Circadian Rhythm Disruption Research Articles

Comparing MitoQ10 and heat therapy: Evaluating mechanisms and therapeutic potential for polycystic ovary syndrome induced by circadian rhythm disruption

ABSTRACT Environmental factors, such as sleep restriction, contribute to polycystic ovary syndrome (PCOS) by causing hyperinsulinemia, hyperandrogenism, insulin resistance, and oligo- or anovulation. This study aimed to evaluate the effects of circadian rhythm disruption on reproductive and metabolic functions and investigate the potential therapeutic benefits of MitoQ10 and hot tub therapy (HTT). Sixty female rats were divided into six groups: control, MitoQ10, HTT, and three groups with PCOS induced by continuous light exposure(L/L). The reproductive, endocrine, and structural manifestations ofL/L-induced PCOS were confirmed by serum biochemical measurements, ultrasound evaluation of ovarian size, and vaginal smear examination at week 14. Subsequently, the rats were divided into the L/L (untreated), L/L+MitoQ10-treated, andL/L+HTT-treated groups. At the end of week 22, all rats were sacrificed. Treatmentwith MitoQ10 or HTT partially reversed the reproductive, endocrine, and structural features of PCOS, leading to a decreased amplitude of isolated uterine contractions, ovarian cystic changes and size, and endometrial thickness. Furthermore, both interventions improved the elevated serum levels of anti-Mullerian hormone (AMH), kisspeptin, Fibulin-1, A disintegrin and metalloproteinase with thrombospondin motifs 19 (ADAMTS-19), lipid profile, homeostatic model assessment for insulin resistance (HOMA-IR), oxidative stress markers, androgen receptors (AR) and their transcription target genes, FKBP52 immunostaining in ovarian tissues, and uterine estrogen receptor alpha (ER-α) and PRimmunostaining. In conclusion, MitoQ10 supplementation and HTT demonstrated the potential for ameliorating metabolic, reproductive, and structural perturbations associated with PCOS induced by circadian rhythm disruption. These findings suggest a potential therapeutic role for these interventions in managing PCOS in women.

Clinical Neurobiology of Sleep and Wakefulness.

This article focuses on novel neuronal mechanisms of sleep and wakefulness and relates basic science developments with potential translational implications in circadian neurobiology, pharmacology, behavioral factors, and the recently integrated potential pathways of sleep-related motor inhibition. During the past decade, remarkable advances in the molecular biology of sleep and wakefulness have taken place, opening a promising path for the understanding of clinical sleep disorders. Newly gained insights include the role of astrocytes in sleep brain homeostasis through the glymphatic system, the promotion of memory consolidation during states of reduced cholinergic activity during slow wave sleep, and the differential functions of melatonin receptors involving regulation of both circadian rhythm and sleep initiation. Ongoing investigations exploring sleep and circadian rhythm disruptions are beginning to unlock pathophysiologic aspects of neurologic, psychiatric, and medical disorders. An understanding of sleep and circadian neurobiology provides coherent and biologically credible approaches to treatments, including the identification of potential targets for neuromodulation.

The memory impairment by hypothyroidism in mice is dependent on time-of-day and sex

Hypothyroidism is an endocrine-metabolic disorder, and as such it compromises a wide range of physiological functions. Memory deficits and, the most recently described, circadian rhythm disruption are among the impairments caused by thyroid dysfunctions. However, although highly likely, there is no evidence connecting these two effects of hypothyroidism. Here, we hypothesized the time-of-day interferes with the memory deficit caused by hypothyroidism. C57BL/6 J mice from both sexes were subjected to novel object recognition (NOR) task during the rest and active phases, corresponding to ZT 2–4 and 14–16, respectively (ZT: Zeitgeber time; ZT 0: lights on at 07:00 am). First, we showed that neither sex nor ZT altered object recognition memory (ORM) in euthyroid mice. Next, animals were divided into control (euthyroid) and hypothyroid [induced with methimazole (0.01%) and perchlorate (0.1%) treatment in the drinking water for 21 days] groups. Under euthyroid conditions, male and female mice recognized the novel object regardless of the time-of-day. However, hypothyroidism impaired ORM at rest phase (ZT 2–4) in both sexes. Surprisingly, in the active phase (ZT 14–16), the hypothyroid males performed the NOR, though a longer time to execute the task was required. In contrast, female hypothyroid mice showed a greater impairment in ORM. Our results suggest that hypothyroidism may disrupt the circadian rhythm in brain areas related to mnemonic processes since in euthyroid condition ORM is not affected by the time-of-day. Furthermore, our findings in an animal model indicate a pronounced deleterious effect of hypothyroidism in women.

