Circadian Disturbances Research Articles

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

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

El control circadiano de la alimentación

Eating is a complex behavior that is primarily governed by energy homeostasis and modulated by hedonic cues. Eating is also structured in time, due to circadian clocks that control its daily rhythmicity. These circadian clocks are organized into a network of several oscillating structures, including a master clock in the suprachiasmatic nuclei of the hypothalamus and several secondary clocks in the brain and peripheral organs. The light-entrainable master clock is a conductor for the secondary clocks via neuroendocrine signals. In contrast to the master clock, most secondary clocks are sensitive to the synchronizing effect of meal time. Besides controlling the daily feeding/fasting cycle, several coupled secondary clocks in the brain defining a so-called “food clock” also adjust the timing of meal anticipation, a rhythmic behavior that mammals exhibit right before scheduled feeding time. There are reciprocal interactions between energy metabolism and circadian rhythmicity. On the one hand, metabolic alterations, like obesity and type 2 diabetes, are frequently associated with circadian disturbances. On the other hand, circadian disturbances have deleterious effects on metabolic health. Feeding cues, such as meal timing, nature of the diet and quantity of ingested food, are strongly involved in these circadian disturbances. For instance, eating many calories at the “wrong” phase of the living cycle (e.g., at night for humans or during daytime in nocturnal animals) has obesogenic consequences. Besides management of total energy intake and expenditure, experimental evidence is given to show that daily timing of calorie intake, duration of eating window, together with a long enough nocturnal fasting are newly identified actors of energy balance. Accordingly, new nutritional strategies should be developed based on personalized chrononutrition.

Effect of a dynamic lighting intervention on circadian rest-activity disturbances in cognitively impaired, older adults living in a nursing home: A proof-of-concept study

Development of non-pharmacological interventions to improve disrupted rest-activity patterns and disturbed behavior in people with dementia is an important research goal. Here we report a proof-of-concept study which evaluates the effect and applicability of a dynamic light intervention to improve rest-activity patterns in cognitively impaired, institutionalized, older adults. The study was a randomized, open-label, proof-of-concept trial of limited sample size conducted at a nursing home for older adults in a non-metropolitan area in Denmark. Participants were 24 older nursing home residents with cognitive deficiencies. Equipment for delivery of a specialized dynamic light intervention was installed in the private apartments (within the nursing home) of the residents in the experimental group (N = 12). Study duration was four weeks. The control group (N = 12) was exposed to conventional lighting. We measured activity and rest using actigraphy, functional disability, behavioral disturbances, and time in bed We performed regression analyses to examine differences between the intervention groups. Participants in the experimental group partially improved on one of three diurnal rhythm variables, but otherwise no differences were observed between the two intervention groups. The improvement was found for the intradaily variability during the first part of the intervention period indicating a more stable and less fragmented 24-h rest-activity rhythm. However, availability of staff assistance in response to impaired physical mobility of the residents seemed to be a stronger determinant of activity level and pattern. The examined intervention showed promising results but did not consistently alter circadian rest-activity patterns in older nursing home residents given the current sample size. Future studies in the field need to consider real-life applicability of the experimental intervention and the interaction and importance of other important zeitgebers than light.

