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Abstract

Regulation of the sleep-waking cycle is complex and involves diverse brain circuits and molecules. On one hand, an interplay among many neuroanatomical and neurochemical systems including acetylcholine, dopamine, noradrenaline, serotonin, histamine, and hypocretin has been shown to control the waking state. On the other hand the sleep-onset is governed by the activity of sleep-promoting neurons placed in the anterior hypothalamus that utilize GABA to inhibit wake-promoting regions. Moreover, brainstem regions inhibited during wakefulness (W) and slow wave sleeps (SWS) become active during rapid eye movement (REM) sleep. Further complexity has been introduced by the recognition of sleep-promoting molecules that accumulate in the brain in prolonged W as well as the physiological role of gene expression during sleep. The sleep-wake cycle is currently undergoing intense research with many new findings leading to new paradigms concerning sleep regulation, brain organization and sleep function. This review provides a broader understanding of our present knowledge in the field of sleep research.

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... [2] Studies show that neurotransmitters such as melatonin play an important role in sleep regulation. [3,4] Melatonin is released in darkness, and it has an effect on the initiation of sleep rather than the total amount of sleep. When melatonin is released, it decreases the body temperature and in this way creates sleepiness. ...
... [5] Experiments also show that brain regions such as the thalamus, cerebral cortex, brain stem, basal forebrain are involved in the regulation of sleep-wakefulness states. [3,5] According to experiments, electrical stimuli in the basal forebrain of cats induce sleep. [3] Sleep deprivation is defined as the disruption of the normal circadian rhythm also, it has many physiological and psychological effects. ...
... [3,5] According to experiments, electrical stimuli in the basal forebrain of cats induce sleep. [3] Sleep deprivation is defined as the disruption of the normal circadian rhythm also, it has many physiological and psychological effects. There are different types of sleep disorders such as insomnia and sleep apnea. ...
Article
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Sleep disruption and related disorders are very common among humans. However, this situation is mostly underestimated. Aside from its contribution to daily life functions, sleep quality is also important as a risk factor for a variety of diseases, including neurodegenerative disorders, metabolic diseases, and cardiovascular diseases. The diagnosis and treatment of such diseases may be difficult, but once they are treated, the patients' quality of life will greatly improve. This review aimed to compile and represent information on sleep deprivation, as well as the relationship between sleep and the immune system.
... Mechanisms relating to different aspects of sleep have been studied in both animals and humans (see [51,52]). Wakefulness is regulated by the basal forebrain, lateral hypothalamus, tuberomammillary nucleus, and brainstem, with involvement of norepinephrine, dopamine, serotonin, acetylcholine, histamine, hypocretin, and neuropeptide S systems (see [53] for review). Sleep onset is induced by cytokines and hormones, adenosine, prostaglandins, anandamide, and urotensin II (see [53] for review). ...
... Wakefulness is regulated by the basal forebrain, lateral hypothalamus, tuberomammillary nucleus, and brainstem, with involvement of norepinephrine, dopamine, serotonin, acetylcholine, histamine, hypocretin, and neuropeptide S systems (see [53] for review). Sleep onset is induced by cytokines and hormones, adenosine, prostaglandins, anandamide, and urotensin II (see [53] for review). A number of neural structures regulate sleep: the suprachiasmatic nucleus (SCN), basal forebrain, medial, lateral, and ventrolateral preoptic nuclei, and brainstem (see [53] for review). ...
... Sleep onset is induced by cytokines and hormones, adenosine, prostaglandins, anandamide, and urotensin II (see [53] for review). A number of neural structures regulate sleep: the suprachiasmatic nucleus (SCN), basal forebrain, medial, lateral, and ventrolateral preoptic nuclei, and brainstem (see [53] for review). The primary neurochemical mechanisms that regulate sleep include gamma-aminobutyric acid and acetylcholine (see [53] for review). ...
Article
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This article provides a narrative review of what is known about romantic love and sleep variations and provides possible explanations for the association. Romantic love and sleep are described using a comprehensive, unifying framework advocated by Tinbergen. We summarise the findings of studies investigating the relationship between romantic love and sleep. Sleep variations are associated with romantic love in adolescents and young adults. We then detail some proximate mechanisms that may contribute to sleep variations in people experiencing romantic love before considering potential evolutionary functions of sleep variations in people experiencing romantic love. The relationship between symptoms of psychopathology and sleep variations in people experiencing romantic love is described. With the current state of knowledge, it is not possible to determine whether sleep variations associated with romantic love are adaptations or by-products of romantic love. We conclude by proposing areas for future research.
... Norepinephrine has long been associated with promoting wakefulness. This action of norepinephrine in vivo likely involves the activation of α 1 adrenergic receptors, in which drugs that antagonize α 1 adrenergic receptors facilitate sleep onset [161]. This is likely a postsynaptic action of norepinephrine, whereas α 2 adrenergic receptor antagonists, which presynaptically increase norepinephrine release, delay sleep. ...
... This is likely a postsynaptic action of norepinephrine, whereas α 2 adrenergic receptor antagonists, which presynaptically increase norepinephrine release, delay sleep. In contrast, α 2 adrenergic receptor agonists inhibit norepinephrine release and decrease wakefulness [161,162]. Drugs that block the uptake of norepinephrine increase or prolong wakefulness [163]. Neurochemical microdialysis studies have shown that extracellular levels of norepinephrine decrease in the transition from wakefulness to sleep [164,165], and lesions of neurons in the locus coeruleus decrease waking [166]. ...
... Neuroimmune between-system neuroadaptations. Cytokines are intercellular signaling peptides that are released by immune cells, neurons, and astrocytes and have been hypothesized to be activated during alcohol withdrawal [95,183] and also influence sleep [161,184], albeit via actions on possibly different circuits. During infections, bacterial cell wall products, such as lipopolysaccharide, may trigger the production of cytokines that then increase NREM sleep and reduce REM sleep [185]. ...
Article
The development of alcohol use disorder (AUD) involves binge drinking to high levels of intoxication that leads to compulsive intake, the loss of control in limiting intake, and a negative emotional state when alcohol is removed. This cascade of events occurs over an extended period within a three-stage cycle: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. These three stages map onto the dysregulation of functional domains of incentive salience/habits, negative emotional states, and executive function, mediated by the basal ganglia, extended amygdala, and frontal cortex, respectively. Sleep disturbances, alterations of sleep architecture, and the development of insomnia are ubiquitous in AUD and also map onto the three stages of the addiction cycle. During the binge/intoxication stage, alcohol intoxication leads to a faster sleep onset, but sleep quality is poor relative to nights when no alcohol is consumed. The reduction of sleep onset latency and increase in wakefulness later in the night may be related to the acute effects of alcohol on GABAergic systems that are associated with sleep regulation and the effects on brain incentive salience systems, such as dopamine. During the withdrawal/negative affect stage, there is a decrease in slow-wave sleep and some limited recovery in REM sleep when individuals with AUD stop drinking. Limited recovery of sleep disturbances is seen in AUD within the first 30 days of abstinence. The effects of withdrawal on sleep may be related to the loss of alcohol as a positive allosteric modulator of GABAA receptors, a decrease in dopamine function, and the overactivation of stress neuromodulators, including hypocretin/orexin, norepinephrine, corticotropin-releasing factor, and cytokines. During the preoccupation/anticipation stage, individuals with AUD who are abstinent long-term present persistent sleep disturbances, including a longer latency to fall asleep, more time awake during the night, a decrease in slow-wave sleep, decreases in delta electroencephalogram power and evoked delta activity, and an increase in REM sleep. Glutamatergic system dysregulation that is observed in AUD is a likely substrate for some of these persistent sleep disturbances. Sleep pathology contributes to AUD pathology, and vice versa, possibly as a feed-forward drive to an unrecognized allostatic load that drives the addiction process.
... The neuropeptide S (NPS) and cognate receptor (NPSR) system is a newly identified sleep-waking regulation system (Adamantidis et al., 2010;Guerrini et al., 2010;Murillo-Rodriguez et al., 2012). Our previous study showed that i.c.v. ...
... injection of NPS dose-dependently reduces the duration of the loss of righting reflex seen after i.p. injection of diazepam in mice (Rizzi et al., 2008) or i.p. injection of ketamine or thiopental in rats (Kushikata et al., 2011). The NPS-NPSR system is a newly identified sleep-waking regulation system that interacts with other arousal systems (Adamantidis et al., 2010;Murillo-Rodriguez et al., 2012), such as the TMN histaminergic and the PeF and LH orexinergic systems in the posterior hypothalamus where exist a high expression of NPSR mRNA (Xu et al., 2004;Clark et al., 2011), to promote wakefulness (Murillo-Rodriguez et al., 2012). Our results showed that NPS (1, 2 and 5 nmol) mainly increased wakefulness and reduced SWS companied by an increase in EEG with fast and low-voltage activity and EMG activity for 1 h in normal rats (Figs. ...
... injection of NPS dose-dependently reduces the duration of the loss of righting reflex seen after i.p. injection of diazepam in mice (Rizzi et al., 2008) or i.p. injection of ketamine or thiopental in rats (Kushikata et al., 2011). The NPS-NPSR system is a newly identified sleep-waking regulation system that interacts with other arousal systems (Adamantidis et al., 2010;Murillo-Rodriguez et al., 2012), such as the TMN histaminergic and the PeF and LH orexinergic systems in the posterior hypothalamus where exist a high expression of NPSR mRNA (Xu et al., 2004;Clark et al., 2011), to promote wakefulness (Murillo-Rodriguez et al., 2012). Our results showed that NPS (1, 2 and 5 nmol) mainly increased wakefulness and reduced SWS companied by an increase in EEG with fast and low-voltage activity and EMG activity for 1 h in normal rats (Figs. ...
Article
Intracerebroventricular injection of NPS reduces the duration of the ketamine- or thiopental-induced loss of the righting reflex in rats. But the specific EEG activities are unknown. We therefore sought to examine the effects of the NPS-NPSR system on anesthetic-induced characteristics of EEG power spectra and sleep-wake profiles. NPS alone or together with an NPSR antagonist was injected intracerebroventricularly, whereas the propofol (50 mg/kg) or ketamine (100 mg/kg) was administrated intraperitoneally. NPS (1 or 2 nmol) significantly reduced the amount of propofol-induced EEG delta activity and slow wave states (SWS). NPS (1 or 5 nmol) significantly reduced the amount of ketamine-induced SWS and EEG delta activity. Cortical EEG power spectral analysis showed that, in saline-pretreated rats, propofol induced a marked increase in delta (0.5–4 Hz) activity, decrease in theta (4.5–8.5 Hz) activity, and decrease in high frequency activity (14.5–60 Hz), while, in rats pretreated with 1 nmol of NPS, the duration of delta activity was reduced, while its spectral pattern was not changed. Whereas injection of ketamine into saline-pretreated rats induced a marked increase in delta (0.5–4 Hz) activity, a moderate increase in theta (4.5–8.5 Hz) activity, and a marked decrease in high frequency (14.5–60 Hz) activity. However, delta activity was reduced while theta activity increased under pretreatment with 1 nmol of NPS. The inhibitory effect of NPS on anesthetic-induced SWS was characterized by a reduced SWS episode duration with no significant change in either episode number or latency to SWS. [D-Val⁵]NPS, an NPSR antagonist (20 nmol), significantly attenuated the arousal-promoting effect of 1 nmol of NPS, but had no effect on SWS when injected alone. We speculate that NPS significantly reduces anesthetic-induced SWS and EEG slow activity by selective activation of the NPSR, which, in turn, would trigger subsequent arousal pathways.
... The relative power of the delta (2-4 Hz), theta (4-8 Hz), alpha (8)(9)(10)(11)(12)(13), and beta (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) frequency bands was calculated for the four participants enrolled in the study. The obtained average values, standard errors, and paired sample t-value between the noon and night are presented in Table.I. ...
