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Schematic drawing showing main projections of orexin neurons.This figure summarizes predicted orexinergic projections in the human brain. Please note that distributions of orexin fibres and receptors (OX1R, OX2R) are predicted from the results of studies on rodent brains, as it is on rodents that most histological studies on the orexin system have been carried out. Circles show regions with strong receptor expression and dense orexinergic projections. Orexin neurons originating in the lateral hypothalamic area (LHA) and posterior hypothalamus (PH) regulate sleep and wakefulness and the maintenance of arousal by sending excitatory projections to the entire CNS, excluding the cerebellum, with particularly dense projections to monoaminergic and cholinergic nuclei in the brain stem and hypothalamic regions24, 25, 26, 27, 28, 29, 30, 31, 32, 38, including the locus coeruleus (LC, containing noradrenaline), tuberomammillary nucleus (TMN, containing histamine), raphe nuclei (Raphe, containing serotonin) and laterodorsal/pedunclopontine tegmental nuclei (LDT/PPT), containing acetylcholine). Orexin neurons also have links with the reward system through the ventral tegmental area (VTA, containing dopamine) and with the hypothalamic nuclei that stimulate feeding behaviour. Anatomical image adapted, with permission, from Ref. 108 © (1996) Appleton & Lange.
Source publication
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) sys...
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Context 1
... . These neurons are variable in size (the cell body diameter ranges from 15-40 μm) and shape (spherical, fusiform or multipolar), and have been assumed to number around 3000 in the rat brain, or 7000 in the human brain 25,26 . From these regions, orexin neurons project widely to the entire neuroaxis, excluding the cerebellum [24][25][26] (FIG. 1). The densest staining of orexin-immunoreactive nerve endings in the brain is found in the paraventricular nucleus of the thalamus, the arcuate nucleus and, most notably, the locus coeruleus (LC, containing noradrenergic neurons), dorsal raphe (DR, which contains sero- tonergic neurons) and tuberomammillary nucleus (TMN, containing ...
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Orexins are novel appetite-stimulating peptides expressed in the lateral hypothalamic area (LHA), and their expression is stimulated by hypoglycemia in fasted rats. We investigated activation of orexin and other neurons during insulin-induced hypoglycemia using the immediate early gene product Fos. Insulin (50 U/kg) lowered plasma glucose by >50% a...
Narcolepsy is a human sleep disorder resulting from the loss of neurons containing the neuropeptide orexin, also known as hypocretin. Cataplexy, which is a sudden loss of muscle tone during waking, is an important diagnostic symptom of narcolepsy. In humans and canines with narcolepsy, cataplexy is considered to be a separate and distinct behaviora...
Hypocretin (Hcrt or orexin) somas are located in the hypothalamus and project widely to forebrain and brainstem regions, densely innervating monoaminergic and cholinergic cells. Loss of Hcrt function results in the sleep disorder narcolepsy. However, the normal pattern of Hcrt release across the sleep-wake cycle is unknown. We monitored Hcrt-1 rele...
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Citations
... Un proceso que pudiera explicar la falta de sueño con el aumento de peso se relaciona con alteraciones de hormonas reguladoras del apetito. Como se mencionó, una serie de estudios ha demostrado a corto plazo que la grelina y la leptina se ven alteradas aún por una o dos noches de sueño reducido; la leptina disminuye y la grelina aumenta, resultando de ello mayor sensación de hambre (Sakurai, 2007). Estos cambios internos temporales podrían ser factores inductores de la sobre ingestión de alimentos, que a largo plazo ante desvelos constantes llevarían a una pérdida del control del apetito, al sobre peso y obesidad. ...
