Circadian Disorders Research Articles

Сон и Covid-19: нейрофизиологические и биохимические аспекты

Functional disorders of the nervous system against the background of Covid-19 are reviewed with the emphasis on sleep and circadian clock disorders during the pandemic. The pandemic is regarded as the strong stress factor that affects sleep and the clock. A large risk group consists of elderly people and people with concomitant somatic pathology. Data on the effect of SARS-CoV-2 on other organs and systems, on the functioning of the immune system, are presented.

Evaluation and Management of Sleep and Circadian Rhythm Disturbance in Cancer.

Sleep and circadian rhythm disturbance are among the most commonly experienced symptoms in patients with cancer. These disturbances occur throughout the spectrum of cancer care from diagnosis, treatment, and long into survivorship. The pathogenesis of these symptoms and disturbances is based on common inflammatory pathways related to cancer and its' treatments. The evaluation of sleep and circadian disorders requires an understanding of how these symptoms cluster with other cancer-related symptoms and potentiate each other. A thorough evaluation of these symptoms and disorders utilizing validated diagnostic tools, directed review of clinical information, and diagnostic testing is recommended. Treatment of sleep and circadian disturbance in cancer patients should be based on the findings of a detailed evaluation, including specific treatment of primary sleep and circadian disorders, and utilize integrative and personalised management of cancer-related symptoms through multiple pharmacologic and non-pharmacologic modalities. Recognition, evaluation, and treatment of sleep and circadian rhythm disturbance in cancer may lead to improved symptom management, quality of life, and outcomes.

Recent Progress in Non-motor Features of Parkinson's Disease with a Focus on Circadian Rhythm Dysregulation.

Parkinson's disease (PD) is the second most common neurodegenerative disease, which manifests with both motor and non-motor symptoms. Circadian rhythm dysregulation, as one of the most challenging non-motor features of PD, usually appears long before obvious motor symptoms. Moreover, the dysregulated circadian rhythm has recently been reported to play pivotal roles in PD pathogenesis, and it has emerged as a hot topic in PD research. In this review, we briefly introduce the circadian rhythm and circadian rhythm-related genes, and then summarize recent research progress on the altered circadian rhythm in PD, ranging from clinical features to the possible causes of PD-related circadian disorders. We believe that future comprehensive studies on the topic may not only help us to explore the mechanisms of PD, but also shed light on the better management of PD.

17-LB: Disruption of Circadian Clocks Promote Progression of Alzheimer’s Disease in Diabetic Mice

Almost all plants and animals exhibit inherent 24-hour oscillations to adapt the Earth’s rotation. The main function of circadian rhythm was to prepare an organism for the potential outer opportunities and challenges. Alzheimer’s disease (AD) is a progressive neurodegenerative disease, which is more popular in patients with type 2 diabetes mellitus (T2DM). However, the effects of circadian disorder on mental and physical health for T2DM patients are not yet fully understood, even though circadian disruption has been confirmed to promote the progression of AD in population. By housing db/db mice on a disrupted (6:18 light/dark cycle) circadian rhythm, we assessed the circadian gene expression, body weight, cognitive ability and AD-related pathophysiology. Our results indicated housing in these conditions had disrupted diurnal circadian rhythms in hippocampus and contributed to weight gain. In the brain, circadian-disrupted db/db mice showed a decreased cognitive ability and an increased hyperphosphorylation of tau protein, even though no difference was found in Aβ deposition. We also found that the hyperphosphorylated tau protein exhibited more disruptive daily oscillations in db/db mice hippocampus under 6:18 light/dark cycle. In conclusion, circadian alterations could promote the development of AD in the patients of T2DM. Disclosure J. Huang: None. Funding National Natural Science Foundation of China (81670754, 81800686, 81974114)

An Open-Access Platform for Translating Diabetes and Cardiometabolic Disease Genetics Into Accessible Knowledge