A Pilot Urinary Proteome Study Reveals Widespread Influences of Circadian Rhythm Disruption by Sleep Deprivation.

It is widely accepted that circadian rhythm disruption caused short- or long-term adverse effects on health. Although many previous studies have focused on exploration of the molecular mechanisms, there is no rapid, convenient, and non-invasive method to reveal the influence on health after circadian rhythm disruption. Here, we performed a high-resolution mass spectrometry-based data-independent acquisition (DIA) quantitative urinary proteomic approach in order to explore whether urine could reveal stress changes to those brought about by circadian rhythm disruption after sleep deprivation. After sleep deprivation, the subjects showed a significant increase in both systolic and diastolic blood pressure compared with routine sleep. More than 2000 proteins were quantified and they contained specific proteins for various organs throughout the body. And a total of 177 significantly up-regulated proteins and 68 significantly down-regulated proteins were obtained after sleep deprivation. These differentially expressed proteins (DEPs) were associated with multiple organs and pathways, which reflected widespread influences of sleep deprivation. Besides, machine learning identified a panel of five DEPs (CD300A, SCAMP3, TXN2, EFEMP1, and MYH11) that can effectively discriminate circadian rhythm disruption. Taken together, our results validate the value of urinary proteome in predicting and diagnosing the changes by circadian rhythm disruption.

Circadian Rhythm Effect in Depression Management: A Psychosocial Approach

Depression is a kind of mental disorder. It is a risk factor for many diseases. Recently, it has been suggested to contribute to the high mortality rate, especially for young-middle ages. The incidence of depression is studied to be associated with sleep-style change that leads to internal circadian rhythm disruption. The circadian rhythm is related to the light-dark cycle of the sun. Dusk and dawn twilight are an important part of internal circadian rhythm synchronization. These moments correlate with the praying time of Muslims. A socio-spiritual approach could be a potential treatment for depressive disorder. At praying time for Muslims, the synchronization process of circadian rhythm is happening so that, hopefully, circadian disruption will resolve. This review aims to understand the impact of circadian rhythm on depression and its potential for depression treatment in the future.

The research progress for the treatment of circadian rhythm disorder

With the development of The Times, more and more people need to work at night, which is different from the normal biological clock of life, the body’s internal time and external environmental cues, resulting in the disturbance of circadian rhythm. Circadian rhythm disruptions are common to many people, and people can suffer from problems like chronic sleep deprivation or insomnia. Not only that, but over time it can lead to a variety of diseases that affect their lives and a greatly reduced sense of happiness. Recent research progress has suggested that patients with other medical conditions can also experience symptoms of circadian rhythm disruption. This suggests that the circadian rhythm disorder and the diseases are connected in two ways. Therefore, research that uses circadian rhythms to treat diseases by altering circadian rhythms will bring benefits to patients. In this review, the author first describes the relationship between circadian rhythm and specific diseases, such as hypertension, glucose metabolism, and immune system disorders, thus demonstrating a bidirectional relationship between circadian rhythm disturbance and many diseases. Then, three therapeutic methods of circadian rhythm disorder, namely light therapy, melatonin therapy and lifestyle change, are discussed, also mentions their combined use. The mechanism of action and therapeutic methods are introduced in detail, and the corresponding clinical data are given. Finally, based on the potential of circadian intervention, the future development possibilities are proposed.

Exploring the Relationship Between Circadian Rhythm Shifts and Postpartum Depression

This review paper explores the relationship between circadian rhythm and postpartum depression (PPD). Postpartum depression is a prevalent and debilitating mood disorder that affects a significant number of women after childbirth. Emerging evidence suggests that disruptions in circadian rhythm may contribute to the development of PPD. This paper provides an overview of the current understanding of circadian rhythm disturbances in the postpartum period, their potential impact on PPD, and the underlying mechanisms involved. Additionally, therapeutic approaches targeting circadian disruptions in the prevention and treatment of PPD are discussed. Further research in this field has the potential to provide novel insights and interventions for the management of PPD.

