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Brain Research Mar 2020Orexin has been implicated in a number of physiological functions, including arousal, regulation of sleep, energy metabolism, appetitive behaviors, stress, anxiety,... (Review)
Review
Orexin has been implicated in a number of physiological functions, including arousal, regulation of sleep, energy metabolism, appetitive behaviors, stress, anxiety, fear, panic, and cardiovascular control. In this review, we will highlight research focused on orexin system in the medial hypothalamic regions of perifornical (PeF) and dorsomedial hypothalamus (DMH), and describe the role of this hypothalamic neuropeptide in the behavioral expression of panic and consequent fear and avoidance responses, as well as sympathetic regulation and possible development of chronic hypertension. We will also outline recent data highlighting the clinical potential of single and dual orexin receptor antagonists for neuropsychiatric conditions including panic, phobia, and cardiovascular conditions, such as in hypertension.
Topics: Animals; Brain; Humans; Hypertension; Hypothalamus, Middle; Neural Pathways; Orexin Receptor Antagonists; Orexins; Panic; Phobic Disorders; Stress, Psychological
PubMed: 30205108
DOI: 10.1016/j.brainres.2018.09.010 -
Frontiers of Neurology and Neuroscience 2021Significant sleep impairments often accompany substance use disorders (SUDs). Sleep disturbances in SUD patients are associated with poor clinical outcomes and treatment... (Review)
Review
Significant 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 a promising therapeutic target for treating SUDs and their comorbid sleep deficits. Here, we review the literature on the role of the orexin system in sleep and drug addiction and discuss the therapeutic potential of orexin receptor antagonists for SUDs. We argue that orexin receptor antagonists may be effective therapeutics for treating addiction because they target orexin's regulation of sleep (top-down) and motivation (bottom-up) pathways.
Topics: Animals; Behavior, Addictive; Humans; Motivation; Orexin Receptor Antagonists; Orexins; Reward; Sleep Initiation and Maintenance Disorders; Substance-Related Disorders
PubMed: 34052815
DOI: 10.1159/000514965 -
Frontiers in Psychiatry 2022Orexins are polypeptides regulating appetite, sleep-wake cycle, and cognition functions, which are commonly disrupted in patients with schizophrenia. Patients with...
BACKGROUND
Orexins are polypeptides regulating appetite, sleep-wake cycle, and cognition functions, which are commonly disrupted in patients with schizophrenia. Patients with schizophrenia show a decreased connectivity between the prefrontal cortex and midline-anterior thalamus, and orexin can directly activate the axon terminal of cells within the prefrontal cortex and selectively depolarize neurons in the midline intralaminar nuclei of the thalamus. To address the relationship between orexin and schizophrenia, this study performed a meta-analysis on the alteration of plasma orexin-A levels in patients with schizophrenia.
METHOD
We searched eligible studies in PubMed, Embase, Cochrane, and China National Knowledge Infrastructure (CNKI) from 1998 to September 3, 2021. A total of 8 case-control studies were included in the meta-analyses, providing data on 597 patients with schizophrenia and 370 healthy controls. The Stata version 16.0 software was used to calculate the Hedges's adjusted g with 95% confidence intervals (CI).
RESULTS
The plasma orexin-A levels were not altered in subjects with schizophrenia ( = 597) when compared to healthy controls ( = 370). Subgroup analyses of gender (male and female vs. only male), country (China vs. other countries), medication (medication vs. non-medication), and the measurement of plasma orexin-A (Enzyme-linked immunosorbent assay vs. radioimmunoassay) revealed heterogeneity ranging from 30.15 to 98.15%, but none showed a significant alteration of plasma orexin-A levels in patients with schizophrenia. Heterogeneity was lower in the other countries and radioimmunoassay subgroup, while other subgroups remained to be highly heterogeneous. No significant evidence of publication bias was found either in Begg's test or the Egger's test.
CONCLUSION
The present meta-analysis indicated that patients with schizophrenia did not show abnormal plasma levels of orexin-A.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021283455, identifier: CRD42021283455.
PubMed: 35693955
DOI: 10.3389/fpsyt.2022.879414 -
Current Biology : CB Apr 2023Waking behaviors such as sitting or standing require suitable levels of muscle tone. But it is unclear how arousal and motor circuits communicate with one another so...
