Dysregulation Of Circadian Rhythms Research Articles

Jet lag, circadian rhythm sleep disturbances, and depression: the role of melatonin and its analogs

Traveling through several time zones results in a constellation of symptoms known as jet lag. These include reduced alertness, daytime fatigue, loss of appetite, reduced cognitive skills, and disruption of the sleep/wake cycle. In susceptible air travel passengers, jet lag may exacerbate affective illness and result in psychiatric morbidity. Dysregulation of circadian rhythms and melatonin secretion represent the common underlying factor in jet lag and other circadian disorders. Recent studies have established the effectiveness of strategically timed administration of melatonin and appropriate timed exposure to environmental schedules including light in counteracting the dysregulation (chronobiologic actions). With the introduction of melatonergic agonists such as ramelteon and tasimelteon, which have both a stronger affinity for MT₁ and MT₂ melatonin receptors and a longer half-life, new therapeutic options now exist for treating the sleep disturbances associated with jet lag. The melatonin analogs are unique inasmuch as they can also enhance daytime alertness. The recently introduced melatonergic antidepressant agomelatine, which has established its supremacy over other antidepressants in having a significant chronobiologic activity, represents a good choice for treating depressive symptoms that are associated with jet lag.

Dysregulation of circadian blood pressure rhythm and patho-genesis of cognitive dysfunction in patients with metabolic syndrome

Dysregulation of circadian blood pressure rhythm and patho-genesis of cognitive dysfunction in patients with metabolic syndrome

Circadian Clock and The Cardiometabolic Risk

BACKGROUND: Epidemiological data reveal parallel trends of decreasing sleep duration and increases in metabolic disorders such as obesity, diabetes and hypertension. There is growing evidence that these trends are mechanistically related.CONTENT: The circadian system orchestrates the temporal organization of many aspects of physiology, including metabolism, in synchrony with the 24 hours rotation of the Earth. The circadian system is a complex feedback network that involves interactions between the central nervous system and peripheral tissues. Circadian regulation is intimately linked to metabolic homeostasis and that dysregulation of circadian rhythms can contribute to disease. Conversely, metabolic signals also feed back into the circadian system, modulating circadian gene expression and behavior.SUMMARY: Both inter- and intraorgan desynchrony may be involved in the pathogenesis of cardiometabolic disease attributable to effects in brain and multiple metabolic tissues including heart, liver, fat, muscle, pancreas and gut. Efforts to dissect the molecular mediators that coordinate circadian, metabolic, and cardiovascular systems may ultimately lead to both improved therapeutics and preventive interventions.KEYWORDS: circadian rhythms, clock genes, nuclear receptor, sleep, obesity, cardiometabolic risk

Genetic variants and abnormal processing of pre-miR-182, a circadian clock modulator, in major depression patients with late insomnia

Previous studies in mice have reported five different microRNAs (miRNAs; miR-219-1/132/183/96/182) to be modulators of the endogenous circadian clock and have presented experimental evidence for some of the genes involved in the molecular clock machinery as target sites. Moreover, disruption of circadian rhythms has long been implicated in the pathophysiology of major depression (MD). We investigated these miRNAs and some of their target sites at the sequence and functional levels as possible predisposing factors for susceptibility to MD and related chronobiological subphenotypes. Mutational screening was performed in a sample of 359 MD patients and 341 control individuals. We found a significant association between the T allele of the rs76481776 polymorphism in the pre-miR-182 and late insomnia in MD patients. Previous studies have reported an association between insomnia and CLOCK gene, a predicted miR-182 target site. A significant overexpression of miR-182 was detected by quantitative real-time polymerase chain reaction in cells transfected with the mutated form of the pre-miR-182 when compared with wild-type form. Moreover, a significant reduction in luciferase activity of plasmids with 3' UTR of ADCY6, CLOCK and DSIP genes was shown when transfecting cells with the mutated form of pre-miR-182 compared with cells that did not express miR-182. These data indicate that abnormal processing of pre-miR-182 in patients carrying the T allele of the rs76481776 polymorphism may contribute to the dysregulation of circadian rhythms in MD patients with insomnia, which could influence expression levels of the mature form of miR-182 and might increase downregulation in some of its target genes.

Effects of repeated light–dark phase shifts on voluntary ethanol and water intake in male and female Fischer and Lewis rats

Several lines of evidence implicate reciprocal interactions between excessive alcohol (ethanol) intake and dysregulation of circadian biological rhythms. Thus, chronic alcohol intake leads to widespread circadian disruption in both humans and experimental animals, while in turn, chronobiological disruption has been hypothesized to promote or sustain excessive alcohol intake. Nevertheless, the effects of circadian disruption on voluntary ethanol intake have not been investigated extensively, and prior studies have reported both increased and decreased ethanol intake in rats maintained under “shift-lag” lighting regimens mimicking those experienced by shift workers and transmeridian travelers. In the present study, male and female inbred Fischer and Lewis rats were housed in running wheel cages with continuous free-choice access to both water and 10% (vol/vol) ethanol solution and exposed to repeated 6-h phase advances of the daily light–dark (LD) cycle, whereas controls were kept under standard LD 12:12 conditions. Shift-lag lighting reduced overall ethanol and water intake, and reduced ethanol preference in Fischer rats. Although contrary to the hypothesis that circadian disruption would increase voluntary ethanol intake, these results are consistent with our previous report of reduced ethanol intake in selectively bred high-alcohol-drinking (HAD1) rats housed under a similar lighting regimen. We conclude that chronic circadian disruption is a form of chronobiological stressor that, like other stressors, can either increase or decrease ethanol intake, depending on a variety of poorly understood variables.