Most associations from genome-wide association studies (GWAS) result from as-yet-unknown alterations of molecular or cellular function; the causal variants and effector genes responsible for them, and the tissues and pathways through which they act, remain largely unknown. Thousands of associated loci have now been identified for each common disease and its related traits. In order to translate GWAS data into biological knowledge, they must be integrated with functional genomic annotations reflecting tissue-specific regulation and with the results of bioinformatic methods that predict the functional effects of associations. However, these data types are typically spread across disparate resources, and working with them requires bioinformatic expertise.To make these results accessible and understandable to the broader diabetes and cardiometabolic disease research communities, we have developed the open-access Common Metabolic Diseases Knowledge Portal (CMDKP; cmdkp.org), which brings together a robust software and data storage platform with a streamlined and intuitive user interface for four disease areas: diabetes (both types 1 and 2); cardiovascular disease; cerebrovascular disease; and sleep and circadian disorders.The CMDKP enables researchers to access and explore a comprehensive matrix of genetic, genomic, and computational results. It includes 3 classes of genomic data: 1) GWAS summary statistics from the most current and authoritative datasets available, as identified by disease-area experts; 2) functional genomic annotations, such as chromatin accessibility, that reflect the tissue-specific regulatory potential of genomic regions; and 3) the results of bioinformatic methods applied to these aggregated data (for example, overlap-aware meta-analysis to determine “bottom-line” p-values, the GREGOR method for determining tissue-specific enrichment of genetic associations, the MAGMA method for generating gene-level association scores, and more). All of these data types are integrated and accessible via interactive tools that allow researchers to explore and evaluate the data in order to identify candidate disease effector genes for further research. The CMDKP provides researchers with the data and tools necessary to translate genetic associations and functional annotations into knowledge about disease mechanisms and potential therapeutic targets.

Desynchrony and synchronisation underpinning sleep–wake cycles

This paper studies mechanisms of synchronisation and loss of synchrony among the three key oscillatory processes controlling sleep–wake cycles in the human brain: the 24-h circadian oscillator, the homeostatic sleep drive, and the environmental light–dark cycle. Synchronisation of these three rhythms promotes sleep and brain clearance and is critical for human health. Their desynchrony, on the other hand, is associated with impaired performance and disease development, including cancer, cardiovascular disease, and mental disorders. A biophysical model of arousal dynamics simulating sleep–wake cycles and circadian rhythms is used as the study system. It is based on established neurobiological mechanisms controlling sleep–wake transitions and incorporates the three oscillatory processes. Nonlinear dynamics methods and synchronisation theory are used to numerically investigate model dynamics under conditions that are not easily achievable in experiments. The role of homeostatic brain clearance rate in synchronisation is investigated, and selective turning on and off of coupling strengths between the oscillators allows us to determine their role in oscillators’ dynamics. We find that, in the absence of coupling between the circadian and homeostatic oscillators, the default state of the model corresponds to the endogenous homeostatic period that is far from $$\sim $$ 24-h rhythm of the circadian and light–dark cycles. Combined action of light and circadian oscillator on the homeostatic rhythm is required to achieve the typical sleep–wake pattern that is observed in young healthy people. Under 12-/12-h light–dark conditions with light at 80 lux, change of homeostatic clearance rate is found to induce two types of desynchronisation: (i) fast clearance rates $$\tau _H<58.1$$ h desynchronise the homeostatic oscillator from the circadian, while the circadian rhythm remains entrained to the light–dark cycle, and (ii) slow clearance rates $$\tau _H>69$$ h maintain synchronisation between the homeostatic and circadian oscillators, but the period of both is different from that of the light–dark cycle. Between these regimes, all three rhythms are synchronised under the studied conditions. The model predicts that the system is highly sensitive to external inputs to the neuronal populations of the sleep–wake switch, which affect the endogenous period of the homeostatic oscillator and can lead to complete loss of sleep. Model dynamics show that loss of synchronisation, which is traditionally ascribed solely to impairment of the circadian oscillator, can be caused by changes in the homeostatic clearance rate of the brain or external input to the neuronal populations of the sleep–wake switch. Thus, changes in circadian, homeostatic, and external factors (combined or specific) may be responsible for conditions of desynchronisation. This has significant implications for understanding individual variability in sleep–wake patterns and in mechanisms of sleep and circadian disorders, indicating that both the homeostatic and circadian mechanisms can be responsible for the same clinical or behavioural presentation of a disease.

