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PubMed2006

Development of a two-dimension manifold to represent high dimension mathematical models of the intracellular Mammalian circadian clock.

A new focus for mathematical models of the circadian pacemaker involves the encapsulation within the models of detailed biological processes responsible for generating those circadian rhythms. Representing greater biological detail requires more mathematical equations, which pose a greater challenge for the analysis of such systems. Development of a method that retains the predominant dynamics while still providing biologically detailed information is advantageous. Two high-dimension mathematical models of intracellular mammalian circadian pacemakers, Leloup-Goldbeter and Forger-Peskin, with 19 and 73 differential equations, respectively, have been published. The authors projected each of these high-dimension models onto their respective manifold using proper orthogonal functions (POFs) obtained from the empirical decomposition of the model's phase space to obtain a 2-dimension model. The resulting 2-dimension model, represented by 2 differential equations, predicts most of the salient characteristics of a biological clock including approximately 24-h oscillations, entrainment to an LD cycle, phase response curves, and the amplitude recovery dynamics that emerge following amplitude suppression. The manifold representation simplifies the mathematical analysis, since only 2 variables need to be observed and analyzed to understand the behavior of the biological clock. This reduced model derived from a model based on biological variables can be used for the development and analysis of mathematical models of the coupled mammalian oscillators to understand the dynamics of the integrated circadian pacemaker.

Animals↗
PubMed1988

Aging alters the circadian rhythm of glucose utilization in the suprachiasmatic nucleus.

We examined the possibility that alterations in the timing of cyclic luteinizing hormone (LH) release during the middle age transition to infertility reflect differences in the circadian pattern of neural function in pacemaker areas of the hypothalamus, particularly the suprachiasmatic nucleus. We measured local cerebral glucose utilization (LCGU) because this parameter is an index of local brain function. We assessed LCGU in several brain areas of young and middle-aged ovariectomized estradiol-treated rats since LH surges are altered when rats are middle-aged. This alteration is correlated with changes in the diurnal pattern of neurotransmitter turnover in several hypothalamic areas that regulate cyclic LH release. The data demonstrate a circadian rhythm in glucose utilization in the dorsal and ventral suprachiasmatic nucleus. In young rats, LCGU increases within 1 hr of lights-on, increases further just prior to the initiation of the LH surge, and decreases within 1 hr of lights-off. In contrast, middle-aged rats show a more gradual increase in LCGU after lights-on, with no further increase prior to the LH surge, and a premature decrease during the afternoon and evening. The data suggest that changes in the circadian pattern of LCGU may be related to the alteration in timing and amplitude of estradiol-induced LH surges in middle-aged rats. Changes in the integrity of the biological clock or in the ability of the biological clock to entrain other neurochemical events may underlie the onset of altered cyclic reproductive function and the transition to irregular estrous cyclicity.

Aging↗
PubMed2001

Intrinsic near-24-h pacemaker period determines limits of circadian entrainment to a weak synchronizer in humans.

Endogenous circadian clocks are robust regulators of physiology and behavior. Synchronization or entrainment of biological clocks to environmental time is adaptive and important for physiological homeostasis and for the proper timing of species-specific behaviors. We studied subjects in the laboratory for up to 55 days each to determine the ability to entrain the human clock to a weak circadian synchronizing stimulus [scheduled activity-rest cycle in very dim (approximately 1.5 lux in the angle of gaze) light-dark cycle] at three approximately 24-h periods: 23.5, 24.0, and 24.6 h. These studies allowed us to test two competing hypotheses as to whether the period of the human circadian pacemaker is near to or much longer than 24 h. We report here that imposition of a sleep-wake schedule with exposure to the equivalent of candle light during wakefulness and darkness during sleep is usually sufficient to maintain circadian entrainment to the 24-h day but not to a 23.5- or 24.6-h day. Our results demonstrate functionally that, in normally entrained sighted adults, the average intrinsic circadian period of the human biological clock is very close to 24 h. Either exposure to very dim light and/or the scheduled sleep-wake cycle itself can entrain this near-24-h intrinsic period of the human circadian pacemaker to the 24-h day.

Adult↗
PubMed2002

The influence of light on circarhythms in humans.

