivational dysfunction.
Topics: Animals; Humans; Orexins; Neuropeptides; Intracellular Signaling Peptides and Proteins; Behavior, Addictive; Motivation; Orexin Receptors
PubMed: 36328706
DOI: 10.1016/j.biopsych.2022.06.027 -
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 -
Current Topics in Behavioral... 2017One decade ago, our laboratory provided the first direct evidence linking orexin/hypocretin signaling with drug seeking by showing that activation of these neurons... (Review)
Review
One decade ago, our laboratory provided the first direct evidence linking orexin/hypocretin signaling with drug seeking by showing that activation of these neurons promotes conditioned morphine-seeking behavior. In the years since, contributions from many investigators have revealed roles for orexins in addiction for all drugs of abuse tested, but only under select circumstances. We recently proposed that orexins play a fundamentally unified role in coordinating "motivational activation" under numerous behavioral conditions, and here we unpack this hypothesis as it applies to drug addiction. We describe evidence collected over the past 10 years that elaborates the role of orexin in drug seeking under circumstances where high levels of effort are required to obtain the drug, or when motivation for drug reward is augmented by the presence of external stimuli like drug-associated cues/contexts or stressors. Evidence from studies using traditional self-administration and reinstatement models, as well as behavioral economic analyses of drug demand elasticity, clearly delineates a role for orexin in modulating motivational, rather than the primary reinforcing aspects of drug reward. We also discuss the anatomical interconnectedness of the orexin system with wider motivation and reward circuits, with a particular focus on how orexin modulates prefrontal and other glutamatergic inputs onto ventral tegmental area dopamine neurons. Last, we look ahead to the next decade of the research in this area, highlighting the recent FDA approval of the dual orexin receptor antagonist suvorexant (Belsomra) for the treatment of insomnia as a promising sign of the potential clinical utility of orexin-based therapies for the treatment of addiction.
Topics: Animals; Behavior, Addictive; Humans; Orexins
PubMed: 28012090
DOI: 10.1007/7854_2016_57 -
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 -
Neurotherapeutics : the Journal of the... Apr 2018The hypothalamus is involved in the regulation of homeostatic mechanisms and migraine-related trigeminal nociception and as such has been hypothesized to play a central... (Review)
Review
The hypothalamus is involved in the regulation of homeostatic mechanisms and migraine-related trigeminal nociception and as such has been hypothesized to play a central role in the migraine syndrome from the earliest stages of the attack. The hypothalamus hosts many key neuropeptide systems that have been postulated to play a role in this pathophysiology. Such neuropeptides include but are not exclusive too orexins, oxytocin, neuropeptide Y, and pituitary adenylate cyclase activating protein, which will be the focus of this review. Each of these peptides has its own unique physiological role and as such many preclinical studies have been conducted targeting these peptide systems with evidence supporting their role in migraine pathophysiology. Preclinical studies have also begun to explore potential therapeutic compounds targeting these systems with some success in all cases. Clinical efficacy of dual orexin receptor antagonists and intranasal oxytocin have been tested; however, both have yet to demonstrate clinical effect. Despite this, there were limitations in these cases and strong arguments can be made for the further development of intranasal oxytocin for migraine prophylaxis. Regarding neuropeptide Y, work has yet to begun in a clinical setting, and clinical trials for pituitary adenylate cyclase activating protein are just beginning to be established with much optimism. Regardless, it is becoming increasingly clear the prominent role that the hypothalamus and its peptide systems have in migraine pathophysiology. Much work is required to better understand this system and the early stages of the attack to develop more targeted and effective therapies aimed at reducing attack susceptibility with the potential to prevent the attack all together.
Topics: Animals; Clinical Trials as Topic; Humans; Hypothalamus; Migraine Disorders; Neuropeptide Y; Nociception; Orexins; Oxytocin; Pituitary Adenylate Cyclase-Activating Polypeptide; Treatment Outcome
PubMed: 29442286
DOI: 10.1007/s13311-017-0602-3