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PubMed2026

GIRK Channels Regulate Circadian Rhythms of Excitability in Prokineticin 2 Neurons of the Suprachiasmatic Nucleus and Modulate Behavioral Circadian Rhythms.

The suprachiasmatic nucleus (SCN), the central circadian clock in mammals, generates robust yet adaptable circadian rhythms through electrically mediated coordination among heterogeneous peptidergic neuronal populations with presumed cell type-specific roles. Previous studies have proposed that circadian changes in membrane excitability of individual SCN neurons arise from time-of-day-dependent shifts in the relative balance of subthreshold Na+ and K+ conductances. Although multiple channels have been implicated in these processes, how nocturnally dominant K+ conductances are implemented in a cell type-specific manner remains poorly understood. Prokineticin 2 (Prok2) has been identified as a SCN signaling peptide essential for behavioral circadian regulation; however, the electrophysiological properties of Prok2-expressing neurons and the mechanisms underlying their diurnal rhythmicity remain largely unexplored. Here, using electrophysiological approaches in mice of either sex, we show that Prok2 neurons exhibit diurnal variations in electrical properties, with higher excitability during the day and reduced excitability at night, and that G-protein-coupled inwardly rectifying potassium (GIRK) channel-mediated basal current contributes to nighttime hyperpolarization. Immunofluorescence and single-cell RT-PCR analyses revealed that GIRK1 and GIRK3 are the predominant GIRK subunits expressed in Prok2 neurons. Moreover, Prok2 neuron-specific deletion of GIRK3 using in vivo genome editing resulted in significant nocturnal depolarization and induced abnormalities in behavioral rhythms, including delayed activity onset and circadian period lengthening, with altered SCN network activity. Together, these findings suggest that tonic, G-protein-dependent regulation of GIRK channels provides a night-specific inhibitory mechanism that contributes to intrinsic diurnal neuronal excitability in Prok2 neurons and supports the regulation of behavioral circadian rhythms.

Animals↗

PubMed1978

Is the rhythm amplitude related to the ability to phase-shift circadian rhythms of shift-workers?

The magnitude of the circadian acrophase adjustment deltaphi to a phase shift of socio-ecologic synchronizers (as in shift-work) varies from subject to subject. According to J. Aschoff, the ability to adjust rapidly to a phase-shift could be associated with having a small amplitude for certain circadian rhythms. To test this hypothesis, the correlation coefficient (r) between the mean circadian rhythm amplitude A and the acrophase shift deltaphi (measured after the first night-shift) were calculated from estimates of chronobiological time series analyses (Halberg's single cosinor method). Data were obtained from two groups of selected shift-workers (20 and 5 subjects, respectively). A negative correlation between A and deltaphi (the smaller the amplitude, the greater the delpaphi) was observed in the circadian rhythms of the following variables: oral temperature (r = .63;P less than .01), peak expiratory flow (r = . 53: P less than . 01), and urinary 17-OHCS (r = . 60; P less than . 01), but not for other variables such as : grip strength, urinary K+ and Na+. The small amplitude of certain circadian rhythms could be considered as an index of an individual's ability to phase-shift easily. However, chronobiological characteristics, other than the small circadian rhythm ampliture, remain to be identified, for both a better detection of one's ability to do shift-work and a better knowledge for practical applications.

17-Hydroxycorticosteroids↗

PubMed2025

Rhythm profiling using COFE reveals multi-omic circadian rhythms in human cancers in vivo.

The study of ubiquitous circadian rhythms in human physiology requires regular measurements across time. Repeated sampling of the different internal tissues that house circadian clocks is both practically and ethically infeasible. Here, we present a novel unsupervised machine learning approach (COFE) that can use single high-throughput omics samples (without time labels) from individuals to reconstruct circadian rhythms across cohorts. COFE can simultaneously assign time labels to samples and identify rhythmic data features used for temporal reconstruction, while also detecting invalid orderings. With COFE, we discovered widespread de novo circadian gene expression rhythms in 11 different human adenocarcinomas using data from The Cancer Genome Atlas (TCGA) database. The arrangement of peak times of core clock gene expression was conserved across cancers and resembled a healthy functional clock except for the mistiming of a few key genes. Moreover, rhythms in the transcriptome were strongly associated with the cancer-relevant proteome. The rhythmic genes and proteins common to all cancers were involved in metabolism and the cell cycle. Although these rhythms were synchronized with the cell cycle in many cancers, they were uncoupled with clocks in healthy matched tissue. The targets of most of FDA-approved and potential anti-cancer drugs were rhythmic in tumor tissue with different amplitudes and peak times. These findings emphasize the utility of considering "time" in cancer therapy, and suggest a focus on clocks in healthy tissue rather than free-running clocks in cancer tissue. Our approach thus creates new opportunities to repurpose data without time labels to study circadian rhythms.

