Sleep Rhythms Research Articles

Exposure to constant artificial light alters honey bee sleep rhythms and disrupts sleep

AbstractArtificial light at night (ALAN) changes animal behavior in multiple invertebrates and vertebrates and can result in decreased fitness. However, ALAN effects have not been studied in European honey bees (Apis mellifera), an important pollinator in which foragers show strong circadian rhythmicity. Colonies can be exposed to ALAN in swarm clusters, when bees cluster outside the nest on hot days and evenings, and, in limited cases, when they build nests in the open. We captured and maintained foragers in incubated cages and subjected them to constant light (LL), constant dark (DD), or 12 h light:12 h dark (LD) cycle, and observed them with infrared cameras. After 79 h, there was a significant interaction of treatment and time because LL bees slept less. In detail, the bees maintained a regular sleep pattern for three days but LL bees showed a shift on the fourth day. LL bees had the largest sleep differences from LD controls, with trends of lengthened periods and increased phase misalignment from both LD and DD bees. LL bees also experienced significantly more disturbances from their nestmates and preferred to sleep in the lower portion of the cages, which had significantly lower light intensity. These findings suggest that ALAN can disrupt the sleep of honey bee foragers, which has implications for their behavior and overall colony health.

Central pattern generator control of a vertebrate ultradian sleep rhythm.

The mechanisms underlying the mammalian ultradian sleep rhythm-the alternation of rapid-eye-movement (REM) and slow-wave (SW) states-are not well understood but probably depend, at least in part, on circuits in the brainstem1-6. Here, we use perturbation experiments to probe this ultradian rhythm in sleeping lizards (Pogona vitticeps)7-9 and test the hypothesis that it originates in a central pattern generator10,11-circuits that are typically susceptible to phase-dependent reset and entrainment by external stimuli12. Using light pulses, we find that Pogona's ultradian rhythm8 can be reset in a phase-dependent manner, with a critical transition from phase delay to phase advance in the middle of SW. The ultradian rhythm frequency can be decreased or increased, within limits, by entrainment with light pulses. During entrainment, Pogona REM (REMP)can be shortened but not lengthened, whereas SW can be dilated more flexibly. In awake animals, a few alternating light/dark epochs matching natural REMP and SW durations entrain a sleep-like brain rhythm, suggesting the transient activation of an ultradian rhythm generator. In sleeping animals, a light pulse delivered to a single eye causes an immediate ultradian rhythm reset, but only of the contralateral hemisphere; both sides resynchronize spontaneously, indicating that sleep is controlled by paired rhythm-generating circuits linked by functional excitation. Our results indicate that central pattern generators of a type usually known to control motor rhythms may also organize the ultradian sleep rhythm in a vertebrate.

Assessment of potential myopia risk factors, including chronotype, in Estonian adolescents: a cross-sectional study

BackgroundMyopia is a growing healthcare concern worldwide. Increasing evidence suggests that sleep and circadian rhythms may be associated with myopia. Furthermore, the risk factors of myopia have not been studied in the Estonian population to date. This study aimed to evaluate chronotype, lifestyle factors, and parental myopia in relation to myopia in Estonian secondary school students.MethodsGrade 10 students from three secondary schools in Tallinn, each with distinct focuses: one science-oriented, one arts-oriented, and one sports-oriented, were invited to participate. They underwent a comprehensive ocular examination, including cycloplegic autorefraction and ocular biometry. Chronotype was evaluated with the Morningness − Eveningness Questionnaire. Participants reported parental myopia and replied to a set of questions, separately for schooldays and free days, to indicate the amount of time they spent outdoors, doing near work and intermediate distance activities. Myopia was defined as cycloplegic SER ≤ − 0.50 D. Logistic regression analysis was performed to assess the association of the studied factors with myopia.ResultsA total of 123 students (57% female) participated in the study, with a mean age of 16.71 years (standard deviation 0.41). In a multivariable regression model, having two myopic parents was associated with higher odds of myopia (OR 3.78, 95% CI 1.15 − 12.42). We found no association between myopia and chronotype. Notably, time spent outdoors and doing near work or intermediate distance work did not affect the likelihood of having myopia. We observed that students attending the sports-oriented school had lower odds of myopia than those attending the science-oriented school (OR 0.12, 95% CI 0.03–0.51).ConclusionChronotype was not associated with myopia in our study sample. Consistent with previous reports, we identified parental myopia as a myopia risk factor. Interestingly, there was no association between myopia and time spent outdoors or near work. However, the odds of myopia varied depending on the school attended by the participants, which may reflect the educational load or lifestyle of participants in earlier childhood.