Sleep disorders in children with asthma.

Asthma and sleep disorders are both common in childhood, and often co-exist in the same child. Moreover, studies have shown that in many children the rate of one is influenced by the other. Sleep disorders can be classified into six different groups-insomnia, hypersomnia, parasomnia, movement disorders, circadian disorders, and sleep-related breathing disorders. Children with asthma often present with complaints of insomnia with poor sleep quality, difficulty falling asleep and sleep disruptions. These complains are often associated with asthma control. They may also complain of daytime sleepiness and have higher rates of parasomnias, such as night terrors and nocturnal enuresis when compared with their healthy peers. Whether movement and circadian disorders are also more prevalent in children with asthma is less clear. Finally, there is a complex bidirectional interaction between sleep-related breathing disorders and asthma: poor sleep and sleep disorders may worsen asthma, and asthma, particularly when it is poorly controlled, may impair sleep. In the current review we examine the association of each of the sleep disorders with asthma and review the common pathophysiological pathways. We hope to convince the reader that appropriate management of asthma must include inquiries into the patient's sleep, and vice versa.

Impact of Time-Restricted Feeding to Late Night on Adaptation to a 6 h Phase Advance of the Light-Dark Cycle in Mice.

In modern society, more and more people suffer from circadian disruption, which in turn affects health. But until now, there are no widely accepted therapies for circadian disorders. Rhythmic feeding behavior is one of the most potent non-photic zeitgebers, thus it has been suggested that it was important to eat during specific periods of time (time-restricted feeding, TRF) so that feeding is aligned with environmental cues under normal light/dark conditions. Here, we challenged mice with a 6 h advanced shift, combined with various approaches to TRF, and found that food restricted to the second half of the nights after the shift facilitated adaptation. This coincided with improved resilience to sepsis. These results raise the possibility of reducing the adverse responses to jet lag by subsequent timing of food intake.

Automatic sleeping time estimation and mild traumatic brain injury (mTBI) detection using actigraphy data

Sleep schedule and circadian phase irregularity are associated with some health problems and diseases, e.g., narcolepsy, circadian disorder, and concussion. Actigraphy has been widely used in the study of sleep and circadian rhythms. This paper presents a method for estimating the sleep/wake state based on the minute-by-minute actigraphy data measured by wrist actigraphy and its associated scoring software. The circadian phase shift is estimated from actigraphy data using an adaptive notch filter algorithm. Compared with the scoring methods used in wrist actigraphy, the estimated wake-onset time from our method is more consistent with the sleep logs reported by the subjects. Concussion detection based on the sleep-related features calculated from actigraphy data is also presented, with detection accuracy up to about 90%. This result implies that the concussion is closely related to sleep and circadian disruption.

Differential DNA methylation in recovery from shift work disorder

The human DNA methylome is responsive to our environment, but its dynamics remain underexplored. We investigated the temporal changes to DNA methylation (DNAme) in relation to recovery from a shift work disorder (SWD) by performing a paired epigenome-wide analysis in an occupational cohort of 32 shift workers (25 men, age = 43.8 ± 8.8 years, 21 SWD cases). We found that the effect of vacation on DNAme was more prominent in the SWD-group as compared to controls, with respect to the amount of significantly differentially methylated positions (DMPs; Punadj < 0.05) 6.5 vs 3.7%, respectively. The vast majority (78%) of these DMPs were hypomethylated in SWD but not in controls (27%) during the work period. The Gene Ontology Cellular component “NMDA glutamate receptor” (PFDR < 0.05) was identified in a pathway analysis of the top 30 genes in SWD. In-depth pathway analyses revealed that the Reactome pathway “CREB phosphorylation through the activation of CaMKII” might underlie the recovery. Furthermore, three DMPs from this pathway, corresponding to GRIN2C, CREB1, and CAMK2B, correlated with the degree of recovery (Punadj < 0.05). Our findings provide evidence for the dynamic nature of DNAme in relation to the recovery process from a circadian disorder, with biological relevance of the emerging pathways.