... The reduction in the complexity becomes more apparent at larger time scales (see Fig.1.(a)). Brain networks consist of multiple interconnected regions, and the whole-brain neural networks, including monoaminergic, dopaminergic, noradrenergic, and serotonergic systems, exhibit circadian rhythms, and their activity peaks during daytime wakefulness [30,31]. The SampEn values derived from the MSE analysis, reflect short-range interactions at lower scales and long-range interactions at larger time scales [32]. ...
Article
Full-text available
Estimating circadian rhythm disturbance is important for differentiating between mental illness and healthy states. Electroencephalogram (EEG) allows brain activity detection directly; however, the recorded signal combines neural activity across multiple time scales, which has been previously quantified using the multiscale entropy (MSE) analysis. We investigated whether MSE analysis of EEG data can detect circadian rhythms. Our results demonstrated increased brain activity complexity in the temporal scale in the daytime; moreover, these changes were more accurately detected by MSE than conventional power analysis. Our method can be applied for EEG-based analysis of circadian rhythms in clinical and healthcare fields.
... Sleep has been suggested to have an antioxidant function and to influence brain excitability especially in epilepsy (49). In the present investigation, PSD for 48 hr during the SRS phase of the rat model of epilepsy precipitated the hyperexcitability state mediated by increased aspartate and decreased GABA and taurine levels. ...
... During REM sleep, the increasing GABAergic activity is protective of seizures (49). Therefore, the present decrease in GABA could be attributed to PSD which may exaggerate the epileptic activity in pilocarpine-treated rats. ...
Article
Full-text available
Objectives: The present study aims to investigate the pathological mechanisms mediating the effect of paradoxical sleep deprivation (PSD) for 48 hr on the spontaneous recurrent seizures (SRS) stage of the pilocarpine rat model of temporal lobe epilepsy. Materials and methods: This was carried out through assessment of amino acid neurotransmitter levels, the main oxidative stress parameters, and the levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in the hippocampus. The experimental animals were divided into 4 groups: control, epileptic, PSD, and epileptic+PSD groups. Results: Data indicated that PSD in epileptic rats induced a significant decrease in GSH levels. TNF-α increased significantly in the PSD group and decreased significantly in both epileptic rats and epileptic rats deprived of paradoxical sleep. PSD induced a significant increase in glutamine, glutamate, and aspartate and a significant decrease in GABA. In epileptic rats and epileptic rats deprived of PS, a significant increase in aspartate and a significant decrease in GABA and taurine were recorded. Conclusion: The present data suggest that exposure to PSD for 48 hr did not worsen the alterations produced in the present epileptic model. However, epileptic, PSD, epileptic + PSD groups showed a state of hyperexcitability and oxidative stress. PSD may increase the susceptibility of animals to the development of epilepsy.
... Esta fase es la que más frecuentemente está asociada con la ensoñación(Colten & Altevogt, 2006;Montes-Rodríguez et al., 2006).4.4.2. Regulación del sueñoDos mecanismos principales se han reconocido en la modulación del sueño: uno que lo promueve, el homeostático; y otro que mantiene la vigilia, el sistema circadiano(Murillo-Rodriguez et al., 2012; Medicine, 2006). En el primero la necesidad de dormir se acumula durante el día, alcanza su punto máximo justo antes de que la persona se acueste por la noche, y se disipa en el transcurso de esta(Colten & Altevogt, 2006). ...
... En el primero la necesidad de dormir se acumula durante el día, alcanza su punto máximo justo antes de que la persona se acueste por la noche, y se disipa en el transcurso de esta(Colten & Altevogt, 2006). En el segundo, se regula el marco de tiempo para dormir durante cada ciclo(Murillo-Rodriguez et al., 2012); es decir, el sistema circadiano contrarresta la necesidad de dormir y promueve la vigilia y el estado de alerta. Con un descanso nocturno adecuado, el impulso homeostático para dormir se reduce, el impulso de vigilia circadiana comienza a aumentar y el ciclo comienza de nuevo(Colten & Altevogt, 2006). ...
Thesis
In modern societies around one third of the workforce uses their voice as the main work tool, with teaching population being the largest subgroup within these workers. Teachers have been widely recognized for having a greater probability of developing voice disorders compared to the general population and other population groups. Insufficient or excessive sleep duration have been associated with inadequate voice performance, and even with the onset and development of voice disorders. Similarly, stress has been identified as one of the most relevant factors associated with voice disorders among teachers. Up to this date, no study has evaluated the possible relation between sleep and voice functioning among college professors. Therefore, the main purpose of this research was to characterize such association, assessing the potential intermediary effect of stress, sociodemographic factors, and the individual working conditions inside and outside the workplaces of professors who worked at Universidad Nacional de Colombia (National University of Colombia). With this in mind, 24 professors were followed-up during 15 continuous days in which daily self-reports and objective measures of sleep quality, sleep time, stress levels and voice functioning were obtained. Generalized linear models were used to determine possible associations. One of the main results was that self-report of intermediate and elevated levels of sleep quality were associated with statistically significant increases in: the standard deviation of sound pressure level in connected speech, with effect of the number of students and the marital status; and, the standard deviation of the fundamental frequency, the mean of the sound pressure level and the minimum sound pressure level in the vowel /i/. In addition, sleep quality was associated with statistically significant reductions in the maximum vowel sound pressure level /i/, mediated by different degrees of stress. Thus, workplace voice health promotion programs may want to include information on these non-evident aspects in their intervention plans.
... Sleep has been suggested to have an antioxidant function and to influence brain excitability especially in epilepsy (49). In the present investigation, PSD for 48 hr during the SRS phase of the rat model of epilepsy precipitated the hyperexcitability state mediated by increased aspartate and decreased GABA and taurine levels. ...
... During REM sleep, the increasing GABAergic activity is protective of seizures (49). Therefore, the present decrease in GABA could be attributed to PSD which may exaggerate the epileptic activity in pilocarpine-treated rats. ...
Article
Full-text available
Objective(s): The present study aims to investigate the pathological mechanisms mediating the effect of paradoxical sleep deprivation (PSD) for 48 hr on the spontaneous recurrent seizures (SRS) stage of the pilocarpine rat model of temporal lobe epilepsy. Materials and Methods: This was carried out through assessment of amino acid neurotransmitter levels, the main oxidative stress parameters, and the levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in the hippocampus. The experimental animals were divided into 4 groups: control, epileptic, PSD, and epileptic+PSD groups.Results: Data indicated that PSD in epileptic rats induced a significant decrease in GSH levels. TNF-α increased significantly in the PSD group and decreased significantly in both epileptic rats and epileptic rats deprived of paradoxical sleep. PSD induced a significant increase in glutamine, glutamate, and aspartate and a significant decrease in GABA. In epileptic rats and epileptic rats deprived of PS, a significant increase in aspartate and a significant decrease in GABA and taurine were recorded. Conclusion: The present data suggest that exposure to PSD for 48 hr did not worsen the alterations produced in the present epileptic model. However, epileptic, PSD, epileptic + PSD groups showed a state of hyperexcitability and oxidative stress. PSD may increase the susceptibility of animals to the development of epilepsy.
... However, these neurodegenerative changes have not been studied in as much detail as the hippocampal pathology, and the specific spatiotemporal pattern of accumulation in the brainstem is yet to be fully elucidated. Interestingly, the LC and dorsal raphe nucleus both play a role in maintaining wakefulness; the neurons in both brainstem nuclei are active during wakefulness and inactive during slow wave sleep and rapid eye movement (REM) sleep [35]. Wake-activated neurons of the LC are impaired or lost entirely in animals exposed to chronic intermittent hypoxia or sleep fragmentation, which are both models of OSA [36,37]. ...
... While the present study did not find a relationship between OSA severity and brainstem pathology, it is possible that the brainstem nuclei, particularly the LC, are more vulnerable to injury in OSA such that even mild OSA is sufficient to induce pathological tau accumulation. The noradrenergic neurons of the LC are most active during wakefulness, decrease their activation during NREM sleep, and are completely inactive during REM sleep [35]. The LC undergoes substantial neuronal loss in animal models of intermittent hypoxia [56] and intermittent short sleep [57]. ...
Article
Obstructive sleep apnea (OSA) involves intermittent cessations of breathing during sleep. People with OSA can experience memory deficits and have reduced hippocampal volume; these features are also characteristic of Alzheimer's disease (AD), where they are accompanied by neurofibrillary tangles (NFTs) and amyloid beta (Aβ) plaques in the hippocampus and brainstem. We have recently shown reduced hippocampal volume to be related to OSA severity, and although OSA may be a risk factor for AD, the hippocampus and brainstems of clinically-verified OSA cases have not yet been examined for NFTs and Aβ plaques. The present study used quantitative immunohistochemistry to investigate post-mortem hippocampi of 34 people with OSA (18 females, 16 males; mean age 67 years) and brainstems of 24 people with OSA for the presence of NFTs and Aβ plaques. OSA severity was a significant predictor of Aβ plaque burden in the hippocampus after controlling for age, sex, BMI and CPAP use. OSA severity also predicted NFT burden in the hippocampus, but not after controlling for age. Although 71% of brainstems contained NFTs and 21% contained Aβ plaques, their burdens were not correlated with OSA severity. These results indicate that OSA accounts for some of the 'cognitively normal' individuals who have been found to have substantial Aβ burdens, and are currently considered to be at a prodromal stage of AD.
... While the behavioural impact of SD is well-known, our knowledge of the responsible underlying neurological mechanism is still limited. Sleep is embedded in a complex network of interconnected brain regions using multiple neurotransmitters and neuromodulators, within which the monoaminergic pathways seem responsible for sleepwake modulation [15,16]. In addition, monoamines play a role in certain cognitive processes that are disrupted by SD [17][18][19]. ...
... The brainstem contains several wake-promoting nuclei: the locus coeruleus (noradrenaline), the dorsal and median raphe nuclei (serotonin), the ventral periaqueductal grey, the substantia nigra and the ventral tegmental area (dopamine). More specifically, monoamines were thought to inhibit sleeppromoting regions such as the ventrolateral optic area (VLPO) [15,16]. Recent evidence suggest that the monoaminergic pathways may not cause sleep promotion, but counteract unpredicted shifts in CRs or effects of stressors [139]. ...
Article
Full-text available
Disruption of the monoaminergic system, e.g. by sleep deprivation (SD), seems to promote certain diseases. Assessment of monoamine levels over the circadian cycle, during different sleep stages and during SD is instrumental to understand the molecular dynamics during and after SD. To provide a complete overview of all available evidence, we performed a systematic review. A comprehensive search was performed for microdialysis and certain monoamines (dopamine, serotonin, noradrenaline, adrenaline), certain monoamine metabolites (3,4-dihydroxyphenylacetic acid (DOPAC), 5-hydroxyindoleacetic acid (5-HIAA)) and a precursor (5-hydroxytryptophan (5-HTP)) in PubMed and EMBASE. After screening of the search results by two independent reviewers, 94 publications were included. All results were tabulated and described qualitatively. Network-meta analyses (NMAs) were performed to compare noradrenaline and serotonin concentrations between sleep stages. We further present experimental monoamine data from the medial prefrontal cortical (mPFC). Monoamine levels varied with brain region and circadian cycle. During sleep, monoamine levels generally decreased compared to wake. These qualitative observations were supported by the NMAs: noradrenaline and serotonin levels decreased from wakefulness to slow wave sleep and decreased further during Rapid Eye Movement sleep. In contrast, monoamine levels generally increased during SD, and sometimes remained high even during subsequent recovery. Decreases during or after SD were only reported for serotonin. In our experiment, SD did not affect any of the mPFC monoamine levels. Concluding, monoamine levels vary over the light-dark cycle and between sleep stages. SD modifies the patterns, with effects sometimes lasting beyond the SD period.
... As previously mentioned, PPAR have been localized in sleep-related brain regions such as the brainstem [111,112]. It is worthy to point-out that this area of the CNS has been linked with control of the sleep-wake cycle [122]. Despite that the data that support the hypothesis that PPAR would modulate sleep are derived from recent areas of research, there are evidence that allows to speculate that PPARα might control sleep and displays a potential therapeutical use for the management of sleep disorders. ...