Sleep and diurnal alternative polyadenylation sites associated with human APA-linked brain disorders

Disruption of sleep and circadian rhythms are a comorbid feature of many pathologies, and can negatively influence many health conditions, including neurodegenerative disease, metabolic illness, cancer, and various neurological disorders. Genetic association studies linking sleep and circadian disturbances with disease susceptibility have mainly focused on changes in gene expression due to mutations, such as single-nucleotide polymorphisms. The interaction between sleep and/or circadian rhythms with the use of Alternative Polyadenylation (APA) has been largely undescribed, particularly in the context of other disorders. APA generates transcript isoforms by utilizing various polyadenylation sites (PASs) from the same gene affecting its mRNA translation, stability, localization, and subsequent function. Here we identified unique APAs expressed in rat brain over time-of-day, immediately following sleep deprivation, and the subsequent recovery period. From these data, we performed a secondary analysis of these sleep- or time-of-day associated PASs with recently described APA-linked human brain disorder susceptibility genes.

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.

The impact of long-haul travel and 13h time change on sleep and rest activity circadian rhythm in speed skaters during World Cup competitions.

Athletes frequently compete only a few days after long-haul travel. Longitudinal real-world data on athletes' sleep and sleep-wake cycle in competitive settings remain scarce. This study assessed the impact of a long-haul travel across ∼13 time zones on sleep patterns, rest-activity circadian rhythms (RAR), and their subsequent effects on neuromuscular function and race performance in the Canadian Short-Track Speed Skating Team. Nineteen athletes (24±4years, 11 women) travelled from Montréal (UTC-5) to Asia (UTC+8, UTC+9) for World Cup races between 2017 and 2019. Actigraphy data were collected before (Baseline) and during travel, during the stay in Asia (SIA), and during competition days. RAR were computed using cosinor analyses on accelerometry data with 24h phase periods. Countermovement jump height (CMJ) was measured in a subsample (n=10). Compared to baseline (7:08±0:53), athletes obtained less sleep during travel (6:16±1:27) and competition days (6:35±1:10), and more during SIA (7:32±0:46; time effect P<0.0001). Sleep efficiency and CMJ were greater in SIA than baseline (P=0.007 and P=0.0004, respectively). During SIA, sleep time increased by 9 min per night until the fifth day (P<0.0001), with a slight decrease in sleep efficiency (P=0.005) and an increase in CMJ (P<0.0001). For RAR, mean activity peaked on day 2, shifting from late evening to ∼15:00. Race performance was not different from other races of the same season (P>0.254). Our results demonstrated that, despite the possible sleep debt from the long-haul travel, athletes recovered within 5 days, highlighting their adaptability to manage sleep debt and jetlag without impacting competitive outcomes.

Sleep disorders in cerebrotendinous xanthomatosis: A case series

Cerebrotendinous xanthomatosis (CTX) is a rare genetic disorder characterized by a variety of neurological and systemic symptoms, including cerebellar ataxia, cataracts, tendon xanthomas, and polyneuropathy. This study aimed to investigate sleep patterns and disorders in four patients diagnosed with cerebrotendinous xanthomatosis. All participants reported significant sleep disturbances, and objective assessments confirmed the presence of insomnia, excessive daytime sleepiness, obstructive sleep apnea, and periodic limb movements. Notably, this is the first study to incorporate sleep assessments into the clinical management of CTX patients, which may be crucial for improving their quality of life. Further research is warranted to deepen our understanding of the potential impact of cholestanol deposits on regions of the central nervous system involved in sleep and circadian rhythm regulation.

Senegenin regulates the mechanism of insomnia through the Keap1/Nrf2/PINK1/Parkin pathway mediated by GAD67.