Humans↗

PubMedDate not supplied

Circadian rhythm and cell cycle: possible entraining mechanisms.

Circadian rhythms and cell cycles are endogenous self-sustained oscillations. They differ in several characteristics of the rhythmicity such as temperature dependency, reaction to external stimuli and the impact of protein synthesis. In multicellular organisms, the cell cycle very often is entrained by a circadian rhythm as has been analyzed in rats and mice, in particular. The same seems to hold true in cell cultures: Yoshida-ascites hepatoma cells, human embryonic fibroblasts, rat liver and rat hepatoma cells show circadian changes in the percentage of cells in G1-, S- and G2 + M-phases. The different phases within the cell cycle were determined by applying impulse cytophotometric methods. Some hypothetical mechanisms of entrainment of the cell cycle by circadian rhythms are discussed. Possible entrancing signals (Zeitgebers) are membrane and transport functions, cyclic nucleotides, nuclear non-histone proteins and their phosphorylation, and RNA synthesis. The maxima of the circadian rhythms of most of these functions in rat liver can be arranged in a certain temporal sequence.

Animals↗

PubMed1979

Photoentrainment, pharmacology, and phase shifts of the circadian rhythm in the rat pineal.

Photoentrainment of circadian rhythms in mammals is mediated by the retinohypothalamic projection to the suprachiasmatic nucleus of the hypothalamus. It should therefore be possible to mimic or block the effects of light on the circadian pacemaker with appropriate pharmacological agents. Such agents and their effects should be useful in identifying the neurotransmitters involved in photoentrainment and their mechanisms of action on the circadian pacemaker. The effects of light on the circadian rhythm in rat pineal serotonin N-acetyltransferase activity are described. Carbachol, a cholinergic agonist, was found to mimic the effects of light on this rhythm, including the acute reduction of nocturnal activity and phase-shifting of the free-running rhythm. These results raise the possibility that acetylcholine is involved in the photoentrainment of mammalian circadian rhythms.

Acetylcholine↗

PubMedDate not supplied

Cortisol circadian rhythm in 70--100-year-old subjects.

The circadian rhythms of plasma cortisol was examined in 25 persons aged between 70 and 100 years by comparison with 5 adults aged between 17 and 38 years. The blood samples were drawn at 16 hundred, 20 hundred, 00 hundred, 04 hundred and 08 hundred hrs. Cortisol was assayed by the fluorimetric method. The experimental data were analyzed by Halberg's mean-cosinor method. The results showed that the circadian rhythm in plasma cortisol changes with age. The characteristic phenomena found were the following: a tendency towards reducing the hourly quantitative differences, comparatively more marked between 90 and 100 years; anticipation of the cortisol maximum level of 08 hundred at 04 hundred hrs in the group of 71 to 80 years, and at 00 hundred hrs in some of the subjects older than 80. A normal circadian rhythm was found in 2 of the 25 cases examined. These changes imply variations of the same kind in the CRF and ACTH levels. The changes in the circadian rhythms of cortisol show that the regulation systems are also implied in the aging process. It is possible that early-morning insomnia of the aged be due to this anticipation in cortisol secretion.

Adolescent↗

PubMed1975

[Studies on circadian rhythm and the feedback mechanism of hormone secretion from the hypothalamic-pituitary-adrenal system --pertaining to the circadian variation of feedback sensitivity in the hypothalamic-pituitary axis-- (author's transl)].

