ABSTRACT
Clinical trials with light therapy (LT) for delayed sleep phase disorder (DSPD) are sparse and little is known about factors that are favorable for improvements. In this study, LT with scheduled rise times was conducted at home for 14 days by 44 participants with DSPD aged 16-26 years. Primary outcomes were sleep onset and sleep offset. Potential predictors were demographic characteristics, chronotype, dim light melatonin onset, the number of days the LT lamp was used, the daily duration of LT, daytime sleepiness, anxiety, depression, worry, and rumination. Significant advances were observed in sleep onset and sleep offset from baseline to the end of treatment. The number of days of LT predicted earlier sleep onset and sleep offset.
Subject(s)
Phototherapy/methods , Sleep Disorders, Circadian Rhythm/therapy , Adolescent , Adult , Female , Humans , Male , Sleep Disorders, Circadian Rhythm/pathology , Young AdultABSTRACT
The success of interplanetary human spaceflight will depend on many factors, including the behavioral activity levels, sleep, and circadian timing of crews exposed to prolonged microgravity and confinement. To address the effects of the latter, we used a high-fidelity ground simulation of a Mars mission to objectively track sleep-wake dynamics in a multinational crew of six during 520 d of confined isolation. Measurements included continuous recordings of wrist actigraphy and light exposure (4.396 million min) and weekly computer-based neurobehavioral assessments (n = 888) to identify changes in the crew's activity levels, sleep quantity and quality, sleep-wake periodicity, vigilance performance, and workload throughout the record-long 17 mo of mission confinement. Actigraphy revealed that crew sedentariness increased across the mission as evident in decreased waking movement (i.e., hypokinesis) and increased sleep and rest times. Light exposure decreased during the mission. The majority of crewmembers also experienced one or more disturbances of sleep quality, vigilance deficits, or altered sleep-wake periodicity and timing, suggesting inadequate circadian entrainment. The results point to the need to identify markers of differential vulnerability to hypokinesis and sleep-wake changes during the prolonged isolation of exploration spaceflight and the need to ensure maintenance of circadian entrainment, sleep quantity and quality, and optimal activity levels during exploration missions. Therefore, successful adaptation to such missions will require crew to transit in spacecraft and live in surface habitats that instantiate aspects of Earth's geophysical signals (appropriately timed light exposure, food intake, exercise) required for temporal organization and maintenance of human behavior.
Subject(s)
Adaptation, Physiological/physiology , Astronauts , Hypokinesia/pathology , Mars , Sleep Disorders, Circadian Rhythm/pathology , Space Flight , Actigraphy , Aerospace Medicine , Analysis of Variance , Confined Spaces , Humans , Hypokinesia/etiology , Neuropsychological Tests , Psychomotor Performance/physiology , Sleep Disorders, Circadian Rhythm/etiologyABSTRACT
OBJECTIVE: The purpose of this study was to determine if there is an association between tentorial length and angle and sleep-wake disturbances in patients with mild traumatic brain injury (TBI). MATERIALS AND METHODS: MRI examinations of the brain of 34 consecutive patients with mild TBI with sleep-wake disturbance and 30 patients with mild TBI without sleep-wake disturbance were retrospectively reviewed. The length of the tentorium on a sagittal T1-weighted image (tentorial length) and the angle formed between the tentorium and a line through the foramen magnum (tentorial angle) were measured. Results were correlated with both neuropsychologic testing and any sleep-wake disturbance. RESULTS: No significant difference existed between patients with and without sleep-wake disturbances in terms of age (p=0.44), sex (p=0.13), Immediate Post-Concussion Assessment Cognitive Test total symptom score (p=0.10), verbal memory score (p=0.32), visual memory score (p=0.31), processing speed (p=0.15), or reaction time (p=0.84). Tentorial length in patients with mild TBI with sleep-wake disturbances was significantly longer than patients with mild TBI without sleep-wake disturbances (p<0.01), and tentorial angle was significantly smaller (p<0.01). Tentorial angle was inversely correlated with length of time to recovery (p=0.002), and tentorial length was directly correlated with length of time to recovery (p<0.001). CONCLUSION: Among patients with mild TBI with similar cognitive function and symptom severity, those with sleep-wake disturbances have significantly longer tentorial length with a flatter angle than do patients with mild TBI without sleep symptoms, with length of time to recovery being directly correlated with tentorial length and indirectly correlated with tentorial angle. Direct impact between the tentorium and the pineal gland during mild TBI may lead to pineal gland injury, disruption of melatonin homeostasis, and sleep-wake disturbances.
