Journal of Circadian Rhythms - Latest Articles

A dynamic model of circadian rhythms in rodent tail skin temperature for comparison of drug effects

Dorothee Girbig — 2012-01-05T00:00:00Z

Menopause-associated thermoregulatory dysfunction can lead to symptoms such as hot fushes severely im-pairing quality of life of affected women. Treatment effects are often assessed by the ovariectomized rat modelproviding time series of tail skin temperature measurements in which circadian rhythms are a fundamental ingre-dient. In this work, a new statistical strategy is presented for analyzing such stochastic-dynamic data with theaim of detecting successful drugs in hot flush treatment. The circadian component is represented by a nonlinear dynamical system which is defined by the van der Pol equation and provides well-interpretable model parameters.Results regarding the statistical evaluation of these parameters are presented.

Magel2, a Prader-Willi Syndrome candidate gene, modulates the activities of circadian rhythm proteins in cultured cells.

Julia Devos — 2011-12-30T00:00:00Z

Background: The Magel2 gene is most highly expressed in the suprachiasmatic nucleus of the hypothalamus, where its expression cycles in a circadian pattern comparable to that of clock-controlled genes. Mice lacking the Magel2 gene have hypothalamic dysfunction, including circadian defects that include reduced and fragmented total activity, excessive activity during the subjective day, but they have a normal circadian period. Magel2 is a member of the MAGE family of proteins that have various roles in cellular function, but the specific function of Magel2 is unknown. Methods: We used a variety of cell-based assays to determine whether Magel2 modifies the properties of core circadian rhythm proteins. Results: Magel2 represses the activity of the Clock:Bmal1 heterodimer in a Per2-luciferase assay. Magel2 interacts with Bmal1 and with Per2 as measured by co-immunoprecipitation in co-transfected cells, and exhibits a subcellular distribution consistent with these interactions when visualized by immunofluorescence. As well, Magel2 induces the redistribution of the subcellular localization of Clock towards the cytoplasm, in contrast to the nucleus-directed effect of Bmal1 on Clock subcellular localization. Conclusion: Consistent with the blunted circadian rhythm observed in Magel2-null mice, these data suggest that Magel2 normally promotes negative feedback regulation of the cellular circadian cycle, through interactions with key core circadian rhythm proteins.

Measuring the Impact of Apnea and Obesity on Circadian Activity Patterns Using Functional Linear Modeling of Actigraphy Data

Jia Wang — 2011-10-13T00:00:00Z

Background: Actigraphy provides a way to objectively measure activity in human subjects. This paper describes a novel family of statistical methods that can be used to analyze this data in a more comprehensive way. Methods: A statistical method for testing differences in activity patterns measured by actigraphy across subgroups using functional data analysis is described. For illustration this method is used to statistically assess the impact of apnea-hypopnea index (apnea) and body mass index (BMI) on circadian activity patterns measured using actigraphy in 395 participants from 18 to 80 years old, referred to the Washington University Sleep Medicine Center for general sleep medicine care. Mathematical descriptions of the methods and results from their application to real data are presented. Results: Activity patterns were recorded by an Actical device (Philips Respironics Inc.) every minute for at least seven days. Functional linear modeling was used to detect the association between circadian activity patterns and apnea and BMI. Results indicate that participants in high apnea group have statistically lower activity during the day, and that BMI in our study population does not significantly impact circadian patterns. Conclusions: Compared with analysis using summary measures (e.g., average activity over 24 hours, total sleep time), Functional Data Analysis (FDA) is a novel statistical framework that more efficiently analyzes information from actigraphy data. FDA has the potential to reposition the focus of actigraphy data from general sleep assessment to rigorous analyses of circadian activity rhythms.

Relationship between daylength and suicide in Finland

Laura Hiltunen — 2011-09-23T00:00:00Z

Background: Many previous studies have documented seasonal variation in suicides globally. We re-assessed the seasonal variation of suicides in Finland and tried to relate it to the seasonal variation in daylength and ambient temperature and in the discrepancy between local time and solar time. Methods: The daily data of all suicides from 1969 to 2003 in Finland (N = 43,393) were available. The calendar year was divided into twelve periods according to the length of daylight and the routinely changing time difference between sun time and official time. The daily mean of suicide mortality was calculated for each of these periods and the 95% confidence intervals of the daily means were used to evaluate the statistical significance of the means. In addition, daily changes in sunshine hours and mean temperature were compared to the daily means of suicide mortality in two locations during these afore mentioned periods. Results: A significant peak of the daily mean value of suicide mortality occurred in Finland between May 15th and July 25th, a period that lies symmetrically around the solstice. Concerning the suicide mortality among men in the northern location (Oulu), the peak was postponed as compared with the southern location (Helsinki). The daily variation in temperature or in sunshine did not have significant association with suicide mortality in these two locations. Conclusions: The period with the longest length of the day associated with the increased suicide mortality. Furthermore, since the peak of suicide mortality seems to manifest later during the year in the north, some other physical or biological signals, besides the variation in daylight, may be involved. In order to have novel means for suicide prevention, the assessment of susceptibility to the circadian misalignment might help.