GAD67 impacts insomnia as a key enzyme catalysing the conversion of glutamate (Glu) to gamma-aminobutyric acid (GABA). Senegenin enhances neuroprotection and is used widely to treat insomnia and other neurological diseases. This study aimed to investigate how senegenin regulates insomnia through a GAD67-mediated signalling pathway. We measured GAD67 expression levels in insomnia patients and evaluated the expression levels of GAD67 and Keap1/Nrf2/Parkin/PINK1-related cytokines following GAD67 lentiviral transfection in PC12 cells and in rat models. We also assessed cellular reactive oxygen species (ROS) and mitochondrial membrane potential levels. Additionally, EEG/EMG was used to analyse the sleep phases of rats and to assess memory and exploration functions. Pathological changes and the expression of GAD67 and sleep-related proteins in the hippocampus were examined. The results showed that GAD67 expression was increased in insomnia patients, ROS levels were elevated, and the mitochondrial membrane potential was decreased in the GAD67-KD group. Insomnia rats exhibited changes in sleep rhythm, learning, and exploration dysfunction, pathological changes in the CA1 region of the hippocampus, and differential expression of GAD67 and sleep-related factors. Inhibitory neurofactor expression levels were decreased in insomnia rats, showing a positive correlation in the GAD67-KD group and a negative correlation in the GAD67-OE group. Conversely, excitatory factor expression levels were increased in insomnia rats, showing a positive correlation in the GAD67-KD group and a negative correlation in the GAD67-OE group. Senegenin intervention modulated cytokine expression levels. In conclusion, GAD67 negatively regulates insomnia, and senegenin can regulate insomnia by mediating the expression of cytokines in the GAD67-regulated Keap1/Nrf2/Parkin/PINK1 pathway.

Orexin Receptor Antagonists for the Prevention and Treatment of Alzheimer's Disease and Associated Sleep Disorders.

Orexins/hypocretins are neuropeptides produced by the hypothalamic neurons, binding two G-protein coupled receptors (orexin 1 and orexin 2 receptors) and playing a critical role in regulating arousal, wakefulness, and various physiological functions. Given the high prevalence of sleep disturbances in Alzheimer's disease (AD) and their reported involvement in AD pathophysiology, the orexin system is hypothesized to contribute to the disease pathogenesis. Specifically, recent evidence suggests that orexin's influence may extend beyond sleep regulation, potentially affecting amyloid-β and tau pathologies. Dual orexin receptor antagonists (DORAs), namely suvorexant, lemborexant, and daridorexant, demonstrated efficacy in treating chronic insomnia disorder across diverse clinical populations. Considering their stabilizing effects on sleep parameters and emerging evidence of a possible neuroprotective role, these agents represent a promising strategy for AD management. This leading article reviews the potential use of orexin receptor antagonists in AD, particularly focusing on their effect in modulating disease-associated sleep disturbances and clinical outcomes. Overall, clinical studies support the use of DORAs to enhance sleep quality in patients with AD with comorbid sleep and circadian sleep-wake rhythm disorders. Preliminary results also suggest that these compounds might influence AD pathology, potentially affecting disease progression. Conversely, research on selective orexin receptor antagonists in AD is currently limited. Further investigation is needed to explore orexin antagonism not only as a symptomatic treatment for sleep disturbances, but also for its broader implications in modifying AD neurodegeneration, emphasizing mechanisms of action and long-term outcomes.

Melatonin in the Regulation of Sleep and Biological Rhythms

Melatonin in the Regulation of Sleep and Biological Rhythms

Sleep Disturbance in Perimenopausal Women

Female sex hormones are involved in various physiological processes including sleep and the circadian cycle. During menopausal transition, various symptoms caused by hormonal changes can occur. Among various perimenopausal symptoms, sleep disturbance is one of the most common and important health issues. More than 40% of perimenopausal women report sleep problems, which not only lower quality of life but also pose substantial health risks including increased cardiovascular risk. Factors contributing to sleep disturbances during perimenopause include direct changes in sleep due to decline of female sex hormones and indirect changes resulting from perimenopausal symptoms. This article will address the influence of female sex hormones on sleep and circadian rhythm, sleep changes in perimenopausal women and their possible mechanisms, prevalent sleep disorders during perimenopause, and their treatments.

Scheduled feeding improves behavioral outcomes and reduces inflammation in a mouse model of Fragile X syndrome.

