Role In Sleep Regulation Research Articles

Melatonin’s role in the timing of sleep onset is conserved in nocturnal mice

Melatonin supplementation strengthens non‐restorative sleep rhythms and its temporal alignment in both humans and night-active rodents. Of note, although the sleep cycle is reversed in day-active and night-active (nocturnal) mammals, both, produce melatonin at night under the control of the circadian clock. The effects of exogenous melatonin on sleep and sleepiness are relatively clear, but its endogenous role in sleep, particularly, in timing sleep onset (SO), remains poorly understood. We show in nocturnal mice that the increases in mid-nighttime sleep episodes, and the mid-nighttime decline in activity, are coupled to nighttime melatonin signaling. Furthermore, we show that endogenous melatonin modulates SO by reducing the threshold for wake-to-sleep transitioning. Such link between melatonin and SO timing may explain phenomena such as increased sleep propensity in circadian rhythm sleep disorders and chronic insomnia in patients with severely reduced nocturnal melatonin levels. Our findings demonstrate that melatonin’s role in sleep is evolutionarily conserved, effectively challenging the argument that melatonin cannot play a major role in sleep regulation in nocturnal mammals, where the main activity phase coincides with high melatonin levels.

Therapeutic potential of Rosa roxburghii folium extract in insomnia treatment: a comprehensive evaluation of behavioral and neurochemical effects in a PCPA-induced mouse model.

Insomnia, a prevalent sleep disorder, detrimentally affects quality of life and is often challenging to manage with conventional treatments. This study delved into identifying and quantifying the main compounds by employing ultra-performance liquid chromatography-Q-Exactive-Orbitrap mass spectrometry, and further to evaluate the therapeutic potential of Rosa roxburghii folium (RRF) extract, with multiple pharmacological activities. Previous research had hinted at the efficacy of glycosides in influencing the γ-aminobutyric acid (GABAergic) system, which plays a pivotal role in sleep regulation. Utilizing a p-chlorophenylalanine-induced insomnia model in BALB/C mice, this investigation aimed to unravel the effects of various dosages of RRF extract on sleep quality and elucidated its mechanism of action. A total of 66 compounds in the RRF extract were analyzed. Behavioral assessments demonstrated notable enhancements in sleep duration and latency. Biochemical analyses further corroborated these findings, revealing modulation in neurotransmitter levels indicative of a potential mechanism through the GABAergic and serotoninergic pathways. Additionally, histological evaluations suggested anti-inflammatory and antioxidant effects of the RRF extract. The findings from this study underscored the therapeutic efficacy of RRF extract in combating insomnia, particularly highlighting its glycoside components' role. The extract's significant improvement in sleep duration and latency, alongside its modulation of neurotransmitter levels, showcases its potential as a natural remedy for insomnia. Through its action on the GABAergic and serotoninergic pathways, as well as its anti-inflammatory and antioxidant effects, RRF extract emerges as a promising candidate for insomnia treatment, offering a holistic approach to sleep disorder management. © 2024 Society of Chemical Industry.

Effects of probiotics on sleep parameters: A systematic review and meta-analysis

AimAlthough sleep is essential for maintaining good health and well-being, sleep disorders are becoming increasingly prevalent. Probiotics may play a role in sleep regulation; therefore, this study aimed to provide a comprehensive overview of the effects of probiotics on sleep parameters. MethodsWe conducted a systematic literature review and meta-analysis, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses methodology. Relevant placebo-controlled randomized controlled trials examining the effects of probiotics on sleep outcomes were identified through systematic searches in the PubMed, Cochrane Library, and Ichushi databases. Data were extracted from eligible studies and the risk of bias was assessed. Statistical analyses were performed to assess the effects of probiotics on various sleep-related variables. ResultsFifteen randomized controlled trials were included in this review. The decrease in Pittsburgh Sleep Quality Index (PSQI) scores in the probiotics group was significantly lower than that in the placebo group after 4–6 weeks and 8–16 weeks, indicating improved sleep quality. The Oguri-Shirakawa-Azumi (OSA) sleep inventory score was also decreased in the probiotics group for Factor 1 “sleepiness on rising” and Factor 4 “refreshing,” indicating improved sleep quality. Some studies however, showed a risk of bias. ConclusionThis systematic review and meta-analysis indicated that probiotics may improve sleep quality, as measured by the PSQI and OSA sleep inventory. However, further research is needed to better understand the effects of probiotics on specific sleep parameters and address the limitations of existing studies.