Estudio y efecto del sobrepeso y obesidad se considera un importante problema de salud en la sociedad que ha ido incrementando en los últimos años, de igual manera a nivel global, se realizó ensayo sobre el índice de masa corporal (IMC) aplicando la metodología propuesta por comité de expertos de la FAO / OMS / UNU (Universidad de las Naciones Unidas), las siguientes ecuaciones para calcular el gasto energético en reposo (lo cual incluye el metabolismo basal y el efecto térmico de los alimentos), de igual manera el gasto energético total para determinar de acuerdo a variables como sexo, edad, talla, actividad física, mediante el método de dieta equilibrada, el requerimiento energético por individuo estudiado. Mediante encuesta se determinó la métrica, una vez que se obtuvieron estos datos se realizó el cálculo correspondiente para el IMC, mediante hoja de cálculo en Excel y con estos datos una tabla de distribución de frecuencias basada en una clasificación del estado nutricional según la OMS.
Mediante el cálculo de IMC, se determinó que el 56% de la población estudiada está en estado nutricio normal de acuerdo con la escala para obtener información sobre la composición corporal, Según Adolph Quetelet “los investigadores han elaborado índices que permiten conocer el grado de adiposidad. El índice peso/talla más utilizado es el Índice de Masa Corporal (IMC) (BMI=Body Mass Index) o Índice de Quetelet” (Quetelet en 1871), el cual se obtiene dividiendo el peso en kilogramos entre la estatura en metros al cuadrado: IMC = Peso (kg)/Estatura (m)2, de acuerdo esta fórmula un 25% de los encuestados sufren sobre peso, obesidad I, el 9%, obesidad II 1% y 2% obesidad III, de igual manera un 5% anda por debajo de la media de lo normal, conocida como desnutrición I, 1% de la población se encuentran en desnutrición II y III respectivamente, de acuerdo al estado nutricional de la población estudiada de la comunidad universitaria de la UNAH, Campos Copán.
En nuestro ensayo de investigación se pudo observar, que el porcentaje de sobrepeso es proporcional a la edad, a medida se crece en edad hay muchos factores entre ellos los más importantes el sedentarismo y la mala alimentación, esto tiene un efecto en la salud, siendo los más comunes, problemas para dormir con un 10%, problemas en la piel 10%, reflujo gastroesofágico 9% y un 45% de la muestra estudiada en un rango de edad en el ciclo de vida de Adolescencia tardía hasta la vejez, no muestran problemas de salud, la solución a los problema de salud se pueden mitigar o mejorar al cambiar hábitos como ser practicar un deporte 24%, hacer ejercicio con regularidad 21%, límite de consumo de alimentos no saludables un 16% (Cereales, dulces refinados, alimentos procesados, bebidas carbonatadas entre otros), consumo de dieta bien equilibrada 14%, mantener un peso corporal saludable 8%, por lo cual estos hábitos son importantes adaptarlos de acuerdo al ciclo de vida del ser humano desde el periodo prenatal hasta la vejez.
... Both orexin receptors are probably capable of binding to G i/o , G s and G q family G proteins; however, this may depend on the texture and specific modulation 20 . Orexins play an important role in appetite, energy homeostasis, feeding, arousal and sleep 21,22 . Studies investigating the orexin-epilepsy relationship have conflicting results. ...
The goal of this study is to clarified the effect of orexinergic system and interaction between orexinergic and cannabinoid systems in WAG/Rij rats. WAG/Rij rats were used to electrocorticogram recordings. 0.6 µg hemopressin, 7.5 µg arachidonyl-2՛-chloroethylamide hydrate (ACEA), 0.50 µg AM-251 and also 4, 8, 16 µg doses of OX-A, 6 and 12 µg doses of SB334867 applied and effective doses were determined. After three hours of baseline recording in rats, the effective doses of the substance were applied by intracerebroventricularly, and recording continued for three more hours. Interaction groups were also subjected to the same procedure. Records were analyzed in terms of seizure duration and number, spike number and amplitude. 8 µg OX-A and 12 µg SB334867 significantly decreased the duration and number of seizures, spike number, excluding amplitude (P<0.05). While hemopressin and ACEA decreased absence seizure activity, AM-251 increased it. When application of OX-A+hemopressin, spike wave discharges (SWDs) activity reduced and it was determined that OX-A showed an activity similar to its own effect. Since the effect of the SB334867+hemopressin group was similar to the effect of SB334867 alone, it is thought that the effect of orexins on the cannabinoid pathway may more effective than the hemopressin. In SB334867+AM-251 groups, SWDs activity significantly reduced and the proconvulsant effect of AM-251 was blocked by SB334867. In OX-A+AM-251 group, SWDs activity decreased. This results may show that the orexinergic system is more effective than the cannabinoid system.