Effect of Withanolide-A on Mice Subjected to Simulated Chronic Jetlag/Shift Work

Objective: Circadian rhythm is maintained by central and peripheral clocks that regulate an organism’s physiological functions. Frequent trans-meridian travel, an irregular sleep-wake cycle, light exposure during the rest period, rotating shift work, and other factors cause desynchronization of central and peripheral clocks, impairing social and occupational behavior. Withanolide-A (WA) is used for its powerful nootropic and neuroprotective properties.Methods: Effects of 13 days consecutive pre-dosing of WA (10 μmol/kg/day) on circadian rhythm disruption caused due to 9 h advance-delay chronic jetlag light-dark shift was studied on re-entrainment rate analyzed through locomotor activity recording of mice using the ClockLab setup, learning and memory studied through Y-maze and Barnes maze tests. In the hippocampus, gene expression of <i>PER1</i> and <i>BDNF</i> was assessed using reverse transcription-quantitative polymerase chain reaction. The effect of WA treatment was also studied on superoxide dismutase, catalase, reactive oxygen species (ROS), and lipid peroxidation in hippocampal tissue.Results: The results showed that WA treatment leads to faster re-entrainment and better performance during Y-maze and Barnes maze tests. <i>PER1</i> and <i>BDNF</i> genes expression was upregulated in the treated group compared to chronic jetlag exposure groups in the hippocampus and suprachiasmatic nuclei. Moreover, the WA-treated group produced fewer ROS and superoxide radicals, and there was also less lipid peroxidation in the treated group.Conclusion: These results suggest that the WA may act as a chronobiotic and neuroprotective agent as treated group mice took fewer transient cycles to re-entrain after chronic light-dark shift. Neuroprotective property is supported by learning-memory behavioral tests, gene studies and biochemical assays.

Circadian disruption and psychostimulants dysregulates plasma acute-phase proteins and circulating cell-free mitochondrial DNA

BackgroundPrevious studies have indicated a close link between the inflammatory response, exacerbated by circadian disruption and psychostimulants such as cocaine and methamphetamine (METH). Indicators of this inflammation include cortisol and acute-phase proteins (APPs) like C-reactive protein (CRP), complement C3 (C3), and serum amyloid A (SAA). The connection between these inflammation markers and circulating mitochondrial DNA (mtDNA) has been gaining attention. However, the specific influence of cocaine and METH on APP, cortisol, and mtDNA levels in mice with disturbed circadian rhythm has yet to be explored, which is the main aim of this research. MethodsIn our study, we employed 10–12-week-old male C57BL/6J mice, which underwent an imposed 6-h phase advance every six days for a total of eight cycles. This process led to the formation of mice with disrupted circadian rhythm and sleep disorders (CRSD). We administered 11 dosages of cocaine and METH 15 mg/kg and 20 mg/kg, respectively to these CRSD mice over the course of 22 days. Quantitative assessments of CRP, C3, SAA, cortisol, and cell-free circulating mtDNA were conducted using enzyme-linked immunosorbent assay (ELISA), Western Blot, and quantitative real-time polymerase chain reaction (qRT-PCR) techniques. ResultsThe experiment revealed that disruption in circadian rhythm alone or cocaine or METH on their own increased CRP, C3, SAA, and cortisol levels in comparison with the control group. CRSD mice, exposed to cocaine and METH, showed a significant rise in CRP, C3, and SAA, while those without exposure remained stable. We also found a reduction in circulating cell-free mtDNA in all CRSD mice, regardless of cocaine and METH exposure. ConclusionsThe findings of our study affirm that the levels of CRP, C3, SAA, and cortisol, which reflect inflammation, are enhanced by circadian disruption, cocaine, and METH, and these levels show a strong correlation with the content of circulating cell-free mtDNA. Furthermore, it also shows the potential link between the disruption of the circadian clock and the inflammatory response triggered by cocaine and METH.