Cyclooxygenase-2 (COX-2)-dependent mechanisms mediate sleep responses to microbial and thermal stimuli

Prostaglandins (PGs) play a crucial role in sleep regulation, yet the broader physiological context that leads to the activation of the prostaglandin-mediated sleep-promoting system remains elusive. In this study, we explored sleep-inducing mechanisms potentially involving PGs, including microbial, immune and thermal stimuli as well as homeostatic sleep responses induced by short-term sleep deprivation using cyclooxygenase-2 knockout (COX-2 KO) mice and their wild-type littermates (WT). Systemic administration of 0.4 µg lipopolysaccharide (LPS) induced increased non-rapid-eye movement sleep (NREMS) and fever in WT animals, these effects were completely absent in COX-2 KO mice. This finding underscores the essential role of COX-2-dependent prostaglandins in mediating sleep and febrile responses to LPS. In contrast, the sleep and fever responses induced by tumor necrosis factor α, a proinflammatory cytokine which activates COX-2, were preserved in COX-2 KO animals, indicating that these effects are independent of COX-2-related signaling. Additionally, we examined the impact of ambient temperature on sleep. The sleep-promoting effects of moderate warm ambient temperature were suppressed in COX-2 KO animals, resulting in significantly reduced NREMS at ambient temperatures of 30 °C and 35 °C compared to WT mice. However, rapid-eye-movement sleep responses to moderately cold or warm temperatures did not differ between the two genotypes. Furthermore, 6 h of sleep deprivation induced rebound increases in sleep with no significant differences observed between COX-2 KO and WT mice. This suggests that while COX-2-derived prostaglandins are crucial for the somnogenic effects of increased ambient temperature, the homeostatic responses to sleep loss are COX-2-independent. Overall, the results highlight the critical role of COX-2-derived prostaglandins as mediators of the sleep-wake and thermoregulatory responses to various physiological challenges, including microbial, immune, and thermal stimuli. These findings emphasize the interconnected regulation of body temperature and sleep, with peripheral mechanisms emerging as key players in these integrative processes.

The role of glial and neuronal Eph/ephrin signaling in Drosophila mushroom body development and sleep and circadian behavior

The Eph receptor, a prototypically large receptor protein tyrosine kinase, interacts with ephrin ligands, forming a bidirectional signaling system that impacts diverse brain functions. Eph receptors and ephrins mediate forward and reverse signaling, affecting neurogenesis, axon guidance, and synaptic signaling. While mammalian studies have emphasized their roles in neurogenesis and synaptic plasticity, the Drosophila counterparts are less studied, especially in glial cells, despite structural similarities. Using RNAi to modulate Eph/ephrin expression in Drosophila neurons and glia, we studied their roles in brain development and sleep and circadian behavior. Knockdown of neuronal ephrin disrupted mushroom body development, while glial knockdown had minimal impact. Surprisingly, disrupting ephrin in neurons or glial cells altered sleep and circadian rhythms, indicating a direct involvement in these behaviors independent from developmental effects. Further analysis revealed distinct sleep phenotypes between neuronal and glial knockdowns, underscoring the intricate interplay within the neural circuits that govern behavior. Glia-specific knockdowns showed altered sleep patterns and reduced circadian rhythmicity, suggesting an intricate role of glia in sleep regulation. Our findings challenge simplistic models of Eph/ephrin signaling limited to neuron-glia communication and emphasize the complexity of the regulatory networks modulating behavior. Future investigations targeting specific glial subtypes will enhance our understanding of Eph/ephrin signaling's role in sleep regulation across species.