PER2-mediated ameloblast differentiation via PPAR\u03b3/AKT1/\u03b2-catenin axis

Circadian rhythm is involved in the development and diseases of many tissues. However, as an essential environmental regulating factor, its effect on amelogenesis has not been fully elucidated. The present study aims to investigate the correlation between circadian rhythm and ameloblast differentiation and to explore the mechanism by which circadian genes regulate ameloblast differentiation. Circadian disruption models were constructed in mice for in vivo experiments. An ameloblast-lineage cell (ALC) line was used for in vitro studies. As essential molecules of the circadian system, Bmal1 and Per2 exhibited circadian expression in ALCs. Circadian disruption mice showed reduced amelogenin (AMELX) expression and enamel matrix secretion and downregulated expression of BMAL1, PER2, PPARγ, phosphorylated AKT1 and β-catenin, cytokeratin-14 and F-actin in ameloblasts. According to previous findings and our study, BMAL1 positively regulated PER2. Therefore, the present study focused on PER2-mediated ameloblast differentiation and enamel formation. Per2 knockdown decreased the expression of AMELX, PPARγ, phosphorylated AKT1 and β-catenin, promoted nuclear β-catenin accumulation, inhibited mineralization and altered the subcellular localization of E-cadherin in ALCs. Overexpression of PPARγ partially reversed the above results in Per2-knockdown ALCs. Furthermore, in in vivo experiments, the length of incisor eruption was significantly decreased in the circadian disturbance group compared to that in the control group, which was rescued by using a PPARγ agonist in circadian disturbance mice. In conclusion, through regulation of the PPARγ/AKT1/β-catenin signalling axis, PER2 played roles in amelogenin expression, cell junctions and arrangement, enamel matrix secretion and mineralization during ameloblast differentiation, which exert effects on enamel formation.

Sleep disorders and main determinants among hospital staffs in a referral hospital in Iran

Introduction: The prevalence rate of sleep disorders among hospital staff is expected to high due to shift work and its related circadian cycle disturbance. Complexity, high prevalence, and health implications related to sleep disorders are of great importance. Objectives: The present study aimed to assess the prevalence and main determinants of sleep disorders among hospital staff. Patients and Methods: This cross-sectional study was performed on 200 head nurses, nurses, midwives, operating room technicians, health care providers, service staffs of all departments, and physicians at Shaheed Rajaei hospital in Tonekabon city, Iran in 2015. The questionnaire which assessed the sleep disturbances was sourced from four scaling systems of Global Sleep Assessment Questionnaire (GSAQ), insomnia severity index (ISI), Pittsburgh Sleep Quality Index (PSQI), and Fatigue Severity Scale (FSS). Results: According to the assessment by the study adopted questionnaire, 78% (78.6% of males and 77.8% of females) suffered from work-related sleep disorders. Regarding association between work shifts and likelihood of sleep disorders, it was shown a significantly higher rate of sleep disturbances in the staffs with morning and evening shifts (100%), morning and night shifts (100%), or evening and night shifts (100%), simultaneously (P<0.001). Marital status, work experience, and gender could not affect sleep quality. Conclusion: Most of the hospital staff especially practical nurses and nurses suffered from sleep disturbances. Simultaneous and multi-sectional work shifts lead to higher likelihood of sleep problem among staffs.

Brain Tumours Involving the Areas of the Circadian System Result in Disturbances in Melatonin Secretion, Fatigue and Poor Quality of Life

Background: Sleep disturbances, circadian abnormalities and poor health are often reported in children with brain tumours. The objective of this study was to examine circadian function, sleep pattern, fatigue and mental health in these children. We hypothesized that children with tumours involving the areas of the circadian system have altered melatonin secretion. Design: Cross-sectional study. Methods: 309 children diagnosed with a tumour in the brain or cervical medulla and aged ≤18 years were identified, 174 met the inclusion criteria, and 68 consented to participate. They were divided according to their tumour location into 1) location involving the areas of the circadian system, i.e. diencephalon, pineal gland, brain stem and cervical medulla and 2) other areas. Sleep-wake patterns were assessed by two weeks of sleep diary recordings and actigraphy in 66 and 61 children, respectively. Diurnal saliva-melatonin levels were measured in 51 children. Sleep quality, fatigue and mental health were assessed in 65 children by Children’s Sleep Habits Questionnaire, Strengths and Difficulties Questionnaire and Pediatric Quality of Life Inventory, Multidimensional Fatigue Scale and Generic Core Scale. Results: All children had normal sleep-wake patterns without significant between-group differences. The children with tumours involving the areas of the circadian system had lower melatonin peak levels (p=0.03) and a tendency of lower levels at 00 h and 04 h (all p=0.06). Three patterns of diurnal melatonin profiles were observed: Normal, low peak and phase-shifted peak. In comparison of the two patient groups, more children with tumours involving the areas of the circadian system had melatonin profiles with low peak values (29% vs 13%) and one had phase-shifted peak (3% vs 0%), although not significant. These children were more affected by mental problems (p<0.01), more cognitive fatigued (p=0.03) and had poorer quality of life (p=0.01) than children with tumours located elsewhere. Conclusion: Children with tumours affecting the areas of the circadian system including the diencephalon, pineal gland, brain stem and cervical medulla have altered melatonin secretion, are fatigued, have poor mental health and poor quality of life. Circadian disturbances may adversely affect health and have negative psychological impact.