Subject(s)
Brain Injuries/complications , Brain Injuries/pathology , Cerebellum/pathology , Magnetic Resonance Imaging/methods , Sleep Disorders, Circadian Rhythm/etiology , Sleep Disorders, Circadian Rhythm/pathology , Adolescent , Adult , Child , Female , Humans , Male , Reproducibility of Results , Sensitivity and Specificity , Young AdultABSTRACT
OBJECTIVE: Shift work is associated with circadian rhythm disorder, impaired sleep and behavioural changes, including eating habits, predisposing to obesity and metabolic dysfunctions. It involves a neuro-hormonal dysregulation of appetite towards positive energy balance, including increased ghrelin and decreased leptin, but little is known about other hormones, such as xenin, derived from the upper gut (like ghrelin), and lower gut hormones. Our objective was to compare night workers with day workers in relation to appetite-regulating hormones and other metabolic parameters. DESIGN: Cross-sectional, observational study. PARTICIPANTS: Twenty-four overweight women, divided into night shift workers (n = 12) and day shift workers (n = 12). MEASUREMENTS: BMI, waist circumference, fat mass percentage; diet composition; Pittsburgh Sleep Quality Index; lipids; adipokines; meal tolerance test curves of glucose, insulin, ghrelin, PYY3-36, oxyntomodulin, xenin, GLP-1; insulin sensitivity (Stumvoll index). RESULTS: Night workers, as compared with day workers, had greater body fat mass percentage and tendency to greater waist circumference despite similar BMI; greater energy intake; impaired sleep; lower insulin sensitivity; increased triglycerides and tendency to increased C-reactive protein; similar levels of leptin and other adipokines. Night workers had a blunted post-meal suppression of ghrelin (AUCi(0-60 min) 19·4 ± 139·9 vs -141·9 ± 9·0 ng/ml·60 min, P < 0·01); blunted rise of xenin (AUC(0-180 min) 8690·9 ± 2988·2 vs 28 504·4 ± 20 308·3 pg/ml·180 min, P < 0·01) and similar curves of PYY3-36, oxyntomodulin and GPL-1. CONCLUSION: Compared with day workers within the same BMI range, night workers presented a disrupted control of ghrelin and xenin, associated with behavioural changes in diet and sleep and increased adiposity and related metabolic alterations.
Subject(s)
Appetite Regulation/physiology , Gastrointestinal Hormones/physiology , Ghrelin/physiology , Neurotensin/physiology , Work Schedule Tolerance/physiology , Adiposity/physiology , Adult , Cross-Sectional Studies , Digestive System/physiopathology , Energy Intake/physiology , Female , Gastrointestinal Hormones/blood , Ghrelin/blood , Glucagon-Like Peptide 1/blood , Humans , Insulin Resistance/physiology , Neurotensin/blood , Overweight/blood , Overweight/pathology , Overweight/physiopathology , Oxyntomodulin/blood , Peptide Fragments/blood , Peptide YY/blood , Sleep Disorders, Circadian Rhythm/blood , Sleep Disorders, Circadian Rhythm/pathology , Sleep Disorders, Circadian Rhythm/physiopathologyABSTRACT
BACKGROUND: Impaired sleep quality and daytime sleepiness have been described in patients with primary biliary cirrhosis (PBC). However, no information is available on their sleep timing/diurnal preference. AIMS: To evaluate such variables and determine their relationship with sleep quality, fatigue, pruritus and quality of life. METHODS: Seventy-four patients with PBC (58 ± 12 years), 79 healthy volunteers (56 ± 8 years) and 60 patients with cirrhosis (58 ± 12 years) underwent formal assessment of sleep quality/timing, diurnal preference and daytime sleepiness. Patients with PBC also underwent assessment of fatigue, quality of life and the daytime course of sleepiness/pruritus. RESULTS: Sleep timing was significantly delayed in both patients with PBC and with cirrhosis, compared to healthy volunteers (sleep onset time: 23:18 ± 01:00 vs. 23:30 ± 01:00 vs. 22:54 ± 00:54 hours, respectively; P < 0.05). In patients with PBC, delayed sleep timing was associated with impaired sleep quality (P < 0.05). Sleepiness showed a physiological daily rhythm, with early afternoon/evening peaks. Pruritus was absent in the morning and increased over the afternoon/evening hours. Both the daytime course of pruritus and sleepiness changed in relation to diurnal preference. Patients with PBC and significant pruritus (upper quartile) had prolonged sleep latency (39 ± 37 vs. 21 ± 23 min, P = 0.05) and earlier wake-up times (5.9 ± 0.8 vs. 6.7 ± 0.9 min, P < 0.05). Significant correlations were observed between sleep timing and quality of life. CONCLUSIONS: Patients with PBC exhibited a delay in sleep timing that was associated with impaired sleep quality/quality of life. In addition, an interplay was observed between diurnal preference and the daytime course of pruritus/sleepiness.