The Effects of Sleep on Human Physiology and Its Regulation

Sleep is an essential aspect of human biology and is crucial for maintaining overall health and cognitive functioning. The significance of sleep, its effects on bodily and cognitive function, and the underlying mechanisms were covered in this essay. One of the primary functions of sleep is to facilitate physical restoration. During sleep, the body engages in critical processes such as immune system regulation, metabolic waste clearance, and cell repair. The brain also undergoes restoration during sleep, consolidates memories, enhances learning, and promotes creativity. Insufficient sleep can lead to physical symptoms such as fatigue and reduced concentration, as well as emotional instability and fluctuations in mood. The mechanisms of sleep regulation are multifaceted, incorporating both physiological and neurological processes. The body's circadian rhythm plays a crucial role in sleep regulation. Sleep quality can be influenced by various environmental and psychological factors. Exposure to artificial light, especially before bedtime, can inhibit the release of melatonin. Stress, anxiety, and depression can also disrupt sleep patterns, making it difficult to obtain restful sleep. In conclusion, sleep is a crucial aspect of human biology that impacts both physical and cognitive function. Further research into sleep regulation and its impact on academic success may provide opportunities for new therapeutic approaches for sleep-related disorders.

Hubungan Gelombang Cahaya Lampu dan Cahaya Biru dengan Kualitas Tidur Remaja Dewasa

Sleep is a crucial part of the human circadian cycle. The quality and quantity of sleep significantly influence various aspects of health, both physical and psychological. The hormone melatonin, which plays a vital role in sleep regulation, is produced as the intensity of light received by the eyes decreases. Currently, the use of lights and electronic devices emitting blue light is widespread, especially among teenagers to adults. This blue light can interfere with the production of melatonin, potentially disrupting sleep quality and patterns. In this age group, most are active students with busy schedules. This study uses a sequential explanatory design approach, combining quantitative and qualitative questionnaires to collect data and measure the impact of light on sleep duration and patterns. The respondents of this study were 71 people, coming from various universities and different study programs in Bandung City, ranging in age from 18 to 25 years. The research data results show that 38.6% of respondents experience sleep disturbances when the light is on, impacting sleep quality. Conversely, sleep quality improvement occurs in 81.4% of respondents when sleeping with the light off. The use of night mode on electronic devices, designed to reduce blue light emissions, positively impacts sleep quality, as felt by 38% of the 67.1% of respondents who use the night mode feature.

PpGpp is present in, and functions to regulate sleep of, Drosophila

Sleep is essential for animals, and receives inputs from circadian, homeostasis, and environment, yet the mechanisms of sleep regulation remain elusive. Discovery of molecules in living systems and demonstration of their functional roles are pivotal in furthering our understanding of the molecular basis of biology. Here, we report that guanosine-5′-diphosphate, 3′-diphosphate (ppGpp) is present in Drosophila, and plays an important role in regulation of sleep and starvation-induced sleep loss (SISL). ppGpp is detected in germ-free Drosophila and hydrolyzed by an enzyme encoded by the mesh1 gene in Drosophila. Nighttime sleep and SISL were defected in mesh1 mutant flies, and rescued by expression of wildtype Mesh1, but not the enzymatically defective mutant Mesh1E66A. Ectopic expression of RelA, the Escherichia coli synthetase for ppGpp, phenocopied mesh1 knockout mutants, whereas overexpression of Mesh1 resulted in the opposite phenotypes, supporting that ppGpp is both necessary and sufficient in sleep regulation. A chemo connectomic screen followed by genetic intersection experiments implicates the Dilp2 neurons in the pars intercerebralis (PI) brain region as the site of ppGpp function. Our results have thus validated the presence of ppGpp in Drosophila and revealed a physiological role of ppGpp in sleep regulation for the first time.

Gut Microbiome Composition and Its Association with Sleep in Major Psychiatric Disorders

Introduction: Sleep disturbances are highly prevalent across most major psychiatric disorders. Alterations in the hypothalamic-pituitary-adrenal axis, neuroimmune mechanisms, and circadian rhythm disturbances partially explain this connection. The gut microbiome is also suspected to play a role in sleep regulation, and recent studies suggest that certain probiotics, prebiotics, synbiotics, and fecal microbiome transplantation can improve sleep quality. Methods: We aimed to assess the relationship between gut-microbiota composition, psychiatric disorders, and sleep quality in this cross-sectional, cross-disorder study. We recruited 103 participants, 63 patients with psychiatric disorders (major depressive disorder [n = 31], bipolar disorder [n = 13], psychotic disorder [n = 19]) along with 40 healthy controls. Sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI). The fecal microbiome was analyzed using 16S rRNA sequencing, and groups were compared based on alpha and beta diversity metrics, as well as differentially abundant species and genera. Results: A transdiagnostic decrease in alpha diversity and differences in beta diversity indices were observed in psychiatric patients, compared to controls. Correlation analysis of diversity metrics and PSQI score showed no significance in the patient and control groups. However, three species, Ellagibacter isourolithinifaciens, Senegalimassilia faecalis, and uncultured Blautia sp., and two genera, Senegalimassilia and uncultured Muribaculaceae genus, were differentially abundant in psychiatric patients with good sleep quality (PSQI >8), compared to poor-sleep quality patients (PSQI ≤8). Conclusion: In conclusion, this study raises important questions about the interconnection of the gut microbiome and sleep disturbances.