623 Melatonin Use in the Pediatric Intensive Care Unit: 5 year single center experience

Abstract Introduction Pediatric patients requiring intensive care are at risk for unavoidable sleep and circadian disturbances because of the frequency and nature of delivering care for severe illness in this setting. There is growing appreciation for sleep as an essential component for neuropsychological and physical health. While exogenous influences (light and noise) and endogenous evaluation (melatonin levels) have been evaluated in this setting, there has not yet been investigation of current practice for exogenously administered melatonin in the pediatric intensive care unit (PICU). We aimed to evaluate baseline practice and changes in melatonin administration after implementation of delirium education. Methods In 2018, pediatric delirium education was implemented and included identification of sleep disturbance. A 5-year retrospective chart review (3-years baseline and 2-years after delirium education) was completed based on a pharmacy database that identified all patients who had melatonin administration while in PICU. Each admission was counted as an unique encounter. Data collection included patient age, date of admission, and length of stay (LOS). Data for melatonin included dose, starting date, duration of treatment (number of days), and indication. Indications for melatonin were (1) delirium, (2) insomnia, (3) circadian sleep wake disorder, (4) previous home medication, and (5) unable to determine from chart review. Results Over 5 years (2015 – 2020), 182 (6.0%) patients admitted to PICU (average age 9.3 +/- 5.8 years, average LOS 24.9 +/- 56.3 days) were given melatonin (average dose 4.0 +/- 2.3 mg). The most frequent indication for melatonin administration was continuation as a home medication (45.9%) and least frequent was sleep-wake disturbance (3.9%). The percentage of patients given melatonin as compared to total PICU admissions, nearly doubled from 4.4% in baseline group to 8.2% in post-delirium-education group. Further, “delirium” as indication for melatonin increased from 5.2% (baseline) to 15.4% (post-education). There were no notable changes for administration indication “insomnia” (18.2% vs 19.2%) or “unknown” (22.1% vs 19.2%). Conclusion This is the first exploratory study to evaluate frequency and indication of melatonin use in the PICU and changes in practice after implementing delirium education. Delirium education that includes sleep disturbance has had significant impact on frequency of melatonin administration. Support (if any):