Estimating Burden of Disease Among Blind Individuals With Non-24-Hour Sleep-Wake Disorder.

Purpose: To quantify the burden of disease in blind patients with Non-24-H Sleep- Wake Disorder (N24HSWD), utilizing longitudinal sleep diary data. N24HSWD is a circadian disorder characterized by a cyclical pattern of aberrant circadian and sleep-wake cycles that are associated with increased frequency of sleep episodes during the school/work day hours. Daytime sleep episodes would be predicted to decrease the opportunity for school/work participation, significantly impacting the quality of life of the patient.Methods: We used the sleep diary data of daytime sleep from a period of ~90 days in blind individuals that presented with a sleep complaint. These subjects were identified from a group of blind individuals with N24HSWD (n = 121) and a control group of blind individuals without N24HSWD (n = 57).Results: N24HSWD patients had more frequent and longer episodes of daytime sleep as compared to a control group. Using duration of daytime sleep as a surrogate for defining a healthy or unhealthy day, N24HSWD patients also had significantly fewer healthy days, defined by daytime sleep free days (DSFD), days without a sleep episode between 9:00 a.m. and 5:00 p.m, as compared to the control group.Conclusion: Daytime sleep free day (DSFD) is a useful and specific measure of disease burden in patients with N24HSWD and it is predicted to be correlated with the standardized HRQOL-4, Healthy Days measurement.

Circadian Rhythm Disorders and Risk of Subsequent Depression: A Systematic Review and Meta-Analysis of Longitudinal Studies

Background: Patients with depression often suffer from circadian rhythm disruptions, such as insomnia and a lower amplitude of daily rhythms of locomotor activity. However, whether circadian disorders precede depression and act as a predictor for subsequent depression have not been unanimously approved. In light of increasing evidence of an association between disrupted circadian rhythms and affective symptoms, a meta-analysis was conducted to examine the effect of circadian disruptions on incident depression. Methods: A systematic search was performed in PubMed, Embase, Web of Science, PsycINFO, PsycArticles, CINAHL database. The search results were restricted to be published in English up to April 10, 2020.Reference lists from included studies and relevant reviews were also screened. We included longitudinal cohort studies that examined the predictive role of all various types of circadian disruption in incident depression. Two reviewers independently extracted information on study design, participants’ characteristics and diagnostic criteria for circadian disruption and depression. Study quality was assessed using the Newcastle-Ottawa Scale. Random-effect models were applied to all meta-analyses given potential heterogeneity. For insomnia, subgroup analyses were performed based on subject’s characteristics, insomnia symptom domains and numbers and the investigated methods. Pool-effect estimates of relative risks to develop incident depression in groups with circadian disruption compared to groups without. This study is registered with PROSPERO, CRD42020179135. Findings: A total of 49 studies were eligible for this meta-analysis. Of 49 eligible studies, included types of circadian disruption were sleep disturbances (n = 45), chronotype (n = 2), cortisol awakening response (n = 1) and rest - activity rhythm (n = 1). Insomnia, hypersomnia, excessive daytime sleepiness (EDS), short sleep duration, obstructive sleep apnea (OSA), restless legs syndrome (RLS), an evening preference, heightened levels of cortisol in awakening response and low robustness of rest - activity rhythm all acted as significant predictors of occurrence of depression. Among insomnia subtypes, difficulty initiating sleep (DIS) and difficulty maintaining sleep (DMS) predicted future depression. Of note, persistent insomnia (OR: 5.02) contributed to more than two - fold risk of incident depression compared to insomnia (OR: 2.34). Moreover, insomnia symptom numbers were associated with incident depression in a gradient trend. Interpretation: Different types of circadian disorders act as risk factors of onset of depression, which clinicians should be informed of. Future research should be aimed to determine the casual relationship between other types of circadian disorders and onset of depression, and moreover to further elucidate the underlying mechanisms. Funding Statement: This work was supported in part by the National Natural Science Foundation of China (no. 81871071 and 81171251) and Beijing Municipal Natural Science Foundation (no. 7162101). Declaration of Interests: All of the authors declare no conflict of interest.