In order to investigate the relationship if any between the circadian rhythm of the hypothalamic-pituitary-adrenal system and of feedback sensitivity in the hypothalamic-pituitary axis, temporal changes of serum corticoid level and of ACTH responsiveness to metyrapone were studied in 5 controls, 4 patients with loss of consciousness due to central nervous system diseases (Group A), 2 blind subjects (Group B) and 2 patients with psychiatric disorders accompanied with sleep-wake cycle disturbance (Group C). Two patients in Group A with normal circadian rhythm of serum corticoid levels exhibited abnormal rhythm in ACTH responsiveness to metyrapone. In contrast, 2 other patients in Group A with normal rhythm in ACTH responsiveness to metyrapone exhibited abnormal circadian rhythms of serum corticoid levels. In spite of the disturbed circadian rhythm of serum corticoid levels, 2 patients in Group B showed normal rhythm in ACTH responsiveness to metyrapone. Two patients in Group C exhibited abnormalities in both circadian changes. It was concluded that there might be different control mechanisms between the circadian rhythmicity of the hypothalamic-pituitary-adrenal system and of the feedback sensitivity.

Adrenal Cortex Hormones↗

PubMed1978

Simultaneous determination of circadian rhythms of locomotor activity and body temperature in the rat.

Stimultaneous determination of the circadian rhythms of locomotor activity and body temperature was carried out in the rat. Deep body temperature was monitored continuously using a telemetric device. The circadian rhythm of locomotor activity was characterized by clustering of several bursts of activity during the dark period. The circadian rhythm of body temperature was also characterized by bursts of small fluctuations which were well correlated with those of locomotor activity. Correlation between the two functions was such that the regression line expressing body temperature as a function of locomotor activity had approximately the same slope for dark and light periods, but a body temperature for a given amount of locomotor activity was significantly higher during the dark period than during the light one. After a prolonged exposure to constant light, the circadian rhythm disappeared in both functions. Both showed bursts of fluctuations which were correlated with each other. These results indicate that the bursts of body temperature increment were dependent on those of the locomotor activity. However, manifestation of the circadian rhythm per se of body temperature could not be explained as resulting exclusively from the circadian fluctuation of locomotor activity.

Animals↗

PubMed2018

Chronotype and cellular circadian rhythms predict the clinical response to lithium maintenance treatment in patients with bipolar disorder.

Bipolar disorder (BD) is a serious mood disorder associated with circadian rhythm abnormalities. Risk for BD is genetically encoded and overlaps with systems that maintain circadian rhythms. Lithium is an effective mood stabilizer treatment for BD, but only a minority of patients fully respond to monotherapy. Presently, we hypothesized that lithium-responsive BD patients (Li-R) would show characteristic differences in chronotype and cellular circadian rhythms compared to lithium non-responders (Li-NR). Selecting patients from a prospective, multi-center, clinical trial of lithium monotherapy, we examined morning vs. evening preference (chronotype) as a dimension of circadian rhythm function in 193 Li-R and Li-NR BD patients. From a subset of 59 patient donors, we measured circadian rhythms in skin fibroblasts longitudinally over 5 days using a bioluminescent reporter (Per2-luc). We then estimated circadian rhythm parameters (amplitude, period, phase) and the pharmacological effects of lithium on rhythms in cells from Li-R and Li-NR donors. Compared to Li-NRs, Li-Rs showed a difference in chronotype, with higher levels of morningness. Evening chronotype was associated with increased mood symptoms at baseline, including depression, mania, and insomnia. Cells from Li-Rs were more likely to exhibit a short circadian period, a linear relationship between period and phase, and period shortening effects of lithium. Common genetic variation in the IP3 signaling pathway may account for some of the individual differences in the effects of lithium on cellular rhythms. We conclude that circadian rhythms may influence response to lithium in maintenance treatment of BD.

Adult↗

PubMed1978

Circadian rhythms of urea formation and argininosuccinate synthetase activity in rat liver.

The circadian rhythms of the urea concentrations in urine, serum, and liver and their generation mechanism were investigated. When rats were allowed to eat freely, the urea concentration and the total urea content of the urine were higher during the night than during the day-time. Consistent with these findings, the urea concentrations in the liver and serum had circadian rhythms with the highest values at 0200 hours and the lowest values at 1400 hours. The amplitude of the rhythm increased with increase in the dietary protein (casein) content. Of the five urea cycle enzymes in the liver, only argininosuccinate synthetase showed fluctuation in activity, and this had the same pattern as the circadian rhythms of urea concentrations. These findings suggest that the circadian rhythm of argininosuccinate synthetase in the liver might be directly responsible for the rhythms of change in urea concentrations in the liver, blood and urine. The circadian increase in enzyme activity was inhibited by cycloheximide, but not by actinomycin D.