Subject(s)
Fatigue/physiopathology , Liver Cirrhosis, Biliary/complications , Pruritus/physiopathology , Sleep Disorders, Circadian Rhythm/pathology , Aged , Fatigue/etiology , Humans , Middle Aged , Multivariate Analysis , Pruritus/etiology , Sleep Disorders, Circadian Rhythm/etiology , Surveys and QuestionnairesABSTRACT
Sleep and circadian rhythm disruption (SCRD) and schizophrenia are often co-morbid. Here, we propose that the co-morbidity of these disorders stems from the involvement of common brain mechanisms. We summarise recent clinical evidence that supports this hypothesis, including the observation that the treatment of SCRD leads to improvements in both the sleep quality and psychiatric symptoms of schizophrenia patients. Moreover, many SCRD-associated pathologies, such as impaired cognitive performance, are routinely observed in schizophrenia. We suggest that these associations can be explored at a mechanistic level by using animal models. Specifically, we predict that SCRD should be observed in schizophrenia-relevant mouse models. There is a rapidly accumulating body of evidence which supports this prediction, as summarised in this review. In light of these emerging data, we highlight other models which warrant investigation, and address the potential challenges associated with modelling schizophrenia and SCRD in rodents. Our view is that an understanding of the mechanistic overlap between SCRD and schizophrenia will ultimately lead to novel treatment approaches, which will not only ameliorate SCRD in schizophrenia patients, but also will improve their broader health problems and overall quality of life.
Subject(s)
Brain/physiopathology , Schizophrenia/complications , Sleep Disorders, Circadian Rhythm/complications , Animals , Brain/pathology , Disease Models, Animal , Humans , Mice , Mutation/genetics , Schizophrenia/epidemiology , Schizophrenia/genetics , Schizophrenia/pathology , Sleep Disorders, Circadian Rhythm/epidemiology , Sleep Disorders, Circadian Rhythm/genetics , Sleep Disorders, Circadian Rhythm/pathologyABSTRACT
Sleep disorders are very prevalent and represent an emerging worldwide epidemic. However, research into the molecular genetics of sleep disorders remains surprisingly one of the least active fields. Nevertheless, rapid progress is being made in several prototypical disorders, leading recently to the identification of the molecular pathways underlying narcolepsy and familial advanced sleep-phase syndrome. Since the first reports of spontaneous and induced loss-of-function mutations leading to hypocretin deficiency in human and animal models of narcolepsy, the role of this novel neurotransmission pathway in sleep and several other behaviors has gained extensive interest. Also, very recent studies using an animal model of familial advanced sleep-phase syndrome shed new light on the regulation of circadian rhythms.
Subject(s)
Genetic Predisposition to Disease/genetics , Narcolepsy/genetics , Narcolepsy/pathology , Sleep Disorders, Circadian Rhythm/genetics , Sleep Disorders, Circadian Rhythm/pathology , Animals , HumansABSTRACT
The 24-h distribution of rapid eye movement (REM) sleep is known to be deeply reshaped among albino rats with neurotoxic lesions in the lateral hypothalamus (LH) or among rodent models of human narcolepsy-cataplexy, with selective damage of orexinergic neurones. We explored the hypothesis that this phenomenon is explained by an enhancement of REM sleep photic masking, as a consequence of damage in the LH. Orexin-B-saporin neurotoxic lesions were induced in the LH of male Sprague-Dawley rats. LH-lesioned and control rats were sleep-recorded successively under 12:12 light/dark (LD) and skeleton photoperiod. Compared to controls, lesioned rats exhibited 50% less and 82% more REM sleep during rest and active phases, respectively, under the 12:12 LD schedule. After transference to a skeleton photoperiod, lesioned rats exhibited an 88% increase in REM sleep during the rest phase, recovering the characteristic rest phase preference of REM sleep observed among control rats. The increase in rest phase REM sleep during the skeleton photoperiod was correlated positively with the magnitude of the LH lesion. Our results suggest that changes in the temporal organization of sleep-wake states observed among rats with neurotoxic lesions in the lateral hypothalamus and rodent models of narcolepsy-cataplexy may be explained by the enhancement of photic masking.
