A phase dynamics model of human circadian rhythms

Nonphotic entrainment of an overt sleep-wake rhythm and a circadian pacemaker-driving temperature/melatonin rhythm suggests existence of feedback mechanisms in the human circadian system. In this study, the authors constructed a phase dynamics model that consisted of two oscillators driving temperature/melatonin and sleep-wake rhythms, and an additional oscillator generating an overt sleep-wake rhythm. The feedback mechanism was implemented by modifying couplings between the constituent oscillators according to the history of correlations between them. The model successfully simulated the behavior of human circadian rhythms in response to forced rest-activity schedules under free-run situations: the sleep-wake rhythm is reentrained with the circadian pacemaker after release from the schedule, there is a critical period for the schedule to fully entrain the sleep-wake rhythm, and the forced rest-activity schedule can entrain the circadian pacemaker with the aid of exercise. The behavior of human circadian rhythms was reproduced with variations in only a few model parameters. Because conventional models are unable to reproduce the experimental results concerned here, it was suggested that the feedback mechanisms included in this model underlie nonphotic entrainment of human circadian rhythms.     

Ultradian, circahoral and circadian structures in endothermic vertebrates and humans

1. For more than 30 years many studies have been carried out concerning rhythms with periods approaching 24 hr (circadian rhythms). 2. The latter have been demonstrated as resulting from environmental 24 hr synchronizers (zeitgebers), but they usually persist in the absence of a 24 hr synchronization, which proves their endogenous nature. 3. Biological rhythms with periods less than 20 hr (ultradian rhythms) and particularly those approaching 1 hr (circahoral rhythms) have been determined: for motility, rest-activity, sleep phases, endocrine secretions and other physiological functions. 4. These ultradian and circahoral rhythms have been found in rodents, birds, monkeys and humans. 5. Existing at all stages of ontogeny, they have been proved to be endogenous and species and strain specific. 6. As these ultradian rhythms can be influenced by environmental factors and sometimes by circadian rhythms they are not truly periodic, so therefore cannot be computed by the usual processes of mathematical time analysis.     

The molecular genetics of circadian rhythms in Arabidopsis.

While a number of physiological and biochemical processes in plants have been found to be regulated in a circadian manner, the mechanism underlying the circadian oscillator remains to be elucidated. Advances in the identification and characterization of components of the plant circadian system have been made largely through the use of genetics in Arabidopsis thaliana. Results so far indicate that the generation of rhythmicity by the Arabidopsis clock relies on molecular mechanisms that are similar to those described for other organisms, but that a totally different set of molecular components has been recruited to perform these functions.     

Internal noise-sustained circadian rhythms in a Drosophila model

Circadian rhythmic processes, mainly regulated by gene expression at the molecular level, have inherent stochasticity. Their robustness or resistance to internal noise has been extensively investigated by most of the previous studies. This work focuses on the constructive roles of internal noise in a reduced Drosophila model, which incorporates negative and positive feedback loops, each with a time delay. It is shown that internal noise sustains reliable oscillations with periods close to 24 h in a region of parameter space, where the deterministic kinetics would evolve to a stable steady state. The amplitudes of noise-sustained oscillations are significantly affected by the variation of internal noise level, and the best performance of the oscillations could be found at an optimal noise intensity, indicating the occurrence of intrinsic coherence resonance. In the oscillatory region of the deterministic model, the coherence of noisy circadian oscillations is suppressed by internal noise, while the period remains nearly constant over a large range of noise intensity, demonstrating robustness of the Drosophila model for circadian rhythms to intrinsic noise. In addition, the effects of time delay in the positive feedback on the oscillations are also investigated. It is found that the time delay could efficiently tune the performance of the noise-sustained oscillations. These results might aid understanding of the exploitation of intracellular noise in biochemical and genetic regulatory systems.     

Disrupted circadian rhythms in a mouse model of schizophrenia

Sleep and circadian rhythm disruption has been widely observed in neuropsychiatric disorders including schizophrenia [1] and often precedes related symptoms [2]. However, mechanistic basis for this association remains unknown. Therefore, we investigated the circadian phenotype of blind-drunk (Bdr), a mouse model of synaptosomal-associated protein (Snap)-25 exocytotic disruption that displays schizophrenic endophenotypes modulated by prenatal factors and reversible by antipsychotic treatment [3, 4]. Notably, SNAP-25 has been implicated in schizophrenia from genetic [5-8], pathological [9-13], and functional studies [14-16]. We show here that the rest and activity rhythms of Bdr mice are phase advanced and fragmented under a light/dark cycle, reminiscent of the disturbed sleep patterns observed in schizophrenia. Retinal inputs appear normal in mutants, and clock gene rhythms within the suprachiasmatic nucleus (SCN) are normally phased both in vitro and in vivo. However, the 24 hr rhythms of arginine vasopressin within the SCN and plasma corticosterone are both markedly phase advanced in Bdr mice. We suggest that the Bdr circadian phenotype arises from a disruption of synaptic connectivity within the SCN that alters critical output signals. Collectively, our data provide a link between disruption of circadian activity cycles and synaptic dysfunction in a model of neuropsychiatric disease.     

