Dysregulation Of Circadian Rhythms Research Articles

Is the Circadian Rhythm Dysregulation a Core Pathogenetic Mechanism of Bipolar Disorder?

Is the Circadian Rhythm Dysregulation a Core Pathogenetic Mechanism of Bipolar Disorder?

Delirium pathophysiology: An updated hypothesis of the etiology of acute brain failure.

Delirium is the most common neuropsychiatric syndrome encountered by clinicians dealing with older adults and the medically ill and is best characterized by 5 core domains: cognitive deficits, attentional deficits, circadian rhythm dysregulation, emotional dysregulation, and alteration in psychomotor functioning. An extensive literature review and consolidation of published data into a novel interpretation of known pathophysiological causes of delirium. Available data suggest that numerous pathological factors may serve as precipitants for delirium, each having differential effects depending on patient-specific patient physiological characteristics (substrate). On the basis of an extensive literature search, a newly proposed theory, the systems integration failure hypothesis, was developed to bring together the most salient previously described theories, by describing the various contributions from each into a complex web of pathways-highlighting areas of intersection and commonalities and explaining how the variable contribution of these may lead to the development of various cognitive and behavioral dysfunctions characteristic of delirium. The specific cognitive and behavioral manifestations of the specific delirium picture result from a combination of neurotransmitter function and availability, variability in integration and processing of sensory information, motor responses to both external and internal cues, and the degree of breakdown in neuronal network connectivity, hence the term acute brain failure. The systems integration failure hypothesis attempts to explain how the various proposed delirium pathophysiologic theories interact with each other, causing various clinically observed delirium phenotypes. A better understanding of the underlying pathophysiology of delirium may eventually assist in designing better prevention and management approaches.

(-)-Epigallocatechin-3-gallate Ameliorates Insulin Resistance and Mitochondrial Dysfunction in HepG2 Cells: Involvement of Bmal1.

Normal physiological processes require a robust biological timer called the circadian clock. Dysregulation of circadian rhythms contributes to a variety of metabolic syndrome, including obesity and insulin resistance. (-)-Epigallocatechin-3-gallate (EGCG) has been demonstrated to possess antioxidant, anti-inflammatory, and cardioprotective bioactivities. The objective of this study was to explore whether the circadian clock is involved in the protective effect of EGCG against insulin resistance. The results demonstrated that EGCG reverses the relatively shallow daily oscillations of circadian clock genes transcription and protein expression induced by glucosamine in HepG2 cells. EGCG also alleviates insulin resistance by enhancing tyrosine phosphorylated levels of IRS-1, stimulating the translocation of GLUT2, and activating PI3K/AKT as well as AMPK signaling pathways in a Bmal1-dependent manner both in HepG2 cells and primary hepatocytes. Glucosamine-stimulated excessive secretions of ROS and depletions of mitochondrial membrane potential were notably attenuated in EGCG co-treated HepG2 cells, which consistent with the recovery in expression of mitochondrial respiration complexes. The results demonstrated that EGCG possesses a Bmal1-dependent efficacy against insulin resistance conditions by strengthening the insulin signaling and eliminating oxidative stress, suggesting that EGCG may serve as a promising natural nutraceutical for the regulation of metabolic disorders relevant to circadian clocks.

Tea polyphenols ameliorates neural redox imbalance and mitochondrial dysfunction via mechanisms linking the key circadian regular Bmal1

Circadian rhythms are autonomous anticipatory oscillators that control a large array of physiological and metabolic processes. Compelling evidence points toward an interplay between circadian rhythms and cellular redox metabolism. Dysregulation of circadian rhythms is associated with neurodegenerative diseases and accelerated aging. Tea polyphenols (TP) is one of the most used antioxidants and exerts beneficial effect on neurodegenerative diseases. The aim of this study is to investigate whether circadian clock mechanisms are involved in the protection effect of TP against neural redox imbalance and mitochondrial dysfunction in SH-SY5Y cells. In the current study, our results revealed that TP, as a Bmal1-enhancing natural compound, can reverse the relatively shallow daily oscillations of circadian clock genes transcription and protein expression in SH-SY5Y neuronal cells under oxidative stress conditions. Furthermore, TP pretreatment significantly ameliorated H2O2-elicited mitochondria impairment via manipulating mitochondrial dynamics and mitochondrial membrane potential, which is consistent with the recovery in expression of mitochondrial respiration complex I-IV in Bmal1-dependent efficiency. Furthermore, Bmal1 is involved in TP-stimulated Nrf2/ARE/HO-1 and AKT/CREB/BDNF signaling pathway. Hence, TP may serve as a nutritional preventive strategy in the recovery of oxidative stress-related neurodegenerative disease via modulating circadian clock.