Biological theory of depression in the light of new evidence

The finding of various structural and chemical abnormalities in the brain through neuroimaging has been the mainstay in depression research the last few years. Research isn't necessarily focused in a specific area of the brain, bur rather combines the pathophysiology of neurochemical communication of various brain areas to specific symptoms. The functionality of various brain areas, such as the prefrontal cortex or the amygdale or nucleus accumbens is theoretically linked with diverse symptom constellations. This might lead to more sophisticated treatment methods. New data on the function of the HPA axis and the role of CRF in stress response, contribute to the further understanding to the neurobiology of depression. As for the present therapeutic implications, the monoaminergic theory of depression is paralleled with the chronobiolgy theory and mainly with the theory of circadian rhythm dysregulation. All of the above lead to the rationale of the correct choice of antidepressants.

Melatonin, circadian rhythms, and the clock genes in bipolar disorder

Sleep disturbances and dysregulation of circadian rhythms are core elements of bipolar disorder that might be involved in its pathogenesis. It has been proposed that patients with bipolar disorder have an abnormally shifted or arrhythmic circadian system and that the disturbance of circadian rhythms may be caused by an alteration in the circadian clock machinery. Chronotherapeutic strategies based on controlled exposures to environmental stimuli that act on biological rhythms have shown good efficacy in the treatment of illness episodes, thus confirming ex juvantibus the clinical relevance of internal timing in this illness.

CIRCADIAN RHYTHM DYSREGULATION IN SEVERE SEPSIS

CIRCADIAN RHYTHM DYSREGULATION IN SEVERE SEPSIS

The phenomenology of bipolar disorder: what drives the high rate of medical burden and determines long-term prognosis?

Bipolar disorder (BD) has been classically described as one of episodic mood disturbances. New evidence suggests that a chronic course and multisystem involvement is the rule, rather than the exception, and that together with disturbances of circadian rhythms, mood instability, cognitive impairment, a high rate of medical burden is often observed. The current diagnostic approach for BD neither describes the multisystem involvement that the recent literature has highlighted nor points toward potential predictors of long- term outcome. In light of the new evidence that the long-term course of BD is associated with a high prevalence of psychiatric comorbidity and an increased mortality from medical disease, we propose a multidimensional approach that includes several symptom domains, namely affective instability, circadian rhythm dysregulation, and cognitive and executive dysfunction, presenting in various combinations that give shape to each individual presentation, and offers potential indicators of overall long-term prognosis.

Melatonin secretion rhythm disorders in patients with senile dementia of Alzheimer’s type with disturbed sleep–waking

Background: There is growing evidence that the dysregulation of circadian rhythms may play an important role in irregular sleep–waking in demented elderly. In this study, we investigated daily variation of the pineal hormone melatonin, which has been reported to possess hypnogenic and synchronizing effects, in patients with senile dementia of Alzheimer’s type. Methods: Serum melatonin secretion rhythms in inpatients with senile dementia of Alzheimer’s type (SDAT group, n = 10, average age = 75.7 years) with disturbed sleep–waking and nondemented elderly (ND group, n = 10, age = 78.3 years) without clinical sleep disorders in the same facility were monitored under a dim light condition without excessive physical exercise. Results: The SDAT group showed a significantly higher degree of irregularities in actigraphically recorded rest–activity (R-A) rhythm during the 7-day baseline period compared with the ND group. The SDAT group simultaneously showed significantly reduced amplitude, larger variation of peak times, and diminished amount of total secretion in the melatonin secretion rhythm compared with the ND group. There were significantly positive correlations between the severity of R-A rhythm disorder and the reduced amplitude as well as diminished amount of total melatonin secretion. Conclusions: The SDAT patients with disturbed sleep–waking possessed melatonin secretion rhythm disorders that may play an important role in irregular sleep–waking in demented elderly.

Day-night rhythm disturbance, pineal function and human disease.

Depression, mania and probably starvation all induce changes in pineal function. At present it is unknown what secondary effects on the endocrine and other systems are produced by these changes. Studies in rats have established an entraining effect of melatonin on locomotor activity and a feedback effect on the pineal itself. Studies of jet-lag and of sleep dysregulation in a blind subject established that melatonin treatment has a synchronizing effect in these conditions. Further investigations will be necessary to establish whether melatonin reduction in depression and other disorders leads secondarily to dysregulation of other circadian rhythms.