Waking behaviors such as sitting or standing require suitable levels of muscle tone. But it is unclear how arousal and motor circuits communicate with one another so that appropriate motor tone occurs during wakefulness. Cataplexy is a peculiar condition in which muscle tone is involuntarily lost during normal periods of wakefulness. Cataplexy therefore provides a unique opportunity for identifying the signaling mechanisms that synchronize motor and arousal behaviors. Cataplexy occurs when hypothalamic orexin neurons are lost in narcolepsy; however, it is unclear if motor-arousal decoupling in cataplexy is directly or indirectly caused by orexin cell loss. Here, we used genomic, proteomic, chemogenetic, electrophysiological, and behavioral assays to determine if grafting orexin cells into the brain of cataplectic (i.e., orexin) mice restores normal motor-arousal behaviors by preventing cataplexy. First, we engineered immortalized orexin cells and found that they not only produce and release orexin but also exhibit a gene profile that mimics native orexin neurons. Second, we show that engineered orexin cells thrive and integrate into host tissue when transplanted into the brain of mice. Next, we found that grafting only 200-300 orexin cells into the dorsal raphe nucleus-a region densely innervated by native orexin neurons-reduces cataplexy. Last, we show that real-time chemogenetic activation of orexin cells restores motor-arousal synchrony by preventing cataplexy. We suggest that orexin signaling is critical for arousal-motor synchrony during wakefulness and that the dorsal raphe plays a pivotal role in coupling arousal and motor behaviors.
Topics: Mice; Animals; Cataplexy; Orexins; Proteomics; Arousal; Wakefulness; Dorsal Raphe Nucleus; Cell Transplantation
PubMed: 37044089
DOI: 10.1016/j.cub.2023.03.077 -
Physiology & Behavior Sep 2020In the brain, long-term memories correspond to changes in synaptic weights after certain patterns of neural activity. Behaviourally, this corresponds to a change in... (Review)
Review
In the brain, long-term memories correspond to changes in synaptic weights after certain patterns of neural activity. Behaviourally, this corresponds to a change in action evoked by a repeating experience. Forming and updating memories (learning, remembering, forgetting) is fundamental for most aspects of cognitive and motor performance. The roles of the cortex, hippocampus, and amygdala have been studied extensively in this context. However, the lateral hypothalamus - a brain-wide projecting region traditionally known as a nutrient-sensor and controller of arousal and motivation - is also critical for updating many types of associative and non-associative memories. Does the hypothalamus play a primary role in learning, or are hypothalamic effects on learning secondary to changes in brain state such as attention/motivation? We argue that such primary and secondary effects are distinguishable under experimental conditions where attention/motivation states are constant or absent, e.g. during sleep or in reduced in vitro preparations. The documented control by hypothalamus-unique transmitters, such as orexin and MCH, of synaptic strength in isolated brain slice preparations implies a primary role for the hypothalamus in synaptic weight updating, rather than a secondary role due to changes in arousal/attention/motivation states (which are absent in brain slices). Such hypothalamic control of memory-related synaptic machinery may enable gating/thresholding/permissive/tagging operations within yet poorly defined logic gates for memory updating. Hypothalamic signals may thus facilitate cost-benefit analysis of learning and memory in real-world settings. Whether the hypothalamus controls only specific types of learning, or broadcasts a global signal for memory updating, remains to be elucidated.
Topics: Hypothalamic Hormones; Hypothalamus; Intracellular Signaling Peptides and Proteins; Melanins; Neurons; Neuropeptides; Orexins; Pituitary Hormones
PubMed: 32485184
DOI: 10.1016/j.physbeh.2020.112988 -
Neuroscience Jun 2020Palatable taste can stimulate appetite in the absence of hunger, and individual differences in hedonic eating may be critical to overeating. Women are more prone to...