... The sleep-wake cycle is under control of different neuroanatomical, neurochemical and molecular networks [122,[141][142][143]. An important additional observation is that sleep is also modulated by sleep-inducing molecules [144][145][146]. ...
Article
Background: There is a general consensus that sleep-wake cycle is controlled by neuroanatomical, neurochemical and molecular systems as well as by homeostatic and circadian complex networks. The research has shown that a molecular element that could be displaying a relevant role in the modulation of sleep is the peroxisome proliferator-activated receptor alpha (PPARα), which belongs to the family of nuclear receptor ligand-activated transcription factors that includes PPARβ/δ and PPARγ. A growing body of evidence supports the notion that PPARα is activated by natural ligands such as the anorexic lipid mediator oleoylethanolamide (OEA) or synthetic compounds including Wy14643 whereas antagonists like MK-886 block the neurobiological outcomes of PPARα. More recently, studies have reported the permissive role of PPARα by modulating diverse neurobiological functions such as inflammation, metabolic disorders, learning, degenerative diseases and sleep. Remarkably, this nuclear receptor has been described in sleep-related brain regions leading to the hypothesis that PPARα might be involved in sleep modulation inasmuch as activation of this protein promotes a robust enhancement of wakefulness while reduces sleep. Objective: In this mini review, the emerging evidence of the putative role of PPARα in sleep control is highlighted. Even though the data are derived from new areas of research, there are many reasons to believe that understanding and appreciation of PPARα functions may provide knowledge of possible mechanisms of action activated by this nuclear receptor in sleep modulation. Conclusion: Novel insights of therapeutic intervention for sleep disorders might be visualized targeting the function of PPARα in sleep abnormalities.
... Regulation of sleep and wakefulness relies on complex functions of several brain areas and neurotransmitters, many of which have been shown to be affected in patients with PD (Stefani and Hogl, 2020). Accordingly, sleep is a complex and active neural process involving several brain structures, such as the hypothalamus, brain stem, amygdala, thalamus, pineal gland, and basal forebrain (Murillo-Rodriguez et al., 2012). Although diverse methods have been used to treat sleep disorders, they lack efficacy and safety (National Institutes of Health, 2005). ...
Article
Full-text available
Sleep is a set of physiological processes mainly under neurobiological regulation that affect several physiological systems, and sleep disorders are a condition where normal sleep patterns are disturbed. Clinical studies have confirmed the effects of acupuncture on sleep duration and quality. Although many studies have explored the therapeutic effects of acupuncture on sleep disorders, the mechanisms are unclear. We investigated the mechanism of acupuncture efficacy in a rodent model of sleep disorders and evaluated the therapeutic effects of acupuncture treatment. According to our results, sleep disorders are associated with several brain regions and neurotransmitters. Furthermore, this review showed that neurological processes, such as catecholamine and BDNF signaling pathways, can be regulated by acupuncture, which is a crucial aspect of the acupuncture mechanism in sleep disorders.
... One-third of the life of an individual is spent sleeping. Healthy sleep is important for physical and mental development, work effectiveness, cognitive status, and even mortality (1). Over the past 40 years, the duration Americans spend sleeping has been reduced by 1.5 to 2 h. ...
Article
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Background The aim of the current study was to investigate the link between human exposure to PAHs with short sleep duration (SSD) and self-reported trouble sleeping. Methods A total of 9,754 participants and 9,777 participants obtained from NHANES 2005–2016 were included in this cross-sectional study about SSD and self-reported trouble sleeping, respectively. The association between urinary PAHs metabolites with the prevalence of SSD and self-reported trouble sleeping by the weighted multivariate logistic regression model, restricted cubic spline (RCS) curves, and weighted quantile sum (WQS) regression. Results After adjusting for all covariates, 1-hydroxynapthalene, 2-hydroxynapthalene, 3-hydroxyfluorene, 2-hydroxyfluorene, 1-hydroxyphenanthrene, and 1-hydroxyphenanthrene demonstrated positive associations with SSD prevalence. Besides, 1-hydroxynapthalene, 2-hydroxynapthalene, 3-hydroxyfluorene, 2-hydroxyfluorene, 1-hydroxyphenanthrene, and 1-hydroxyphenanthrene exhibited positive associations with the prevalence of self-reported trouble sleeping following the adjustment for all covariates. RCS curves confirmed the non-linear associations between 1-hydroxynapthalene, 2-hydroxynapthalene, 3-hydroxyfluorene, 2-hydroxyfluorene, and 1-hydroxyphenanthrene with the prevalence of SSD, and 1-hydroxynapthalene, 3-hydroxyfluorene, and 2-hydroxyfluorene with the prevalence of self-reported trouble sleeping. The WQS results showed that mixed exposure to PAH metabolites had a significant positive association with the prevalence of SSD (OR: 1.087, 95% CI: 1.026, 1.152, p = 0.004) and self-reported trouble sleeping (OR: 1.190, 95% CI: 1.108, 1.278, p < 0.001). Conclusion Urinary concentrations of PAH metabolites exhibited a close association with the prevalence of SSD and self-reported trouble sleeping in US adults. More emphasis should be placed on the importance of environmental effects on sleep health.
... Hypocretin is a neuropeptide that functions to regulate arousal and wakefulness. These hypocretin-containing neurons will then project to the thalamus, which has widespread projections throughout the brain [29]. ...
Article
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Sleep disturbance can occur when sleep centers of the brain, regions that are responsible for coordinating and generating healthy amounts of sleep, are disrupted by glioma growth or surgical resection. Several disorders cause disruptions to the average duration, quality, or patterns of sleep, resulting in sleep disturbance. It is unknown whether specific sleep disorders can be reliably correlated with glioma growth, but there are sufficient numbers of case reports to suggest that a connection is possible. In this manuscript, these case reports and retrospective chart reviews are considered in the context of the current primary literature on sleep disturbance and glioma diagnosis to identify a new and useful connection which warrants further systematic and scientific examination in preclinical animal models. Confirmation of the relationship between disruption of the sleep centers in the brain and glioma location could have significant implications for diagnostics, treatment, monitoring of metastasis/recurrence, and end-of-life considerations.
... CBD operates by modulating the circadian cycle, as evidenced by research suggesting that perhaps the CB1 receptor being distributed with in the brain and consequently regulates the sleeping pattern and anandamide stimulation prolongs REM sleep while minimising wakefulness. So CBDs could be used to some extent to treat sleeping disorders (Behl et al. 2020;Hanlon 2020;Murillo-Rodriguez et al. 2012). ...
Article
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Parkinson's disease is a neurodegenerative disorder which is characterised mostly by loss of dopaminergic nerve cells throughout the nigral area mainly as a consequence of oxidative stress. Muscle stiffness, disorganised bodily responses, disturbed sleep, weariness, amnesia, and voice impairment are all symptoms of dopaminergic neuron degeneration and existing symptomatic treatments are important to arrest additional neuronal death. Some cannabinoids have recently been demonstrated as robust antioxidants that might protect the nerve cells from degeneration even when cannabinoid receptors are not triggered. Cannabinoids are likely to have property to slow or presumably cease the steady deterioration of the brain's dopaminergic systems, a condition for which there is now no treatment. The use of cannabinoids in combination with currently available drugs has the potential to introduce a radically new paradigm for treatment of Parkinson's disease, making it immensely useful in the treatment of such a debilitating illness.
... Acetylcholine is thought to play at important role in arousal (Jones, 2008;Murillo-Rodriguez et al., 2012;Iwanczuk and Guzniczak, 2015;Schwartz and Kilduff, 2015;Saper and Fuller, 2017). Much of the evidence comes from early pharmacological studies. ...
Article
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Wakefulness is necessary for consciousness, and impaired wakefulness is a symptom of many diseases. The neural circuits that maintain wakefulness remain incompletely understood, as do the mechanisms of impaired consciousness in many patients. In contrast to the influential concept of a diffuse “reticular activating system,” the past century of neuroscience research has identified a focal region of the upper brainstem that, when damaged, causes coma. This region contains diverse neuronal populations with different axonal projections, neurotransmitters, and genetic identities. Activating some of these populations promotes wakefulness, but it remains unclear which specific neurons are necessary for sustaining consciousness. In parallel, pharmacological evidence has indicated a role for special neurotransmitters, including hypocretin/orexin, histamine, norepinephrine, serotonin, dopamine, adenosine and acetylcholine. However, genetically targeted experiments have indicated that none of these neurotransmitters or the neurons producing them are individually necessary for maintaining wakefulness. In this review, we emphasize the need to determine the specific subset of brainstem neurons necessary for maintaining arousal. Accomplishing this will enable more precise mapping of wakefulness circuitry, which will be useful in developing therapies for patients with coma and other disorders of arousal.
... Good sleep shapes better athletes, and it is generally recommended that athletes should get between seven and nine hours of sleep to ensure adequate physical and mental recovery after training [74]. Meanwhile, during training and competitions, athletes can get better quality sleep by maintaining a dark sleep environment [75], avoiding caffeine intake before bedtime [76], going to sleep, and waking up at regular times [77], and avoiding electronic screens before bedtime [78], among others. ...
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Excellent response inhibition is the basis for outstanding competitive athletic performance, and sleep may be an important factor affecting athletes’ response inhibition. This study investigates the effect of sleep deprivation on athletes’ response inhibition, and its differentiating effect on non-athlete controls’ performance, with the aim of helping athletes effectively improve their response inhibition ability through sleep pattern manipulation. Behavioral and event-related potential (ERP) data were collected from 36 participants (16 table tennis athletes and 20 general college students) after 36 h of sleep deprivation using ERP techniques and a stop-signal task. Sleep deprivation’s different effects on response inhibition in the two groups were explored through repeated-measures ANOVA. Behavioral data showed that in a baseline state, stop-signal response time was significantly faster in table tennis athletes than in non-athlete controls, and appeared significantly longer after sleep deprivation in both groups. ERP results showed that at baseline state, N2, ERN, and P3 amplitudes were lower in table tennis athletes than in non-athlete controls, and corresponding significant decreases were observed in non-athlete controls after 36 h of sleep deprivation. Table tennis athletes showed a decrease in P3 amplitude and no significant difference in N2 and ERN amplitudes, after 36 h of sleep deprivation compared to the baseline state. Compared to non-athlete controls, table tennis athletes had better response inhibition, and the adverse effects of sleep deprivation on response inhibition occurred mainly in the later top-down motor inhibition process rather than in earlier automated conflict detection and monitoring.
... T. gondii can disseminate to brain in infected hosts [3], and we hypothesize that T. gondii can involve brain structures related with sleep leading to sleep problems as insomnia. Several neurotransmitters are involved in sleep including for instance, dopamine and gamma-aminobutyric acid (GABA) [19], and T. gondii infections impact on these two neurotransmitters. T. gondii infections alter the dopamine metabolism [20], and GABAergic synapses and signaling in the central nervous system [21]. ...
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We determined the association between Toxoplasma gondii ( T . gondii ) infection and insomnia. Through an age-and gender-matched case-control study, 577 people with insomnia (cases) and 577 people without insomnia (controls) were tested for anti- T . gondii IgG and IgM antibodies using commercially available enzyme-immunoassays. Anti- T . gondii IgG antibodies were found in 71 (12.3%) of 577 individuals with insomnia and in 46 (8.0%) of 577 controls (OR = 1.62; 95% CI: 1.09–2.39; P = 0.01). Men with insomnia had a higher (16/73: 21.9%) seroprevalence of T . gondii infection than men without insomnia (5/73: 6.8%) (OR: 3.81; 95% CI: 1.31–11.06; P = 0.009). The rate of high (>150 IU/ml) anti- T . gondii IgG antibody levels in cases was higher than the one in controls (OR = 2.21; 95% CI: 1.13–4.31; P = 0.01). Men with insomnia had a higher (8/73: 11.0%) rate of high anti- T . gondii IgG antibody levels than men without insomnia (0/73: 0.0%) ( P = 0.006). The rate of high anti- T . gondii IgG antibody levels in cases >50 years old (11/180: 6.1%) was higher than that (3/180: 1.7%) in controls of the same age group (OR: 3.84; 95% CI: 1.05–14.00; P = 0.05). No difference in the rate of IgM seropositivity between cases and controls was found (OR = 1.33; 95% CI: 0.57–3.11; P = 0.50). Results of this seroepidemiology study suggest that infection with T . gondii is associated with insomnia. Men older than 50 years with T . gondii exposure might be prone to insomnia. Further research to confirm the association between seropositivity and serointensity to T . gondii and insomnia is needed.