Animals↗

PubMed1976

Schedule of protein ingestion and circadian rhythm of certain hepatic enzyme activities involved in glucose metabolism in the rat.

The circadian rhythms of liver glycogen, plasma glucose, corticosterone and insulin, and hepatic activity of PK, G6PDH, ME, Ac, CoA carbox. PEP-CK and GPT were studied in adult rats. Animals either received a mixed diet ad libitum (8% protein) or a protein meal (1.1 g protein) given at 05:00 or 17:00 h, with free access to a protein-free diet (separately fed). When the protein meal was ingested during the lighted period (17:00) the 24-hour average level of liver PEP-CK was greater than in rats consuming protein during darkness (05:00). In the latter case, modification of the circadian rhythm of liver glycogen and of circadian rhythm of liver PK, G6PDH, ME and Ac.CoA carbox. activity (increase of 24 h average level, extension of period of high activity, sudden increase after ingestion of protein meal) were observed. Conversely, the circadian rhythm of plasma insulin and corticosterone and of liver PEP-CK and GPT activity were only slightly affected by the mode of feeding.

Acetyl-CoA Carboxylase↗

PubMed1979

Intraventricular carbachol mimics the effects of light on the circadian rhythm in the rat pineal gland.

Environmental lighting regulates numerous circadian rhythms, including the cycle in pineal serotonin N-acetyltransferase activity. Brief exposure of rats to light can shift the phase of this enzyme's circadian rhythm. Light also rapidly reduces nocturnal enzyme activity. Intraventricular injections of carbachol, a cholinergic agonist, can mimic both of these effects. Light and carbachol presumably act on the suprachiasmatic nucleus of the hypothalamus. These experiments demonstrate the feasibility of using a neuropharmacologic approach to the mechanisms underlying mammalian circadian rhythms.

Acetyltransferases↗

PubMed1979

Neural mechanisms for entrainment and generation of mammalian circadian rhythms.

The identification of a direct retinohypothalamic tract (RHT) terminating in the supra-chiasmatic nuclei (SCN) has focused attention on the role of these structures in the entrainment and generation of circadian rhythms in mammals. Light effects on circadian rhythms are mediated by both the RHT and portions of the classical visual system. The complex interactions of these systems are reflected both in their direct anatomical connections and in the functional changes in entrainment produced by interruption of either set of projections. Destruction of the RHT/SCN eliminated both normal entrainment and normal free-running circadian rhythms. No circadian rhythms has survived SCN ablation in rodents, but a variety of non-circadian cycles can be generated by lesioned animals. The complex behavioral patterns produced by SCN-lesioned hamsters suggest that circadian oscillators continue to function in these animals, but that their activity is no longer integrated into a single circadian framework. The available evidence indicates that the mammalian pacemaking system comprises a set of independent oscillators normally regulated by the SCN and by light information that is transmitted via several retinofugal pathways.

Animals↗

PubMed1977

Pubertal manifestation of sex difference in circadian rhythm of corticotrophin-releasing activity in the rat hypothalamus.

Post-natal development of the circadian rhythm of hypothalamic content of corticotrophin-releasing factor (CRF) was examined in male and female rats, separately. CRF activity was estimated by the intrapituitary injection technique. The circadian rhythm of the CRF content observed at the third week was without any noticeable sex difference: both male and female rats began their circadian rhythm with higher values in the afternoon than in the morning. Male rats maintained this pattern up to maturity. In contrast, female rats showed a marked change at ages of fifth to sixth week: the CRF rhythm in female rats changed to a female pattern, with higher values in the morning than in the afternoon. During this period, the vaginal opening occurred concurrently with a marked afternoon rise in the plasma corticosterone, characteristic of mature female rats. On the other hand, no essential difference could be observed between male and female rats in the developmental change in the circadian rhythm of locomotor activity. These results indicate that a sex difference in the CRF rhythm is not essentially related to the process of sex differentiation in the central nervous system, but is rather related to changes in ovarian activity following the onset of puberty.