Prevalence and associated factors of circadian rhythm sleep-wake disorders and insomnia among visually impaired Japanese individuals

BackgroundAlthough earlier studies have demonstrated that circadian rhythm sleep-wake disorders (CRSWD) are more prevalent in visually impaired individuals, the actual prevalence of CRSWD and insomnia among the visually impaired Japanese population remains unclear. The aim of this cross-sectional, telephone-based study was to estimate the prevalence of CRSWD and insomnia, and explore factors associated with CRSWD and insomnia among visually impaired Japanese individuals.MethodsA nationwide telephone survey was conducted among visually-impaired individuals through local branches of the Japan Federation of the Blind. In total, 157 visually impaired individuals were eligible for this study. Demographic information and information about visual impairments, lifestyle, and sleep patterns were assessed using questionnaires and subsequent telephone interviews. CRSWD and insomnia were defined according to the International Classification of Sleep Disorders-Third Edition criteria.ResultsThe prevalence of CRSWD in visually impaired individuals was 33.1%. Among those with CRSWD, a non-24-h/irregular sleep-wake rhythm type was the most frequently observed (26.8%), followed by an advanced sleep-wake phase type and a delayed sleep-wake phase type (3.8 and 2.5%, respectively). Furthermore, 28.7% of the visually impaired individuals were found to have insomnia. In the visually impaired individuals, the absence of light perception, unemployment, living alone, and use of hypnotics were significantly associated with CRSWD, whereas only the use of hypnotics was extracted as a marginally associated factor of insomnia.ConclusionsCRSWD and insomnia were highly prevalent in visually impaired Japanese individuals. The presence of CRSWD among the visually impaired individuals was associated with a lack of light perception and/or social zeitgebers.

Regular exercise counteracts circadian shifts in core body temperature during long-duration bed rest

With NASA’s plans for the human exploration of Mars, astronauts will be exposed to mission durations much longer than current spaceflight missions on the International Space Station. These mission durations will increase the risk for circadian misalignment. Exercise has gained increasing interest as a non-pharmacological aid to entrain the circadian system. To assess the potential of exercise as a countermeasure to mitigate the risk for circadian disorders during spaceflight, we investigated the effects of long-term head-down tilt bed rest (HDBR) with and without exercise on the circadian rhythm of core body temperature. Core body temperature was recorded for 24 h using a rectal probe in sixteen healthy men (age: 30.5 ± 7.5 years (mean ± SD)) after 7 days and 49 days of HDBR. Five participants underwent HDBR only (CTR), five participants underwent HDBR and performed resistive exercises (RE), and six participants underwent HDBR and performed resistive exercises superimposed with vibrations (RVE). The exercise was scheduled three times per week. CTR showed a phase delay of 0.69 h. In contrast, both exercise groups were characterized by a phase advance (0.45 h for RE and 0.45 h for RVE; p = 0.026 for interaction between time and group). These findings suggest that resistive exercise (with or without vibration) may also serve as a countermeasure during spaceflight to mitigate circadian misalignments. The results could also be important for increasing awareness about the role of circadian disorders in long-term bedridden patients.