Relationship between psychosomatic complaints and circadian rhythm irregularity assessed by salivary levels of melatonin and growth hormone

Mitsuo Nagane — 2011-09-14T00:00:00Z

Background: In university health care settings, students with psychosomatic complaints often have chronotypic problems. For this reason, we investigated a potential connection between psychosomatic complaints and circadian rhythm irregularity assessed by salivary levels of melatonin and growth hormone. Methods: Fifteen healthy students between 21 and 22 years of age were examined for physiological parameters of chronotypes based on melatonin and growth hormone secretion patterns, using a fluorescence enzyme immunoassay. Salivary samples were collected from subjects at home five times each day (20:00, 24:00, 04:00, 08:00, and 12:00 h). In addition, the subjects rated their psychosomatic symptoms twice (at 08:00 and 20:00 h). Results: A group with irregular circadian rhythm of melatonin (ICR) showed more psychosomatic complaints than a group with the regular circadian rhythm (RCR), especially for anxiety. Conclusion: Psychosomatic symptoms, particularly anxiety, may be associated with irregularity in melatonin and growth hormone rhythms, which can be altered by basic lifestyle habits even in healthy students.

Polymorphisms in melatonin synthesis pathways: possible influences on depression

Daniel Kripke — 2011-08-09T00:00:00Z

Background: It has been reported that rs4446909, a single nucleotide polymorphism (SNP) in the promoter of acetylserotonin methyltransferase (ASMT), influences the expression of the ASMT enzyme. The common G allele is associated with lower ASMT activity, and therefore, diminishes conversion of N-acetylserotonin to melatonin. The G allele was associated with recurrent depressive disorder in a Polish group. ASMT might also affect bipolar relapse, given evidence that N-acetylserotonin might stimulate TRKB receptors, and TRKB may influence mood relapse in bipolar disorder. Additionally, arylalkylamine N-acetyltransferase (AANAT) polymorphisms have been reported associated with depression, perhaps through their influence upon N-acetylserotonin or melatonin synthesis. Results: To replicate and further explore these ideas, rs4446909 was genotyped in four research groups, as part of a panel of 610 SNPs surveyed by an Illumina Golden Gate assay. In 768 cases with delayed sleep phase disorder or matched controls, rs4446909 was indeed associated with the depressive symptoms on a self-report scale (P = 0.01, R2 = 0.007). However, there was no significant association of rs4446909 with self-reported depression in a sleep clinic patient group or with two groups of elderly men and women from multicenter studies, nor was the response to lithium treatment associated with rs4446909 in bipolar patients. No associations of two AANAT SNPs with depression were found. Conclusions: The evidence did not support a strong influence of rs4446909 upon mood, but the partial replication may be consistent with a modest effect. It is possible that larger or younger subject groups with improved phenotype ascertainment might demonstrate more persuasive replication.

Effects of restraint stress on the daily rhythm of hydrolysis of adenine nucleotides in rat serum

Andressa Souza — 2011-07-28T00:00:00Z

Background: Adenosine 5-triphosphate (ATP) and its breakdown products ADP and adenosine can act as extracellular messengers in a range of biological processes. Extracellular adenine nucleotides are metabolized by a number of enzymes including NTPDases and 5'-nucleotidase, which are considered to be the major regulators of purinergic signaling in the blood. Previous work by our group demonstrated that ATPase and ADPase activities in rat serum exhibit a 24-h temporal pattern, with higher enzyme activity during the dark (activity) phase. It was found that stress can cause disruptions in biological circadian rhythms and in the cardiovascular system. Therefore, the aim of the present study was to examine the influence of acute stress exposure upon temporal patterns of NTPDase and 5-nucleotidase enzyme activities in rat blood serum. Methods: Adult male Wistar rats were divided into 4 groups: ZT0, ZT6, ZT12 and ZT18. Each group was subdivided in 4 groups: control, immediately, 6 h and 24 h after one hour of restraint stress. ATP, ADP and AMP hydrolysis were assayed in the serum. Results: All stressed groups showed significant decreases in all enzyme activities at ZT 12 and ZT 18 when compared with control. Conclusion: Acute stress provokes a decrease in nucleotidase activities dependent on the time that this stress occurs and this effect appears to persist for at least 24 hours. Stress can change levels of nucleotides, related to increased frequency of cardiovascular events during the activity phase. Altered levels of nucleotides in serum may be involved in cardiovascular events more frequent during the activity phase in mammals, and with their etiology linked to stress.