Exogenous Ketosis Improves Sleep Efficiency and Counteracts the Decline in REM Sleep after Strenuous Exercise.

Available evidence indicates that ketone bodies may improve sleep quality. Therefore, we determined whether ketone ester (KE) intake could counteract sleep disruptions induced by strenuous exercise. Ten well-trained cyclists with good sleep quality participated in a randomized crossover design consisting of two experimental sessions each involving a morning endurance training and an evening high-intensity interval training ending 1 h before sleep, after which polysomnography was performed overnight. Postexercise and 30 min before sleeping time, subjects received either 25 g of KE (EX KE ) or a placebo drink (EX CON ). A third session without exercise but with placebo supplements (R CON ) was added to evaluate the effect of exercise per se on sleep. Blood d -β-hydroxybutyrate concentrations transiently increased to ~3 mM postexercise and during the first part of the night in EX KE but not in EX CON or R CON . Exercise significantly reduced rapid eye movement sleep by 26% ( P = 0.001 vs R CON ) and increased wakefulness after sleep onset by 95% ( P = 0.004 vs R CON ). Interestingly, KE improved sleep efficiency by 3% ( P = 0.040 vs EX CON ) and counteracted the exercise-induced decrease in rapid eye movement sleep ( P = 0.011 vs EX CON ) and the increase in wakefulness after sleep onset ( P = 0.009 vs EX CON ). This was accompanied by a KE-induced increase in dopamine excretion ( P = 0.033 vs EX CON ), which plays a pivotal role in sleep regulation. In addition, exercise increased sleep spindle density by 36% ( P = 0.005 vs R CON ), suggesting an effect on neural plasticity processes during sleep. These data indicate that KE ingestion improves sleep efficiency and quality after high-intensity exercise. We provide preliminary evidence that this might result from KE-induced increases in dopamine signaling.

Branched-chain amino acids and sleep: a population-derived study of Australian children aged 11-12 years and their parents.

Micronutrients, particularly amino acids, are thought to play an important role in sleep regulation and maintenance. While tryptophan is a known predictor of sleep, less is known about branched-chain amino acids (BCAAs), which compete with tryptophan for transport across the blood-brain barrier. The aim of this study was to determine the association between BCAAs and actigraphy-derived sleep duration, timing and efficiency, and self-reported trouble sleeping. This study examined data on children and adults collected as part of the Child Health CheckPoint study. Linear mixed models, adjusted for geographic clustering, were used to determine the association between BCAAs and sleep characteristics. Complete-case analysis was conducted for 741 children aged 11-12 years old (51% females) and 941parents (87% mothers). While BCAAs were significantly associated with children's sleep duration, timing and self-reported trouble sleeping, no associations were observed in adults, in fully adjusted models. In children, higher levels of BCAAs are associated with shorter sleep duration, delayed sleep timing, and more frequent reports of trouble sleeping.

The Putative Role of Neuroinflammation in the Interaction between Traumatic Brain Injuries, Sleep, Pain and Other Neuropsychiatric Outcomes: A State-of-the-Art Review

Sleep disturbances are widely prevalent following a traumatic brain injury (TBI) and have the potential to contribute to numerous post-traumatic physiological, psychological, and cognitive difficulties developing chronically, including chronic pain. An important pathophysiological mechanism involved in the recovery of TBI is neuroinflammation, which leads to many downstream consequences. While neuroinflammation is a process that can be both beneficial and detrimental to individuals' recovery after sustaining a TBI, recent evidence suggests that neuroinflammation may worsen outcomes in traumatically injured patients, as well as exacerbate the deleterious consequences of sleep disturbances. Additionally, a bidirectional relationship between neuroinflammation and sleep has been described, where neuroinflammation plays a role in sleep regulation and, in turn, poor sleep promotes neuroinflammation. Given the complexity of this interplay, this review aims to clarify the role of neuroinflammation in the relationship between sleep and TBI, with an emphasis on long-term outcomes such as pain, mood disorders, cognitive dysfunctions, and elevated risk of Alzheimer's disease and dementia. In addition, some management strategies and novel treatment targeting sleep and neuroinflammation will be discussed in order to establish an effective approach to mitigate long-term outcomes after TBI.