... Sleep is an altered consciousness phenomenon that occurs not only in humans but also across all animal species and is essential in maintaining good health and quality of life [1]. The quality of sleep has a profound effect on mental health, especially on emotional regulation [2]. ...
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Background and Objective It is widely known that poor sleep quality is closely related to depression, but there are limited studies on the mediating factors.Methods Based on national health survey data, the relationship between sleep quality and depressive symptoms was explored, and structural equations were drawn to determine whether emotional regulation activities, such as regular breakfast, regular exercise, smoking, and drinking contribute to poor sleep quality-induced depression.Results There was a significant correlation between poor sleep quality and depressive symptoms. Regular breakfast tended to mediate between poor sleep quality and depression the most, followed by smoking, drinking, and regular exercise.Conclusions Several emotional regulation activities including regular breakfast, can play a protective role in the process leading to poor sleep quality-induced depression. A follow-up study is required to examine the clinical aspect of how regular breakfast can prevent the process of poor sleep quality to depression.
... The circadian sleep process is based on the function of the SCN, located in the anterior hypothalamus, which receives information from the retina about light exposure and passes it to peripheral receptors via the neuroendocrine system, which will be described later [50]. Signaling in this region provokes vigilance, whereas loss of function causes fatigue and sleepiness [51]. ...
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Background: The ratio of the second finger length to the fourth finger length (2D:4D ratio) is considered to be negatively correlated with prenatal androgen exposure (PAE) and positively correlated with prenatal estrogen. Coincidentally, various brain regions are sensitive to PAE, and their functions in adults may be influenced by the prenatal actions of sex hormones.
... Several sleep mutants with dramatically different mechanisms of action emerged from unbiased genetic screens, including fumin (fmn: defective dopamine reuptake), redeye (rye: nicotinic acetylcholine receptor loss-of-function), and sleepless (sss: dysregulated membrane potential and excessive GABA degradation) [7][8][9][10] . Importantly, these mechanisms are well-conserved regulators of sleep-wake in mammals 11 . In addition to pinpointing mechanisms regulating sleep amount, Drosophila has been an increasingly fruitful model for discerning how sleep regulates aspects of metabolism, including lipid homeostasis and autophagy, that are highly conserved across vertebrates 12,13 . ...
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Chronic sleep loss profoundly impacts health in ways coupled to metabolism; however, much existing literature links sleep and metabolism only on acute timescales. To explore the impact of chronically reduced sleep, we conducted unbiased metabolomics on heads from three Drosophila short-sleeping mutants. Common features included elevated ornithine and polyamines; and lipid, acyl-carnitine, and TCA cycle changes suggesting mitochondrial dysfunction. Biochemical studies of overall, circulating, and excreted nitrogen in sleep mutants demonstrate a specific defect in eliminating nitrogen, suggesting that elevated polyamines may function as a nitrogen sink. Both supplementing polyamines and inhibiting their synthesis with RNAi regulated sleep in control flies. Finally, both polyamine-supplemented food and high-protein feeding were highly toxic to sleep mutants, suggesting their altered nitrogen metabolism is maladaptive. Together, our results suggest polyamine accumulation specifically, and nitrogen stress in general, as potential mechanisms linking chronic sleep loss to adverse health outcomes.
... And, as mentioned earlier, one of the most important brain functions is sleep. Therefore, it is likely that the complex changes occurring during sleep are not limited to certain cerebral areas, but are instead function of the entire brain (80). It would follow then that any disruption in the cerebral structure can impair sleep to a greater or lesser degree. ...
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Malignant brain tumors are among the most aggressive human neoplasms. One of the most common and severe symptoms that patients with these malignancies experience is sleep disruption. Disrupted sleep is known to have significant systemic pro-tumor effects, both in patients with other types of cancer and those with malignant brain lesions. We therefore provide a review of the current knowledge on disrupted sleep in malignant diseases, with an emphasis on malignant brain tumors. More specifically, we review the known ways in which disrupted sleep enables further malignant progression. In the second part of the article, we also provide a theoretical framework of the reverse process. Namely, we argue that due to the several possible pathophysiological mechanisms, patients with malignant brain tumors are especially susceptible to their sleep being disrupted and compromised. Thus, we further argue that addressing the issue of disrupted sleep in patients with malignant brain tumors can, not just improve their quality of life, but also have at least some potential of actively suppressing the devastating disease, especially when other treatment modalities have been exhausted. Future research is therefore desperately needed.
... They indicated that GRE acts via a GABAergic mechanism to aid sleep in a rodent model, too [27]. The sleep-onset is controlled by the activity of sleep-promoting neurons located in the anterior hypothalamus which utilize GABA to inhibit wake-promoting regions [28]. In this regard, the mechanism of hypnotic effect of lettuce has been considered from a molecular point of view. ...
Article
Objectives Insomnia and sleep disorders are common and can be severe amongst patients with cancer, especially during chemotherapy. The aim of this study was to evaluate the efficacy of lettuce seed syrup in breast cancer patients who suffer from insomnia or disordered sleep. Methods This pilot study was a double-blinded randomized controlled clinical trial conducted in Shoha - e-Tajrish Hospital (Tehran, Iran) from September 2018 to June 2019. 50 adult patients with breast cancer with insomnia or sleep disorders were enrolled. Participants were randomly allocated to lettuce seed syrup (5 mL twice daily), or placebo syrup at the same dose for four weeks. The Pittsburgh Sleep Quality Index (PSQI) was used to evaluate sleep quality before and after the intervention. Results Compared to placebo, the mean of the total PSQI score decreased significantly in participants who received lettuce seed syrup (p=0.014). In addition, there were statistically significant reductions in the mean scores of subject quality sleep (p=0.002), sleep duration (p=0.038), habitual sleep efficacy (p=0.029) and sleep disturbance (p=0.032) in patients who received lettuce seed syrup. Conclusions Lettuce seed syrup may improve self-reported sleep quality in participants with breast cancer. Larger trials are indicated in diverse samples of participants with caner to learn if these finds are generalizable.
... 19 Meanwhile, this region is also found to activate in general anesthesia, which in turn inhibits arousal-promoting circuits. 20,21 As such, we hypothesized that the lateral septum may be involved in both natural sleep-wakefulness and general anesthesia regulation. ...
Article
Background The γ-aminobutyric acid–mediated (GABAergic) inhibitory system in the brain is critical for regulation of sleep–wake and general anesthesia. The lateral septum contains mainly GABAergic neurons, being cytoarchitectonically divided into the dorsal, intermediate, and ventral parts. This study hypothesized that GABAergic neurons of the lateral septum participate in the control of wakefulness and promote recovery from anesthesia. Methods By employing fiber photometry, chemogenetic and optogenetic neuronal manipulations, anterograde tracing, in vivo electrophysiology, and electroencephalogram/electromyography recordings in adult male mice, the authors measured the role of lateral septum GABAergic neurons to the control of sleep–wake transition and anesthesia emergence and the corresponding neuron circuits in arousal and emergence control. Results The GABAergic neurons of the lateral septum exhibited high activities during the awake state by in vivo fiber photometry recordings (awake vs. non–rapid eye movement sleep: 3.3 ± 1.4% vs. –1.3 ± 1.2%, P < 0.001, n = 7 mice/group; awake vs. anesthesia: 2.6 ± 1.2% vs. –1.3 ± 0.8%, P < 0.001, n = 7 mice/group). Using chemogenetic stimulation of lateral septum GABAergic neurons resulted in a 100.5% increase in wakefulness and a 51.2% reduction in non–rapid eye movement sleep. Optogenetic activation of these GABAergic neurons promoted wakefulness from sleep (median [25th, 75th percentiles]: 153.0 [115.9, 179.7] s to 4.0 [3.4, 4.6] s, P = 0.009, n = 5 mice/group) and accelerated emergence from isoflurane anesthesia (514.4 ± 122.2 s vs. 226.5 ± 53.3 s, P < 0.001, n = 8 mice/group). Furthermore, the authors demonstrated that the lateral septum GABAergic neurons send 70.7% (228 of 323 cells) of monosynaptic projections to the ventral tegmental area GABAergic neurons, preferentially inhibiting their activities and thus regulating wakefulness and isoflurane anesthesia depth. Conclusions The results uncover a fundamental role of the lateral septum GABAergic neurons and their circuit in maintaining awake state and promoting general anesthesia emergence time. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New
... Moreover, some studies suggest that Pilates exert positive effects on body satisfaction, attitude, and quality of life (45), and consequently improves health (13), which is helpful for sleep quality. However, sleep regulation is very complex and involves many factors (46). In postmenopausal and postpartum women and the elderly, the factors that affect sleep quality are particularly varied and complex. ...
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Objective: Pilates exercise is increasingly used to improve sleep quality, but relevant evidence remains unclear. We aimed to estimate the effect of Pilates on sleep quality. Methods: Five databases were searched for articles published until 10 December 2019. Two investigators screened the articles and extracted data from each included study. A meta-analysis was performed to evaluate the effect of Pilates on sleep quality, assessed using the Pittsburgh Sleep Quality Index (PSQI). Results: Six randomized controlled trials (RCTs) comprising 477 participants were included according to the inclusion and exclusion criteria in the study. All included studies reported the positive effects Pilates had on sleep quality. The Pilates group (PG) significantly lowered the PSQI total score (MD = −3.60, 95%CI: [−5.41, −1.78), P = 0.0001, I2 = 97%) compared to the non-exercising control group (CG), whereas no significant improvement in use of sleep medication was observed (MD = −0.33, 95%CI: [−0.73, −0.06), P = 0.10, I2 = 68%). However, in a subgroup analysis, we found that there was no significant reduction in the PSQI total score for healthy participants over 40 years old (MD = −3.73, 95%CI: [−7.89, 0.42], P = 0.08, I2 = 98%) and for postmenopausal women (MD = −5.55, 95%CI: [−13.98, −2.89], P = 0.20, I2 = 98%). Conclusions: Overall, Pilates improved sleep quality but had no significant effect on the use of sleep medication. However, Pilates showed no significant impact on sleep quality for healthy individuals over 40 years old and for postmenopausal women. Well-designed and large-scale RCTs are needed in the future.
... This work was supported by The University of California Institute for Mexico and the United States (UC MEXUS) and Consejo Nacional de Ciencia y Tecnología (CONACyT; Grant# CN-[17][18][19] and Escuela de Medicina, Universidad Anáhuac Mayab (Grant: PresInvEMR2017) given to E M-R. ...
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Aging is an inevitable process that involves changes along life in multiple neurochemical, neuroanatomical, hormonal systems, and many others. In addition, these biological modifications lead to an increase in age-related sickness such as cardiovascular diseases, osteoporosis, neurodegenerative disorders, and sleep disturbances, among others that affect activities of daily life. Demographic projections have demonstrated that aging will increase its worldwide rate in the coming years. The research on chronic diseases of the elderly is important to gain insights into this growing global burden. Novel therapeutic approaches aimed for treatment of age-related pathologies have included the endocannabinoid system as an effective tools since this biological system shows beneficial effects in preclinical models. However, and despite these advances, little has been addressed in the arena of the endocannabinoid system as option for treating sleep disorders in aging since experimental evidence suggests that some elements of the endocannabinoid system modulate the sleep-wake cycle. This article addresses this less-studied field, focusing on the likely perspective of the implication of the endocannabinoid system in the regulation of sleep problems reported in aged. We conclude that beneficial effects regarding the putative efficacy of the endocannabinoid system as therapeutic tools in aging is either inconclusive or still missing.