246 Maintenance of Circadian/Daily Activity Patterns and Cognitive Resilience to Alzheimer’s Pathology in Late Life

Abstract Introduction Many individuals remain free from dementia despite substantial plaque and tangle deposits, the hallmarks of Alzheimer’s disease (AD). Understanding of this cognitive resilience is poor. Evidence suggests that circadian disturbances predict increased risk of incident AD, and that circadian regulation deteriorates as clinical AD progresses. We hypothesize that circadian robustness protects against dementia, and the effect is stronger in individuals with AD pathology than those without. Methods We studied 575 deceased participants (age at death: 91.1□6.2; female: 414) in the Rush Memory and Aging Project who underwent brain autopsy at death, had clinical diagnostic opinion of dementia and motor activity assessments with actigraphy of ~10 days before death. Using actigraphy proximate to death, we calculated four circadian metrics: amplitude, acrophase, interdaily stability, and intradaily variability. Logistic regressions, stratified by postmortem pathologic AD diagnosis, were used to examine associations of circadian metrics with odds of dementia, and separately cognitive impairment (CI, including both dementia and mild cognitive impairment [MCI]), adjusting for age at death, sex, education, and time-lag between actigraphy and death. Results Based on postmortem assessment, 378 participants met the NIA-Reagan criteria for high/intermediate likelihood AD (AD group), including 197 clinically diagnosed with dementia, 86 MCI, and 85 cognitively intact. Non-AD group consisted of the remaining 197 participants, including 36 with clinical dementia, 47 MCI, and 114 cognitively intact. In the AD group, greater amplitude, greater interdaily stability, and lower intradaily variability were associated with lower odds of CI and dementia, i.e., odds ratios [OR] for CI corresponding to 1-SD changes were 0.54 (95% CI: 0.40-0.71), 0.70 (0.54-0.91), and 0.63 (0.47-0.84), and were 0.46 (0.35-0.60), 0.55 (0.43-0.70), and 0.61 (0.48-0.78) for dementia. In the non-AD group, only amplitude was associated with the odds of CI or dementia, i.e., the ORs corresponding to 1-SD increase was 0.61 (0.42-0.88) and 0.50 (0.31-0.82), respectively. Conclusion Better preserved circadian function, as characterized by more pronounced, more stable and less fragmented rest-activity rhythms, links to lower risk of CI or dementia in older people, especially those with pathological AD. Support (if any) NIH RF1AG064312, RF1AG059867, R01AG017917, R01AG56352; and the BrightFocus Foundation A2020886S.

Deciphering the Interacting Mechanisms of Circadian Disruption and Alzheimer's Disease.

Alzheimer's disease (AD) is one of the crucial causative factors for progressive dementia. Neuropathologically, AD is characterized by the extracellular accumulation of amyloid beta plaques and intracellular neurofibrillary tangles in cortical and limbic regions of the human brain. The circadian system is one of the many affected physiological processes in AD, the dysfunction of which may reflect in the irregularity of the sleep/wake cycle. The interplay of circadian and sleep disturbances inducing AD progression is bidirectional. Sleep-associated pathological alterations are frequently evident in AD. Understanding the interrelation between circadian disruption and AD may allow for earlier identification of AD pathogenesis as well as better suited approaches and potential therapies to combat dementia. In this article, we examine the existing literature related to the molecular mechanisms of the circadian clock and interacting mechanisms of circadian disruption and AD pathogenesis.

Metabolic Profiling of Suprachiasmatic Nucleus Reveals Multifaceted Effects in an Alzheimer's Disease Mouse Model.

Background:Circadian rhythm disturbance is commonly observed in Alzheimer’s disease (AD). In mammals, these rhythms are orchestrated by the superchiasmatic nucleus (SCN). Our previous study in the Tg2576 AD mouse model suggests that inflammatory responses, most likely manifested by low GABA production, may be one of the underlying perpetrators for the changes in circadian rhythmicity and sleep disturbance in AD. However, the mechanistic connections between SCN dysfunction, GABA modulation, and inflammation in AD is not fully understood.Objective:To reveal influences of amyloid pathology in Tg2576 mouse brain on metabolism in SCN and to identify key metabolic sensors that couple SCN dysfunction with GABA modulation and inflammation.Methods:High resolution magic angle spinning (HR-MAS) NMR in conjunction with multivariate analysis was applied for metabolic profiling in SCN of control and Tg2576 female mice. Immunohistochemical analysis was used to detect neurons, astrocytes, expression of GABA transporter 1 (GAT1) and Bmal1.Results:Metabolic profiling revealed significant metabolic deficits in SCN of Tg2576 mice. Reductions in glucose, glutamate, GABA, and glutamine provide hints toward an impaired GABAergic glucose oxidation and neurotransmitter cycling in SCN of AD mice. In addition, decreased redox co-factor NADPH and glutathione support a redox disbalance. Immunohistochemical examinations showed low expression of the core clock protein, Bmal1, especially in activated astrocytes. Moreover, decreased expression of GAT1 in astrocytes indicates low GABA recycling in this cell type.Conclusion:Our results suggest that redox disbalance and compromised GABA signaling are important denominators and connectors between neuroinflammation and clock dysfunction in AD.