Palatable taste can stimulate appetite in the absence of hunger, and individual differences in hedonic eating may be critical to overeating. Women are more prone to obesity and binge eating than men, which warrants comparisons of hedonic versus physiological consumption and the underlying neural substrates in both sexes. The current study examined palatable (high-sugar) food consumption in male and female rats under physiological hunger and satiety, and the role of the neuropeptide orexin/hypocretin (ORX). Across multiple tests, females consistently consumed similar amounts of palatable food regardless of whether they were hungry or sated prior to testing. In contrast, males typically adjusted their consumption according to their hunger/satiety state. This difference was specific to palatable food consumption, as both sexes ate standard chow according to their hunger state. ORX is important in food motivation and reward behaviors. Thus, to begin to determine the neuronal mechanisms of hedonic eating, we examined activation and signaling of ORX neurons. We systematically characterized Fos induction patterns of ORX neurons across the entire rostrocaudal extent of the lateral hypothalamus and found that they were activated by food and by fasting in both sexes. Then, we showed that systemic blockade of ORX receptor 1 signaling with SB-334867 decreased palatable food consumption in hungry and sated rats of both sexes. These results demonstrate sex differences in hedonic eating; increased susceptibility in females to overeat palatable food regardless of hunger state, and that ORX is a critical neuropeptide mechanism of hedonic eating in both sexes.
Topics: Animals; Bulimia; Eating; Female; Hunger; Male; Motivation; Orexins; Rats; Sex Characteristics
PubMed: 32283183
DOI: 10.1016/j.neuroscience.2020.04.008 -
The Journal of Pharmacy Technology :... Oct 2022To review the safety, efficacy, and tolerability of daridorexant in treating insomnia characterized by difficulties with sleep onset and/or sleep maintenance in adult... (Review)
Review
To review the safety, efficacy, and tolerability of daridorexant in treating insomnia characterized by difficulties with sleep onset and/or sleep maintenance in adult patients. A literature search was performed through PubMed using the following key terms: , and . Selected articles included those which described clinical studies of the pharmacokinetics, efficacy, safety, or tolerability of daridorexant. Daridorexant works through antagonism of the dual orexin receptor. It is the third agent in this class of medications approved by the U.S. Food and Drug Administration (FDA). Daridorexant, at a dose of 25 mg to 50 mg, was shown to be effective in improving sleep parameters in phase 3 clinical studies and was well tolerated. Adverse event rates from phase 2 and 3 clinical trials were low with fatigue, nasopharyngitis, gait disturbance, somnolence, diarrhea, and headache most commonly reported. All currently available agents for treating insomnia have received a "weak" recommendation in the clinical practice guidelines, including the dual orexin receptor antagonist class of medications. Initial data suggest that with routine use daridorexant does not impair next day functioning, a common issue with other agents used to treat insomnia. In addition, daridorexant appears to be as safe and effective in treating insomnia in patients of all ages including those ≥65 years of age.
PubMed: 36046352
DOI: 10.1177/87551225221112546 -
The Journal of Neuroscience : the... Aug 2022The ability to perform skilled arm movements is central to everyday life, as limb impairments in common neurologic disorders such as stroke demonstrate. Skilled arm...
The ability to perform skilled arm movements is central to everyday life, as limb impairments in common neurologic disorders such as stroke demonstrate. Skilled arm movements require adaptation of motor commands based on discrepancies between desired and actual movements, called sensory errors. Studies in humans show that this involves predictive and reactive movement adaptations to the errors, and also requires a general motivation to move. How these distinct aspects map onto defined neural signals remains unclear, because of a shortage of equivalent studies in experimental animal models that permit neural-level insights. Therefore, we adapted robotic technology used in human studies to mice, enabling insights into the neural underpinnings of motivational, reactive, and predictive aspects of motor adaptation. Here, we show that forelimb motor adaptation is regulated by neurons previously implicated in motivation and arousal, but not in forelimb motor control: the hypothalamic orexin/hypocretin neurons (HONs). By studying goal-oriented mouse-robot interactions in male mice, we found distinct HON signals occur during forelimb movements and motor adaptation. Temporally-delimited optosilencing of these movement-associated HON signals impaired sensory error-based motor adaptation. Unexpectedly, optosilencing affected neither task reward or execution rates, nor motor performance in tasks that did not require adaptation, indicating that the temporally-defined HON signals studied here were distinct from signals governing general task engagement or sensorimotor control. Collectively, these results reveal a hypothalamic neural substrate regulating forelimb motor adaptation. The ability to perform skilled, adaptable movements is a fundamental part of daily life, and is impaired in common neurologic diseases such as stroke. Maintaining motor adaptation is thus of great interest, but the necessary brain components remain incompletely identified. We found that impaired motor adaptation results from disruption of cells not previously implicated in this pathology: hypothalamic orexin/hypocretin neurons (HONs). We show that temporally confined HON signals are associated with skilled movements. Without these newly-identified signals, a resistance to movement that is normally rapidly overcome leads to prolonged movement impairment. These results identify natural brain signals that enable rapid and effective motor adaptation.