Subject(s)
Hypothalamus/pathology , Intracellular Signaling Peptides and Proteins/pharmacology , Neuropeptides/pharmacology , Ribosome Inactivating Proteins, Type 1/pharmacology , Sleep, REM/physiology , Animals , Cell Count , Electroencephalography , Hypothalamus/drug effects , Hypothalamus/physiopathology , Male , Neurons/drug effects , Neurons/physiology , Orexins , Photic Stimulation , Rats , Rats, Sprague-Dawley , Saporins , Sleep Disorders, Circadian Rhythm/pathology , Sleep Disorders, Circadian Rhythm/physiopathology , Wakefulness/physiologyABSTRACT
PURPOSE OF REVIEW: This article provides an overview of circadian physiology and discusses common presentations and treatment strategies for the circadian rhythm sleep-wake disorders. RECENT FINDINGS: Circadian rhythms are present throughout the body, and appreciation for the role that circadian dysregulation plays in overall health is increasing, with mounting associations between circadian disruption and cardiometabolic disease risk. SUMMARY: It is important to recognize the ubiquitous role that circadian rhythms play throughout the brain and body. An understanding of circadian neurophysiology will provide insight into the means by which patients with a variety of neuropathologies at the level of the retina, optic nerve, or hypothalamus may also be at risk for circadian dysfunction.
Subject(s)
Chronobiology Disorders/physiopathology , Circadian Rhythm/physiology , Sleep Disorders, Circadian Rhythm/physiopathology , Chronobiology Disorders/pathology , Humans , Sleep Disorders, Circadian Rhythm/pathologyABSTRACT
From an evolutionary point of view, vitamin D and melatonin appeared very early and share functions related to defense mechanisms. In the current clinical setting, vitamin D is exclusively associated with phosphocalcic metabolism. Meanwhile, melatonin has chronobiological effects and influences the sleep-wake cycle. Scientific evidence, however, has identified new actions of both molecules in different physiological and pathological settings. The biosynthetic pathways of vitamin D and melatonin are inversely related relative to sun exposure. A deficiency of these molecules has been associated with the pathogenesis of cardiovascular diseases, including arterial hypertension, neurodegenerative diseases, sleep disorders, kidney diseases, cancer, psychiatric disorders, bone diseases, metabolic syndrome, and diabetes, among others. During aging, the intake and cutaneous synthesis of vitamin D, as well as the endogenous synthesis of melatonin are remarkably depleted, therefore, producing a state characterized by an increase of oxidative stress, inflammation, and mitochondrial dysfunction. Both molecules are involved in the homeostatic functioning of the mitochondria. Given the presence of specific receptors in the organelle, the antagonism of the renin-angiotensin-aldosterone system (RAAS), the decrease of reactive species of oxygen (ROS), in conjunction with modifications in autophagy and apoptosis, anti-inflammatory properties inter alia, mitochondria emerge as the final common target for melatonin and vitamin D. The primary purpose of this review is to elucidate the common molecular mechanisms by which vitamin D and melatonin might share a synergistic effect in the protection of proper mitochondrial functioning.