Impaired response of the bronchial epithelium to inflammation characterizes severe equine asthma

BackgroundSevere equine asthma is a naturally occurring lung inflammatory disease of mature animals characterized by neutrophilic inflammation, bronchoconstriction, mucus hypersecretion and airway remodeling. Exacerbations are triggered by inhalation of dust and microbial components. Affected animals eventually are unable of aerobic performance. In this study transcriptomic differences between asthmatic and non-asthmatic animals in the response of the bronchial epithelium to an inhaled challenge were determined.ResultsPaired endobronchial biopsies were obtained pre- and post-challenge from asthmatic and non-asthmatic animals. The transcriptome, determined by RNA-seq and analyzed with edgeR, contained 111 genes differentially expressed (DE) after challenge between horses with and without asthma, and 81 of these were upregulated. Genes involved in neutrophil migration and activation were in central location in interaction networks, and related gene ontology terms were significantly overrepresented. Relative abundance of specific gene products as determined by immunohistochemistry was correlated with differential gene expression. Gene sets involved in neutrophil chemotaxis, immune and inflammatory response, secretion, blood coagulation and apoptosis were overrepresented among up-regulated genes, while the rhythmic process gene set was overrepresented among down-regulated genes. MMP1, IL8, TLR4 and MMP9 appeared to be the most important proteins in connecting the STRING protein network of DE genes.ConclusionsSeveral differentially expressed genes and networks in horses with asthma also contribute to human asthma, highlighting similarities between severe human adult and equine asthma. Neutrophil activation by the bronchial epithelium is suggested as the trigger of the inflammatory cascade in equine asthma, followed by epithelial injury and impaired repair and differentiation. Circadian rhythm dysregulation and the sonic Hedgehog pathway were identified as potential novel contributory factors in equine asthma.

Dietary tea polyphenols ameliorate metabolic syndrome and memory impairment via circadian clock related mechanisms

SCOPECircadian rhythms allow organisms to anticipate and exploit daily environmental changes, and food components can adjust internal rhythms in peripheral tissues or even suprachiasmatic nucleus. Dysregulation of circadian rhythms is associated with many pathological conditions. The aim of the current study is to determine potential effects of tea polyphenols on modulating circadian rhythms regarding ameliorating diabetes, metabolic syndrome, and memory disorders. ResultsResults demonstrated that tea polyphenols can reverse the relatively shallow daily oscillations of circadian clock genes transcription and protein expression in both liver and hypothalamus triggered by constant darkness. These compounds also alleviate insulin resistance and disorder of glucose/lipid metabolism in constant darkness-treated mice. Concomitantly, tea polyphenols prevented constant darkness-induced memory impairment by inhibiting neuron damage and elevating the expression of neurotropic factor related genes. ConclusionTea polyphenols supplementation might serve as future strategies to combat obesity, metabolic syndrome and cognitive disorder induced by circadian dysfunction.

Sleep quality and duration in relation to memory in the elderly: Initial results from the Hellenic Longitudinal Investigation of Aging and Diet