The present review discusses two types of biological rhythms, namely, circadian rhythms and circannual rhythms. Humans possess a circadian rhythm of approximately 24 hours, which is regulated by neural and hormonal processes. The synchronisation of this rhythm with the solar day and night is maintained through entrainment mainly by light. Dark environments completely lacking windows may have a negative effect on well-being and work capacity. During shift work the biological clock tends to maintain its normal 'diurnal' rhythm, which may lead to extreme tiredness and increased risk of accidents. Negative effects such as these may be partially alleviated by means of bright light during the night. During air travel across several time zones there is little time for the biological clock to adjust, but the resulting 'jet lag' may possibly be overcome by means of appropriately timed exposure to bright light. In countries situated far from the equator, the biological clock may become seriously disrupted during the short days of the dark season. Characterised by fatigue, sadness and sleep problems, these seasonal affective disorders may be cured or alleviated by means of regular periods outdoors, better lighting indoors, or, in the most serious cases, light therapy.

Circadian Rhythm↗
PubMed2006

A network of (autonomic) clock outputs.

The circadian clock in the suprachiasmatic nuclei (SCN) is composed of thousands of oscillator neurons, each of which is dependent on the cell-autonomous action of a defined set of circadian clock genes. A major question is still how these individual oscillators are organized into a biological clock producing a coherent output that is able to time all the different daily changes in behavior and physiology. We investigated which anatomical connections and neurotransmitters are used by the biological clock to control the daily release pattern of a number of hormones. The picture that emerged shows projections contacting target neurons in the medial hypothalamus surrounding the SCN. The activity of these pre-autonomic and neuro-endocrine target neurons is controlled by differentially timed waves of, among others, vasopressin, GABA, and glutamate release from SCN terminals. Together our data indicate that, with regard to the timing of their main release period within the light-dark (LD) cycle, at least 4 subpopulations of SCN neurons should be discerned. The different subgroups do not necessarily follow the phenotypic differences among SCN neurons. Thus, different subgroups can be found within neuron populations containing the same neurotransmitter. Remarkably, a similar distinction of 4 differentially timed subpopulations of SCN neurons was recently also discovered in experiments determining the temporal patterns of rhythmicity in individual SCN neurons by way of the electrophysiology or clock gene expression. Moreover, the specialization of the SCN may go as far as a single body structure; i.e., the SCN seems to contain neurons that specifically target the liver, pineal, and adrenal.

Adrenal Glands↗
PubMed2000

Chemistry and Biology of Plant Leaf Movements.

The leaves of Mimosa pudica L. are well known for their rapid movement when touched. Recently, we were able to isolate an excitatory substance in small quantities from this plant, which consists of three different components (potassium L-malate, magnesium trans-aconitate, and dimethylammonium salt). Many plants close their leaves in the evening, as if to sleep, and open them early in the morning (nyctinastic leaf movement). This circadian rhythm is known to be controlled by the biological clock of such plants. Extensive studies on other nyctinastic plants led to the isolation of a variety of leaf-opening substances (LOSs) and leaf-closing substances (LCSs). Based on our experiments on these bioactive substances, we found that the circadian rhythmic leaf movement of these plants is initiated by the regulated balance of LOSs and LCSs. The balance of concentration between the two leaf-movement factors (LMFs) is inversed during the day. The glycoside-type LMF is hydrolyzed with beta-glucosidase, the activity of which is regulated by the biological clock. The circadian rhythm observed in the leaf movement is introduced by activation of beta-glucosidase regulated by the biological clock.

Journal Article↗
PubMed1994

The interiorized environment.

Biological reactions occur regularly at the right time, on the right place and in the right quantity. How does this biological order work? Mechanicistics and vitalists fail to explain it and holism is an alternative that misses the very point. Our investigation is restricted to the relation between the organism and its specific environment, stressing their mutual penetration, common to twins. The twin organisms/environment in organisms as a whole, in the cellular environment of DNA and around the biological clock.

Adaptation, Biological↗
PubMed2004

The brain's calendar: neural mechanisms of seasonal timing.