Subject(s)
Melatonin/metabolism , Mitochondria/metabolism , Oxidative Stress/genetics , Vitamin D/metabolism , Animals , Apoptosis/genetics , Humans , Melatonin/genetics , Mitochondria/genetics , Reactive Oxygen Species/metabolism , Renin-Angiotensin System/genetics , Seasons , Sleep Disorders, Circadian Rhythm/genetics , Sleep Disorders, Circadian Rhythm/metabolism , Sleep Disorders, Circadian Rhythm/pathology , Vitamin D/geneticsABSTRACT
BACKGROUND: Intrinsically photosensitive retinal ganglion cells (ipRGCs) control non-visual light responses (e.g. pupillary light reflex and circadian entrainment). Patients with diabetic retinopathy (DR) show reduced ipRGC function, as inferred by abnormalities in the post illumination pupil response (PIPR). We explored whether ipRGC function in DR is associated with circadian outputs and sleep/wake behavior. METHODS: Forty-five participants (15 without diabetes, 15 with type 2 diabetes (T2D) and no DR, 15 with T2D and DR) participated. ipRGC function was inferred from the PIPR (pupil size following stimulus offset). Circadian outputs were melatonin amplitude (overnight urinary 6-sulfatoxymelatonin (aMT6s)) and timing (dim light melatonin onset (DLMO)), and evening salivary cortisol levels. Sleep/wake patterns were measured with wrist actigraphy and insomnia symptoms were assessed subjectively. RESULTS: Patients with T2D and DR had smaller PIPR and lower urinary aMT6s than other groups (p < 0.001). In adjusted regression models, smaller PIPR was associated with lower urinary aMT6s (ß = 4.552, p = 0.005). Patients with DR were more likely to have no detectable DLMO (p = 0.049), higher evening salivary cortisol, greater insomnia symptoms and greater sleep variability compared to other groups. Sleep duration, efficiency and rest-activity rhythms were similar. CONCLUSION: Reduced ipRGC function in DR is associated with circadian dysregulation and sleep disturbances, although a causal relationship cannot be established in this cross-sectional study. Prospective mechanistic and intervention studies examining circadian and sleep health in these patients are warranted.
Subject(s)
Adie Syndrome/metabolism , Circadian Clocks/physiology , Diabetes Mellitus, Type 2/metabolism , Diabetic Retinopathy/metabolism , Retinal Ganglion Cells/physiology , Sleep Disorders, Circadian Rhythm/metabolism , Adie Syndrome/pathology , Aged , Cells, Cultured , Cross-Sectional Studies , Diabetes Mellitus, Type 2/pathology , Diabetic Retinopathy/pathology , Female , Humans , Hydrocortisone/metabolism , Male , Melatonin/analogs & derivatives , Melatonin/metabolism , Melatonin/urine , Middle Aged , Reflex, Pupillary , Sleep Disorders, Circadian Rhythm/pathology , Sleep Initiation and Maintenance DisordersABSTRACT
Disturbed sleep is the most common effect of shift work. A large corpus of research indicates an association between sleep disturbance and depressive symptom in shift workers. In this study, we proposed the mediating role of grey matter (GM) structure in the relationship between sleep disturbance and depressive symptom. We collected structural MRI (sMRI) data as well as assessing the level of sleep disturbance and depressive symptom with the Pittsburgh Sleep disturbance Index and Zung Self-Rating Depression Scale, respectively, in 20 shift-working nurses and 19 day-working nurses. The shift-working nurses reported greater severity of sleep disturbance and depressive symptom, and furthermore, they exhibited reduced GM volume in the left postcentral gyrus (PostCG), right PostCG, right paracentral lobule, and left superior temporal gyrus (STG), compared to the day-working nurses. For each of the four brain regions, we formulated a mediation hypothesis by developing a mediation model that represents a causal chain between GM volume, sleep disturbance, and depressive symptom. Tests of the hypothesis on the mediation of GM volume revealed that inter-individual variations in left PostCG volume and left STG volume accounted for the influence of sleep disturbance on depressive symptom. These results suggest that structural alterations in PostCG and STG play an intervening role in the development of depressive symptom following sleep disturbance. We propose the need of considering neuroanatomical abnormalities in explaining and understanding symptomatic changes induced by sleep disturbance.
Subject(s)
Depression/etiology , Gray Matter/pathology , Nurses , Occupational Diseases/etiology , Occupational Exposure/adverse effects , Occupational Health , Shift Work Schedule/adverse effects , Sleep Disorders, Circadian Rhythm/etiology , Adult , Depression/diagnostic imaging , Depression/pathology , Female , Gray Matter/diagnostic imaging , Humans , Magnetic Resonance Imaging , Middle Aged , Occupational Diseases/diagnostic imaging , Occupational Diseases/pathology , Organ Size , Severity of Illness Index , Sleep Disorders, Circadian Rhythm/diagnostic imaging , Sleep Disorders, Circadian Rhythm/pathology , Young AdultABSTRACT
PURPOSE: To analyze the topography of the epileptogenic zone (EZ) and the etiologic substrate as risk factors for sleep-related focal epilepsy. METHODS: Three hundred three patients (172 males and 131 females, mean age at surgery 25.6 +/- 13.1 years), who were seizure-free after resective surgery for drug-resistant focal epilepsy, were retrospectively reviewed. Statistical analysis was conducted to evaluate the risk of presenting sleep-related epilepsy (SRE) against topography of resection (assumed to correspond or to include the EZ) and results of histology. RESULTS: Thirty-nine patients (12.8%) presented with an SRE. At bivariate analysis, a higher frequency of SRE was associated with a frontal lobe EZ (p = 1.94 x 10(-9)) and Taylor's FCD (TFCD, p = 2.20 x 10(-16)), whereas architectural FCD (p = 0.00977), ganglioglioma (p = 0.02508), and mesial temporal sclerosis (p = 2.47 x 10(-5)) were correlated with a reduced frequency of SRE. Multivariate analysis demonstrated that the only variable significantly associated with SRE was the presence of a TFCD, which increased 14-fold the risk of SRE [p = 1.66 x 10(-10); risk ratio (RR) = 14.44]. DISCUSSION: In this study, we have demonstrated a significant and strong association between SRE and TFCD in a select population of patients with drug-resistant focal epilepsy submitted to surgical resection of the EZ. Although our results cannot be applied to the entire spectrum of SRE, the presence of TFCD as the underlying etiology should be considered when evaluating patients with SRE, because surgery can provide excellent results on seizures in these cases.