Topics: Animals; Forelimb; Humans; Male; Mice; Movement; Orexins; Stroke; Upper Extremity
PubMed: 35790405
DOI: 10.1523/JNEUROSCI.0705-22.2022 -
Autonomic Neuroscience : Basic &... Nov 2020Orexin (OX), which regulates sleep and wakefulness and feeding behaviors has 2 isoforms, orexin-A and -B (OXA and OXB). In this study, the distribution of OXA and OXB...
Orexin (OX), which regulates sleep and wakefulness and feeding behaviors has 2 isoforms, orexin-A and -B (OXA and OXB). In this study, the distribution of OXA and OXB was examined in the rat superior salivatory nucleus (SSN) using retrograde tracing and immunohistochemical and methods. OXA- and OXB-immunoreactive (-ir) nerve fibers were seen throughout the SSN. These nerve fibers surrounded SSN neurons retrogradely labeled with Fast blue (FB) from the corda-lingual nerve. FB-positive neurons had pericellular OXA- (47.5%) and OXB-ir (49.0%) nerve fibers. Immunohistochemistry for OX receptors also demonstrated the presence of OX1R and OX2R in FB-positive SSN neurons. The majority of FB-positive SSN neurons contained OX1R- (69.7%) or OX2R-immunoreactivity (57.8%). These neurons had small and medium-sized cell bodies. In addition, half of FB-positive SSN neurons which were immunoreactive for OX1R (47.0%) and OX2R (52.2%) had pericellular OXA- and OXB-ir nerve fibers, respectively. Co-expression of OX1R- and OX2R was common in FB-positive SSN neurons. The present study suggests a possibility that OXs regulate the activity of SSN neurons through OX receptors.
Topics: Animals; Autonomic Fibers, Preganglionic; Facial Nerve; Immunohistochemistry; Male; Orexin Receptors; Orexins; Rats; Rats, Wistar; Sublingual Gland; Submandibular Gland
PubMed: 32721850
DOI: 10.1016/j.autneu.2020.102712 -
Physiology & Behavior May 2021The intranasal (IN) administration of neuropeptides, such as insulin and orexins, has been suggested as a treatment strategy for age-related cognitive decline (ARCD).... (Review)
Review
The intranasal (IN) administration of neuropeptides, such as insulin and orexins, has been suggested as a treatment strategy for age-related cognitive decline (ARCD). Because dysfunctional neuropeptide signaling is an observed characteristic of ARCD, it has been suggested that IN delivery of insulin and/or orexins may restore endogenous peptide signaling and thereby preserve cognition. IN administration is particularly alluring as it is a relatively non-invasive method that directly targets peptides to the brain. Several laboratories have examined the behavioral effects of IN insulin in young, aged, and cognitively impaired rodents and humans. These studies demonstrated improved performance on various cognitive tasks following IN insulin administration. Fewer laboratories have assessed the effects of IN orexins; however, this peptide also holds promise as an effective treatment for ARCD through the activation of the cholinergic system and/or the reduction of neuroinflammation. Here, we provide a brief overview of the advantages of IN administration and the delivery pathway, then summarize the current literature on IN insulin and orexins. Additional preclinical studies will be useful to ultimately uncover the mechanisms underlying the pro-cognitive effects of IN insulin and orexins, whereas future clinical studies will aid in the determination of the most efficacious dose and dosing paradigm. Eventually, IN insulin and/or orexin administration may be a widely used treatment strategy in the clinic for ARCD.
Topics: Administration, Intranasal; Aged; Cognitive Dysfunction; Humans; Insulin; Neuropeptides; Orexin Receptors; Orexins
PubMed: 33621561
DOI: 10.1016/j.physbeh.2021.113370