... For example, loss of orexin function promotes narcolepsy-cataplexy as well as increased body weight in narcoleptic patients [83]. Conversely, orexin release maintains wakefulness and increased orexin levels correlate with weigh reduction in adolescents [84], indicating that increased orexin signaling promotes obesity resistance (for review on the relationships between orexin and body weight, see Sakurai [85], Perez-Leighton et al. [86], Mahoney et al. [87]). ...
The hypothalamic neuropeptide system of orexin (hypocretin) neurons provides projections throughout the neuraxis and has been linked to sleep regulation, feeding and motivation for salient rewards including drugs of abuse. However, relatively little has been done to examine genes associated with orexin signaling and specific behavioral phenotypes in humans. Here, we tested for association of twenty-seven genes involved in orexin signaling with behavioral phenotypes in humans. We tested the full gene set, functional subsets, and individual genes involved in orexin signaling. Our primary phenotype of interest was Externalizing, a composite factor comprised of behaviors and disorders associated with reward-seeking, motivation, and behavioral regulation. We also tested for association with additional phenotypes that have been related to orexin regulation in model organism studies, including alcohol consumption, problematic alcohol use, daytime sleepiness, insomnia, cigarettes per day, smoking initiation, and body mass index. The composite set of 27 genes corresponding to orexin function was highly associated with Externalizing, as well as with alcohol consumption, insomnia, cigarettes per day, smoking initiation and BMI. In addition, all gene subsets (except the OXR2/HCRTR2 subset) were associated with Externalizing. BMI was significantly associated with all gene subsets. The “validated factors for PPOX/HCRT” and “PPOX/HCRT upregulation” gene subsets also were associated with alcohol consumption. Individually, 8 genes showed a strong association with Externalizing, 12 with BMI, 7 with smoking initiation, 3 with alcohol consumption, and 2 with problematic alcohol use, after correction for multiple testing. This study indicates that orexin genes are associated with multiple behaviors and disorders related to self-regulation in humans. This is consistent with prior work in animals that implicated orexin signaling in motivational activation induced by salient stimuli, and supports the hypothesis that orexin signaling is an important potential therapeutic target for numerous behavioral disorders.
... On a biological level, this relationship is supported by evidence suggesting that depression is often linked to imbalances in cholinergic and monoaminergic neurotransmitters [86], which play crucial roles in regulating rapid eye movement (REM) sleep [87]. Another important factor influencing sleep quality is orexin (hypocretin) [88] a neuropeptide involved in both sleep-wake regulation and the modulation of emotions and depression [89]. In summary, our findings validate the initial hypothesis that depression mediates the relationship between social network site addiction and sleep quality in adolescents, with this conclusion further supported by biological evidence. ...
Background and objectives
Social network site addiction is strongly correlated with sleep quality among adolescents. However, the underlying mechanisms driving these relationships require further exploration. This study aims to supplement the understanding of the psychological mechanisms linking social network site addiction and sleep quality by investigating depression as a mediating factor and difficulty describing feelings as a moderating factor.
Methods
A self-report survey was conducted with 1,670 adolescents in China, assessing social network site addiction, sleep quality, depression, and difficulty describing feelings. Descriptive and correlational analyses were performed on these variables, followed by the construction of a moderated mediation model.