A State-of-Art Review of the Vicious Circle of Sleep Disorders, Diabetes and Neurodegeneration Involving Metabolism and Microbiota Alterations

In the context of neurodegenerative disorders, cognitive decline is frequently reported in older population. Recently, numerous metabolic pathways have been implicated in neurodegeneration, including signaling disruption of insulin and other glucose-regulating hormones. In fact, Alzheimer’s disease has now been considered as “type-3 diabetes”. In this review, we tried to clarify the role of sleep impairment as the third major player in the complex relationship between metabolic and neurodegenerative diseases. Altered sleep may trigger or perpetuate these vicious mechanisms, leading to the development of both dementia and type 2 diabetes mellitus. Finally, we analyzed these reciprocal interactions considering the emerging role of the gut microbiota in modulating the same processes. Conditions of dysbiosis have been linked to circadian rhythm disruption, metabolic alterations, and release of neurotoxic products, all contributing to neurodegeneration. In a future prospective, gut microbiota could provide a major contribution in explaining the tangled relationship between sleep disorders, dementia and diabetes.

Differential Effects of Cocaine and Morphine on the Diurnal Regulation of the Mouse Nucleus Accumbens Proteome.

Substance use disorders are associated with disruptions in sleep and circadian rhythms that persist during abstinence and may contribute to relapse risk. Repeated use of substances such as psychostimulants and opioids may lead to significant alterations in molecular rhythms in the nucleus accumbens (NAc), a brain region central to reward and motivation. Previous studies have identified rhythm alterations in the transcriptome of the NAc and other brain regions following the administration of psychostimulants or opioids. However, little is known about the impact of substance use on the diurnal rhythms of the proteome in the NAc. We used liquid chromatography coupled to tandem mass spectrometry-based quantitative proteomics, along with a data-independent acquisition analysis pipeline, to investigate the effects of cocaine or morphine administration on diurnal rhythms of proteome in the mouse NAc. Overall, our data reveal cocaine and morphine differentially alter diurnal rhythms of the proteome in the NAc, with largely independent differentially expressed proteins dependent on time-of-day. Pathways enriched from cocaine altered protein rhythms were primarily associated with glucocorticoid signaling and metabolism, whereas morphine was associated with neuroinflammation. Collectively, these findings are the first to characterize the diurnal regulation of the NAc proteome and demonstrate a novel relationship between the phase-dependent regulation of protein expression and the differential effects of cocaine and morphine on the NAc proteome. The proteomics data in this study are available via ProteomeXchange with identifier PXD042043.

Wearable-based accelerometer activity profile as digital biomarker of inflammation, biological age, and mortality using hierarchical clustering analysis in NHANES 2011–2014

Repeated disruptions in circadian rhythms are associated with implications for health outcomes and longevity. The utilization of wearable devices in quantifying circadian rhythm to elucidate its connection to longevity, through continuously collected data remains largely unstudied. In this work, we investigate a data-driven segmentation of the 24-h accelerometer activity profiles from wearables as a novel digital biomarker for longevity in 7,297 U.S. adults from the 2011–2014 National Health and Nutrition Examination Survey. Using hierarchical clustering, we identified five clusters and described them as follows: “High activity”, “Low activity”, “Mild circadian rhythm (CR) disruption”, “Severe CR disruption”, and “Very low activity”. Young adults with extreme CR disturbance are seemingly healthy with few comorbid conditions, but in fact associated with higher white blood cell, neutrophils, and lymphocyte counts (0.05–0.07 log-unit, all p < 0.05) and accelerated biological aging (1.42 years, p < 0.001). Older adults with CR disruption are significantly associated with increased systemic inflammation indexes (0.09–0.12 log-unit, all p < 0.05), biological aging advance (1.28 years, p = 0.021), and all-cause mortality risk (HR = 1.58, p = 0.042). Our findings highlight the importance of circadian alignment on longevity across all ages and suggest that data from wearable accelerometers can help in identifying at-risk populations and personalize treatments for healthier aging.

