Circadian Rhythm Sleep-Wake Disorders.

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.

Sleep disturbance-related depressive symptom and brain volume reduction in shift-working nurses.

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.

Relationship between Intrinsically Photosensitive Ganglion Cell Function and Circadian Regulation in Diabetic Retinopathy.

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.

Daily and seasonal mitochondrial protection: Unraveling common possible mechanisms involving vitamin D and melatonin.

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.

Genomics of circadian rhythms in health and disease.

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.

Circadian and wake-dependent changes in human plasma polar metabolites during prolonged wakefulness: A preliminary analysis.

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.

Circadian misalignment has differential effects on affective behavior following exposure to controllable or uncontrollable stress.

In modern 24 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.

Light Therapy With Scheduled Rise Times in Young Adults With Delayed Sleep Phase Disorder: Therapeutic Outcomes and Possible Predictors.

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.

The sleep-wake cycle and Alzheimer's disease: what do we know?

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.

Mechanisms underlying sleep-wake disturbances in alcoholism: focus on the cholinergic pedunculopontine tegmentum.

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.

Chronic upper airway obstruction induces abnormal sleep/wake dynamics in juvenile rats.

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.

Proton pump inhibition increases rapid eye movement sleep in the rat.

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.

Evaluation of tentorial length and angle in sleep-wake disturbances after mild traumatic brain injury.

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.

Motor activity and intra-individual variability according to sleep-wake states in preschool-aged children with iron-deficiency anemia in infancy.

BACKGROUND: A chronic or acute insult may affect the regulatory processes that guide motor and behavioral performance, leading to increased intra-individual variability (IIV). Increased variability is often interpreted as an indication of regulatory dysfunction. Iron plays an important role in the regulatory processes of the nervous system and affects motor activity. To our knowledge, no study has examined the long-lasting patterns and IIV of motor activity following iron-deficiency anemia in human infants. AIMS: This study compared 48-h motor activity and variability in preschool-aged children with or without iron-deficiency anemia (IDA) in infancy. METHODS: Motor activity was recorded through actigraphs during two week-days in 47 4-year-old Chilean children (23 former IDA and 24 non-anemic in infancy). All were given oral iron as infants. Sleep-wake states were identified by means of automated software. The frequency of movement units per minute was determined for each waking/sleep state during the individual day and night periods; data were examined in blocks of 15 min. Analyses of mean frequency and duration and intra-individual variability were conducted using multivariate mixed models. RESULTS: For daytime sleep, former IDA children were more active without a difference in the total duration. They also spent less time awake throughout the individual day period. Motor activity intra-individual variability was higher in former IDA children. CONCLUSIONS: The findings suggest that IDA in infancy sets the stage for long lasting dysfunction in the neural processes regulating sleep-wake states and spontaneous motor activity patterns.

Factors associated with shift work disorder in nurses working with rapid-rotation schedules in Japan: the nurses' sleep health project.

Workers who meet the criteria for shift work disorder (SWD) have elevated levels of risk for various health and behavioral problems. However, the impact of having SWD on shiftworkers engaged in rapid-rotation schedules is unknown. Moreover, the risk factors for the occurrence of SWD remain unclear. To clarify these issues, we conducted a questionnaire-based, cross-sectional survey on a sample of shiftworking nurses. Responses were obtained from 1202 nurses working at university hospitals in Tokyo, Japan, including 727 two-shift workers and 315 three-shift workers. The questionnaire included items relevant to age, gender, family structure, work environment, health-related quality of life (QOL), diurnal type, depressive symptoms, and SWD. Participants who reported insomnia and/or excessive sleepiness for at least 1 mo that was subjectively relevant to their shiftwork schedules were categorized as having SWD. The prevalence of SWD in the sampled shiftworking nurses was 24.4%; shiftworking nurses with SWD showed lower health-related QOL and more severe depressive symptoms, with greater rates of both actual accidents/errors and near misses, than those without SWD. The results of logistic regression analyses showed that more time spent working at night, frequent missing of nap opportunities during night work, and having an eveningness-oriented chronotype were significantly associated with SWD. The present study indicated that SWD might be associated with reduced health-related QOL and decreased work performance in shiftworking nurses on rapid-rotation schedules. The results also suggested that missing napping opportunities during night work, long nighttime working hours, and the delay of circadian rhythms are associated with the occurrence of SWD among shiftworking nurses on rapid-rotation schedules.

Mars 520-d mission simulation reveals protracted crew hypokinesis and alterations of sleep duration and timing.

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.

Sleep-Wake profiles in patients with primary biliary cirrhosis.

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.

Appetite-regulating hormones from the upper gut: disrupted control of xenin and ghrelin in night workers.

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.

Evaluating the links between schizophrenia and sleep and circadian rhythm disruption.

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.

The circadian mutation PER2(S662G) is linked to cell cycle progression and tumorigenesis.

Circadian oscillation and cell cycle progression are the two most essential rhythmic events present in almost all organisms. Circadian rhythms keep track of time and provide temporal regulation with a period of about 24 h. The cell cycle is optimized for growth and division, but not for time keeping. Circadian gated cell divisions are observed in nearly all organisms. However, the implications of this coupling to the physiology of mammals are unknown. A mutation (S662G) in the clock protein PERIOD2 (PER2) is responsible for familial advanced sleep phase syndrome in which sleep onset occurs in the early evening and wakefulness occurs in the early morning. Here, we provide evidence that the PER2(S662) mutation leads to enhanced resistance to X-ray-induced apoptosis and increased E1A- and RAS-mediated oncogenic transformation. Accordingly, the PER2(S662) mutation affects tumorigenesis in cancer-sensitized p53(R172H/+) mice. Finally, analyzing the clock-controlled cell cycle genes p21, c-Myc, Cyclin D1 and p27, we found that the relative phases between p21 and Cyclin D expression profiles have been changed significantly in these Per2 allele mutant mouse embryonic fibroblasts. This key role of the Per2-mediated phase alteration of p21 provides what we believe to be a novel mechanism in understanding cell cycle progression, its plasticity and its resistance to interference.