Is ADHD a sleep disorder? can adhd improve by treating the comorbid sleep disorder(S)? a research update

IntroductionResearch has shown that ADHD and sleep disorders are intimately intertwined in the majority of patients in both childhood and adulthood. Circadian rhythm sleep disturbances, esp. the delayed sleep phase syndrome, as well as several other sleep disorders, such as Insomnia, Restless Legs, Periodic Limb Movement Disorder and Sleep apnea are associated with ADHD. With a prevalence rate of 80% of sleep disorders in adults with ADHD, the question not only is what is chicken and egg, but even if both conditions share a joint pathophysiology.ObjectivesTo investigate the consequences of this comorbid sleep disorders on severity of ADHD, mood and health, as well as to find evidence on improvement of ADHD by treatment of the sleep disorder(s).MethodsRecent research will be evaluated to formulate answers to these questions.ResultsSleep loss resulting from sleep disorders increases ADHD severity due to more impairment of cognition and memory as well as mood instability. Sleep loss in the longer term also leads to obesity, with negative consequences for health in general. First studies showing a decrease of ADHD symptoms by treatment of sleep disorders will be discussed.ConclusionsADHD and sleep disorders come together in the majority of patients and need both assessment and treatment. Treatment of ADHD by improving sleep, is an intriguing research question with potential new treatment options.

Psychological state during pregnancy is associated with sleep quality: preliminary findings from MY-CARE cohort study

ABSTRACT Psychological distress during pregnancy may increase the risk of adverse maternal and infant outcomes. Past studies have demonstrated the association between circadian disturbances with psychological health. However, the roles of chronotype and social jetlag on psychological state during pregnancy are yet to be identified. We aimed to examine the psychological state in pregnant women and its relations to chronotype, social jetlag (SJL), sleep quality and cortisol rhythm. The current study included a subsample of participants from an ongoing cohort study. A total of 179 primigravidas (mean age 28.4 ± 4.0 years) were recruited. Chronotype and sleep quality during the second trimester were assessed using the Morning-Eveningness Questionnaire (MEQ) and Pittsburgh Sleep Quality Index (PSQI), respectively. SJL was calculated based on the difference between mid-sleep on workdays and free days. Psychological state of participants was evaluated using the Depression, Anxiety, and Stress Scale-21 (DASS-21). Subsamples (n = 70) provided salivary samples at 5 time points over a 24 h period during the second trimester for cortisol assay. A higher proportion of pregnant women experienced moderate to severe anxiety symptoms (n = 77, 43.0%), followed by depressive (n = 17, 9.5%) and stress (n = 14, 7.8%) symptoms. No association was observed between chronotype and psychological distress during pregnancy. There was no significant difference in cortisol rhythms in relation to psychological distress. SJL and sleep quality were significantly associated with stress symptoms among pregnant women in the second trimester. Poor sleep quality, particularly daytime dysfunction (β = 0.37, p = .006) and sleep disturbances (β = 0.23, p = .047), were significantly associated with psychological distress (depressive, anxiety and stress symptoms) during the second trimester. The findings suggest that sleep is a potential modifiable lifestyle factor that can be targeted to improve psychological health among pregnant women.

Sleep Abnormalities in Schizophrenia: State of the Art and Next Steps.

Sleep disturbances are commonly observed in schizophrenia, including in chronic, early-course, and first-episode patients. This has generated considerable interest, both in clinical and research endeavors, in characterizing the relationship between disturbed sleep and schizophrenia. Sleep features can be objectively assessed with EEG recordings. Traditionally, EEG studies have focused on sleep architecture, which includes non-REM and REM sleep stages. More recently, numerous studies have investigated alterations in sleep-specific rhythms, including EEG oscillations, such as sleep spindles and slow waves, in individuals with schizophrenia compared with control subjects. In this article, the author reviews state-of-the-art evidence of disturbed sleep in schizophrenia, starting from the relationship between sleep disturbances and clinical symptoms. First, the author presents studies demonstrating abnormalities in sleep architecture and sleep-oscillatory rhythms in schizophrenia and related psychotic disorders, with an emphasis on recent work demonstrating sleep spindles and slow-wave deficits in early-course and first-episode schizophrenia. Next, the author shows how these sleep abnormalities relate to the cognitive impairments in patients diagnosed with schizophrenia and point to dysfunctions in underlying thalamocortical circuits, Ca+ channel activity, and GABA-glutamate neurotransmission. Finally, the author discusses some of the next steps needed to further establish the role of altered sleep in schizophrenia, including the need to investigate sleep abnormalities across the psychotic spectrum and to establish their relationship with circadian disturbances, which in turn will contribute to the development of novel sleep-informed treatment interventions.