Chapter 22 - Melatonin and the circadian system: Keys for health with a focus on sleep

Melatonin (MLT), secreted during the night by the pineal gland, is an efferent hormonal signal of the master circadian clock located in the suprachiasmatic nucleus (SCN). Consequently, it is a reliable phase marker of the SCN clock. If one defines as "chronobiotic," a drug able to influence the phase and/or the period of the circadian clock, MLT is a very potent one. The most convincing data obtained so far come from studies on totally blind individuals. Exogenous MLT administered daily entrains the sleep-wake cycle of these individuals to a 24-h cycle. MLT, however, is not essential to sleep. In nocturnally, active mammals, MLT is released during the night concomitantly with the daily period of wakefulness. Therefore, MLT cannot be simply considered as a sleep hormone, but rather as a signal of darkness. Its role in the circadian system is to reinforce nighttime physiology, including timing of the sleep-wake cycle and other circadian rhythms. MLT exerts its effects on the sleep cycle especially by a direct action on the master circadian clock. The sleep-wake cycle is depending not only on the circadian clock but also on an orchestrated network of different centers in the brain. Thus, the control of sleep-wake rhythm might be explained by a parallel and concomitant action of MLT on the master clock (chronobiotic effect) and on sleep-related structures within the brain. MLT acts through two high-affinity membrane receptors (MT1 and MT2) with striking differences in their distribution pattern. MLT is a powerful synchronizer of human circadian rhythms, thus justifying the use of MLT and MLT agonists in clinical medicine as pharmacological tools to manipulate the sleep-wake cycle, and to treat sleep disorders and other circadian disorders. Available MLT analogs/drugs are all nonspecific MT1/MT2 agonists. The development of new ligands which are highly selectivity for each subtype is clearly a new challenge for the field and will be at the root of new therapeutic agents for curing specific pathologies, including sleep disorders.

Abstract 17233: Clock Modulating Small Molecule SR9011 Enhances Cell Cycle Arrest in Pulmonary Arterial Hypertension

Background: Pulmonary arterial hypertension (PAH) is a rapidly progressing disease of the lung vasculature, characterized by the remodeling of small pulmonary arteries in which pulmonary arterial smooth muscle cells (PASMCs) exhibit a cancer-like phenotype, with uncontrolled replication, self-sustaining growth signals, evasion of growth suppressors and resistance to apoptosis. In healthy cells, cell division is controlled by the circadian clock resulting in timed mitosis and rhythmic DNA replication. This suggests that impaired circadian clock might be involved in the cell cycle disorders seen in PAH. Especially, impaired function of the nuclear receptor Rev-Erbα (a core clock protein) has been associated with circadian clock impairment and cell cycle disorders in cancer. Hypothesis: Rev-Erbα impairment is involved in PAH pathogenesis. Methods &amp; Results: We synchronized (Zeitgeber method using 50% horse serum for 2 hours) human PASMCs isolated from 4 PAH patients and 4 controls, and demonstrated a reduced (p=0.0192) (immunoblot) expression of Rev-Erbα 12 hours post synchronization in PAH-PASMCs compared to controls, associated with increased proliferation (Ki67 assay) and resistance to apoptosis (annexin V assay) (p&lt;0.05), which were reversed by the Rev-Erbα agonist SR9011 (10μM for 24h). RNAseq (n=4/group) demonstrated that most of the downregulated (2-fold cut-off) genes following SR9011 treatments were involved in cytokinesis, meiosis, mitotic processes, cell cycle progression, chromosome segregation and recombination (p&lt;0.05). In vivo , Rev-Erbα was also significantly decreased in male and female monocrotaline rats. SR9011 treatments (n=15/group) for 2 weeks (50mg/kg, i.p.) improved PA hemodynamics ( RVSP:47.80mmHg vs 75.29mmHg \mPAP:26.69mmHg vs 44.36mmHg, p&lt;0.0001); vascular remodeling, decreased proliferation(p=0.0001), increased apoptosis(p=0.0002)) and decreased RV hypertrophy (Fulton Index:0.3869 vs 0.5093 p=0.0006) compare to vehicle treated rats. These results were also repeated in the Fawn Hooded rats model. Conclusion: Our results suggest the involvement of Clock pathways in PAH etiology and thus open new avenue of investigation in PAH and new therapeutic options using clock-modulating small molecules.

Interaction Between Circadian Rhythms, Energy Metabolism, and Cognitive Function.