BackgroundSleep is crucial for cognition, particularly for memory, given its complex association with neurodegenerative processes. The aim of the present study was to examine the association between sleep quality as well as sleep duration and memory performance in a Greek elderly population. SettingCross-sectional design in the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD), a population representative study of Greek elderly (65years or older). MethodsData from 1589 participants free of sleep medication were included. Sleep quality was estimated by using the Sleep Scale from the Medical Outcomes Study. An extensive neuropsychological assessment examining memory was administered to each participant. Linear regression analyses were used to examine whether sleep quality (higher score, poor quality) and/or sleep duration were associated with memory expressed in the form of a z-score. Age, sex, education, and body mass index were included as covariates. The main analyses were conducted first on the total sample, then with the exclusion of demented participants, and finally with the exclusion of both demented and participants with Mild Cognitive Impairment (MCI). We then conducted further analyses on the non-demented, non-MCI group, initially stratified by Apolipoprotein E-ε4 gene. We further examined the role of co-morbidities, as well as the association between sleep duration groups and memory. We also explored any interaction effect between sex and sleep quality/duration on memory. We then examined the associations between components of sleep measures and memory scores. Lastly, we examined the associations between sleep quality/duration and verbal/non-verbal memory separately. ResultsIn the total sample, we noted significant associations between sleep duration and memory (B=−0.001, p≤0.0001), but not for sleep quality and memory (B=−0.038, p=0.121). After excluding the demented participants, the associations were significant for: sleep quality and memory (B=−0.054, p=0.023), and sleep duration and memory (B=−0.001, p≤0.0001). After excluding both the MCI and the demented subjects, the associations between sleep quality and memory (B=−0.065, p=0.006), and sleep duration and memory (B=−0.001, p=0.003) were still significant. The association between the sleep duration groups and memory function was also significant, such that poor memory performance was associated with the longer sleep duration group. The results remained significant even after controlling for the co-morbidities, as well as after adding in the model anxiety and depression as covariates. Associations between sleep quality and memory, and sleep duration and memory were present in the ApoE-ε4 non-carriers. The individual sleep questions that were probably shown to be driving the associations between sleep and memory were: time to fall asleep, sleep not quiet, getting enough sleep to feel rested upon waking in the morning, and getting the amount of sleep needed. Sleep duration was associated with both verbal and non-verbal memory, while sleep quality was only associated with verbal memory. ConclusionPoor sleep quality and longer sleep duration were linked to low memory performance, independent of demographic and clinical factors, in a large sample of cognitively healthy older Greek adults. Other parameters than sleep and memory measurements could play an important role on the association. Levels of melatonin, or circadian rhythms dysregulation might play a crucial role in the above associations.

Circadian Rhythm Dysregulation in Bipolar Spectrum Disorders.

We review recent evidence for circadian rhythm dysregulation in bipolar spectrum disorders (BSDs). We examine evidence for endogenous abnormalities in the biological clock and disruptions in the external entrainment of circadian rhythms in BSDs. We also address whether circadian dysregulation provides vulnerability to onset of BSD and evidence for a new integration of reward and circadian dysregulation in BSD. Relative circadian phase delay (e.g., later melatonin peak, evening chronotype) is associated with BSD, particularly in the depressive phase. More consistent evidence supports irregularity of social rhythms, sleep/wake and activity patterns, and disruptions of social rhythms by life events, as stable trait markers of BSD and potential vulnerabilities for BSD onset. Growing research supports an integrative reward/circadian model. Both endogenous abnormalities in the biological clock pacemaking function and disruptions in the external entrainment of circadian rhythms by physical and social cues are involved in BSDs. Circadian dysregulation may provide vulnerability to BSD onset.

Age-related desynchronosis in primary open-angle glaucoma patients: cause or consequence? Correction possibilities

Purpose of this investigation was to study the circadian biologic rhythm dysregulation of intraocular pressure (IOP), blood pressure (BP), and heart rate (HR) in primary open-angle glaucoma (POAG) patients of different age groups. Objectives: to reveal the desynchronosis pattern of biologic rhythm parameters in POAG patients, to study the influence of peptide bioregulatory complex on the synchronization of chosen parameters, to investigate correction possibilities from the perspective of the optic nerve tolerance enhancement, ischemia decrease and ocular perfusion improvement.Materials and methods. At the first stage, we performed a representative selection of patients with BP, HR and IOP dysregulation among POAG patients and subjects without glaucoma of corresponding age (n = 330). For mathematic justification of the desynchronosis identification, we used cosinor-analysis of circadian changes of functional indices. At the second stage, we performed a randomized study with parallel comparison groups masked for the investigator estimating the results. Patients with revealed desynchronosis (n = 56) were randomly divided into two groups for comparison. The main group consisted of 27 patients who, in addition to systemic and local pressure-lowering therapy, received 1 tablet of epifamin (Longvi-Farm, Russia) 3 times a day for 30 days; сortexin (Geropharm, Russia) 10 mg daily for 10 days; retinalamin (Geropharm, Russia) 5 mg daily as peribulbar injections for 10 days. 29 control group patients received traditional treatment (vitamins, spasmolytics, antioxydants) together with local and systemic pressure-lowering therapy. In compared groups, we calculated the tolerant pressure level, investigated the dynamics of retinal sensitivity mean deviation (MD), registrated the oscillatory potentials (OP) with the OP index calculation.Results. In elderly patients with glaucoma, significant changes of the temporal order of physiological parameters were found (deviation of IOP daily rhythm curves, systolic blood pressure (SBP), diastolic blood pressure (DBP), and hemodynamic indices).Conclusion. Through hemodynamic, nootropic, neurotrophic effects of the investigated bioregulatory peptide complex, the optic nerve tolerance to the stress influence of IOP, SBP and DBP asynchronous fluctuations increased, and ocular perfusion enhanced.