Sleep-wake rhythms determined by actigraphy during in-hospital stay following discharge from an intensive care unit.

Sleep and circadian disturbances play a major role in recovery after critical illness. Ample research has shown sleep to be disturbed during the stay at the intensive care unit (ICU); however, the trajectory of sleep after ICU discharge is sparsely described. The current study aimed to describe the development of the sleep-wake rhythm in subjects discharged from ICU to a hospital ward. Following discharge from the ICU to a general hospital ward, the participants were monitored with an ActiGraph for sleep assessment for 7days or until hospital discharge or death. Data were analysed for day-to-day change with t-tests and for the whole period with repeated measures analysis. For the 38 included patients, repeated measures analysis showed no significant improvement in total sleep time and wake time. However, for secondary outcomes, improvements for wake after sleep onset (P=.02) and reduction in the number of naps (P=.03) both in the day-to-day and overall trend analysis were observed. The duration of sleep and wake time did not improve during ward stay. However, sleep became less fragmented and naps during the day declined. Due to the small sample size further, larger trials are needed.

Gangguan Tidur pada Pasien Stroke Fase Akut

Stroke is a condition when a person has a sudden neurological deficit caused by a disruption in the blood vessels of the brain. About 21-77% of stroke patients have sleep disorders that occur after a stroke. The sleep cycle is regulated by the brain and strokes can cause sleep disturbances due to abnormalities that can occur in the brain structures that regulate sleep. Post Stroke Sleep Disoder (PSSD) is the most common symptom after stroke. Sleep disorders after stroke include Sleep Disordered Breathing (SDB), insomnia, circadian rhythm sleep disturbance, hypersomnia, parasomnia and sleep-related movement disorders. Sleep has many benefits, one of which is the restoration of physical and mental functions, the consolidation of memory and improving the learning ability of a person both motorically and sensitively. Other studies have also shown a correlation between electrographic sleep time and cognitive function of stroke patients during recovery. Another experimental study also indicated that sleep disorders can increase the expression of neurocans, which are genes that inhibit nerve growth. Sleep disorders in stroke patients can reduce the efficiency and effectiveness of stroke rehabilitation

Circadian and Sleep Dysfunctions in Neurodegenerative Disorders-An Update.

Disruptions of sleep and circadian rhythms are among the most debilitating symptoms in patients with neurodegenerative diseases. Their underlying pathophysiology is multilayered and multifactorial. Recent evidence suggests that sleep and circadian disturbances may influence the neurodegenerative processes as well as be their consequence. In this perspective, we provide an update of the current understanding of sleep and circadian dysregulation in Alzheimer’s, Parkinson’s, and Huntington’s diseases.

Primary role for melatonin MT2 receptors in the regulation of anhedonia and circadian temperature rhythm