... There is compelling evidence that sleep-wake cycle is regulated by neuroanatomical, neurochemical and molecular complex networks (Monti and Jantos 2008;Szymusiak and McGinty 2008;Arias-Carrión et al., 2011a;Jones 2011;Porkka-Heiskanen and Kalinchuk, 2011;Brown et al., 2012;Murillo-Rodríguez et al., 2012;Huang et al., 2011Huang et al., , 2014Dauvilliers et al., 2015). For example, several compounds have been associated with the sleep-wake cycle modulation. ...
Article
The peroxisome proliferator-activated receptor alpha (PPARα) is a member of the nuclear receptor superfamily that has been suggested as a modulator of several physiological functions. The PPARα recognizes as an endogenous ligand the anorexic lipid mediator oleoylethanolamide (OEA) which displays wake-inducing properties. Despite that recent evidence indicates that activation of PPARα by synthetic agonists such as Wy14643 enhances waking as well as the extracellular contents of wake-related neurotransmitters, the role of PPARα in sleep recovery after prolonged waking has not been fully described. Thus, the aim of this study was to characterize if PPARα regulates sleep rebound after total sleep deprivation (TSD). We report that after 6h of TSD activation of PPARα by pharmacological systemic administration of OEA (10, 20 or 30mg/Kg, i.p.) promoted alertness by blocking the sleep rebound after TSD. Besides, wake-linked compounds such as dopamine, norepinephrine, serotonin, or adenosine collected from nucleus accumbens were enhanced after TSD in OEA-treated animals. These sleep and neurochemical results were mimicked after injection of PPARα agonist Wy14643 (10, 20, 30mg/Kg, i.p.). However, similar findings from the sham of vehicle groups were observed if PPARα antagonist MK-886 was administered to rats (10, 20, 30mg/Kg, i.p.). Our results strengthened the hypothesis that PPARα might modulate sleep and neurochemical homeostasis after sleep deprivation.
... There is compelling evidence that sleep-wake cycle is regulated by neuroanatomical, neurochemical and molecular complex networks (Monti and Jantos 2008;Szymusiak and McGinty 2008;Arias-Carrión et al., 2011a;Jones 2011;Porkka-Heiskanen and Kalinchuk, 2011;Brown et al., 2012;Murillo-Rodríguez et al., 2012;Huang et al., 2011Huang et al., , 2014Dauvilliers et al., 2015). For example, several compounds have been associated with the sleep-wake cycle modulation. ...
... The results of our study demonstrated that triterpene acids significantly inhibited seizures induced by both MES and PTZ, which suggests that triterpene acids may achieve antiepileptic effects through modulation of GABA. In addition to GABA, there are several other endogenous neurotransmitters that play important roles in sleep mechanisms such as dopamine, acetylcholine, histamine, serotonin and neuropeptides (Murillo-Rodriguez et al. 2012). Glu, which is an excitatory neurotransmitter, plays an opposite role to GABA in the central nervous system (Albrecht et al. 2010). ...
Article
Context: Triterpenes from Poria cocos Wolf (Polyporaceae) have been used to treat various diseases in traditional Chinese medicine. However, the antiepileptic effects and mechanism are not fully understood. Objective: The objective of this study is to investigate the antiepileptic properties of total triterpenes (TTP) from the whole P. cocos. Materials and methods: The ethanol extract TTP was identified by HPLC fingerprint analysis. Male ICR mice were gavaged (i.g.) with TTP (5, 20, 80 or 160 mg/kg) or reference drugs twice a day for 7 d. Antiepileptic activities of TTP were evaluated by maximal electroshock (MES)- and pentylenetetrazole (PTZ)-induced seizures in mice for 30 and 60 min, respectively. Locomotor activity and Rota-rod tests were performed for 60 min and 5 min, respectively. The levels of glutamic acid (Glu), aspartic acid (Asp), γ-aminobutyric acid (GABA) and glycine (Gly) in convulsive mice were estimated. The chronic epileptic model of Wistar rats was built to measure expressions of glutamate decarboxylase 65 (GAD65) and GABAA in rat brain after TTP treatment. Results: The LC50 of TTP (i.g.) was above 6 g/kg. TTP (5-160 mg/kg) protected mice against MES- and PTZ-induced convulsions at 65.0% and 62.5%, respectively, but have no effect on rota-rod treadmill; TTP (20-160 mg/kg) significantly reduced the locomotor activities, shortened the onset of pentobarbital sodium-induced sleep; TTP decreased Glu and Asp levels in convulsive mice, but increased the GAD65 and GABAA expressions in chronic epileptic rats at doses usage. Discussion and conclusion: TTP extracted from P. cocos possessed potential antiepileptic properties and is a candidate for further antiepileptic drug development.
... The sleep-wake cycle is regulated by a neurobiological complex network (Murillo-Rodríguez et al., 2012). For instance, specific anatomic areas modulate wakefulness (W), such as lateral hypothalamus (LH) whereas sleep is governed by nucleus placed in the basal forebrain (Szymusiak and McGinty, 2008;Brown et al., 2012). ...
... Finally, the participation of D 1 receptors in mitogen-activated protein kinase (MAP-K) phosphorylat-ion [15,16] enables the hypothesis that MOD could induce alertness upon the activation of MAP-K and subsequent down-stream events. To test this hypothesis, we examined the effects of MOD after its intrahypothalamic administration on MAP-K expression in hypothalamus and pons, both wake-related brain areas [17][18][19][20][21]. . Additionally, four miniature stainless steel screws were implanted over the frontal and occipital cortex. ...
Article
Obesity is a world-wide health problem that requires different experimental perspectives to understand the onset of this disease, including the neurobiological basis of food selection. From a molecular perspective, obesity has been related with activity of several endogenous molecules, including the mitogen-activated protein kinases (MAP-K). The aim of this study was to characterize MAP-K expression in hedonic and learning and memory brain-associated areas such as nucleus accumbens (AcbC) and hippocampus (HIPP) after food selection. We show that animals fed with cafeteria diet during 14 days displayed an increase in p38 MAP-K activity in AcbC if chose cheese. Conversely, a diminution was observed in animals that preferred chocolate in AcbC. Also, a decrease of p38 MAP-K phosphorylation was found in HIPP in rats that selected either cheese or chocolate. Our data demonstrate a putative role of MAP-K expression in food selection. These findings advance our understanding of neuromolecular basis engaged in obesity.
... Notably, for all participants low mood and poor sleep quality were highly correlated both in summer and winter. We suggest that this may be due to a common regulation of mood and sleep mediated by serotonin (Murillo-Rodriguez et al., 2012) or through interaction between mood and sleep. Sleep disturbances often coincide with a diagnosis of depression (Vandeputte and de Weerd, 2003;BaHammam et al., 2015) and disruptions of circadian rhythms are common in depression, in particular seasonal affective disorder, and vice versa, depressive mood causes rumination and increased latency to sleep. ...
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View largeDownload slide Cross-sectional neuroimaging studies suggest that serotonin transporter levels show season-dependent fluctuations. In a longitudinal study, Mc Mahon et al . report that patients with seasonal affective disorder show similar serotonin transporter levels to non-depressed controls in summer, but fail to downregulate serotonin transporter levels in winter. View largeDownload slide Cross-sectional neuroimaging studies suggest that serotonin transporter levels show season-dependent fluctuations. In a longitudinal study, Mc Mahon et al . report that patients with seasonal affective disorder show similar serotonin transporter levels to non-depressed controls in summer, but fail to downregulate serotonin transporter levels in winter.
... © 2015 Published by Elsevier Ireland Ltd. The sleep–wake cycle is regulated by a neurobiological com- Q2 plex network (Murillo-Rodríguez et al., 2012). For instance, specific anatomic areas modulate wakefulness (W), such as lateral hypothalamus (LH) whereas sleep is governed by nucleus placed in the basal forebrain (Szymusiak and McGinty, 2008; Brown et al., 2012). ...
Article
The peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear protein that plays an essential role in diverse neurobiological processes. However, the role of PPARα on the sleep modulation is unknown. Here, rats treated with an intrahypothalamic injection of Wy14643 (10μg/1μL; PPARα agonist) enhanced wakefulness and decreased slow wave sleep and rapid eye movement sleep whereas MK-886 (10μg/1μL; PPARα antagonist) promoted opposite effects. Moreover, Wy14643 increased dopamine, norepinephrine, serotonin, and adenosine contents collected from nucleus accumbens. The levels of these neurochemicals were diminished after MK-886 treatment. The current findings suggest that PPARα may participate in the sleep and neurochemical modulation.
Article
Background Cholinergic hypofunction and sleep disturbance are hallmarks of Alzheimer’s disease (AD), a progressive disorder leading to neuronal deterioration. Muscarinic acetylcholine receptors (M1-5 or mAChRs), expressed in hippocampus and cerebral cortex, play a pivotal role in the aberrant alterations of cognitive processing, memory, and learning, observed in AD. Recent evidence shows that two mAChRs, M1 and M3, encoded by CHRM1 and CHRM3 genes, respectively, are involved in sleep functions and, peculiarly, in rapid eye movement (REM) sleep. Methods We used twenty microarray datasets extrapolated from post-mortem brain tissue of nondemented healthy controls (NDHC) and AD patients to examine the expression profile of CHRM1 and CHRM3 genes. Samples were from eight brain regions and stratified according to age and sex. Results CHRM1 and CHRM3 expression levels were significantly reduced in AD compared with ageand sex-matched NDHC brains. A negative correlation with age emerged for both CHRM1 and CHRM3 in NDHC but not in AD brains. Notably, a marked positive correlation was also revealed between the neurogranin (NRGN) and both CHRM1 and CHRM3 genes. These associations were modulated by sex. Accordingly, in the temporal and occipital regions of NDHC subjects, males expressed higher levels of CHRM1 and CHRM3, respectively, than females. In AD patients, males expressed higher levels of CHRM1 and CHRM3 in the temporal and frontal regions, respectively, than females. Conclusion Thus, substantial differences, all strictly linked to the brain region analyzed, age, and sex, exist in CHRM1 and CHRM3 brain levels both in NDHC subjects and in AD patients.
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Introdução. O declínio cognitivo e o aumento do risco de demências estão entre os principais efeitos dos distúrbios relacionados ao sono em idosos. Objetivo. Investigar as relações entre duração do sono diurno e noturno e o estado cognitivo em idosos usuários da Atenção Básica em Saúde. Método. Foi realizado estudo transversal com 201 idosos atendidos em três unidades de saúde selecionadas por sorteio. O tempo de sono diurno e noturno foi autorrelatado. O estado cognitivo foi avaliado pela Prova Cognitiva de Leganés, com pontuação variando de 0 a 32. As demais variáveis compreenderam estado de saúde física e mental e aspectos sociodemográficos. Foram testados dois modelos de regressão linear múltipla com intervalo de confiança de 95%. Resultados. A amostra caracterizou-se por ser maioria do sexo feminino (77,1%); média de idade de 68,13±6,88 anos; de escolaridade 5,62±4,12 anos; e, estado cognitivo 26,52±3,29. A média de tempo de sono diurno foi de 35,11±76,68 minutos; a média de sono noturno foi de 396,74±94,93 minutos. Tempo de sono diurno e noturno foram relacionados negativamente com o estado cognitivo, independentemente do estado de saúde e aspectos sociodemográficos. Conclusão. As orientações direcionadas aos idosos devem ser pautadas na qualidade do sono, em detrimento do tempo de sono. A avaliação e intervenção nas condições do sono de idosos que frequentam a atenção básica em saúde são essenciais para prevenir agravos em saúde, especialmente em idosos que dormem muitas horas durante a noite, mas principalmente ao longo do dia.