School start time influences melatonin and cortisol levels in children and adolescents – a community-based study

ABSTRACTSchool start time influences sleep parameters. Differences between circadian sleep parameters on weekends and weekdays have been associated with obesity, sleep, and psychiatric disorders. Moreover, circadian rhythm dysregulation affects the secretion of some hormones, such as melatonin and cortisol. In the current study, we investigate the effect of school start time on cortisol and melatonin levels in a community sample of Brazilian children and adolescents. This was a cross-sectional study of 454 students (mean age, 12.81 ± 2.56 years; 58.6% female). From this sample, 80 participants were randomly selected for saliva collection to measure melatonin and cortisol levels. Circadian sleep parameters were assessed by self-reported sleep and wake up schedules and the Morningness–Eveningness Questionnaire. The outcomes, salivary melatonin and cortisol levels, were measured in morning, afternoon and night saliva samples, and behavior problems were assessed using the Child Behavior Checklist (CBCL). The main results revealed that morning school start time decreased the secretion of melatonin. Morning melatonin levels were significantly positively correlated with the sleep midpoint on weekdays and on weekends. Afternoon melatonin levels were positively correlated with the sleep midpoint on weekends in the morning school students. Conversely, in the afternoon school students, night melatonin levels were negatively correlated with the sleep midpoint on weekdays. Cortisol secretion did not correlate with circadian sleep parameters in any of the school time groups. In conclusion, school start time influences melatonin secretion, which correlated with circadian sleep parameters. This correlation depends on the presence of psychiatric symptoms. Our findings emphasize the importance of drawing attention to the influence of school start time on the circadian rhythm of children and adolescents.

The Small Molecule Nobiletin Targets the Molecular Oscillator to Enhance Circadian Rhythms and Protect against Metabolic Syndrome

Dysregulation of circadian rhythms is associated with metabolic dysfunction, yet it is unclear whether enhancing clock function can ameliorate metabolic disorders. In an unbiased chemical screen using fibroblasts expressing PER2::Luc, we identified Nobiletin (NOB), a natural polymethoxylated flavone, as a clock amplitude-enhancing small molecule. When administered to diet-induced obese (DIO) mice, NOB strongly counteracted metabolic syndrome and augmented energy expenditure and locomotor activity in a Clock gene-dependent manner. In db/db mutant mice, the clock is also required for the mitigating effects of NOB on metabolic disorders. In DIO mouse liver, NOB enhanced clock protein levels and elicited pronounced gene expression remodeling. We identified retinoid acid receptor-related orphan receptors as direct targets of NOB, revealing a pharmacological intervention that enhances circadian rhythms to combat metabolic disease via the circadian gene network.

Diurnal Corticosterone Presence and Phase Modulate Clock Gene Expression in the Male Rat Prefrontal Cortex.

Mood disorders are associated with dysregulation of prefrontal cortex (PFC) function, circadian rhythms, and diurnal glucocorticoid (corticosterone [CORT]) circulation. Entrainment of clock gene expression in some peripheral tissues depends on CORT. In this study, we characterized over the course of the day the mRNA expression pattern of the core clock genes Per1, Per2, and Bmal1 in the male rat PFC and suprachiasmatic nucleus (SCN) under different diurnal CORT conditions. In experiment 1, rats were left adrenal-intact (sham) or were adrenalectomized (ADX) followed by 10 daily antiphasic (opposite time of day of the endogenous CORT peak) ip injections of either vehicle or 2.5 mg/kg CORT. In experiment 2, all rats received ADX surgery followed by 13 daily injections of vehicle or CORT either antiphasic or in-phase with the endogenous CORT peak. In sham rats clock gene mRNA levels displayed a diurnal pattern of expression in the PFC and the SCN, but the phase differed between the 2 structures. ADX substantially altered clock gene expression patterns in the PFC. This alteration was normalized by in-phase CORT treatment, whereas antiphasic CORT treatment appears to have eliminated a diurnal pattern (Per1 and Bmal1) or dampened/inverted its phase (Per2). There was very little effect of CORT condition on clock gene expression in the SCN. These experiments suggest that an important component of glucocorticoid circadian physiology entails CORT regulation of the molecular clock in the PFC. Consequently, they also point to a possible mechanism that contributes to PFC disrupted function in disorders associated with abnormal CORT circulation.