The suprachiasmatic nucleus (SCN) of the hypothalamus is the principal component of the mammalian biological clock, the neural timing system that generates and coordinates a broad spectrum of physiological, endocrine and behavioural circadian rhythms. The pacemaker of the SCN oscillates with a near 24 h period and is entrained to the diurnal light-dark cycle. Consistent with its role in circadian timing, investigations in rodents and non-human primates furthermore suggest that the SCN is the locus of the brain's endogenous calendar, enabling organisms to anticipate seasonal environmental changes. The present review focuses on the neuronal organization and dynamic properties of the biological clock and the means by which it is synchronized with the environmental lighting conditions. It is shown that the functional activity of the biological clock is entrained to the seasonal photic cycle and that photoperiod (day length) may act as an effective zeitgeber. Furthermore, new insights are presented, based on electrophysiological and molecular studies, that the mammalian circadian timing system consists of coupled oscillators and that the clock genes of these oscillators may also function as calendar genes. In summary, there are now strong indications that the neuronal changes and adaptations in mammals that occur in response to a seasonally changing environment are driven by an endogenous circadian clock located in the SCN, and that this neural calendar is reset by the seasonal fluctuations in photoperiod.

Animals↗
PubMed1995

Mutations in the clk-1 gene of Caenorhabditis elegans affect developmental and behavioral timing.

We have identified three allelic, maternal-effect mutations that affect developmental and behavioral timing in Caenorhabditis elegans. They result in a mean lengthening of embryonic and postembryonic development, the cell cycle period and life span, as well as the periods of the defecation, swimming and pumping cycles. These mutants also display a number of additional phenotypes related to timing. For example, the variability in the length of embryonic development is several times larger in the mutants than in the wild type, resulting in the occasional production of mutant embryos developing more rapidly than the most rapidly developing wild-type embryos. In addition, the duration of embryonic development of the mutants, but not of the wild type, depends on the temperature at which their parents were raised. Finally, individual variations in the severity of distinct mutant phenotypes are correlated in a counterintuitive way. For example, the animals with the shortest embryonic development have the longest defecation cycle and those with the longest embryonic development have the shortest defecation cycle. Most of the features affected by these mutations are believed to be controlled by biological clocks, and we therefore call the gene defined by these mutations clk-1, for "abnormal function of biological clocks."

Alleles↗
PubMed2006

A network of (autonomic) clock outputs.

The circadian clock in the suprachiasmatic nuclei (SCN) is composed of thousands of oscillator neurons, each dependent on the cell-autonomous action of a defined set of circadian clock genes. A major question is still how these individual oscillators are organized into a biological clock that produces a coherent output capable of timing all the different daily changes in behavior and physiology. We investigated which anatomical connections and neurotransmitters are used by the biological clock to control the daily release pattern of a number of hormones. The picture that emerged shows projections contacting target neurons in the medial hypothalamus surrounding the SCN. The activity of these pre-autonomic and neuro-endocrine target neurons is controlled by differentially timed waves of vasopressin, GABA, and glutamate release from SCN terminals, among other factors. Together our data indicate that, with regard to the timing of their main release period within the LD cycle, at least four subpopulations of SCN neurons should be discernible. The different subgroups do not necessarily follow the phenotypic differences among SCN neurons. Thus, different subgroups can be found within neuron populations containing the same neurotransmitter. Remarkably, a similar distinction of four differentially timed subpopulations of SCN neurons was recently also discovered in experiments determining the temporal patterns of rhythmicity in individual SCN neurons by way of the electrophysiology or clock gene expression. Moreover, the specialization of the SCN may go as far as a single body structure, i.e., the SCN seems to contain neurons that specifically target the liver, pineal gland, and adrenal gland.

Animals↗
PubMed2025

Convergent latitudinal erosion of circadian systems in a rapidly diversifying order of fishes.

Biological clocks enable organisms to anticipate cyclical environmental changes. Some habitats, such as those at high latitudes or deep sea, experience seasonally diminished or absent diel cues upon which species entrain their circadian rhythms. Fishes of the order Perciformes have rapidly diversified and adapted to these arrhythmic ecosystems, raising the possibility that evolutionary modifications to their circadian biology contributes to their success as one of the most species-rich orders of vertebrates. Here, we used a comparative genomic approach to investigate patterns of biological clock gene loss and circadian rhythms across 33 perciform and six outgroup species. We found both widespread and lineage-specific loss and relaxed selection in core clock genes, particularly in the convergently evolving polar and deep-sea Notothenioidei and Cottioidei suborders. This trend of circadian gene loss was significantly correlated with latitude, with higher-latitude species showing greater loss. Whether these losses and relaxed selection lead to changes in circadian rhythms is unknown for most perciforms. To address this, we performed metabolic phenotyping on three notothenioid species and found no circadian metabolic oscillations during the late austral fall, including in the sub-Antarctic Eleginops maclovinus, sister to the Antarctic adaptive radiation. We propose that diminished reliance on endogenous biological clocks may be an adaptive feature that facilitates the survival and diversification of perciform fishes in polar and arrhythmic environments.