Results
Social network site addiction was significantly positively correlated with sleep quality, depression, and difficulty describing feelings among adolescents. Difficulty describing feelings was also significantly positively correlated with depression. Depression partially mediated the relationship between social network site addiction and sleep quality, while difficulty describing feelings intensified the relationship between social network site addiction and depression.
Conclusion
This study further elucidates the psychological mechanisms linking social network site addiction and sleep quality in adolescents. Depression acts as a mediating factor, while difficulty describing feelings strengthens the relationship between social network site addiction and depression. These findings highlight the role of difficulty describing feelings in the interplay between social network site addiction and sleep quality, offering valuable insights for a more comprehensive understanding and targeted interventions aimed at improving sleep quality in adolescents.
... We also found a significant decrease in the activity of orexin A neurons in LH regions in tributyrin-treated mice. A large body of evidence indicates that LH Ox neurons play an important role in the generation of wakefulness [50], and the dysfunction of LH Ox networks has been proposed to be related to the pathophysiology of insomnia. Either orexin overexpression or orexin neuron hyperactivity was shown to be involved in the pathology of insomnia [51]. ...
Sleep interacts reciprocally with the gut microbiota. However, mechanisms of the gut microbe-brain metabolic axis that are responsible for sleep behavior have remained largely unknown. Here, we showed that the absence of the gut microbiota can alter sleep behavior. Sleep deprivation reduced butyrate levels in fecal content and the hypothalamus in specific pathogen-free mice but not in germ-free mice. The microbial metabolite butyrate can promote sleep by modulating orexin neuronal activity in the lateral hypothalamic area in mice. Insomnia patients had lower serum butyrate levels and a deficiency in butyrate-producing species within the gut microbiota. Transplantation of the gut microbiota from insomnia patients to germ-free mice conferred insomnia-like behaviors, accompanied by a decrease in serum butyrate levels. The oral administration of butyrate rescued sleep disturbances in recipient mice. Overall, these findings reveal the causal role of microbial metabolic pathways in modulating insomnia-like behaviors, suggesting potential therapeutic strategies for treating sleep disorders.
... TNF-α has been documented to suppress the expression of the orexin receptor 2 (OX2R) 24 , a specific target for orexin ligands 25,26 . Previous research has demonstrated that OX2R knockout mice exhibit narcolepsy-like phenotypes, and the administration of an OX2R agonist can enhance wakefulness [27][28][29] . We also found a pronounced reduction in mRNA expression of the Hcrtr2 gene, encoding the OX2R, in the PVT on day 1 after LPS injection. ...
... Previous research has demonstrated that OX2R are important for maintaining wakefulness. For example, OX2R knockout mice exhibit narcolepsy-like phenotypes 27,28 , and the administration of an OX2R agonist can enhance wakefulness in mice 29 . OX2R pathway may mediate the reduction in neuronal activity in the PVT associated with neuroinflammation and the subsequent sleepiness. ...
Sleepiness is commonly associated with neuroinflammation; however, the underlying neuroregulatory mechanisms remain unclear. Previous research suggests that the paraventricular thalamus (PVT) plays a crucial role in regulating sleep‐wake dynamics; thus, neurological abnormalities in the PVT may contribute to neuroinflammation-induced sleepiness. To test this hypothesis, we performed electroencephalography recordings in mice treated with lipopolysaccharide (LPS) and found that the mice exhibited temporary sleepiness lasting for 7 days. Using the Fos-TRAP method, fiber photometry recordings, and immunofluorescence staining, we detected temporary PVT neuron hypoactivation and microglia activation from day 1 to day 7 post-LPS treatment. Combining the results of bulk and single-cell RNA sequencing, we found upregulation of aconitate decarboxylase 1 (Acod1) in PVT microglia post-LPS treatment. To investigate the role of Acod1, we manipulated Acod1 gene expression in PVT microglia via stereotactic injection of short hairpin RNA adenovirus. Knockdown of Acod1 exacerbated inflammation, neuronal hypoactivation, and sleepiness. Itaconate is a metabolite synthesized by the enzyme encoded by Acod1. Finally, we confirmed that exogenous administration of an itaconate derivative, 4-octyl itaconate, could inhibit microglia activation, alleviate neuronal dysfunction, and relieve sleepiness. Our findings highlight PVT’s role in inflammation-induced sleepiness and suggest Acod1 as a potential therapeutic target for neuroinflammation.