Circadian desynchronization disrupts physiological rhythms of prefrontal cortex pyramidal neurons in mice

Disruption of circadian rhythms, such as shift work and jet lag, are associated with negative physiological and behavioral outcomes, including changes in affective state, learning and memory, and cognitive function. The prefrontal cortex (PFC) is heavily involved in all of these processes. Many PFC-associated behaviors are time-of-day dependent, and disruption of daily rhythms negatively impacts these behavioral outputs. Yet how disruption of daily rhythms impacts the fundamental function of PFC neurons, and the mechanism(s) by which this occurs, remains unknown. Using a mouse model, we demonstrate that the activity and action potential dynamics of prelimbic PFC neurons are regulated by time-of-day in a sex specific manner. Further, we show that postsynaptic K+ channels play a central role in physiological rhythms, suggesting an intrinsic gating mechanism mediating physiological activity. Finally, we demonstrate that environmental circadian desynchronization alters the intrinsic functioning of these neurons independent of time-of-day. These key discoveries demonstrate that daily rhythms contribute to the mechanisms underlying the essential physiology of PFC circuits and provide potential mechanisms by which circadian disruption may impact the fundamental properties of neurons.

Abstract A048: The importance of time: Circadian rhythm disruption and prostate cancer

Abstract Circadian rhythms are evolutionarily created cycles programmed to integrate human behavior, physiology, and metabolism with the surrounding environment. The core clock machinery is composed of an autoregulatory network. The positive components of the loop are CLOCK and BMAL transcription factors, which heterodimerize to regulate expression of key circadian genes through E-box elements. CLOCK/BMAL regulate expression of cryptochrome (CRY1 and CRY2) and period (PER1, PER2, and PER3) genes, which are the negative components of the circadian loop. CRYs and PERs repress CLOCK/BMAL activity, thus conferring daily rhythmicity of cellular, metabolic, and physiological functions for homeostatic maintenance. Disruption to these rhythms, via nighttime light exposure or other forms of desynchronization, has been linked to poor health outcomes. Specifically, circadian disruption is designated as a probable carcinogen by the World Health Organization. Subsequent epidemiology research identified pilots and other shift workers have an increased risk of prostate cancer (PCa). Additional genomic studies identified multiple core clock genes (CCGs) with associated upregulation and/or downregulation in prostatic tumor tissues compared to benign samples. CCGs have also been found to impact several key oncogenic pathways including cell cycle control, apoptosis, DNA repair, and metabolic regulation. In order to further clarify the risk of an altered circadian genome, we analyzed multiple publicly available human PCa datasets to identify clinical correlates in both primary and metastatic disease. Intriguingly, we found genomic alterations in circadian rhythm were associated with increased Gleason score, cancer staging, and positive node status in primary disease. Furthermore, within a subset of patients with castrate-resistant prostate cancer (CRPC), those with concurrent altered CCGs had a decreased survival compared to patients without altered CCGs. This data further emphasizes the importance of circadian rhythm consideration in the context of malignancy and preventative medicine. With so many unknown questions and a high potential to identify subtypes of tumors with altered CCGs and aggressive disease, future studies are needed to improve therapeutic efficacy. Analysis of circadian genomic alterations with subsequent comparison of demographics including ethnicity, occupation, and sleep habits would expand the understanding of everyday variables on circadian disruption. Additionally, the comparison of short-term versus long-term circadian synchronizations should be analyzed to identify higher-risk populations. Lastly, the long-term goal should be to discover potential circadian targeted treatments or to identify ways of involvement of circadian rhythmicity in cancer treatment, including chronotherapy (i.e., time of day of treatment) to optimize the impact of cancer therapeutics to enhance patient outcome. Citation Format: Sierra T. Pence, Ayesha A. Shafi. The importance of time: Circadian rhythm disruption and prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A048.

Use of a Fitbit-like device in rats: Sex differences, relation to EEG sleep, and use to measure the long-term effects of adolescent ethanol exposure.