Subject(s)
Cerebral Cortex/pathology , Epilepsies, Partial/epidemiology , Malformations of Cortical Development/epidemiology , Malformations of Cortical Development/pathology , Sleep Disorders, Circadian Rhythm/epidemiology , Adult , Brain Mapping , Cerebral Cortex/surgery , Comorbidity , Disease-Free Survival , Drug Resistance , Electroencephalography/methods , Electroencephalography/statistics & numerical data , Epilepsies, Partial/drug therapy , Epilepsies, Partial/surgery , Epilepsy, Frontal Lobe/diagnosis , Epilepsy, Frontal Lobe/epidemiology , Epilepsy, Frontal Lobe/pathology , Epilepsy, Temporal Lobe/diagnosis , Epilepsy, Temporal Lobe/epidemiology , Epilepsy, Temporal Lobe/pathology , Female , Humans , Male , Multivariate Analysis , Retrospective Studies , Risk Factors , Sclerosis/pathology , Sleep Disorders, Circadian Rhythm/pathologyABSTRACT
Establishing circadian and wake-dependent changes in the human metabolome are critical for understanding and treating human diseases due to circadian misalignment or extended wake. Here, we assessed endogenous circadian rhythms and wake-dependent changes in plasma metabolites in 13 participants (4 females) studied during 40-hours of wakefulness. Four-hourly plasma samples were analyzed by hydrophilic interaction liquid chromatography (HILIC)-LC-MS for 1,740 metabolite signals. Group-averaged (relative to DLMO) and individual participant metabolite profiles were fitted with a combined cosinor and linear regression model. In group-level analyses, 22% of metabolites were rhythmic and 8% were linear, whereas in individual-level analyses, 14% of profiles were rhythmic and 4% were linear. We observed metabolites that were significant at the group-level but not significant in a single individual, and metabolites that were significant in approximately half of individuals but not group-significant. Of the group-rhythmic and group-linear metabolites, only 7% and 12% were also significantly rhythmic or linear, respectively, in ≥50% of participants. Owing to large inter-individual variation in rhythm timing and the magnitude and direction of linear change, acrophase and slope estimates also differed between group- and individual-level analyses. These preliminary findings have important implications for biomarker development and understanding of sleep and circadian regulation of metabolism.
Subject(s)
Circadian Rhythm/physiology , Metabolome , Plasma/metabolism , Sleep Disorders, Circadian Rhythm/metabolism , Sleep Disorders, Circadian Rhythm/pathology , Sleep/physiology , Wakefulness/physiology , Adult , Female , Humans , Lighting , Male , Young AdultABSTRACT
Circadian clocks are endogenous oscillators that control 24-h physiological and behavioral processes. The central circadian clock exerts control over myriad aspects of mammalian physiology, including the regulation of sleep, metabolism, and the immune system. Here, we review advances in understanding the genetic regulation of sleep through the circadian system, as well as the impact of dysregulated gene expression on metabolic function. We also review recent studies that have begun to unravel the circadian clock's role in controlling the cardiovascular and nervous systems, gut microbiota, cancer, and aging. Such circadian control of these systems relies, in part, on transcriptional regulation, with recent evidence for genome-wide regulation of the clock through circadian chromosome organization. These novel insights into the genomic regulation of human physiology provide opportunities for the discovery of improved treatment strategies and new understanding of the biological underpinnings of human disease.