A neural theory of circadian rhythms: The gated pacemaker

This article describes a behaviorally, physiologically, and anatomically predictive model of how circadian rhythms are generated by each suprachiasmatic nucleus (SCN) of the mammalian hypothalamus. This gated pacemaker model is defined in terms of competing on-cell off-cell populations whose positive feedback signals are gated by slowly accumulating chemical transmitter substances. These components have also been used to model other hypothalamic circuits, notably the eating circuit. A parametric analysis of the types of oscillations supported by the model is presented. The complementary reactions to light of diurnal and nocturnal mammals as well as their similar phase response curves are obtained. The “dead zone” of the phase response curve during the subjective day of a noctural rodent is also explained. Oscillations are suppressed by high intensities of steady light. Operations that alter the parameters of the model transmitters can phase shift or otherwise change its circadian oscillation. Effects of ablation and hormones on model oscillations are summarized. Observed oscillations include regular periodic solutions, periodic plateau solutions, rippled plateau solutions, period doubling solutions, slow modulation of oscillations over a period of months, and repeating sequences of oscillation clusters. The model period increases inversely with the transmitter accumulation rate but is insensitive to other parameter choices except near the breakdown of oscillations. The model's clocklike nature is thus a mathematical property rather than a formal postulate. A singular perturbation approach to the model's analysis is described.     

The coevolution of blue-light photoreception and circadian rhythms

Sunlight is a primary source of energy for life. However, its UV component causes DNA damage. We suggest that the strong UV component of sunlight contributed to the selective pressure for the evolution of the specialized photoreceptor cryptochrome from photolyases involved in DNA repair and propose that early metazoans avoided irradiation by descending in the oceans during the daytime. We suggest further that it is not coincidental that blue-light photoreception evolved in an aquatic environment, since only blue light can penetrate to substantial depths in water. These photoreceptors were then also critical for sensing the decreased luminescence that signals the coming of night and the time to return to the surface. The oceans and the 24-h light-dark cycle therefore provided an optimal setting for an early evolutionary relationship between blue-light photoreception and circadian rhythmicity.     

Mosquito circadian and circa-bi-dian flight rhythms: a two-oscillator model

Summary Circadian rhythmicity was found in the flight activity ofCuliseta incidens recorded in constant darkness for up to 14 weeks. The first nonhuman circa-bi-dian (about-two-day) rhythms were also found (Figs. 6–7). Circadian periods were either stable, remaining <24h (Fig. 1), or labile, with a change from <24h to >24 h (Fig. 2). Inactivity phenomena (day-skipping) were common in the latter group only (Fig. 5). The period at activity onset was much more labile than the period at offset (Fig. 4). The activity patterns of some period-lengthened animals suggested control by two oscillators which could temporarily or permanently uncouple (Figs. 8–9).A pacemaker model consisting of a labile evening (E) oscillator mutually coupled to a stable morning (M) oscillator is the most economical proposal which can account for these results. The view that E and M uncouple and run with different periods can account for many records in which the period was labile. Circa-bi-dian rhythms can be explained by the period of E lengthening to where it synchronizes with M in a 21 mode. Thus, E and M are proposed to behave similarly to the human activity and temperature oscillators. It is speculated that day-skipping might indicate that E oscillates between circadian and circa-bi-dian ranges without overt activity being expressed.Abbreviations LD1212 alternating 12h light, 12h dark - DD constant dark - LL constant light - period of rhythm - _on period at activity onset - _off period at activity offset - activity time - mean activity time     

The circahoral rhythm of the functional activity of rat adrenocorticocytes]

Functional manifestations of biological ultradian rhythms in the adrenal cortex were first confirmed on the cytologic level. The cycle of the ultradian rhythm in the cells of the adrenal cortex fascicular zone consisted was determined to involve three phases: accumulation of lipids, delipoidization, and the rest period. A definite volume of cells and their nuclei, certain nuclear-cytoplasmic relations, the number of liposomes and mitochondria on the square unit are characteristic of each phase. The activity of cells is especially high during the second phase which is characterized by the increase in nuclear sizes and nuclear-cytoplasmatic relations, by the decrease in cell volume and in the number of liposomes in their cytoplasm; this is indicative of the rised synthesis and secretion of hormones. It is underlined that the cell volume increases when liposomes are accumulated in the cytoplasm to decrease upon their disappearance.     

Melanocytes--a UV-sensitive neural network and circadian rhythms.

The melanocytes are acutely sensitive to a single pulse of UV and express neural differentiation. The present work was undertaken to observe whether the melanocyte can sense variations in the duration of UV exposure. Whole skin organ cultures from marginal zone in vitiligo were exposed to a single pulse of UV, 30, 60, 90 and 120 s each. Catecholoxidase levels in the marginal melanocytes and the volume of melanocytes were used to calculate and quantitate the changes in enzyme production. The melanocytes' dendricity, volume and enzyme production increases with the duration of UV exposure. This sensitivity of the marginal melanocytes, to changes in the duration of UV exposure, simulates the coat color changes in weasels and the polar fox exposed to extreme variations in the day/night cycles. The UV response is associated with proliferation of melanocytes as it is G2-phase dependent. Thus the melanocytes form a UV-sensitive neural network responding to annual changes in the photoperiodicity.