Circadian rhythms disturbance is widely observable in patients with major depression (MD) and is also associated with depression vulnerability. Of them, disturbed melatonin secretion rhythm is particularly relevant to MD and is strongly phase-locked to core body temperature (CBT) rhythm.Here we aim to study the specific role of each melatonin receptor (MT1 and MT2) subtype in melatonin regulation of circadian CBT and its possible relationship with depressive-like behaviors.MT1-/- , MT2-/- and WT (C57BL/6) mice were used. Anhedonia, using the sucrose intake test, circadian CBT, environmental place preference (EPP) conditioning and vulnerability to chronic social defeat stress (CSDS) procedure were studied. Moreover, the antidepressant effects of reboxetine (15 mg/kg/day, i.p.) for three weeks or ketamine (15 mg/kg i.p. every four days, 4 doses in total) were studied. Further, exposure to ultra-mild stress induced by individual housing for several weeks was also studied in these mice.MT2-/- mice showed anhedonia and lower CBT compared to WT and MT1-/-. In addition, while reward exposure raised nocturnal CBT in WT this increase did not take place in MT2-/- mice. Further, MT2-/- mice showed an enhanced vulnerability to stress-induced anhedonia and social avoidance as well as an impaired acquisition of novelty seeking behavior. Both reboxetine and ketamine reverted anhedonia and induced a clear anti-helpless behavior in the tail suspension test (TST). Reboxetine raised CBT in mice and reverted ultra-mild stress-induced anhedonia.Our findings show a primary role for MT2 receptors in the regulation of circadian CBT as well as anhedonia and suggest that these receptors could be involved in depressive disorders associated to disturbed melatonin function.

Insomnia, sleep loss, and circadian sleep disturbances in mood disorders: a pathway toward neurodegeneration and neuroprogression? A theoretical review.

The present paper aims at reviewing and commenting on the relationships between sleep and circadian phasing alterations and neurodegenerative/neuroprogressive processes in mood disorder. We carried out a systematic review, according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, in PubMed, PsycINFO, and Embase electronic databases for literature related to mood disorders, sleep disturbances, and neurodegenerative/neuroprogressive processes in relation to (1) neuroinflammation, (2) activation of the stress system, (3) oxidative stress, (4) accumulation of neurotoxic proteins, and (5) neuroprotection deficit. Seventy articles were collectively selected and analyzed. Experimental and clinical studies revealed that insomnia, conditions of sleep loss, and altered circadian sleep may favor neurodegeneration and neuroprogression in mood disorders. These sleep disturbances may induce a state of chronic inflammation by enhancing neuroinflammation, both directly and indirectly, via microglia and astrocytes activation. They may act as neurobiological stressors that by over-activating the stress system may negatively influence neural plasticity causing neuronal damage. In addition, sleep disturbances may favor the accumulation of neurotoxic proteins, favor oxidative stress, and a deficit in neuroprotection hence contributing to neurodegeneration and neuroprogression. Targeting sleep disturbances in the clinical practice may hold a neuroprotective value for mood disorders.

Genomic perspectives on the circadian clock hypothesis of psychiatric disorders.

Circadian rhythm disturbances are frequently described in psychiatric disorders such as major depressive disorder, bipolar disorder, and schizophrenia. Growing evidence suggests a biological connection between mental health and circadian rhythmicity, including the circadian influence on brain function and mood and the requirement for circadian entrainment by external factors, which is often impaired in mental illness. Mental (as well as physical) health is also adversely affected by circadian misalignment. The marked interindividual differences in this combined susceptibility, in addition to the phenotypic spectrum in traits related both to circadian rhythms and mental health, suggested the possibility of a shared genetic background and that circadian clock genes may also be candidate genes for psychiatric disorders. This hypothesis was further strengthened by observations in animal models where clock genes had been knocked out or mutated. The introduction of genome-wide association studies (GWAS) enabled hypothesis-free testing. GWAS analysis of chronotype confirmed the prominent role of circadian genes in these phenotypes and their extensive polygenicity. However, in GWAS on psychiatric traits, only one clock gene, ARNTL (BMAL1) was identified as one of the few loci differentiating bipolar disorder from schizophrenia, and macaque monkeys where the ARNTL gene has been knocked out display symptoms similar to schizophrenia. Another lesson from genomic analyses is that chronotype has an important genetic correlation with several psychiatric disorders and that this effect is unidirectional. We conclude that the effect of circadian disturbances on psychiatric disorders probably relates to modulation of rhythm parameters and extend beyond the core clock genes themselves.

Circadian fragmentation: a harbinger of Alzheimer's disease?

Circadian fragmentation: a harbinger of Alzheimer's disease?