Subject(s)
Circadian Rhythm/genetics , Genomics , Animals , Circadian Clocks/genetics , Gene Regulatory Networks , Host-Pathogen Interactions/genetics , Humans , Immune System/metabolism , Signal Transduction/genetics , Sleep Disorders, Circadian Rhythm/genetics , Sleep Disorders, Circadian Rhythm/pathologyABSTRACT
In modern 24â¯h society, circadian disruption is pervasive, arising from night shift work, air travel across multiple time zones, irregular sleep schedules, and exposure to artificial light at night. Disruption of the circadian system is associated with many adverse health consequences, including mood disorders. Here we investigate whether inducing circadian misalignment using a phase advance protocol interferes with the ability to cope with a stressor, thereby increasing susceptibility to the negative consequences of stress. Male rats were maintained on a standard 12:12 light: dark (LD) cycle or subjected to a chronic phase advance (CPA) protocol involving 4 weekly 6 h phase shifts (earlier light onset) of the LD cycle. Rats were then exposed to escapable stress (ES), inescapable stress (IS), or no stress (home cage control; HC) and performance on juvenile social exploration and active escape learning in the two-way shuttlebox test was assessed 24 h and 48 h following stress, respectively. CPA alone had no effect on pre-stress juvenile social exploration, and it also did not interfere with the protective effect of ES on the stress-induced reduction in juvenile social exploration. In contrast, CPA impaired escape learning in the two-way shuttlebox to the same extent as IS in all subjects, regardless of stress history. Additionally, CPA produced somatic alterations that included increased body mass, increased epididymal adiposity, and decreased adrenal mass. These data indicate that CPA differentially modulated the stress-protective effects of behavioral control depending on the type of affective behavior examined.
Subject(s)
Affect , Behavior, Animal , Circadian Rhythm , Sleep Disorders, Circadian Rhythm/psychology , Stress, Psychological , Adiposity , Adrenal Glands/pathology , Adrenal Glands/physiopathology , Affect/physiology , Animals , Behavior, Animal/physiology , Circadian Rhythm/physiology , Disease Models, Animal , Exploratory Behavior/physiology , Learning/physiology , Male , Rats, Sprague-Dawley , Resilience, Psychological , Sleep Disorders, Circadian Rhythm/pathology , Sleep Disorders, Circadian Rhythm/physiopathology , Social Behavior , Stress, Psychological/pathology , Stress, Psychological/physiopathology , Weight Gain/physiologyABSTRACT
OBJECTIVES: Conventional scoring of sleep provides little information about the process of transitioning between vigilance-states. We used the state space technique to explore whether rats with chronic upper airway obstruction (UAO) have abnormal sleep/wake states, faster movements between states, or abnormal transitions between states. DESIGN: The tracheae of 22-day-old Sprague-Dawley rats were surgically narrowed to increase upper airway resistance with no evidence for frank obstructed apneas or hypopneas; 24-h electroencephalography of sleep/wake recordings of UAO and sham-control animals was analyzed using state space technique. This non-categorical approach allows quantitative and unbiased examination of vigilance-states and state transitions. Measurements were performed 2 weeks post-surgery at baseline and following administration of ritanserin (5-HT2 receptor antagonist) the next day to stimulate sleep. MEASUREMENTS AND RESULTS: UAO rats spent less time in deep (delta-rich) slow wave sleep (SWS) and near transition zones between states. State transitions from light SWS to wake and vice versa and microarousals were more frequent and rapid in UAO rats, indicating that obstructed animals have more regions where vigilance-states are unstable. Ritanserin consolidated sleep in both groups by decreasing the number of microarousals and trajectories between wake and light SWS, and increasing deep SWS in UAO. CONCLUSIONS: State space technique enables visualization of vigilance-state transitions and velocities that were not evident by traditional scoring methods. This analysis provides new quantitative assessment of abnormal vigilance-state dynamics in UAO in the absence of frank obstructed apneas or hypopneas.