Sleep difficulties and rhythm disturbances are some of the problems associated with adolescent binge drinking. Recently, animal models of alcohol-induced insomnia have been developed. However, studies in human subjects have recently focused not only on nighttime EEG findings but also on daytime sleepiness and disrupted activity levels as typically measured by activity tracking devices such as the "Fitbit." We sought to develop and test a Fitbit-like device (the "FitBite") in rats and use it to track rest-activity cycles following adolescent alcohol exposure. The effects of 5 weeks of adolescent ethanol vapor or control conditions were evaluated in 48 male and female Wistar rats using FitBite activity while intoxicated, and during acute (24 h post-vapor exposure) and chronic withdrawal (4 weeks post-vapor exposure). Data were analyzed using activity count and cosinor analyses. Fourteen rats were subsequently implanted with cortical electrodes, and data from the FitBite were compared with EEG data to determine how well the FitBite could identify sleep and activity cycles. Female rats were generally more active than males, with higher circadian rhythm amplitudes and mesors (rhythm-adjusted means) across a 24-h period. There were significant correlations between EEG-estimated sleep and activity counts using the FitBite. When the rats were tested during intoxication after 4 weeks of ethanol vapor exposure, they had significantly less overall activity. Disruptions in circadian rhythm were also found with significant decreases in the circadian amplitude, mesor, and a later shift in the acrophase. At 24 h of ethanol withdrawal, rats had more episodes of activity with shorter durations during the daytime, when rats are expected to spend more of their time sleeping. This effect remained at 4 weeks following withdrawal, but circadian rhythm disruptions were no longer present. A Fitbit-like device can be successfully used in rats to assess rest-activity cycles. Adolescent alcohol exposure produced circadian rhythm disturbances that were not observed after withdrawal. Fragmentation of ultradian rest-activity cycles during the light period was found at 24 h and 4 weeks after withdrawal and support data demonstrating the presence of sleep disturbance long after alcohol withdrawal.

Effects of Na/K‐ATPase Inhibitor Marinobufagenin on Gene Expression and Cognition in a Mouse Model of Alzheimer’s Disease

AbstractBackgroundAlzheimer’s disease (AD) is characterized by brain amyloid‐β plaque formation, neuroinflammation and neurodegeneration, which lead to cognitive impairment (CI) and disruption of circadian rhythm. Bioactive steroidal Na/K‐ATPase inhibitor marinobufagenin (MBG) modulates neuroinflammation. In 16‐mo old double transgenic APPswe/PS1dE9 AD mice with advanced AD, treatment with MBG reduced mRNA expression of inflammatory markers. Here, we investigated whether treatment with MBG at early‐stage AD may impact AD manifestation in this AD mouse model.MethodsFive months old male AD mice (n = 15) and WT mice (n = 28) were administered MBG (100 µg/day/kg body weight) (AD‐MBG, n = 8; WT‐MBG, n = 14) or vehicle for control (AD‐C, n = 7; WT‐C, n = 14) via subcutaneous ALZET osmotic minipumps for 3 months. At 8‐mo of age, the mice underwent turn‐based discrimination learning in a water T‐maze (WTM) to assess procedural learning and 72‐hour home cage activity (HCA) analysis to assess circadian rhythm. The hippocampal inflammatory and AD mRNAs (by qPCR) and MBG levels (by immunoassay) were measured.ResultsMBG administration increased plasma MBG levels in WT and AD mice (Table 1). AD‐C mice exhibited greater home cage activity disruption vs. WT‐C (Fig.1a); in WTM, AD‐C required more trials to learn the turn‐based task than WT‐C (Fig. 1b). Though statistically insignificant, trends showed that MBG numerically worsened activity disruption by HCA and decreased ability to learn turn‐based task by WTM in WT mice, while numerically improving both measures in AD mice. During the reversal phase of WTM where response requirements were reversed, WT‐C mice performed significantly better than AD‐C mice, measured by the cumulative amount of time spent in the incorrect arm until reaching criterion performance (p = 0.038). Similar patterns of numerical improvement in AD‐MBG compared to AD‐C are shown (Fig. 1c). Hippocampal inflammatory and AD markers mRNAs were upregulated in AD‐C vs. WT‐C, and MBG treatment downregulated the expression of TNF and GFAP in AD mice (Table 1).ConclusionsBehavioral testing results illustrate CI and circadian impairment in 8‐mo old AD mice compared to WT. Numerical trends show a potential protective effect of MBG on AD CI likely via downregulation of hippocampal TNF and GFAP genes.0Supported by the NIH/NIA Intramural Research Program