Chronic inhibition of endoplasmic reticulum calcium-release channels and calcium-ATPase lengthens the period of hepatic clock gene Per1

Adrian Baez-Ruiz — 2011-07-08T00:00:00Z

Background: The role played by calcium as a regulator of circadian rhythms is not well understood. The effect of the pharmacological inhibition of the ryanodine receptor (RyR), inositol 1,4,5-trisphosphate receptor (IP3R), and endoplasmic-reticulum Ca2+-ATPase (SERCA), as well as the intracellular Ca2+-chelator BAPTA-AM was explored on the 24-h rhythmicity of the liver-clock protein PER1 in an experimental model of circadian synchronization by light and restricted-feeding schedules. Methods: Liver explants from Period1-luciferase (Per1-luc) transgenic rats with either free food access or with a restricted meal schedule were treated for several days with drugs to inhibit the activity of IP3Rs (2-APB), RyRs (ryanodine), or SERCA (thapsigargin) as well as to suppress intracellular calcium fluctuations (BAPTA-AM). The period of Per1-luc expression was measured during and after drug administration. Results: Liver explants from rats fed ad libitum showed a lengthened period in response to all the drugs tested. The pharmacological treatments of the explants from meal-entrained rats induced the same pattern, with the exception of the ryanodine treatment which, unexpectedly, did not modify the Per1-luc period. All effects associated with drug application were reversed after washout, indicating that none of the pharmacological treatments was toxic to the liver cultures. Conclusions: Our data suggest that Ca2+ mobilized from internal deposits modulates the molecular circadian clock in the liver of rats entrained by light and by restricted meal access.

Time-of-day dependence of neurological deficits induced by sodium nitroprusside in young mice

Mamane Sani — 2011-06-17T00:00:00Z

Sodium nitroprusside (SNP) is widely used in pharmacological studies as a potent vasodilator or a nitric oxide donor. SNP-induced ataxic effects were assessed in mice by the Joulou-Couvoisier test. Swiss albino mice of both genders, 2-8 weeks of age, were acclimated at least for 2 weeks to 12 h light (rest span)/12 h dark (activity span). In 2 and 4 week old mice, maxima of ataxia were found following intraperitoneal administration of a dose ranging from 3 to 3.6 mg.kg-1 SNP at ≈ 1 and 13 HALO (Hours After Light Onset). The sublethal toxicity was statistically dosing-time dependent (χ2 test: P < 0.005). No rhythm was validated in neurotoxicity by cosinor analyses. At the 8th week of post-natal development (PND), SNP-induced ataxia was greatest at ≈ 1 HALO (69% in males vs. 49% in females) and lowest at ≈ 13 HALO (21% in males vs. 11% in females) (χ2 test: P < 0.00001). Cosinor analysis also revealed no statistically significant rhythm in mice injected with 3 or 3.3 mg.kg-1. However, a significant circadian (τ = 24 h) rhythm was detected by adjusted cosinor in 3.6 mg.kg-1-treated mice (P < 0.004). In all studied groups, SNP-induced motor impairment (expressed in %) was lower during the dark than the light phase. Furthermore, there was a non-significant gender-related difference in SNP-induced neuronal toxicity with the males more sensitive than females at every studied PND. The ataxic effects were inversely proportional to the lag time from injection and to the age of animals (with P < 0.05 only between 2 and 8 week old mice). These data indicate that both the administration time and age of the animal significantly affect the neurotoxic effects of SNP.

Validation of Actigraphy to Assess Circadian Organization and Sleep Quality in Patients with Advanced Lung Cancer

James Grutsch — 2011-05-18T00:00:00Z

Background: Many cancer patients report poor sleep quality, despite having adequate time and opportunity for sleep. Satisfying sleep is dependent on a healthy circadian time structure and the circadian patterns among cancer patients are quite abnormal. Wrist actigraphy has been validated with concurrent polysomnography as a reliable tool to objectively measure many standard sleep parameters, as well as daily activity. Actigraphic and subjective sleep data are in agreement when determining activity-sleep patterns and sleep quality/quantity, each of which are severely affected in cancer patients. We investigated the relationship between actigraphic measurement of circadian organization and self-reported subjective sleep quality among patients with advanced lung cancer. Methods: This cross-sectional and case control study was conducted in 84 patients with advanced non-small cell lung cancer in a hospital setting for the patients at Midwestern Regional Medical Center (MRMC), Zion, IL, USA and home setting for the patients at WJB Dorn Veterans Affairs Medical Center (VAMC), Columbia, SC, USA. Prior to chemotherapy treatment, each patient's sleep-activity cycle was measured by actigraphy over a 4-7 day period and sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) questionnaire. Results: The mean age of our patients was 62 years. 65 patients were males while 19 were females. 31 patients had failed prior treatment while 52 were newly diagnosed. Actigraphy and PSQI scores showed significantly disturbed daily sleep-activity cycles and poorer sleep quality in lung cancer patients compared to healthy controls. Nearly all actigraphic parameters strongly correlated with PSQI self-reported sleep quality of inpatients and outpatients. Conclusions: The correlation of daily activity/sleep time with PSQI-documented sleep indicates that actigraphy can be used as an objective tool and/or to complement subjective assessments of sleep quality in patients with advanced lung cancer. These results suggest that improvements to circadian function may also improve sleep quality.