Role of MicroRNAs in the Regulation of Sleep/wakefulness and Their Expression Changes in the Brain Following Sleep Deprivation

Background and Objectives The circadian rhythm has 24-hour oscillators and is introduced as an internal sleep/wakefulness cycle regulator. This system is regulated by transcription-translation feedback loops. MicroRNAs (miRNAs) include non-coding RNAs, which are essential in the post-translational modification of mRNA transcripts. MiRNAs play a significant role in circadian rhythm regulation, and it has been demonstrated that sleep loss can alter brain miRNA levels. Nowadays, sleep deprivation has turned into a daunting challenge in modern societies, considering that sleep disorder is the source of many diseases, and numerous studies have examined the association between sleep disorder and miRNA dysfunction. Therefore, it appears that it is critical to assess the relationship between microRNA, circadian rhythm, and sleep disorder. Subjects and Methods For this purpose, a query was conducted on various databases (Google Scholar, Scopus, Web of Science, and PubMed) for English articles from 1998 to 2021. Results The current evidence confirms that miRNAs are involved in the molecular regulation of circadian rhythms by regulating sleep duration and intensity. Some of these miRNAs include miRNA-155, miRNA-7b, MiR-182, miRNA-126, miRNA-192/194, miRNA142-3p, miRNA-132, and miRNA-219-1. Lack of sleep can cause widespread changes in protein expression throughout the brain by altering miRNA (miR-1b, miRNA-125a-3p, miR146a, miR-26a/b-3p, and miR-138) levels. Conclusion As reviewed in this study, miRNAs are uniquely expressed at different times and in various structures in the brain, playing a key role in sleep regulation. These findings suggest that understanding the abnormalities in the expression of circadian miRNAs could be used to treat numerous disorders following sleep deprivation

A benchmark for hypothalamus segmentation on T1-weighted MR images

The hypothalamus is a small brain structure that plays essential roles in sleep regulation, body temperature control, and metabolic homeostasis. Hypothalamic structural abnormalities have been reported in neuropsychiatric disorders, such as schizophrenia, amyotrophic lateral sclerosis, and Alzheimer's disease. Although mag- netic resonance (MR) imaging is the standard examination method for evaluating this region, hypothalamic morphological landmarks are unclear, leading to subjec- tivity and high variability during manual segmentation. Due to these limitations, it is common to find contradicting results in the literature regarding hypothalamic volumetry. To the best of our knowledge, only two automated methods are available in the literature for hypothalamus segmentation, the first of which is our previous method based on U-Net. However, both methods present performance losses when predicting images from different datasets than those used in training. Therefore, this project presents a benchmark consisting of a diverse T1-weighted MR image dataset comprising 1381 subjects from IXI, CC359, OASIS, and MiLI (the latter created specifically for this benchmark). All data were provided using automatically generated hypothalamic masks and a subset containing manually annotated masks. As a baseline, a method for fully automated segmentation of the hypothalamus on T1-weighted MR images with a greater generalization ability is presented. The pro- posed method is a teacher-student-based model with two blocks: segmentation and correction, where the second corrects the imperfections of the first block. After using three datasets for training (MiLI, IXI, and CC359), the prediction performance of the model was measured on two test sets: the first was composed of data from IXI, CC359, and MiLI, achieving a Dice coefficient of 0.83; the second was from OASIS, a dataset not used for training, achieving a Dice coefficient of 0.74. The dataset, the baseline model, and all necessary codes to reproduce the experiments are available at https://github.com/MICLab-Unicamp/HypAST and https://sites.google.com/ view/calgary-campinas-dataset/hypothalamus-benchmarking. In addition, a leaderboard will be maintained with predictions for the test set submitted by anyone working on the same task.

Melatonin Treatment for Pediatric Patients with Insomnia: Is There a Place for It?