The Role of bHLH Transcription Factor Bmal2 in Arterial Endothelial Circadian Rhythms and Remodeling: Sex Dependent Effects in Mice\r

Cardiovascular disease remains the number one cause of mortality in humans (Murphy, Kochanek, Xu, &amp; Arias, 2020). An important influence in the progression of artery disease is the long-term effect of disruptions in daily patterns or circadian rhythms. Not sleeping well at night and daytime sleepiness both associate with cardiovascular disease. In addition, a cardiovascular system that does not rest well at night is also bad. A blood pressure reading that does not decrease at night, called non-dipping hypertension, worsens cardiovascular disease. One important impact of broken rhythms is to cause disease in arteries. Thus, understanding the mechanisms that control 24-hour daily patterns is important. One key component gene of circadian rhythm is the transcription factor Bmal1. Vascular disease is a progression that begins as an adaptation to hypertension, diabetes, and hypercholesterolemia, whereby blood vessels change their structure in response to these changes in the bloodstream through a process called vascular remodeling. Remodeling is a process whereby arteries, arterioles, and even veins change their size and cellular structure (muscularity). Using mouse models of genetic disruption, our lab previously found that Bmal1 has an important role to control vascular remodeling, and when Bmal1 was disrupted, a vascular disease phenotype occurred. The lab also found that the endothelial cell layer of arteries contributes to the disease in Bmal1 knockout (KO) mice. These observations seemed the same in both males and females, thus, were sex independent. Bmal2, is a paralog of Bmal1. Bmal2 interacts with Bmal1 and is more selectively expressed in the endothelium. However, the role of Bmal2 in remodeling is not clear. To understand the role of Bmal2 in vascular disease, I have implemented a widely used experimental animal model of arterial ligation to induce vascular remodeling. I have ligated the left common carotid artery (LC) in two groups of mice, control wild-type (WT) mice (no genetic mutation) and the experimental Bmal2-KO (global knockout) mice. After two weeks, I isolated the LC and fixed the arteries in optimal cutting temperature (O.C.T.) compound and conducted histological processing (cut cross sections with a cryotome and staining with hematoxylin and eosin). I then quantified the changes in structure in the artery using the ImageJ program on digitized microscope images. My findings show that inward remodeling and wall-hypertrophy in male Bmal2- KO mice are similar to wild-type mice. The inward remodeling observed in the male WT and male Bmal2-KO mice is consistent with the normal response of what has been observed in this ligation model, inward accompanied by wall hypertrophy. However, I saw something different in the female Bmal2-KO mice undergoing the ligation for two weeks. Female Bmal2-KO mice exhibited robust inward remodeling that was accompanied by intimal hyperplasia. My data suggest that there are sex-specific differences in remodeling controlled by Bmal2.

The history of circadian rhythm research in Austria.

In view of the recent revival of interest in circadian biology and circadian epidemiology at the Medical University of Vienna, it seems appropriate to highlight the rich and pioneering history of circadian research in Austria. Among the forefathers of circadian research in Vienna are Otto Marburg (1874-1948), who discovered important elements of the pineal gland physiology, Robert Hofstätter (1883-1970), who used pineal gland extract in obstetrics/gynecology, and Paul Engel (1907-1997), who discovered that the pineal gland was controlled by light. More recently, Vera Lapin (1920-2007) showed that surgical removal of the pineal gland increased tumor growth, while Franz Waldhauser (*1946) investigated melatonin in conjunction with night work. Michael Kundi (*1950) and his team conducted among the first studies demonstrating differences in rhythms of night workers and early evidence for health impairments among them. Furthermore, Vienna-born Erhard Haus (1926-2013) pioneered the discovery of the role and importance of melatonin in relation to numerous diseases. This rich pioneering contribution of scientists in Vienna or with roots in Vienna is continued today by anew generation of chronobiologists, epidemiologists and clinicians in Vienna whose new insights contribute to the rapidly developing field of circadian rhythms research. Current topics and contributions relate to the impact of circadian rhythm disruption on health, and the application of chronotherapeutic approaches in clinical and preventive settings.