Article
Objective Previous studies indicate that propofol can help with recovery from sleep deprivation and has anti-anxiety effects. However, the underlying neurochemical mechanism remains unclear. This study aimed to investigate the effects of dopamine transporter (DAT) in the ventral tegmental area (VTA) on sleep and anxiety recovery after propofol anesthesia in rats with 24 h total sleep deprivation (TSD). Methods Adult male Sprague-Dawley rats were in natural sleep or sleep deprived for 24 h in a sleep deprivation rat system. The rats received propofol anesthesia (75 mg/kg, i.p.) or natural sleep. Dopamine transporter knockdown was performed by microinjection of AAV-DAT-RNAi vector. EEG was measured in each group to evaluate the subsequent sleep. The elevated plus maze test (EPMT) and open field test (OFT) were used to evaluate locomotion and anxiety level in rats. Immunofluorescence was used to verify virus location and transfection efficiency. Results Compared with NC group, the anxiety level of Propofol group showed no significant difference, but REM sleep decreased. Compared with the TSD group, the anxiety level of the TSD + Propofol group was reduced and the sleep recovery was closer to baseline. Compared with TSD + AAV-NC group, anxiety level and sleep time increased in TSD + AAVi group, REM increased within 24 h after sleep deprivation. The sleep time of TSD + AAVi + Propofol group was between those of TSD + AAV-NC group and TSD + AAVi group. TSD + AAV-NC + Propofol group had the least sleep time and the lowest anxiety level. Conclusion 1. Propofol did not change anxiety level in normal rats, but reduced REM sleep, while it could accelerate sleep recovery and reduce anxiety level in sleep-deprived rats. 2. In sleep deprived rats with DAT knockdown, propofol improved sleep and anxiety levels more slowly, especially producing more REM rebound, suggesting that the improvement of sleep and anxiety levels in sleep-deprived rats with propofol may be related to DAT in VTA region.
Chapter
The prevalence of sleep disorders in adults with intellectual disability (ID) and/or low-functioning autism spectrum disorder (ASD) seems to vary between 8.5% and 34.1%, and in the most severe forms it reaches 9.2%. There are many distinct sleep disorders characterized by excessive daytime sleepiness, difficulties initiating or maintaining sleep, and abnormal movements occurring during sleep that cause both distress and impaired functioning during the daytime. There are several biological (including genetic) and psychosocial risk factors that predispose an individual with ID and/or ASD to sleep abnormalities. Difficulty in diagnosing sleep disorders depends on the high comorbidity of medical, neurological, and psychiatric disorders. Intervention strategies for adults with ID and/or ASD experiencing sleep problems concentrate on the pharmacological treatment of sleep problems. However, current evidence primarily supports the use of non-pharmacological interventions.KeywordsSleep problemSleep abnormalitiesInsomnia disorderHypersomnolence disorderNarcolepsyBreathing-related sleep disordersIntellectual disabilityAutism
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Epilepsy is a neurological condition that affects approximately more than 50 million people around the globe, out of which the prevalence of this disease is also seen in developed countries. Epilepsy can be clinical defined by two or more non triggered seizures. A seizure can be characterized as a paroxysmal event which is caused due to hyper–synchronization in the neurons that many have various reasons of manifestation. The neuronal discharge maybe focal spreading in specific brain cortex or widespread throughout the cortex. An Electroencephalogram (EEG) is used to in diagnosis and management of epilepsy and can be used for routine examinations, it also considered to be the golden standard investigation of epileptic syndrome. While using EEG the distribution, presence and frequency of interictal epileptiform discharges IEDs are suggestive diagnosis of epilepsy. In other words the presence of IEDs in an individual’s EEG is a diagnosis of epilepsy. IEDs are predominantly found in EEG that is performed during sleep which can give basic diagnosis and prognosis of sleep related epilepsies in patients. During sleep latent interictal discharge are activated. Sleep IEDs are said to greatly affect the epilepsy management. These interaction mechanisms of sleep and epilepsies tends to bring about changes in behaviour of the seizure.
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Neurotransmitters (NTs) and their metabolites play crucial roles in the regulation of the sleep-wake cycle. Thus, a comprehensive quantitative analysis of NTs would be useful in elucidating the potential mechanisms involved in sedative-hypnotic activities. In this study, we developed a high-throughput quantitative method based on a two-dimensional chromatography-mass spectrometry technique to simultaneously analyze 63 NTs and their metabolites in rat plasma, brain homogenate, and microdialysis samples from five different sleep-associated regions of the brain. Moreover, this method was used to study the neurochemical mechanism of an adenosine analog sedative-hypnotic candidate YZG-331. Most of the correlations between NTs were lost after the administration of the sedative, particularly in the caudate putamen (CPu) and dorsal raphe nucleus (DRN), indicating that the sleep-wake balance was affected. Administration of the adenosine analog YZG-331 could act similar as accumulation of adenosine, inducing adenosine and its metabolite adenine were decreased significantly in the CPu, accompanying with GABA, aspartate, and glutamate changed slightly by the communications between different neurons to further promote sleep. In addition, YZG-331 affected the metabolism of tryptophan and serotonin (5-HT) in the DRN and orbital frontal cortex (OFC). Melatonin and 5-hydroxyindole-3-acetic acid (a metabolite of 5-HT) were significantly increased in the OFC, and the levels of glutamate/glutamine, asparagine, and adrenaline were altered. Sleep homeostasis is a balance between the duration of sleep and wakefulness and is coordinated by all NTs. The high-throughput quantitative method introduced in this study may aid in revealing the temporal cohesion among NTs, evaluating sleep homeostasis, and determining the effects of sedative-hypnotic drugs.
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Aim To determine the association between Toxoplasma gondii ( T. gondii ) infection and insomnia. Materials and methods Through an age-and gender-matched case-control study, 577 people with insomnia (cases) and 577 people without insomnia (controls) were tested for anti- T. gondii IgG and IgM antibodies using commercially available enzyme-immunoassays. Results Anti- T. gondii IgG antibodies were found in 71 (12.3%) of 577 individuals with insomnia and in 46 (8.0%) of 577 controls (OR=1.62; 95% CI: 1.09-2.39; P =0.01). Men with insomnia had a higher (16/73: 21.9%) seroprevalence of T. gondii infection than men without insomnia (5/73: 6.8%) (OR: 3.81; 95% CI: 1.31-11.06; P =0.009). The rate of high (>150 IU/ml) anti- T. gondii IgG antibody levels in cases was higher than the one in controls (OR=2.21; 95% CI: 1.13-4.31; P =0.01). Men with insomnia had a higher (8/73: 11.0%) rate of high anti- T. gondii IgG antibody levels than men without insomnia (0/73: 0.0%) ( P =0.006). The rate of high anti- T. gondii IgG antibody levels in cases >50 years old (11/180: 6.1%) was higher than that (3/180: 1.7%) in controls of the same age group (OR: 3.84; 95% CI: 1.05-14.00; P =0.05). No difference in the rate of IgM seropositivity between cases and controls was found (OR=1.33; 95% CI: 0.57-3.11; P =0.50). Conclusions Results of this seroepidemiology study suggest that infection with T. gondii is associated with insomnia. Men older than 50 years with T. gondii exposure might be prone to insomnia. Further research to confirm the association between seropositivity and serointensity to T. gondii and insomnia are needed.
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Background. It is known that sleep and sleep deprivation affect the EEG findings, onset, frequency and semiology of the seizures. Generalized spike and wave discharges were found more common in drowsiness and sleep states, especially in childhood and juvenile absence epilepsy syndromes. Aim. In this study we aimed to show the effects of short sleep on the interictal and ictal discharges of the patients with genetic generalized epileptic seizures and to show the effects of treatment on the discharges during awake and sleep states. Method. 37 patients (29 females and 8 males) with a diagnosis of genetic generalized epilepsy syndrome were included. All the patients were investigated with video-EEG recording during awake, sleep and post sleep states. Epileptic discharges were counted manually. Discharge numbers and their relation with triggers were analyzed to see the difference between different vigilance states. Results. Number of ictal discharges is found to be increased after sleep. There was no difference in the control EEGs, which were taken under treatment. Conclusion. Sleep is a trigger of epileptic discharges in ictal nature, but an effective antiepileptic treatment prevents this effect.
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Shared neurophysiology of addiction and sleep disorders results in a bidirectional interplay. Diagnosing and treating primary sleep disorders, particularly in adolescents, can prevent the development of addiction in susceptible individuals. Addressing sleep issues in early recovery, and throughout maintenance, can prevent relapse. Cannabis use for insomnia shows mixed results; assisting with onset sleep latency in early use, this subsides with chronic use and holds addiction risk. Insomnia is a primary complaint of cannabis withdrawal syndrome and a primary cause of relapse in cannabis use disorder. An ideal sleep aid would prevent relapse and have low abuse potential. Pharmaceutical and behavioral options include suvorexant, mirtazapine, trazodone, and aerobic exercise, but clinical trials are lacking to demonstrate efficacy.
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Sen oraz czuwanie to dwa przeciwstawne stany ośrodkowego układu nerwowego (OUN) występujące naprzemiennie i cyklicznie. Prawidłowa praca mózgu oraz architektura snu, a także płynne przechodzenie ze stanu czuwania w sen są regulowane przez skomplikowane i precyzyjne mechanizmy. Jednym z nich jest mechanizm homeostatycznej regulacji, który jest procesem złożonym, generujący cykliczne zmiany w aktywności poszczególnych obszarów mózgu pozwalające na płynne przechodzenie pomiędzy tymi stanami. Stan czuwania to wzmożona aktywność struktur czołowych, wzgórza oraz niektórych obszarów podwzgórza, podtrzymywana przez liczne neuroprzekaźniki syntetyzowane i uwalniane przez poszczególne grupy neuronów. Najistotniejszą rolę odgrywają tutaj: peptyd hipokretyna, aminy biogenne, takie jak katecholaminy, histamina czy też serotonina. Hipokretyna oraz histamina syntetyzowane są przez neurony określonych obszarów podwzgórza, natomiast pniu mózgu. Wyhamowanie aktywności tych neuroprzekaźników i przejście w stan snu zachodzi poprzez wzrost uwalniania neurotransmitera hamującego GABA produkowanego przez neurony projekcyjne z jądra przedwzrokowego podwzgórza, które hamując uwalnianie hipokretyny zapoczątkowują całą kaskadę wyciszania obszarów kory mózgowej.
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Objectives: The purpose of this study was to investigate the psychological characteristics of the Sasang constitutions by using Braverman nature assessment (BNA). Methods: One hundred seventy-four students participated in this study, and among them, the 142 individuals who had clearly identified Sasang constitutional types were used for the analysis. Sasang constitutions and the Braverman temperaments of the subjects were determined by using a questionnaire for the Sasang constitution classification (QSCC) II and BNA, respectively. Body mass index (BMI) was used to compare the inclinations of the Sasang constitutions and Braverman temperament types. Results: Significant differences in Braverman temperament type existed among the Sasang constitutions (P = 0.042), and the relations between Soyangin and the dopamine type and between Taeeumin and the gamma-aminobutyric acid (GABA) type were meaningful. Significant differences were also shown in the comparison with the Yin and the Yang constitutions (P = 0.017), and the post-hoc analysis showed a strong and significant relation between the Yang constitution and the dopamine type and between the Yin constitution and the GABA type. The one-way analysis of variance (ANOVA) and the independent t-test were conducted to examine the BMI and the degree of obesity among the Sasang constitutions and the Braverman temperament types. Concerning the BMI, Taeeumin showed a bigger BMI than the other constitutions (P < 0.001), but no significant differences in the BMI were observed between the Braverman temperament types. Conclusion: Soyangin has a close relationship to the dopamine type and Taeeumin has a close relationship to the GABA type. The correlation between two types were more clear when the Yin and the Yang types were compared to Braverman temperaments. These results may serve as a basis for identifying the psychological traits of Sasang constitutional types, especially in regard to the characteristics related to the four Braverman temperament types.