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by the abnormal expansion of CGG repeats in the fragile X mental retardation 1 (FMR1) gene. Many FXS patients experience sleep disruptions, and we sought to explore these symptoms along with the possible benefits of a scheduled feeding intervention using the Fmr1 knockout (KO) mouse model. These mutants displayed clear evidence for sleep and circadian disturbances including delay in the onset of sleep and fragmented activity rhythms with increases in cycle-to-cycle variability. The Fmr1 KO mice exhibited deficits in their circadian behavioral response to light with reduced masking, longer time to resetting to shifts in the LD cycle, altered synchronization to a skeleton photoperiod and lower magnitude light-induced phase shifts of activity rhythms. Investigation of the retinal input to the surprachiasmatic nucleus (SCN) with the neurotracer cholera toxin (β subunit) and quantification of the light-evoked cFos expression in the SCN revealed an abnormal retinal innervation of the SCN in the Fmr1 KO, providing a possible mechanistic explanation for the observed behavioral deficits. Interestingly, disruptions in social and repetitive behavior correlated with sleep duration and fragmentation. Understanding the nature of the deficits, we decided to apply a scheduled feeding regimen (6-hr/18-hr feed/fast cycle) as a circadian-based strategy to boast circadian rhythms independently of light. This intervention significantly improved the activity rhythms and sleep in the mutants. Strikingly, the scheduled feeding ameliorated social interactions and reduced repetitive behaviors as well as the levels of Interferon-gamma and Interleukin-12 in the Fmr1 KO mutants, suggesting that timed eating may be an effective way to reduce inflammation. Collectively, this work adds support to efforts to develop circadian based interventions to help with symptoms of neurodevelopmental disorders.

Rest-Activity Rhythm Phenotypes in Adults with Epilepsy and Intellectual Disability.

Sleep and rest-activity rhythms (RARs) are perturbed in many forms of neuropsychiatric illness. In this study, we applied wrist actigraphy to describe the extent of RAR perturbations in adults with epilepsy and intellectual disability ("E+ID"), using a cross-sectional case-control design. We examined whether RAR phenotypes correlated with epilepsy severity, deficits in adaptive function and/or comorbid psychopathology. Primary caregivers of E+ID adults provided informed consent during routine ambulatory clinic visits and were asked to complete standardized surveys of overall epilepsy severity (GASE, Global Assessment of Severity of Epilepsy), adaptive function (ABAS-3, Adaptive Behavior Assessment System-3) and psychopathology (ABCL, Adult Behavior Checklist). Caregivers were also asked to ensure that subjects wore an Actiwatch-2 device continuously on their nondominant wrist for at least ten days. From recorded actograms, we calculated RAR amplitude, acrophase, robustness, intradaily variability (IV), interdaily stability (IS) and estimates of sleep quantity and timing. We compared these RAR metrics against those from (i) a previously published cohort of adults with epilepsy without ID (E-ID), and (ii) a cohort of age- and sex-matched intellectually able subjects measured within the Study of Latinos (SOL) Ancillary actigraphy study (SOL). Within E+ID subjects, we applied k-means analysis to divide subjects into three actigraphically distinct clusters. 46 E+ID subjects (median age 26 [20-68], 47% female) provided a median recording duration of 11 days [range 6-27]. Surveys reflected low to extremely low levels of adaptive function (ABAS3 General Adaptive Composite score: median 50 [49-75]), and low/subclinical levels of psychopathology (ABCL total score: median 54.5 [25-67]). Compared with E-ID (n=57) and SOL (n=156) cohorts, E+ID subjects displayed significantly lower RAR amplitude, robustness and IS, with significantly higher IV and total daily sleep. K-means clustering of E+ID subjects recognized an intermediate cluster "B", with RAR values indistinguishable to E-ID. Cluster "A" subjects displayed pronounced hypoactivity and hypersomnia with high rates of rhythm fragmentation, while cluster "C" subjects featured hyper-robust and high amplitude RARs. All three clusters were similar in age, body mass index, antiseizure medication (ASM) polytherapy, ABAS3 and ABCL scores. We qualitatively describe RAR examples from all three clusters. We show that adults with epilepsy and intellectual disability display a wide spectrum of RAR phenotypes that do not neatly correlate with measures of adaptive function or epilepsy severity. Prospective studies are necessary to determine whether continuous actigraphic monitoring can sensitively capture changes in chronobiological health that may arise with disease progression, iatrogenesis (e.g., ASM toxicity) or acute health deteriorations (e.g., seizure exacerbation, pneumonia). Similar long-term data is necessary to recognize whether behavioral interventions targeted to 'normalize' RARs may promote improvements in adaptive function and therapy engagement.