Development of hypertension – clinical impact of dysregulation of circadian rhythms and implications for treatment

Development of hypertension – clinical impact of dysregulation of circadian rhythms and implications for treatment Kristen Solocinski,1,2 Michelle L Gumz1,2 1Department of Medicine, 2Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL, USA Abstract: Blood pressure, like most physiological processes, exhibits a circadian pattern of variation. Disruption of the normal circadian rhythm of blood pressure is associated with end organ damage and increased risk of adverse cardiovascular outcomes. In this review, we discuss the role of the renin angiotensin aldosterone system and the molecular clock in maintaining circadian blood pressure patterns. We also consider disrupted circadian blood pressure rhythms and hypertension in distinct populations and the role of chronotherapy in the treatment of hypertension. Keywords: clock, kidney, adrenal, aldosterone, chronotherapy, sleep

The development and course of bipolar spectrum disorders: an integrated reward and circadian rhythm dysregulation model.

In this article, we present and review the evidence for two major biopsychosocial theories of the onset and course of bipolar spectrum disorders (BSDs) that integrate behavioral, environmental, and neurobiological mechanisms: the reward hypersensitivity and the social/circadian rhythm disruption models. We describe the clinical features, spectrum, age of onset, and course of BSDs. We then discuss research designs relevant to demonstrating whether a hypothesized mechanism represents a correlate, vulnerability, or predictor of the course of BSDs, as well as important methodological issues. We next present the reward hypersensitivity model of BSD, followed by the social/circadian rhythm disruption model of BSD. For each model, we review evidence regarding whether the proposed underlying mechanism is associated with BSDs, provides vulnerability to the onset of BSDs, and predicts the course of BSDs. We then present a new integrated reward/circadian rhythm (RCR) dysregulation model of BSD and discuss how the RCR model explains the symptoms, onset, and course of BSDs. We end with recommendations for future research directions.

Living a healthier lifestyle.

The roles of diet, activity, and exercise have long been recognized as essential to a healthy lifestyle. As Plato stated, “Lack of activity destroys the good condition of every human being, while movement and methodical physical exercise save it and preserve it.” In his Physiology is Medicine

Circadian abnormalities in a mouse model of high trait anxiety and depression

Introduction. Dysregulation of circadian rhythms is a key symptom of mood disorders, including anxiety disorders and depression. Whether the circadian abnormalities observed in depressed patients are cause or consequence of the disease remains elusive. Here we aimed to explore potential disturbances of circadian rhythms in a validated genetic animal model of high trait anxiety and co-morbid depression and examine its molecular correlates.Materials and methods. Mice selectively bred for high (HAB) and normal (NAB) anxiety- and co-segregating depression-like behavior were subjected to analysis of circadian wheel-running activity to determine light-entrained (LD) and free-running circadian (DD) rhythms and a light-induced phase shift. Clock gene expression in HAB/NAB hippocampal tissue was analyzed by qRT-PCR and verified by Western blotting.Results. Compared to NABs, HAB mice were found to present with altered DD length of daily cycle, fragmented ultradiem rhythms, and a blunted phase shift response. Clock gene expression analysis revealed a selective reduction of Cry2 expression in hippocampal tissue of HAB mice.Discussion. We provide first evidence for a dysregulation of circadian rhythms in a mouse model of anxiety and co-morbid depression which suggests an association between depression and altered circadian rhythms at the genetic level and points towards a role for Cry2.