... The orexin system is crucial for the regulation of the sleep-wake cycle [47,48]; hence, it is reasonable to assume that this system is involved in CJL-induced symptoms [49,50]. However, to the best of our knowledge, no published studies have shown that CJL and/ or CRSD are associated with changes in the orexin system. ...
Cognitive flexibility and working memory are important executive functions mediated by the prefrontal cortex and can be impaired by circadian rhythm disturbances such as chronic jet lag (CJL) or shift work. In the present study, we used mice to investigate whether (1) simulated CJL impairs cognitive flexibility, (2) the orexin system is involved in such impairment, and (3) nasal administration of orexin A is able to reverse CJL-induced deficits in cognitive flexibility and working memory. Mice were exposed to either standard light-dark conditions or simulated CJL consisting of series of advance time shifts. Experiment (1) investigated the effects of a mild CJL protocol on cognitive flexibility using the attentional set shifting task. Experiment (2) used a stronger CJL protocol and examined CJL effects on the orexin system utilizing c-Fos and orexin immunohistochemistry. Experiment (3) tested whether nasal orexin application can rescue CJL-induced deficits in cognitive flexibility and working memory, the latter by measuring spontaneous alternation in the Y-maze. The present data show that CJL (1) impairs cognitive flexibility and (2) reduces the activity of orexin neurons in the lateral hypothalamus. (3) Nasal administration of orexin A rescued CJL-induced deficits in working memory and cognitive flexibility. These findings suggest that executive function impairments by circadian rhythm disturbances such as CJL are caused by dysregulation of orexinergic input to the prefrontal cortex. Compensation of decreased orexinergic input by nasal administration of orexin A could be a potential therapy for CJL- or shift work-induced human deficits in executive functions.
... L6b neurons furthermore project to cortical layer 1 (L1) (Clancy and Cauller, 1999) (Tsunematsu et al., 2011). The significance of orexin in brain state control is especially apparent in narcolepsy, wherein loss of orexin signalling results in state instability, including sleep attacks and fragmented sleep (Sakurai, 2007). L6b has been postulated to be involved in brain state control by forming an orexin gated feed-forward loop driving brain state control (Hay et al., 2015). ...
One of the most distinctive features of the mammalian cerebral cortex is its laminar structure. Of all cortical layers, layer 6b (L6b) is by far the least-studied, despite exhibiting direct sensitivity to orexin and having widespread connectivity, suggesting an important role in regulating cortical oscillations and brain state. We performed chronic electroencephalogram (EEG) recordings in mice in which a subset of L6b neurons was conditionally silenced, during undisturbed conditions, after sleep deprivation (SD), and after intracerebroventricular (ICV) administration of orexin. While the total amount of waking and sleep or the response to SD were not altered, L6b-'silenced' mice showed a slowing of theta-frequency (6-9 Hz) during wake and REM sleep, and a marked reduction of total EEG power, especially in NREM sleep. The infusion of orexin A increased wakefulness in both genotypes, but the effect was more pronounced in L6b-silenced mice, while the increase in theta-activity by orexin B was attenuated in L6b silenced animals. In summary, we show the role of cortical L6b in state-dependent brain oscillations and global vigilance state control, which could be mediated by orexinergic neurotransmission. Our findings provide new insights in the understanding of abnormal regulation of arousal states in neurodevelopmental and anxiety disorders.