Exploration of sleep quality and rest-activity rhythms characteristics in Bilateral Vestibulopathy patients

Sleep and circadian timing systems are constantly regulated by both photic and non-photic signals. Connections between the vestibular nuclei and the biological clock raise the question of the effect of peripheral vestibular loss on daily rhythms, such as the sleep-wake cycle and circadian rhythm. To answer this question, we compared the sleep and rest-activity rhythm parameters of 15 patients with bilateral vestibulopathy (BVP) to those of 15 healthy controls. Sleep and rest-activity cycle were recorded by a device coupling actimetry with the heart rate and actigraphy at home over 7 days. Subjective sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI). Sleep efficiency and subjective sleep quality were significantly reduced, and sleep fragmentation was increased in BVP patients compared to controls. BVP patients displayed a damped amplitude of the rest-activity rhythm and higher sleep fragmentation, reflected by a higher nocturnal activity compared to controls. These results suggest that both rest-activity and sleep cycles are impaired in BVP patients compared to healthy controls. BVP patients seem to have greater difficulty maintaining good sleep at night compared to controls. BVP pathology appears to affect the sleep-wake cycle and disturb the circadian rhythm synchronization. Nevertheless, these results need further investigation to be confirmed, particularly with larger sample sizes.

Sleep and circadian disruption in bipolar disorders: From psychopathology to digital phenotyping in clinical practice.

Sleep and biological rhythms are integral to mood regulation across the lifespan, particularly in bipolar disorder (BD), where alterations in sleep phase, structure, and duration occur in all mood states. These disruptions are linked to poorer quality of life, heightened suicide risk, impaired cognitive function, and increased relapse rates. This review highlights the pathophysiology of sleep disturbances in BD and aims to consolidate understanding and clinical applications of these phenomena. It also summarizes the evolution of sleep and biological rhythms assessment methods, including ecological momentary assessment (EMA) and digital phenotyping. It underscores the importance of recognizing circadian rhythm involvement in mood regulation, suggesting potential therapeutic targets. Future research directions include elucidating circadian clock gene mechanisms, understanding environmental impacts on circadian rhythms, and investigating the bidirectional relationship between sleep disturbances and mood regulation in BD. Standardizing assessment methods and addressing privacy concerns related to EMA technology and digital phenotyping are essential for advancing research. Collaborative efforts are crucial for enhancing clinical applicability and understanding the broader implications of biological rhythms in BD diagnosis and treatment. Overall, recognizing the significance of sleep and biological rhythms in BD offers promise for improved outcomes through targeted interventions and a deeper understanding of the disorder's underlying mechanisms.

Closed-loop auditory stimulation targeting alpha and theta oscillations during REM sleep induces phase-dependent power and frequency changes.

Alpha and theta oscillations characterize the waking human electroencephalogram (EEG) and can be modulated by closed-loop auditory stimulation (CLAS). These oscillations also occur during rapid eye movement (REM) sleep, but their function here remains elusive. CLAS represents a promising tool to pinpoint how these brain oscillations contribute to brain function in humans. Here we investigate whether CLAS can modulate alpha and theta oscillations during REM sleep in a phase-dependent manner. We recorded high-density EEG during an extended overnight sleep period in 18 healthy young adults. Auditory stimulation was delivered during both phasic and tonic REM sleep in alternating 6s ON and 6s OFF windows. During the ON windows, stimuli were phase-locked to four orthogonal phases of ongoing alpha or theta oscillations detected in a frontal electrode. The phases of ongoing alpha and theta oscillations were targeted with high accuracy during REM sleep. Alpha and theta CLAS induced phase-dependent changes in power and frequency at the target location. Frequency-specific effects were observed for alpha trough (speeding up) and rising (slowing down) and theta trough (speeding up) conditions. CLAS-induced phase-dependent changes were observed during both REM sleep substages, even though auditory evoked potentials were very much reduced in phasic compared to tonic REM sleep. This study provides evidence that faster REM sleep rhythms can be modulated by CLAS in a phase-dependent manner. This offers a new approach to investigate how modulation of REM sleep oscillations affects the contribution of this vigilance state to brain function.