Journal Article↗
PubMed2001

Identification of the suprachiasmatic nucleus in birds.

Circadian rhythms are generated by an internal biological clock. The suprachiasmatic nucleus (SCN) in the hypothalamus is known to be the dominant biological clock regulating circadian rhythms in mammals. In birds, two nuclei, the so-called medial SCN (mSCN) and the visual SCN (vSCN), have both been proposed to be the avian SCN. However, it remains an unsettled question which nuclei are homologous to the mammalian SCN. We have identified circadian clock genes in Japanese quail and demonstrated that these genes are expressed in known circadian oscillators, the pineal and the retina. Here, we report that these clock genes are expressed in the mSCN but not in the vSCN in Japanese quail, Java sparrow, chicken, and pigeon. In addition, mSCN lesions eliminated or disorganized circadian rhythms of locomotor activity under constant dim light, but did not eliminate entrainment under light-dark (LD) cycles in pigeon. However, the lesioned birds became completely arrhythmic even under LD after the pineal and the eye were removed. These results indicate that the mSCN is a circadian oscillator in birds.

Animals↗
PubMed2006

Lcg is a light-inducible and clock-controlled gene expressed in the chicken pineal gland.

The circadian clock is an autonomous biological clock that is entrainable to environmental 24-h cycles by receiving time cues such as light. Generally, light given at early and late subjective night, respectively, delays and advances the phase of the circadian oscillator. We previously searched for the chicken pineal genes that are induced by light in a phase-dependent manner. The present study undertook cDNA cloning and characterization of a gene whose expression was remarkably up-regulated by light at late subjective night. The mRNA level of this gene exhibited robust diurnal change in the pineal gland, with a peak in the early (subjective) day under light-dark cycles and constant dark condition, and hence it was designated Lcg (Light-inducible and Clock-controlled Gene). Chicken Lcg encodes a coiled-coil protein composed of 560 amino acid residues. Among chicken tissues, the pineal gland and the retina exhibited relatively high expression levels of LCG. LCG was colocalized with gamma-tubulin, a centrosomal protein, when expressed in COS7 cells, and LCG is the first example of a clock-related molecule being accumulated at the centrosome. Coimmunoprecipitation of LCG with gamma-tubulin in the chicken pineal lysate suggests a link between the circadian oscillator and the centrosomal function.

Amino Acid Sequence↗
PubMed2004

Cirrhosis progression as a model of accelerated senescence: affecting the biological aging clock by a breakthrough biophysical methodology.

To test new treatment modalities, a pilot study with a novel noninvasive biophysical methodology (Delta-S DVD) that can artificially exert a "decrease of entropy" through the patented electromagnetic-driven delivery of "energy clusters" was designed. This process has been modulated and integrated by the body as a "self" source to support the energy-dependent functional stores, thus modifying reparative into regenerative mechanisms of liver parenchyma. Seven long-standing hepatitis C virus-positive (Child A-B) cirrhosis patients with overt symptoms and portal hypertension and failure or side effects of antiviral drug treatment underwent 40-min sessions of Delta-S DVD daily for six months and were followed up monthly. At the end of the first month, rapid improvement of symptoms and a decrease of portal hypertension were noted. At the end of treatment, all patients showed either a complete (80%) or a partial (20%) regression of fatigue (FISK score), peripheral edema, pruritus, and palmar erythema. As observed, despite having stopped beta-blockers, F1 esophageal varices disappeared (60%), whereas F2 decreased to F1. The Doppler ultrasound aspect of partial (40%) or total (20%) atrophy was either reduced (60%) or reverted to normal (20%), and the respiratory dynamics of the portal vein improved (80%) or normalized (20%), whereas gross scarring nodules disappeared in 40% of cases. These promising data pave the way for an innovative physiopathological approach with extensive clinical applications.

Aging↗
PubMed1985

Forecasting cephalosporin and monobactam antibiotic half-lives in humans from data collected in laboratory animals.