The interaction between meal timing and light regulates circadian rhythms in mammals and not only determines the sleep-wake pattern but also the activity of the endocrine system. Related with that, the necessity to fulfill energy needs is a driving force that requires the participation of cognitive skills whose performance has been shown to undergo circadian variations. These facts have led to the concept that cognition and feeding behaviour can be analysed from a chronobiological perspective. In this context, research carried out during the last two decades has evidenced the link between feeding behaviour/nutritional habits and cognitive processes, and has highlighted the impact of circadian disorders on cognitive decline. All that has allowed hypothesizing a tight relationship between nutritional factors, chronobiology, and cognition. In this connection, experimental diets containing elevated amounts of fat and sugar (high-fat diets; HFDs) have been shown to alter in rodents the circadian distribution of meals, and to have a negative impact on cognition and motivational aspects of behaviour that disappear when animals are forced to adhere to a standard temporal eating pattern. In this review, we will present relevant studies focussing on the effect of HFDs on cognitive aspects of behaviour, paying particular attention to the influence that chronobiological alterations caused by these diets may have on hippocampaldependent cognition.

1770-P: Role of Prolactin Rhythm in the Development of Nonalcoholic Fatty Liver Disease

Circadian disorder such as light exposure at night are risk factors for NAFLD Prolactin (PRL), a pituitary derived hormone, is recently shown to improve fatty liver. Noteworthy, PRL is secreted in an oscillating pattern. We aimed to explore the role of PRL rhythm in hepatic lipid metabolism. Serum PRL levels in 8:00, 16:00, and 24:00 of subjects without or with NAFLD were evaluated. A cosine model was fitted to the curve of dynamic PRL levels. Luciferase report assay, ChIP and EMSA were used to examine the mechanism of PRL rhythm. Hight fat diet (HFD) C57BL/6 mice were categorized into HFD, HFD+jet-lag group for 16 weeks and serum PRL levels at ZT0, ZT4, ZT8, ZT12, ZT16, ZT20 were determined. Then mice in HFD+jet-lag group were randomly assigned to HFD+ jet lag and HFD+jet-lag+PRL for 14 days. Hepatic lipid content, clock genes and lipid metabolic genes in liver were detected. PRL in 8:00, 16:00 and 24:00 were all significantly lower in NAFLD group than in controls. Cosine curve analysis showed that NAFLD patients had reduced amplitude and delayed phase shift of PRL levels. After adjusted for confounders, light exposure at night is a risk factor for NAFLD, yet this association was dampened after adjusted for PRL rhythm. Luciferase report assay in 293T cell and EMSA assay in human pituitary tissue showed that Prl can be transactivated by core clock gene Rorα via RORα response element RORE. In mice, dynamic PRL attained highest levels at ZT12 in HFD mice but remained low in HFD+jet-lag mice. ChIP analysis showed that binding of Rorα and Prl promoter in HFD mouse pituitary at ZT12 was inhibited under HFD+jet-lag. Furthermore, hepatic lipid content was significantly higher in HFD+jet-lag group than that in HFD, and can be mitigated after 14 days PRL intervention at ZT12. We also found that PRL injection reversed changes of clock and lipid metabolic gene rhythm caused by jet-lag. PRL can serve as an endocrine sensor that transmits rhythmic signals from central nervous system to liver and thus regulating hepatic lipid metabolism. Disclosure B. Yan: None. P. Zhang: None. D. Zhu: None. Funding National Natural Science Foundation of China (81900787, 81770819)