Sleep is a vital physiological function that is impaired in ranges from 10% in the typically developing pediatric population to over 80% in populations of children with neurodevelopmental disorders and/or psychiatric comorbidities. Pediatric insomnia disorder is an increasing public health concern given its negative impact on synaptic plasticity involved in learning and memory consolidation but also on mood regulation, hormonal development and growth, and its significant impact on quality of life of the child, the adolescent and the family. While first-line treatment of pediatric insomnia should include parental education on sleep as well as sleep hygiene measures and behavioural treatment approaches, pharmacological interventions may be necessary if these strategies fail. Melatonin treatment has been increasingly used off-label in pediatric insomnia, given its benign safety profile. This article aims to identify the possible role of melatonin treatment for pediatric insomnia, considering its physiological role in sleep regulation and the differential effects of immediate release (IR) versus prolonged release (PR) melatonin. For the physician dealing with pediatric insomnia, it is particularly important to be able to distinguish treatment rationales implying different dosages and times of treatment intake. Finally, we discuss the benefit-risk ratio for melatonin treatment in different pediatric populations, ranging from the general pediatric population to children with different types of neurodevelopmental disorders, such as autism spectrum disorder or ADHD.

The melanin-concentrating hormone system as a target for the treatment of sleep disorders.

Given the widespread prevalence of sleep disorders and their impacts on health, it is critical that researchers continue to identify and evaluate novel avenues of treatment. Recently the melanin-concentrating hormone (MCH) system has attracted commercial and scientific interest as a potential target of pharmacotherapy for sleep disorders. This interest emerges from basic scientific research demonstrating a role for MCH in regulating sleep, and particularly REM sleep. In addition to this role in sleep regulation, the MCH system and the MCH receptor 1 (MCHR1) have been implicated in a wide variety of other physiological functions and behaviors, including feeding/metabolism, reward, anxiety, depression, and learning. The basic research literature on sleep and the MCH system, and the history of MCH drug development, provide cause for both skepticism and cautious optimism about the prospects of MCH-targeting drugs in sleep disorders. Extensive efforts have focused on developing MCHR1 antagonists for use in obesity, however, few of these drugs have advanced to clinical trials, and none have gained regulatory approval. Additional basic research will be needed to fully characterize the MCH system’s role in sleep regulation, for example, to fully differentiate between MCH-neuron and peptide/receptor-mediated functions. Additionally, a number of issues relating to drug design will continue to pose a practical challenge for novel pharmacotherapies targeting the MCH system.

Regulation of sleep quantity and intensity by long and short isoforms of SLEEPY kinase.

In Sleepy (Sik3Slp) or Sik3S551A mice, deletion or mutation of inhibitory phosphorylation site serine551 from salt-inducible kinase 3 (SIK3) markedly increases daily non-rapid eye movement sleep (NREMS) amount, accompanied with constitutively elevated NREMS delta power density-a measure of sleep intensity. Multiple SLP/SIK3 isoforms are expressed in mouse brain neurons, however, their respective roles in sleep regulation remain to be elucidated. Here, we identified a new and most abundant short isoform of SLP/SIK3 and examined sleep phenotypes resulted from isoform-specific expression of SLP-short (S) and long (L) isoforms. Adeno-associated virus (AAV)-mediated adult brain chimeric (ABC)-expression of SLP-S in neurons, but not in astrocytes, significantly and constitutively elevates NREMS delta power, whereas slightly increases NREMS amount. The ability of SLP-S to regulate sleep quantity/intensity is abrogated by kinase-inactivating mutations, suggesting that the sleep-promoting activity of SLP-S is dependent on its kinase activity. In Sik3S551A-L knock-in mice, isoform-specific expression of SIK3S551A-L (or SLP-L) significantly increases NREMS amount with a modest effect on NREMS delta power. ABC-expression of SLP-S complements the sleep phenotypes of heterozygous Sik3S551A-L mice by further increasing NREMS amount and NREMS delta power to levels of Sik3Slp or Sik3S551A mice. Taken together, these results indicate that both SLP-L and SLP-S isoforms contribute critically to the increases of sleep quantity and intensity in Sik3Slp or Sik3S551A mice.

LKB1 is physiologically required for sleep from Drosophila melanogaster to the Mus musculus.