The postdistribution half-lives of 10 cephalosporin and 2 monobactam antibiotics in humans were predicted from data obtained in other mammals. This forecasting was accomplished with the allometric equation t1/2 = aWb, where a is the y intercept and b is the slope obtained from the log-log plot of antibiotic half-life (t1/2) versus body weight (W). Dimensionless similarity criteria were used to produce a biological clock for ceftizoxime elimination. The creation of the biological clock, which measured physiologic time (heartbeats) rather than chronologic time (minutes), demonstrated that ceftizoxime half-life was identical in five mammals. This methodology will contribute to infectious disease research through a greater understanding of pharmacokinetic scaling in mammals.

Animals↗
PubMed2006

[A chronobiological approach in treatment of sleep disturbances in Alzheimer's dementia patients].

Alzheimer's dementia (AD) is a neurodegenerative disease that is often accompanied by severe sleep disturbances. The manifestation of the sleep disturbances is twofold: nighttime hyperarousal sometimes accompanied by irritability and agitation, and daytime excessive sleepiness. Thus, although treatment with sedatives or hypnotics may offer some relief to the nighttime hyperarousal, the daytime excessive sleepiness remains mostly unresolved. Recently, however, more promising results in relief of excessive daytime sleepiness, as well as nighttime hyperarousal, are offered by the chronobiological approach. This approach attributes the sleep problems of AD patients to a dysfunction in a broader neuronal mechanism, namely the biological clock, that paces various physiological functions, among which is the sleep-wake cycle. The biological clock, situated in the suprachiasmatic nuclei (SCN) of the hypothalamus, receives environmental light input via neuronal signals from the retina. The SCN, in turn, innervates the pineal gland, that is responsible for the production and release of melatonin. Light stimulus causes the attenuation of melatonin secretion from the pineal gland; whereas the cessation of light increases melatonin secretion. In diurnal mammals, the dim light melatonin onset (DLMO) is in accordance with sleep onset. The chronobiological approach offers two main treatments to the sleep problems in AD patients: morning exposure to bright light and evening administration of melatonin, both of which show at least moderate success in restoring the sleep-wake cycle in AD patients, that is more marked in the early stages of the disease.

Alzheimer Disease↗
PubMed1999

[Biologic rhythms: their changes in night-shift workers].

ENVIRONMENTAL STRESS: Environmental cycles, such as the light-dark cycle, provide information used by the biological clock in the hypothalamus to synchronize the biological systems and maintain the organism's internal cohesion. In persons whose work schedules include night hours (approximately 20% of the working population in France) the sleep-wake cycles are not in phase with these environmental cycles. BIOLOGICAL RHYTHMS: What effect does the conflicting information perceived by night-shift workers have on their biological rhythms? Indices of the processes going on in the cerebral clock, these biological rhythms are the only tool available in man to determine possible dysfunction of the clock. Several studies have identified these rhythms in night-shift workers but results have been contradictory. PARTIAL ADAPTATION: Recently we made repeated measurements every 10 min over a 24 hour period in night-shift workers to determine the precise melatonin, cortisol, and thyrotropin (TSH) patterns, which reflect the endogenous clock, and prolactin (PRL) and growth hormone (GH) patterns which are influenced by sleep but also have a circadian component. This study demonstrated that there is some, but partial, adaptation of the biological rhythms in these persons. The shift in the melatonin pattern is quite variable from one individual to another. Night work causes a distortion in the cortisol and TSH rhythms. This partial adaptation is also seen in the GH and PRL curves, mainly related to sleep, but whose endogenous component previously described in other experimental situations is found in night workers with a distribution incompletely adapted to the secretory episodes. RESEARCH PERSPECTIVES: Both daytime sleep and night-time work are associated with perturbed endocrine functions which could explain certain health problems and sleep disorders observed (or avowed) after several years of night-shift work. These problems require further research into factors susceptible of resynchronizing the biological clock.

Adaptation, Physiological↗
PubMed1975

Deep hypothermia and its effect on the 24-hour clock of rats and hamsters.

Intensive hypothermia in rats and hamsters whose breathing and heartbeat had stopped for 1-4 hours was used as a setting in which to study the 24-hour biological clock. Pre- and post-hypothermia analyses depended on behavior wherein spontaneous running activity in revolving drums was used as a "hand" of the biological clock. Hypothermia had various effects. In some cases the clock was temporaily stopped, i.e., reset. In others it was simply slowed. Some clocks were both reset and slowed. Others ran without interruption even though breathing and heartbeat had stopped for 3-4 hours.

Animals↗