Efficacy study comparing a CBT-I developed for shift workers (CBT-I-S) to standard CBT-I (cognitive behavioural therapy for insomnia) on sleep onset latency, total sleep time, subjective sleep quality, and daytime sleepiness: study protocol for a parallel group randomised controlled trial with online therapy groups of seven sessions each

BackgroundShift workers are at an increased risk of developing sleep disorders. The standard therapy recommended for sleep disorders is cognitive behavioural therapy for insomnia (CBT-I). Many of its interventions are based on a regular sleep and wake rhythm, which is difficult to apply for shift workers. We have therefore developed a new therapy manual specifically for shift workers (CBT-I-S), which should be more applicable to their needs. In particular, all interventions that require regularity have been removed, and instead, interventions that address factors that proved to be relevant to sleep in our preliminary study have been integrated. We now want to test this manual for its effectiveness.MethodsA randomised controlled trial with N = 142 will be conducted to compare two conditions: the newly developed therapy manual will be carried out in the experimental group, while cognitive behavioural therapy for insomnia will be employed in the standard group. Both treatments will be conducted online via MS Teams in a group setting with seven sessions each. Data will be collected at three measurement points (pre, post, 6-month follow-up) and analysed using linear mixed models. The study will investigate whether the two treatments have led to significant improvements in total sleep time, sleep onset latency, subjective sleep quality and daytime sleepiness in shift workers. It will also examine whether the new therapy manual is superior to standard therapy in shift workers and whether these effects are stable.DiscussionWe assume that interventions designed to address depressive mood, anxiety, worry, rumination, dysfunctional thought patterns and attitudes towards sleep will also improve sleep. If this is indeed the case, these interventions could replace previous ones that require regularity. This could significantly improve the treatment of insomnia in shift workers.Trial registrationGerman Clinical Trials Registry DRKS DRKS00032086. Registered on August 16, 2023.

The association between maternal sleep and circadian rhythms during pregnancy and infant sleep and socioemotional outcomes.

Studies have established that maternal sleep and circadian rhythm disturbances during pregnancy are associated with poor prenatal and perinatal outcomes for mothers and offspring. However, little work has explored its effects on infant sleep or socioemotional outcomes. The current study examined the relationship between maternal sleep and circadian rhythm disturbances during pregnancy and infant sleep and socioemotional outcomes in a diverse sample of N = 193 mothers and their infants (51% White; 52% Female; Mage = 11.95months). Maternal sleep and circadian rhythms during pregnancy were assessed using self-reports and actigraphy. Mothers reported on infants' sleep and socioemotional outcomes when infants were one year old. When controlling for infant sex, age, gestational age at birth, family income-to-needs ratios, and maternal depression, mothers who reported more sleep problems during pregnancy had infants with more sleep disturbances when they were one year old. Moreover, mothers who had later sleep timing (i.e., went to bed and woke up later, measured via actigraphy) during pregnancy had infants with more dysregulation (e.g., increased feeding difficulties, sensory sensitivities) and externalizing problems, and mothers with increased intra-daily variability in rest-activity rhythms (as measured via actigraphy) had infants with more externalizing problems. Findings suggest that maternal sleep and circadian rhythm disturbances during pregnancy may be a risk factor for infant sleep problems and socioemotional difficulties.

Multidimensional Sleep Profiles via Machine learning and Risk of Dementia and Cardiovascular Disease.

Sleep health comprises several dimensions such as duration and fragmentation of sleep, circadian activity, and daytime behavior. Yet, most research has focused on individual sleep characteristics. Studies are needed to identify sleep profiles incorporating multiple dimensions and to assess how different profiles may be linked to adverse health outcomes. To identify actigraphy-based 24-hour sleep/circadian profiles in older men and to investigate whether these profiles are associated with the incidence of dementia and cardiovascular disease (CVD) events over 12 years. Data came from a prospective sleep study with participants recruited between 20032005 and followed until 2015-2016. Multicenter population-based cohort study. Among the 3,135 men enrolled, we excluded 331 men with missing or invalid actigraphy data and 137 with significant cognitive impairment at baseline, leading to a sample of 2,667 participants. Leveraging 20 actigraphy-derived sleep and circadian activity rhythm variables, we determined sleep/circadian profiles using an unsupervised machine learning technique based on multiple coalesced generalized hyperbolic mixture modeling. Incidence of dementia and CVD events. We identified three distinct sleep/circadian profiles: active healthy sleepers (AHS; n=1,707 (64.0%); characterized by normal sleep duration, higher sleep quality, stronger circadian rhythmicity, and higher activity during wake periods), fragmented poor sleepers (FPS; n=376 (14.1%); lower sleep quality, higher sleep fragmentation, shorter sleep duration, and weaker circadian rhythmicity), and long and frequent nappers (LFN; n=584 (21.9%); longer and more frequent naps, higher sleep quality, normal sleep duration, and more fragmented circadian rhythmicity). Over the 12-year follow-up, compared to AHS, FPS had increased risks of dementia and CVD events (Hazard Ratio (HR)=1.35, 95% confidence interval (CI)=1.02-1.78 and HR=1.32, 95% CI=1.08-1.60, respectively) after multivariable adjustment, whereas LFN showed a marginal association with increased CVD events risk (HR=1.16, 95% CI=0.98-1.37) but not with dementia (HR=1.09, 95%CI=0.86-1.38). We identified three distinct multidimensional profiles of sleep health. Compared to healthy sleepers, older men with overall poor sleep and circadian activity rhythms exhibited worse incident cognitive and cardiovascular health. These results highlight potential targets for sleep interventions and the need for more comprehensive screening of poor sleepers for adverse outcomes.