... As a consequence of this, the awake state is further demonstrated by the activity and movements contained within the eyes. Furthermore, multiple investigations [21] have demonstrated that, it is through the stimulation of the autonomic nervous system (ANS) through links to the ventrolateral medulla (VLM) and spinal cord that orexin is able to modulate alertness in the ANS. This stimulation ultimately leads to the suppression of sleep. ...
Annually, the global economy suffers significant financial losses due to decreased productivity of work, accidents, and crashes in traffic resulting from microsleep. To reduce the adverse impacts of microsleep, it is necessary to have a discreet, dependable, and socially acceptable method of detecting microsleep episodes consistently throughout the day, every single day. Regrettably, the current solutions fail to match these specified criteria. Moreover, by utilizing sophisticated features and employing machine learning techniques, it is possible to process electroencephalogram (EEG) information in a highly efficient manner, enabling the rapid and successful detection of microsleep. The selection of an optimum channel and the use of a competent classification algorithm are crucial for effective microsleep detection. One unique channel selecting strategy has been introduced in the current study to evaluate the classifying accuracy of microsleep detection based on EEG. This strategy is based on correlation coefficients and utilizes the K-Nearest Neighbor (KNN) method. Furthermore, the Fast Fourier Transform (FFT) was employed for extracting the feature, so validating the endurance of the proposed technique. In order to enhance the speed of the microsleep detecting system, the study was performed using 3 distinct time windows: 0.5s, 0.75s, and 1s. The study revealed that the suggested approach achieved a classification accuracy of 98.28% within a time window of 0.5 seconds to detect microsleep using EEG signal. The exceptional effectiveness of the given system can be efficiently utilized in detecting microsleep using EEG signal.
... These promising outcomes underscore the potential utility of Orx 1 R antagonists as a novel avenue for therapeutic interventions in a spectrum of psychiatric conditions, offering new possibilities for managing and alleviating symptoms related to emotional and fear-related disorders. It is noteworthy that Orx 1 R has undergone more extensive investigation regarding its role in memory (Li et al. 2014), whereas Orx 2 R (Sakurai et al. 1998) is primarily associated with sleep and wakefulness (Sakurai 2007;Saitoh and Sakurai 2023). However, recent studies have shown that Orx 1 R plays an additional role in the regulation of wakefulness and Orx 2 R in the neurobiology of fear (Soares et al. 2021;Yaeger et al. 2020Yaeger et al. , 2022aSaitoh and Sakurai 2023). ...
Rationale
Despite the existing anatomical and physiological evidence pointing to the involvement of orexinergic projections from the lateral hypothalamus (LH) in regulating fear-related responses, little is known regarding the contribution of the orexin system in the prelimbic cortex (PL) on contextual fear.
Objectives
We investigated the role of orexin-A (OrxA) and orexin type 1 receptors (Orx1R) in the PL during the expression of contextual conditioned fear in mice.
Methods
Neural tract tracing of the LH-PL pathway and Orx1R immunoreactivity in the PL of C57BL/6 male mice were performed. In a pharmacological approach, the animals were treated with either the Orx1R selective antagonist SB 334,867 (3, 30, and 300 nM/0.1 µL) or OrxA (28, 70, and 140 pmol/0.1 µL) in the PL before the test session of contextual fear conditioning.
Results
Neural tract tracing deposits in the LH showed some perikarya, mainly axons and terminal buttons in the PL, suggesting LH-PL reciprocate pathways. Furthermore, we showed a profuse network comprised of Orx1R-labeled thin varicose fibers widely distributed in the same field of LH-PL pathways projection. The selective blockade of Orx1R with SB 334,867 at 30 and 300 nM in the PL caused a decrease in freezing response, whereas the treatment with OrxA at 140 pmol promoted an increase in freezing response.
Conclusion
In summary, these data confirmed an anatomical link between LH and PL, established the presence of Orx1R in the PL, and a modulatory role of the orexin system in such structure, possibly mainly via Orx1R, during contextual fear conditioning.