Liver Kinase B1 (LKB1) is known as a master kinase for 14 kinases related to the adenosine monophosphate-activated protein kinase. Two of them salt inducible kinase 3 and adenosine monophosphate-activated protein kinase α have previously been implicated in sleep regulation. We generated loss-of-function mutants for Lkb1 in both Drosophila and mice. Sleep, but not circadian rhythms, was reduced in Lkb1-mutant flies and in flies with neuronal deletion of Lkb1. Genetic interactions between Lkb1 and threonine to alanine mutation at residue 184 of adenosine monophosphate-activated protein kinase in Drosophila sleep or those between Lkb1 and Threonine to Glutamic Acid mutation at residue 196 of salt inducible kinase 3 in Drosophila viability have been observed. Sleep was reduced in mice after virally mediated reduction of Lkb1 in the brain. Electroencephalography analysis showed that nonrapid eye movement sleep and sleep need were both reduced in Lkb1-mutant mice. These results indicate that liver kinase B1 plays a physiological role in sleep regulation conserved from flies to mice.

Altered thalamic functional connectivity and cerebral blood flow in insomnia disorder: a resting-state functional magnetic resonance imaging study

Background and purposeThe thalamus plays a crucial role in sleep regulation, but few studies have examined functional connectivity of the thalamus in insomnia disorder. This study aimed to investigate the connectivity patterns and perfusion of the thalamus in patients with insomnia disorder using resting-state functional connectivity and three-dimensional arterial spin labeling (3D ASL). Materials and methodsIn total, 56 patients with insomnia disorder and 59 healthy control participants with a similar age-, gender-, and education lever distribution underwent resting-state functional magnetic resonance imaging (rs-fMRI) and 3D-ASL. The thalamus was selected as the seed region. Whole-brain connectivity was assessed using rs-fMRI. Cerebral blood flow (CBF) of the bilateral thalamus was measured with 3D-ASL using region-of-interest (ROI) analysis. All participants completed a series of neuropsychological assessments. Sleep parameters were assessed via polysomnography (PSG). The relationships between imaging parameters and clinical variables were assessed with Pearson correlation analysis. ResultsCompared with healthy controls, patients with insomnia disorder exhibited increased connectivity between the left thalamus and right precentral gyrus, and right thalamus and left middle frontal gyrus (MFG), right superior parietal lobule (SPL) and right superior frontal gyrus (SFG). Whereas decreased connectivity was noted between the right thalamus and left posterior cerebellar lobe including Crus I, Crus II, and VII b/VII. Connectivity between the right thalamus and left Crus I was positively correlated with MoCA scores (r = 0.286, P = 0.036) in insomnia disorder. ConclusionsOur findings illustrate functional abnormalities in brain connectivity and their relationship with cognitive impairments in insomnia disorder, providing novel insight into the neural mechanisms of insomnia disorder.

A Novel Theanine Complex, Mg-L-Theanine Improves Sleep Quality via Regulating Brain Electrochemical Activity.

L-Theanine is commonly used to improve sleep quality through inhibitory neurotransmitters. On the other hand, Mg2+, a natural NMDA antagonist and GABA agonist, has a critical role in sleep regulation. Using the caffeine-induced brain electrical activity model, here we investigated the potency of L-theanine and two novel Mg-L-theanine compounds with different magnesium concentrations on electrocorticography (ECoG) patterns, GABAergic and serotonergic receptor expressions, dopamine, serotonin, and melatonin levels. Furthermore, we evaluated the sleep latency and duration in the pentobarbital induced sleep model. We herein showed that L-theanine, particularly its various complexes with magnesium increases the expression of GABAergic, serotonergic, and glutamatergic receptors, which were associated with decreased ECoG frequency, increased amplitude, and enhanced delta wave powers. Besides increased dopamine, serotonin, and melatonin; decreased MDA and increased antioxidant enzyme levels were also observed particularly with Mg-complexes. Protein expression analyses also showed that Mg-L-theanine complexes decrease inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) levels significantly. In accordance with these results, Mg complexes improved the sleep latency and duration even after caffeine administration. As a result, our data indicate that Mg-L-theanine compounds potentiate the effect of L-theanine on sleep by boosting slow-brain waves, regulating brain electrical activity, and increasing neurotransmitter and GABA receptor levels.