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Neurons which discharge selectively during waking (waking selective) have been found in the tuberomamillary nucleus (TM) and adjacent areas of the posterior hypothalamus. Although they share some electrophysiological properties with aminergic neurons, there is no direct evidence that they are histaminergic. We have recorded from posterior hypothalamic neurons during the sleep–wake cycle in freely moving cats, and investigated the effects on waking selective neurons of specific ligands of histaminergic H3-receptors, which autoregulate the activity of histaminergic neurons. Two types of neurons were seen.Waking selective neurons, termed “waking-on (W-on),” were located exclusively within the TM and adjacent areas, and discharged at a low regular rate during waking (1.71–2.97 Hz), decreased firing during light slow wave sleep (SWS), became silent during deep SWS and paradoxical sleep (PS) and resumed their activity on, or a few seconds before, awakening. “Waking-related” neurons, located in an area dorsal to the TM, displayed a similar, although less regular, low rate of firing (1.74–5.41 Hz) and a similar discharge profile during the sleep–wake cycle; however, unlike “W-on” neurons, they did not completely stop firing during deep SWS and PS. Intramuscular (i.m.) injection of ciproxifan (an H3-receptor antagonist, 1mg/kg), significantly increased the discharge rate of W-on neurons and induced c-fos expression in histamine-immunoreactive neurons, whereas i.m. injection of imetit (an H3-receptor agonist, 1mg/kg) or microinjection of �-methylhistamine (another H3-receptor agonist, 0.025–0.1�g/0.2�l) in the vicinity of these cells significantly decreased their discharge rate. Moreover, the effect of the antagonist was reversed by the agonists and vice versa. In contrast, “waking-related” neurons were unaffected by these H3-receptor ligands. These data provide evidence for the histaminergic nature of “W-on” neurons and their role in cortical desynchronization during waking, and highlight the heterogeneity of posterior hypothalamic neuronal populations, which might serve different functions during the wakefulness. © 2003 Elsevier Science B.V. All rights reserved
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Hypocretinergic/orexinergic neurons, which are known to be implicated in narcolepsy, project to the pontine tegmentum areas involved in the control of rapid eye movement (REM) sleep. Here, we report the effects on sleep-wakefulness produced by low-volume microinjections of hypocretin (Hcrt)1 (20-30 nL, 100, 500 and 1000 microm) and carbachol (20-30 nL, 0.1 m) delivered in two areas of the oral pontine tegmentum of free-moving cats with electrodes for chronic sleep recordings: in the dorsal oral pontine tegmentum (DOPT) and in the ventral part of the oral pontine reticular nucleus (vRPO). Carbachol in the DOPT produced dissociate polygraphic states, with some but not all REM sleep signs. In contrast, carbachol in the vRPO produced a shift with short latency from wakefulness (W) to REM sleep with all of its polygraphic and behavioral signs. Hcrt-1 in the DOPT increased W and decreased both slow-wave sleep (SWS) and REM sleep during the first 3 h post-drug. The same doses of Hcr-1 in the vRPO produced a significant suppression of REM sleep without a definitive trend for changes in the other states. Both groups showed significant decreases in the number of transitions from SWS to REM sleep. Thus, Hcrt-1 produced distinct effects in cholinoceptive areas of the oral pontine tegmentum; in the DOPT it promoted W, suppressed SWS and probably defacilitated REM sleep, and in the vRPO it directly inhibited REM sleep. Hypocretinergic/orexinergic signaling is lost in narcoleptics and this absence would mean that pontine defacilitation/inhibition of REM sleep would also be absent, explaining why these patients can fall directly into REM sleep from W.
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Pathways mediating the generation and/or maintenance of sleep reside within the preoptic/anterior hypothalamus (POAH). Reproduction, water balance, thermoregulation, and neuroendocrine functions are also associated with POAH, but it is not fully understood whether sleep is consolidated with these behavioral and physiological functions, or whether sleep-related circuitry is segregated from other POAH regions. Recent studies indicate that sleep mechanisms may be localized to the ventrolateral preoptic area (VLPO) and that this region sends inhibitory projections to waking/arousal-related neurons in the histaminergic tuberomammillary nucleus (TM), the noradrenergic locus coeruleus (LC), and the serotonergic dorsal raphe (DR). The present study is a quantitative investigation of preoptic area efferents to these monoaminergic groups. The results demonstrate that biotinylated dextran injections in the VLPO region reveal a robust innervation of TM that was as much as five times greater than innervation derived from other POAH subregions. The innervation of TM originated almost exclusively from injection sites in the region of galanin neurons. VLPO projections to the LC were moderately dense and were greater than in other POAH regions except for equivalent input from the medial preoptic area. Projections to the dorsal raphe were equivalent to LC innervation and were generally two to three times greater from VLPO than from other POAH regions, except for projections from the lateral preoptic region, which were similar in magnitude. The rostral and caudal levels projected more to the TM, whereas the midrostral region of VLPO strongly innervated the LC core. These findings, with recent studies demonstrating medial and lateral extensions of the sleep-related VLPO neuronal group, indicate that descending arousal state control may be mediated by this specific galaninergic/γ-aminobutyric acid (GABA)ergic cell group. J. Comp. Neurol. 429:638–653, 2001.
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This chapter discusses the basic mechanisms underlying control of wakefulness and sleep. Sleep may be divided into two phases. The first phase of sleep, rapid eye movement (REM) sleep, is most often associated with vivid dreaming and a high level of brain activity. The other phase of sleep, non-REM (NREM) sleep or slow-wave sleep, is usually associated with reduced neuronal activity; thought content during this state in humans usually is non-visual and consists of ruminative thoughts. In utero, mammals spend a large percentage of time in REM sleep, some 50%–80% of a 24-hour day. At birth, animals born with an immature nervous system spend a larger percentage of sleep time in REM sleep than adults of the same species. Sleep in the human newborn occupies two thirds of any day, and REM sleep accounts for half of the total sleep time or about a third of the entire 24-hour period. The percentage of REM sleep declines rapidly during early childhood so that by approximately age 10 years, the percentage of REM sleep is the same as for adults, 20% of total sleep time.
Article
Recent experiments suggest that brainstem GABAergic neurons may control rapid-eye-movement (REM) sleep. However, understanding their pharmacology/physiology has been hindered by difficulty in identification. Here we report that mice expressing green fluorescent protein (GFP) under the control of the GAD67 promoter (GAD67-GFP knock-in mice) exhibit numerous GFP-positive neurons in the central gray and reticular formation, allowing on-line identification in vitro. Small (10-15 microm) or medium-sized (15-25 microm) GFP-positive perikarya surrounded larger serotonergic, noradrenergic, cholinergic and reticular neurons, and > 96% of neurons were double-labeled for GFP and GABA, confirming that GFP-positive neurons are GABAergic. Whole-cell recordings in brainstem regions important for promoting REM sleep [subcoeruleus (SubC) or pontine nucleus oralis (PnO) regions] revealed that GFP-positive neurons were spontaneously active at 3-12 Hz, fired tonically, and possessed a medium-sized depolarizing sag during hyperpolarizing steps. Many neurons also exhibited a small, low-threshold calcium spike. GFP-positive neurons were tested with pharmacological agents known to promote (carbachol) or inhibit (orexin A) REM sleep. SubC GFP-positive neurons were excited by the cholinergic agonist carbachol, whereas those in the PnO were either inhibited or excited. GFP-positive neurons in both areas were excited by orexins/hypocretins. These data are congruent with the hypothesis that carbachol-inhibited GABAergic PnO neurons project to, and inhibit, REM-on SubC reticular neurons during waking, whereas carbachol-excited SubC and PnO GABAergic neurons are involved in silencing locus coeruleus and dorsal raphe aminergic neurons during REM sleep. Orexinergic suppression of REM during waking is probably mediated in part via excitation of acetylcholine-inhibited GABAergic neurons
Article
Cross circulation experiments were performed on rabbits to determine whether an electrographic sleeplike state induced in the donor by thalamic stimulation, or an electrographic arousal induced by reticular stimulation, influence the recipient brain by extraneuronal humoral mechanisms. We found that stimulation of the mediocentral intralaminary thalamus in the donor induces a significant increase of the delta voltage (computed with an automatic frequency analyzer) after four stimulations (142 ± 20.6%). Synchronously the recipient, crossed with the donor, shows a statistically significant increase of the delta voltage (121 ± 13.3%), usually after the fourth stimulation of the donor. Liminal stimulation of the midbrain reticular system in the donor induces arousal, with significant decrease in delta voltage to 48 ± 13.3% after the first and second stimulation. Parallel to this, the delta voltage decreases significantly in the recipient, to 68 ± 10.6% after the first and second stimulation. These electrographic and statistical results bring new evidence of the possibility that the brain activity of the recipient animal in cross circulation experiments can be influenced humorally by the donor in which experimental sleep or arousal are induced.
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Extracellular levels of adenosine increase in basal forebrain following prolonged wakefulness. Moreover, perfusion of adenosine into basal forebrain increases sleep. In this study we have examined the adenosine receptor subtypes, A1 and A2A, for changes in the levels of mRNA using RT-PCR and in situ hybridization and the receptor ligand binding efficiency using autoradiography following 3 and 6 h of sleep deprivation. We observed that A1 receptor mRNA levels increased in basal forebrain with no changes in other forebrain areas examined. A1 receptor binding was not affected. A2A receptor mRNA and ligand binding were undetectable in basal forebrain. However, in the olfactory tubercle, A2A mRNA and receptor binding decreased significantly. Based on the significant increase in the A1 but not in A2A receptor, we hypothesize that the effects of sleep deprivation-induced increased adenosine are mediated by A1 receptor in basal forebrain of rats.
Article
Anandamide (ANA) alters sleep by increasing the amount of time spent in slow wave sleep 2 (SWS2) and rapid eye movement sleep (REMS) at the expense of wakefulness (W) in rats. In this report, we describe a similar effect of ANA when injected itracerebroventricularly (i.c.v.) or into the peduriculopontine tegmental nucleus (PPTg) and the lack of an effect when ANA is administered into the medial preoptic area (MPOA). Furthermore, the i.c.v. or PPTg administration of SR141716A, a CB1 antagonist, or U73122, a PLC inhibitor, 15 min prior to ANA, readily prevents the ANA induced changes in sleep. The present results suggest that a cannabinoid system in the PPTg may be involved in sleep regulation and that the cannabinoid effect is mediated by the CB1 receptor coupled to a PLC second messenger system.
Article
The origins of the cholinergic and other afferents of several thalamic nuclei were investigated in the rat by using the retrograde transport of wheat germ agglutinin conjugated-horseradish peroxidase in combination with the immunohistochemical localization of choline acetyltransferase immunoreactivity. Small injections placed into the reticular, ventral, laterodorsal, lateroposterior, posterior, mediodorsal, geniculate, and intralaminar nuclei resulted in several distinct patterns of retrograde labelling. As expected, the appropriate specific sensory and motor-related subcortical structures were retrogradely labelled after injections into the principal thalamic nuclei. In addition, other basal forebrain and brainstem structures were also labelled, with their distribution dependent on the site of injection. A large percentage of these latter projections was cholinergic.