Age Factors↗

PubMed1979

[Circadian rhythms of the parameters of the mouse esophagus epithelial cell kinetics].

Circadian rhythms of the mitotic activity, DNA synthesis and the parameters of the mitotic cells of the mouse esophagus epithelium were studied during the periods of maximum and minimum proliferation. The number of mitoses and DNA-synthetizing cells increases rhythmically at 1--7 a. m. from 22 p. m. to 4 a. m., respectively. When 3H-thymidine was injected to the mice at 2 a. m., tG2min was 1h; tG2+1/2 M was 2h; tS was 7.1; tG1+1/2 M was 2h; tS was 7.1; tG1+1/2 M was 15.9h. When 3H-thymidine was injected at 2 p. m., tS rose up to 8.2 and tG1+1/2 M up to 14.8h. The mitotic cycle in both series of experiments totalled 25 h. Thus, the duration of various phases of the mitotic cycle depends on the time of the day and correlates with circadian rhythms of the mitotic activity and the number of DNA-synthetizing cells. Duration of the mitotic cycle of the cells passing through it at varying time of the day is the same and approximates the period of the circadian rhythm of mitoses and DNA synthesis in esophagus epithelium.

Animals↗

PubMed1975

[Circadian rhythms op ventilatory mechanical factors in healthy children].

Circadian rhythms in lung resistance (R1) and dynamic compliance (C1dyn) of 7 healthy children (6 to 10 years) were validated (p less than .05) and then quantified (cosinor method); subjects' synchronization: light on at 0700; light off at 2100. Measurements were performed at fixed per hours (0730, 1130, 1630 and 2230) before and after the inhalation of a beta sympathomimetic bronchodilatator: minus 2mg orciprenaline. The measurements carried out after orciprenaline inhalation show a flattening of the curves, both circadian rhythms in R1 and C1 dyn are not detected (p greater than .05).

Airway Resistance↗

PubMed1977

Renal electrolyte circadian rhythms: independence from feeding and activity patterns.

The interrelationships between urinary electrolyte circadian rhythms and rhythms of feeding, drinking and activity were studied in six conscious chair-acclimatized squirrel monkeys (Saimiri sciureus) kept in temperature-controlled isolation chambers on a light-dark (LD) 12:12 h cycle. With lights on (600 lx) from 0800 to 2000 h and off (less than 1 lx) from 2000 to 0800 h, renal potassium excretion in monkeys fed ad libitum fell to a daily minimum of 64 +/- 6 mueq/h at 0500 h and rose to a maximum of 274 +/- 13 mueq/h at 1700 h. Sodium excretion fell to a minimum of 13 +/- 2 mueq/h at 1000 h and rose to a maximum of 43 +/- 6 mueq/h at 2100 h, while water excretion fell to a minimum of 869 +/- 63 mul/h at 0500 h and rose to a maximum of 2,307 +/- 222 mul/h at 1700 h. Feeding, drinking, and activity occurred only during the lights-on period. Independence of the urinary rhythms from diurnal variations in feeding, drinking, and activity was established a) by depriving monkeys of food, b) by depriving monkeys of water, and c) by training monkeys to perform a 2-hourly schedule of feeding, drinking, and activity throughout day and night. None of these three regimens resulted in major reductions of the amplitude, or changes in the phase of the circadian rhythms of urinary electrolyte or water excretion. These findings indicate that the circadian rhythms of urinary potassium, sodium, and water excretion are controlled by mechanisms that are not passively dependent on the behavioral patterns of feeding, drinking, and activity.

Animals↗

PubMed1975

Absence of a circadian rhythm in crypt cell mitotic rate following chemical sympathectomy in rats.

The circadian rhythms in both consumption of food by rats and in the mitotic rate in epithelial cells lining the bases of the crypts of Lieberkühn of the proximal jejunum were studied in normal and in chemically sympathectomised rats. In normal rats both food consumption and crypt cell mitotic rat showed a distinct circadian rhythm, both parameters having a peak around 00.00 to 04.00 hours. Following chemical sympathectomy the circadian rhythm in food consumption was essentially unchanged whereas that in the crypt cell mitotic rate was abolished.

Animals↗