Subject(s)
Sleep Apnea, Obstructive/complications , Sleep Disorders, Circadian Rhythm/etiology , Sleep Disorders, Circadian Rhythm/pathology , Airway Resistance/physiology , Animals , Arousal/physiology , Electroencephalography , Rats , Rats, Sprague-Dawley , Ritanserin , Statistics, Nonparametric , Trachea/pathology , Trachea/surgeryABSTRACT
Increased bodily CO2 concentration alters cellular pH as well as sleep. The proton pump, which plays an important role in the homeostatic regulation of cellular pH, therefore, may modulate sleep. We investigated the effects of the proton pump inhibitor "lansoprazole" on sleep-wakefulness. Male Wistar rats were surgically prepared for chronic polysomnographic recordings. Two different doses of lansoprazole (low: 1 mg/kg; high: 10 mg/kg) were injected intraperitoneally in the same animal (n = 7) and sleep-wakefulness was recorded for 6 hrs. The changes in sleep-wakefulness were compared statistically. Percent REM sleep amount in the vehicle and lansoprazole low dose groups was 9.26 ± 1.03 and 9.09 ± 0.54, respectively, which increased significantly in the lansoprazole high dose group by 31.75% (from vehicle) and 34.21% (from low dose). Also, REM sleep episode numbers significantly increased in lansoprazole high dose group. Further, the sodium-hydrogen exchanger blocker "amiloride" (10 mg/kg; i.p.) (n = 5) did not alter sleep-wake architecture. Our results suggest that the proton pump plays an important role in REM sleep modulation and supports our view that REM sleep might act as a sentinel to help maintain normal CO2 level for unperturbed sleep.
Subject(s)
Carbon Dioxide/blood , Lansoprazole/administration & dosage , Sleep Disorders, Circadian Rhythm/pathology , Sleep, REM/drug effects , Animals , Male , Polysomnography , Proton Pump Inhibitors/administration & dosage , Rats , Rats, Wistar , Sleep Disorders, Circadian Rhythm/drug therapy , Sleep, REM/physiologyABSTRACT
Sleep-wake disturbances are a highly prevalent and often disabling feature of Alzheimer's disease (AD). A cardinal feature of AD includes the formation of amyloid plaques, associated with the extracellular accumulation of the amyloid-ß (Aß) peptide. Evidence from animal and human studies suggests that Aß pathology may disrupt the sleep-wake cycle, in that as Aß accumulates, more sleep-wake fragmentation develops. Furthermore, recent research in animal and human studies suggests that the sleep-wake cycle itself may influence Alzheimer's disease onset and progression. Chronic sleep deprivation increases amyloid plaque deposition, and sleep extension results in fewer plaques in experimental models. In this review geared towards the practicing clinician, we discuss possible mechanisms underlying the reciprocal relationship between the sleep-wake cycle and AD pathology and behavior, and present current approaches to therapy for sleep disorders in AD.
Subject(s)
Alzheimer Disease/complications , Alzheimer Disease/physiopathology , Brain/physiopathology , Sleep Disorders, Circadian Rhythm/complications , Sleep Disorders, Circadian Rhythm/physiopathology , Alzheimer Disease/pathology , Amyloid beta-Peptides/metabolism , Animals , Brain/pathology , Disease Models, Animal , Disease Progression , Humans , Plaque, Amyloid , Sleep , Sleep Disorders, Circadian Rhythm/pathologyABSTRACT
Sleep-wake (S-W) disturbances are frequently associated with alcohol use disorders (AUD), occurring during periods of active drinking, withdrawal, and abstinence. These S-W disturbances can persist after months or even years of abstinence, suggesting that chronic alcohol consumption may have enduring negative effects on both homeostatic and circadian sleep processes. It is now generally accepted that S-W disturbances in alcohol-dependent individuals are a significant cause of relapse in drinking. Although significant progress has been made in identifying the socio-economic burden and health risks of alcohol addiction, the underlying neurobiological mechanisms that lead to S-W disorders in AUD are poorly understood. Marked progress has been made in understanding the basic neurobiological mechanisms of how different sleep stages are normally regulated. This review article in seeking to explain the neurobiological mechanisms underlying S-W disturbances associated with AUD, describes an evidence-based, easily testable, novel hypothesis that chronic alcohol consumption induces neuroadaptive changes in the cholinergic cell compartment of the pedunculopontine tegmentum (CCC-PPT). These changes include increases in N-methyl-d-aspartate (NMDA) and kainate receptor sensitivity and a decrease in gamma-aminobutyric acid (GABAB)-receptor sensitivity in the CCC-PPT. Together these changes are the primary pathophysiological mechanisms that underlie S-W disturbances in AUD. This review is targeted for both basic neuroscientists in alcohol addiction research and clinicians who are in search of new and more effective therapeutic interventions to treat and/or eliminate sleep disorders associated with AUD.