Article
The organization of hypothalamic projections to the cerebral cortex in the rat has been studied using retrograde and anterograde tracer methods. Four separate populations of hypothalamic neurons, which constitute a major source of diffuse cortical innervation, were identified: Tuberal lateral hypothalamic (LHAt) neurons which innervate the cerebral cortex tend to cluster in the perifornical region, in the zona incerta, and along the medial edge of the cerebral peduncle, at levels roughly coextensive with the ventromedial hypothalamic nucleus. Most of these neurons project to the ipsilateral cortex; a small percentage innervate the contralateral cortex, but this varies among cortical terminal fields. The perifornical neurons are organized in a roughly topographic medial-to-lateral relationship with respect to their cortical terminal fields. Field of Forel (FF) neurons, which project primarily to the frontal cortex of the ipsilateral hemisphere, are located just ventral to the medial edge of the medial lemniscus, at the level of the ventromedial basal thalamic nucleus. The more laterally placed neurons innervate the lateral frontal, insular and perirhinal cortex; the more medial neurons, around the mammillothalamic tract, innervate the medial frontopolar, prelimbic, infralimbic, and anterior cingulate cortex. Posterior lateral hypothalamic (LHAp) neurons form a dense cluster spanning the lateral hypothalamus, from the cerebral peduncle to the posterior hypothalamic area at premammillary levels, and extending into the supramammillary nucleus and the adjacent ventral tegmental area. LHAp neurons innervate the entire cerebral cortex, predominantly on the ipsilateral side. Populations of LHAp neurons projecting to different cortical target areas show considerable spatial overlap, but computer plots of the centers of these populations demonstrate a strict topographic relationship with respect to the cerebral cortex. Tuberomammillary (TMN) neurons form a sheet along the ventrolateral surface of the premammillary hypothalamus. About twice as many TMN neurons innervate the ipsilateral, as compared to the contralateral hemisphere; it is not known whether single neurons project to both hemispheres. No topographic organization of the TMN cortical projection is apparent. Injections of different-colored fluorescent dyes into various cortical areas demonstrate that hypothalamic neurons in general have rather restricted cortical terminal fields. Only occasional neurons are found, primarily in LHAt, which are double labeled by injections into different cytoarchitectonic areas. Anterograde tracing of fibers from LHAp, with the aid of the autoradiographic method, demonstrated two efferent pathways to cerebral cortex: a medial pathway runs through the medial forebrain bundle, traverses the diagonal band and medial septal nuclei, and enters the fornix and the cingulate bundle, from which it distributes to the hippocampal formation and to medial cortical fields, respectively. The lateral pathway runs through the lateral part of the medial forebrain bundle, then turns laterally through the substantia innominata to enter the external capsule, from which it distributes to lateral cortical fields. LHAp fibers in the hippocampus primar- ily innervate the outer part of the dentate granule cell layer; there is also a lighter projection to the CA2 and CA3a fields. In the neocortex, the densest LHAp innervation is in layer V and the deep part of layer VI, adjacent to the internal capsule. There is more sparse innervation also of layers I and 111. TMN fibers distribute in a similar, though much less dense, distribution.
Article
The basal forebrain including the preoptic area and anterior hypothalamus plays an important role in regulation of slow wave sleep. To examine whether this area is concerned also in a neural mechanism of paradoxical sleep, single neuronal activity in and around the preoptic area along with cortical EEG and neck EMG was recorded in undrugged, 12-h sleep-deprived rats whose head was fixed painlessly. The neurons whose activity was recorded during all states of sleep and wakefulness (n = 98) were classified into following 5 groups according to their firing behavior in relation to sleep-waking states. (1) Neurons most active during paradoxical sleep (n = 26). (2) Those most inactive during paradoxical sleep, some of which were inactive also during slow wave sleep (n = 16). (3) Those specifically active during slow wave sleep (n = 14). (4) Those less active during slow wave sleep than during wakefulness and paradoxical sleep (n = 9). (5) Those whose activity showed no clear correlation with the sleep-waking states (n = 33). About one third of neurons in each of groups (1) to (4) began to increase their sleep-related activity in advance of the shift of sleep/wakefulness state recognized in EEG. These results suggest that the preoptic and anterior hypothalamic areas are involved, at least in rats, in regulation of not only slow wave sleep but also paradoxical sleep.
Article
In cats, putative serotonergic neurons (PSNs) recorded from the dorsal raphe nucleus (DRN) across the sleep-wake cycle exhibit the so-called rapid eye movement sleep-off (REM-off) discharge pattern. Since, the sleep-wake discharge patterns of DRN neurons in behaving rats is poorly known, the present study examined this neuronal populations. The PSNs recorded in this study exhibited: (1) progressive decrease in discharge rate from waking to NREM to REM sleep; (2) long action potential duration, and (3) reduction of discharge rate after systemic administration of a selective 5-HT1A agonist, (±)-8-hydroxy-2-(di-n-propylamino) tetralin hydrobromide (8-OH-DPAT). Evidence supports the hypothesis that NREM sleep is modulated by thermoregulatory mechanisms localized in the preoptic area and adjacent basal forebrain (POA/BF). We previously reported that POA/BF warming suppresses the discharge of wake-promoting neurons in the posterior hypothalamus and the basal forebrain. Since the DRN is one component of the brainstem arousal system and receives projections from POA/BF, we examined the effects of local POA/BF warming by 1.5–2.0°C during waking on the discharge of DRN neurons. POA/BF warming reduced the discharge in 14 of 19 PSNs and in 12 of 17 other wake-related neurons in the DRN. DRN neuronal discharge reduction occurred without accompanying EEG frequency or behavioral changes. These results suggest that PSNs recorded in DRN in unrestrained and unanesthetized rats exhibit a “wake-active REM-off” discharge pattern and further support the hypothesis that the POA/BF warm-sensitive hypnogenic system induces sleep by a coordinated inhibition of multiple arousal systems including that modulated by the DRN.
Article
We have described elsewhere neurons in the ventral basal forebrain of cats that have elevated discharge rates during sleep and during transitions from waking to sleep, yet have comparatively low discharge rates during waking. These sleep-active neurons may mediate the hypnogenic properties of the basal forebrain. To further evaluate their role in the control of sleep, we examined the effects of basal forebrain lesions produced by microinjections of the relatively cell-selective neurotoxin, kainic acid, on sleep. Lesions were made bilaterally in two regions that contain high densities of sleep-active neurons: the horizontal limb of the diagonal bands of Broca and the lateral preoptic area-substantia innominata. Twelve-hour polygraph recordings were made before and at various intervals after basal forebrain damage in a total of eight cats. The lesions resulted in reduced time spent in deep, nonrapid eye-movement sleep and REM sleep, and increased time spent awake. These abnormalities persisted through 6 to 7 weeks postlesion. Reductions in deep non-REM sleep were due to decreases in bout number, particularly in the number of extended deep non-REM episodes (i.e., those >5 min in duration). The number of REM sleep episodes was also significantly reduced. The average duration of epochs of waking was elevated throughout the postlesion period. Thus, in the postlesion period, cats exhibited an impaired ability to initiate and maintain consolidated periods of sleep, particularly of deeper sleep stages. Lesions were also associated with reduced EEG spindling during sleep. These results are consistent with our hypothesis that sleep-active neurons are a component of a basal forebrain sleep- and EEG-regulating mechanism.
Article
Numerous lesion, stimulation and recording studies in experimental animals demonstrate the importance of neurons within the preoptic/anterior hypothalamic area (POA) in the regulation of sleep induction and sleep maintenance. Recently, a discrete cluster of cells in the ventrolateral POA (vlPOA) of rats was found to exhibit elevated c-fos gene expression during sleep, indicating that these neurons are strongly activated during nonREM and/or REM sleep stages. We examined neuronal discharge during wakefulness and sleep throughout the dorsal to ventral extent of the lateral POA in rats, using chronic microwire technique. We found that neurons with elevated discharge rates during sleep, compared to waking, were localized to the vlPOA. As a group, vlPOA neurons displayed elevated discharge rates during both nonREM and REM sleep. Discharge of vlPOA neurons reflected the depth of sleep, i.e., discharge rates increased significantly from light to deep nonREM sleep. During recovery sleep following 12–14 h of sleep deprivation, vlPOA neurons displayed increased sleep-related discharge, compared to baseline sleep. Neurons in the vlPOA displaying increased neuronal discharge during sleep were located in the same area where neurons exhibit increased c-fos gene expression during sleep. Such neurons are likely components of a rostral hypothalamic mechanism that regulates sleep onset and sleep maintenance.
Article
With increasing age, sleep becomes more shallow and fragmented and sleep-associated growth hormone (GH) release declines. GH secretion is regulated physiologically by opposite actions of GH-releasing hormone (GHRH) and somatostatin (SRIF). The administration of GHRH promotes sleep in both young and elderly controls, whereas SRIF does not induce sleep-EEG changes in young subjects. Because the influence of peripheral SRIF administration on sleep EEG in the elderly is unknown, we administered 50 μg SRIF-14 every hour between 2200 and 0100 hours to controls with an age range from 60 to 73 years (mean ± SD 67.4 ± 5.1 years). After SRIF administration, total sleep time and rapid eye movement (REM) sleep decreased significantly, and more time was spent awake in the first sleep cycle, suggesting that SRIF induces sleep deterioration in the elderly. The peptide may become more effective on sleep EEG in older than in younger subjects because of the decline of GHRH-GH axis activity, which may contribute to sleep disturbances in aging. The increased efficacy of SRIF in the elderly also may be explained by enhanced leakage of the blood-brain barrier.
Article
The presence of central cannabinoid receptor (CB1), involving the N-terminal 14 amino acid peptide, was demonstrated in the rat brain by immunohistochemistry. Intensely stained neurons were observed in the principal neurons of the hippocampus, striatum, substantia nigra, cerebellar cortex, including the Purkinje cells. Moderate CB1-IR cell bodies and fibers were present in the olfactory bulb, cingulate, entorhinal and piriform cortical areas, amygdala and nucleus accumbens. The perivascular glial fibers have shown moderate to high density CB1-IR in olfactoric and limbic structures. Low density was detected in the thalamus and hypothalamus and area postrema. The CB1 receptor was widely distributed in the forebrain and sparsely in the hindbrain.These new data support the view that the endogenous cannabinoids play an important role in different neuronal functions as neuromodulators or neurotransmitters.
Article
Electrographic and behavioral observations were made on five rodent species under controlled conditions. These were:Mus musculus, Rattus norvegicus, Mesocricetus auratus, Citellus tridecemlineatus and Chinchilla laniger. Normative values for sleep characteristics of the five species were derived from 48 hr recording periods. Analysis of sleep pattern characteristics showed: (1) well defined stages of slow wave sleep and paradoxical sleep in all animals; (2) sleep occupied from 52–60 per cent of each day for the different species; (3) different species differed in percentage of paradoxical sleep ranging from 10 per cent for the mouse to 24 per cent for hamsters and ground squirrels; (4) hibernators slept in significantly longer periods, had higher percentages of paradoxical sleep and slightly higher percentages of total sleep time. Hibernators also seemed to sleep more deeply than non-hibernators.
Article
The effects of mild POAH warming and cooling on EEG frequency patterns within sustained periods of NREM sleep were examined. EEG spectral power analysis showed that POAH warming increased delta (0.5–4.0 Hz) activity, but had no effect on theta or sigma frequencies. Delta power was also increased during a 1 h recovery period, following warming. POAH cooling had no EEG effects. Since delta power is thought to be an index of sleep depth, our findings suggest that POAH thermoregulatory mechanisms participate in the regulation of the depth of NREM sleep.
Article
We have previously described a population of neurons in the magnocellular basal forebrain which have selectively elevated discharge rates during slow-wave sleep compared to waking, we postulate that these sleep-active neurons are a component of a basal forebrain sleep-promoting system. The purpose of the present experiment was to determine if sleep-active neurons contribute axons to recently described basal forebrain projection pathways. In cats prepared for chronic single unit and EEG-sleep recordings, stimulating electrodes were placed in the mesencephalic reticular formation, and the external capsule and anterior cingulate bundle, fiber bundles known to contain axons of basal forebrain projection neurons. Fifty-nine neurons were antidromically driven, differences in antidromic response latencies were related to sleep-waking discharge profiles. Of the cells with short antidromic latencies (<5 msec), the majority (9 of 12) had high discharge rates during waking and low rates during slow-wave sleep. Cells with long antidromic latencies had either very low discharge rates (< 1 spike/sec) across all states, or had elevated discharge rates in slow-wave sleep. Sleep-active neurons were antidromically driven from external capsule (n = 9), anterior cingulate bundle (n=9), or mesencephalic reticular formation (n = 5). Projection sleep-active neurons were recorded in the substantia innominata, ventral to the globus pallidus and medial to the central nucleus of the amygdala. Our study found that identified basal forebrain projection neurons in cats exhibit a variety of sleep-waking discharge patterns and conduction velocities. Sleep-active neurons were found to have slowly conducting axons, and to be a source of both ascending and descending projections.