Chinese formula Guben-Jiannao Ye alleviates the dysfunction of circadian and sleep rhythms in APP/PS1 mice implicated in activation of the PI3K/AKT/mTOR signaling pathway

Ethnopharmacological relevanceThe Chinese formula Guben-Jiannao Ye (GBJNY) formula has a long history of usage in traditional Chinese medicine (TCM) for the treatment of learning and memory disorders as well as senile insomnia. This formulation is derived from Sun Simiao's five tonic pills. Furthermore, modern pharmacological investigations have revealed its ability to improve cognitive impairment and ameliorate sleep-wake circadian rhythm disorders. However, the precise mechanism underlying its efficacy remains elusive. Aim of the studyThe current research explored the modulatory effects and possible mechanisms of GBJNY in circadian rhythm sleep-wake disorders and cognitive dysfunction in Alzheimer's disease using transcriptome sequencing and experimental validation. Materials and methodsThe LC-MS/MS tandem technology was utilized to qualitatively discern the active components present in GBJNY. The APP/PS1 mice received continuous treatment with GBJNY or Melatonin for 3 months. The learning and memory abilities of mice were assessed utilizing the Morris water maze (MWM) test, while sleep changes were studied utilizing the electroencephalogram (EEG) and electromyogram (EMG). Concurrently, mice's hippocampus clock gene rhythmicity was investigated. Subsequently, we employed HE staining, Golgi staining, and immunofluorescence to observe GBJNY's impact on synaptic damage and neuronal loss. We performed high-throughput sequencing to analyze the mRNA expression profiles of mice, aiming to identify differentially expressed genes (DEGs). Subsequently, we conducted GO and KEGG enrichment analyses to explore associated signaling pathways. Furthermore, we evaluated the expression levels of proteins involved in the PI3K/AKT/mTOR pathway and Aβ deposition in the hippocampus of mice. Through this comprehensive approach, we sought to elucidate and validate the potential mechanisms of action of GBJNY in APP/PS1 mice. ResultsResults showed 216 DEGs. Following this, we conducted GO enrichment and KEGG pathway analyses to delve deeper into the distinctions and fundamental functions of the mRNA target genes. The enrichment analysis underscored the prominence of the PI3K/Akt/mTOR signaling pathway as the most pivotal among them. Through in vivo experiments, it was further demonstrated that the administration of GBJNY enhanced memory and learning capacities in APP/PS1 mice. Additionally, GBJNY treatment resulted in alterations in the sleep-wake circadian rhythm, characterized by reduced wakefulness and an increase in non-rapid eye movement (NREM) sleep. Moreover, alterations in the peak expression of Per1, Per2, Clock, Cry1, Cry2, and Bmal1 mRNA were noted in the hippocampus of treated mice. Particularly noteworthy were the observed reductions in amyloid-beta (Aβ) deposition within the hippocampus, improvements in neuronal synaptic integrity, and upregulation of mTOR, Akt, and PI3K protein expression in the hippocampal region. These findings underscore the critical involvement of the PI3K/Akt/mTOR signaling pathway in mitigating disturbances in sleep-wake circadian rhythms. ConclusionsGBJNY enhanced the cognitive performance of APP/PS1 mice and altered clock gene expression patterns, alleviating sleep-wake circadian rhythm disruptions. The fundamental mechanism appears to be linked to the PI3K/Akt/mTOR pathway regulation, offering a foundation for potential clinical applications.