0288 Multidimensional Sleep Health and Cognitive Function in Retired Night Shift Workers and Retired Day Workers

Abstract Introduction Night shift work is associated with compromised cognitive function, and with chronic exposure, may place shift workers at elevated risk for dementia. Given that former night shift workers experienced prior long-term sleep and circadian rhythm disruption, their sleep in retirement—after returning to a daytime schedule—may be particularly salient for cognitive function. This study examined associations between multidimensional sleep health and neurocognitive function among retired night shift workers and retired day workers. Methods Participants (N = 61; mean age: 67.9 +/- 4.7 years; 61% females; 13% non-Hispanic White) were 31 RDW and 30 RNSW equated on age, sex, race/ethnicity, premorbid IQ, and years in retirement. Multidimensional sleep health was quantified using wrist actigraphy measures of sleep efficiency, timing, duration, and regularity, and diary measures of alertness and satisfaction. Each component was dichotomized and summed to create a composite score (0-6); higher values indicated better sleep health. Participants completed a neurocognitive battery assessing six cognitive domains (language, visuospatial ability, attention, immediate and delayed memory, executive function) and self-reported cognitive function. Linear regression models tested associations of multidimensional sleep health and its individual components with cognitive domains in each group, adjusting for age, sex, and education. Results Retired night shift workers and retired day workers did not differ on multidimensional sleep health or its individual components. Among retired night shift workers, poorer multidimensional sleep health was associated with poorer self-reported global cognitive function (beta = 0.51, p = .018), and more irregular sleep timing was associated with poorer self-reported memory (beta = 0.41, p = .054). Multidimensional sleep health and its individual components were unrelated to cognitive function in retired day workers. Conclusion Retired night shift workers may be cognitively vulnerable to poor sleep health in retirement, possibly due to a history of long-term sleep and circadian rhythm disruption while working. Given that self-reported cognitive difficulties often precede more objective cognitive changes, future research should determine whether associations of sleep health with cognitive function are found in more objective cognitive measures as retired night shift workers age. Support (if any) R01AG047139, R01AG047139-S1, K01AG075171

0677 Blunted daily light rhythm amplitude in adults with opioid use disorder (OUD)

Abstract Introduction Accumulating evidence implicates sleep and circadian rhythm disruption in substance use disorders, including opioid use disorder (OUD). Blunted amplitude in daily rhythms of circadian-relevant variables (e.g., activity, light) may be a marker of psychopathology, as depressed adults demonstrate a smaller activity amplitude compared with healthy controls. The present study compared the light and activity amplitudes of adults with OUD with healthy controls. Methods Light and activity data were collected from adults with OUD who were recently stabilized on medication-assisted treatment (N=27; Mage=44.25±13.21). Participants wore an Actiwatch for an average of 14.5 (SD=4.14) days. Light and activity data collected from healthy adults (N=15; Mage=22.88±2.76) who wore an Actiwatch an average of 11.59 (SD=1.07) days in a separate study were included as a comparison group. Light and activity amplitudes for each day and a composite amplitude for the sampling period were calculated using non-orthogonal spectral analysis. Results Results of mixed model ANOVA with subject as a random factor and group and day as fixed factors revealed a significant main effect of group on daily light amplitude (p&amp;lt;.01), such that the OUD group exhibited lower daily light amplitudes compared to healthy controls, and a trend-level main effect of group on daily activity amplitude (p=.09), such that the OUD group exhibited lower daily activity amplitudes compared to healthy controls. With age included as a covariate in the model, the main effect of group on light remained significant, whereas the trend-level effect on activity became non-significant. Results of between-subjects t-tests indicated significantly lower composite light and activity amplitudes during the entire sampling period in the OUD group compared to healthy controls (p’s&amp;lt;.05). Conclusion These findings indicate that OUD is characterized by blunted light amplitude, which could both reflect and contribute to disruptions in circadian physiology in OUD. Light amplitude may be a novel target for behavioral OUD interventions. Future research is needed to determine whether blunted light amplitude is associated with OUD treatment outcomes and to further examine activity amplitude in OUD with larger sample sizes. Support (if any) U01 HL150596; T32 HL149646; CTSA Grant UL1 TR002535; Office of Naval Research MURI N00014-15-1-2809