0045 Biobehavioral Markers for Sleep/Wake Disturbance and Fatigue in Young Childhood Brain Tumor Survivors

Abstract Introduction Survivors of childhood and adolescent brain tumors and subsequent treatment may experience many neurological processes involving the forebrain, brainstem, and hypothalamus as well as the symptom cluster of stress, sleep, and fatigue. As a result, the impact of brain tumor treatment (chemotherapy/biotherapy, radiotherapy, and surgery) may have lasting biobehavioral effects. Description of symptoms during early survivorship is not always evident in the literature. Methods Convenience sampling and the following inclusion criteria were utilized: brain tumor survivors ages 8–17 years; ≥6 months, &amp;lt;6 years from completion of treatment; disease free or stable disease. Participants completed polysomnography (PSG) followed by a multiple sleep latency test (MSLT), and subjective measures of sleep, fatigue, stress, and pubertal status. Collection of salivary biomarkers for stress (cortisol) and sleep (melatonin) was completed the evening of and morning after the PSG. Results Analysis of the first 12 participants (5 males; 3 Hispanic/Latino; average age 14 years; 9–72 months post treatment) revealed mean (minutes) total sleep time (TST) 442, sleep latency (SL) 42 and waking (WASO) 88; sleep efficiency (SE) mean 83%, There were large magnitude correlations between several variables of interest, notably PM Cortisol with fatigue, TST (r= .472; -.453); AM Cortisol with SL (r=.479); AM Melatonin with SE, SL, WASO (r= -.459; .692; .458). Average AM melatonin level (26.6 pg/dl) was higher than PM (6.66 pg/dl). Seven participants were diagnosed with clinical sleep disorders, including one with narcolepsy and two with hypersomnia. Conclusion During early survivorship after pediatric brain tumor treatment, survivors may be at high risk for sleep/wake disturbance (SWD). Morning melatonin and biomarker correlations with sleep and fatigue in this sample warrant further exploration and may be related to first night effect versus circadian rhythm differences or clinical sleep disorder. Recommendations for future practice include developmentally matched protocols and routine screening of biobehavioral markers to assess risk for stress, SWD, and fatigue. Support 1. Center for Oncology Education and Research Harris College of Nursing &amp; Health Sciences Texas Christian University 2. Neuro-Oncology Program Hematology/Oncology Center Cook Children’s Health Care System 3. Nursing Research and Evidence-Based Practice James A. “Buddy” Davidson Endowed Fund

0050 Identification of a Plasma Metabolome-Based Biomarker for Dim-Light Melatonin Offset and Onset in Humans

Abstract Introduction Easily measuring individual circadian timing is increasingly important to inform personalized chronotherapy, screen for circadian disorders and circadian misalignment, and advance circadian research. Findings from multiple studies show that transcriptomics is a viable method to estimate dim-light melatonin onset (DLMO), but no published omics-based findings have predicted dim-light melatonin offset (DLMOff), and only one known study has used metabolomics to predict DLMO. Here, we developed and tested a plasma metabolomics-based biomarker of circadian phase using DLMO and DLMOff as phase markers. Methods Sixteen (8M/8F) healthy participants aged 22.4 ± 4.8y (mean ± SD) completed an in-laboratory study with 3 baseline days (9h sleep opportunity/night), followed by a randomized cross-over protocol with 9h sleep and 5h sleep conditions, each lasting 5 days. Blood was collected every 4h on the final 24h of each condition for untargeted metabolomics analyses. DLMO and DLMOff were determined during the final 24h of each condition. Samples from all conditions were randomly split into training (68%) and test (32%) datasets. DLMO and DLMOff models were developed using partial least squares regression in the training dataset and validated in the test dataset. Results When validating with the test dataset, R2 for the DLMO model was 0.60, median absolute error (MdAE) was 2.2 ± 2.8h (± interquartile range), and 44% of samples had MdAE under 2h. R2 for the DLMOff model was 0.62, MdAE was 1.8 ± 2.6, and 51% of samples had MdAE under 2h. The DLMOff model predicted baseline samples, under conditions of 9h sleep and controlled food intake, with an R2 of 0.91 and MdAE 1.1 ± 1.1h. Conclusion These findings show promise for metabolomics-based biomarkers of circadian phase and highlight the need for biomarker efforts to predict multiple circadian phase markers. Additional analyses with an independent validation dataset will help advance these initial findings. Support NIH-R01HL085705, NIH-R01HL109706, NIH-R01HL132150, NIH-K01HL145099, NIH-F32DK111161, and NIH-UL1TR000154; and Sleep Research Society Foundation 011-JP-16;