RNA-sequencing of the brain transcriptome implicates dysregulation of neuroplasticity, circadian rhythms and GTPase binding in bipolar disorder

RNA-sequencing (RNA-seq) is a powerful technique to investigate the complexity of gene expression in the human brain. We used RNA-seq to survey the brain transcriptome in high-quality postmortem dorsolateral prefrontal cortex from 11 individuals diagnosed with bipolar disorder (BD) and from 11 age- and gender-matched controls. Deep sequencing was performed, with over 350 million reads per specimen. At a false discovery rate of <5%, we detected five differentially expressed (DE) genes and 12 DE transcripts, most of which have not been previously implicated in BD. Among these, Prominin 1/CD133 and ATP-binding cassette-sub-family G-member2 (ABCG2) have important roles in neuroplasticity. We also show for the first time differential expression of long noncoding RNAs (lncRNAs) in BD. DE transcripts include those of serine/arginine-rich splicing factor 5 (SRSF5) and regulatory factor X4 (RFX4), which along with lncRNAs have a role in mammalian circadian rhythms. The DE genes were significantly enriched for several Gene Ontology categories. Of these, genes involved with GTPase binding were also enriched for BD-associated SNPs from previous genome-wide association studies, suggesting that differential expression of these genes is not simply a consequence of BD or its treatment. Many of these findings were replicated by microarray in an independent sample of 60 cases and controls. These results highlight common pathways for inherited and non-inherited influences on disease risk that may constitute good targets for novel therapies.

Skin, Reactive Oxygen Species, and Circadian Clocks

Skin, a complex organ and the body's first line of defense against environmental insults, plays a critical role in maintaining homeostasis in an organism. This balance is maintained through a complex network of cellular machinery and signaling events, including those regulating oxidative stress and circadian rhythms. These regulatory mechanisms have developed integral systems to protect skin cells and to signal to the rest of the body in the event of internal and environmental stresses. Interestingly, several signaling pathways and many bioactive molecules have been found to be involved and even important in the regulation of oxidative stress and circadian rhythms, especially in the skin. It is becoming increasingly evident that these two regulatory systems may, in fact, be interconnected in the regulation of homeostasis. Important examples of molecules that connect the two systems include serotonin, melatonin, vitamin D, and vitamin A. Excessive reactive oxygen species and/or dysregulation of antioxidant system and circadian rhythms can cause critical errors in maintaining proper barrier function and skin health, as well as overall homeostasis. Unfortunately, the modern lifestyle seems to contribute to increasing alterations in redox balance and circadian rhythms, thereby posing a critical problem for normal functioning of the living system. Since the oxidative stress and circadian rhythm systems seem to have areas of overlap, future research needs to be focused on defining the interactions between these two important systems. This may be especially important in the skin where both systems play critical roles in protecting the whole body.

Circadian regulation of renal function and potential role in hypertension

Previous studies have shown that a variety of specific renal functions exhibit circadian oscillations. This review aims to provide an update on the molecular mechanisms underlying circadian rhythms in the kidney, and to discuss how dysregulation of circadian rhythms can interfere with kidney function. The molecular mechanism responsible for generating and maintaining circadian rhythms has been unraveled in great detail. This mechanism, known as the circadian clock, drives circadian oscillation in expression levels of a large number of renal mRNA transcripts. Several proteins critically involved in renal homeostatic functions have been shown to exhibit significant circadian oscillation in their expression levels or in their posttranslational modifications. In transgenic mouse models, disruption of circadian clock activity results in dramatic changes in the circadian pattern of urinary sodium and potassium excretion and causes significant changes in arterial blood pressure. A growing amount of evidence suggests that dysregulation of circadian rhythms is associated with the development of hypertension and accelerated progression of chronic kidney disease and cardiovascular disease in humans. Chronotherapy studies have shown that the efficacy of antihypertensive medication is greatly dependent on the circadian time of drug administration. Recent research points to the major role of circadian rhythms in renal function and in control of blood pressure.

Sleep and circadian rhythm dysregulation in schizophrenia

Sleep-onset and maintenance insomnia is a common symptom in schizophrenic patients regardless of either their medication status (drug-naive or previously treated) or the phase of the clinical course (acute or chronic). Regarding sleep architecture, the majority of studies indicate that non-rapid eye movement (NREM), N3 sleep and REM sleep onset latency are reduced in schizophrenia, whereas REM sleep duration tends to remain unchanged. Many of these sleep disturbances in schizophrenia appear to be caused by abnormalities of the circadian system as indicated by misalignments of the endogenous circadian cycle and the sleep-wake cycle. Circadian disruption, sleep onset insomnia and difficulties in maintaining sleep in schizophrenic patients could be partly related to a presumed hyperactivity of the dopaminergic system and dysfunction of the GABAergic system, both associated with core features of schizophrenia and with signaling in sleep and wake promoting brain regions. Since multiple neurotransmitter systems within the CNS can be implicated in sleep disturbances in schizophrenia, the characterization of the neurotransmitter systems involved remains a challenging dilemma.