Time in the biological sense is measured by cycles that range from milliseconds to years. Circadian rhythms, which measure time on a scale of 24 h, are generated by one of the most ubiquitous and well-studied timing systems. At the core of this timing mechanism is an intricate molecular mechanism that ticks away in many different tissues throughout the body. However, these independent rhythms are tamed by a master clock in the brain, which coordinates tissue-specific rhythms according to light input it receives from the outside world.

Coordination of circadian timing in mammals

1980 Preface * 1999 Preface * 1999 Acknowledgements * Introduction * 1 Circular Logic * 2 Phase Singularities (Screwy Results of Circular Logic) * 3 The Rules of the Ring * 4 Ring Populations * 5 Getting Off the Ring * 6 Attracting Cycles and Isochrons * 7 Measuring the Trajectories of a Circadian Clock * 8 Populations of Attractor Cycle Oscillators * 9 Excitable Kinetics and Excitable Media * 10 The Varieties of Phaseless Experience: In Which the Geometrical Orderliness of Rhythmic Organization Breaks Down in Diverse Ways * 11 The Firefly Machine 12 Energy Metabolism in Cells * 13 The Malonic Acid Reagent ('Sodium Geometrate') * 14 Electrical Rhythmicity and Excitability in Cell Membranes * 15 The Aggregation of Slime Mold Amoebae * 16 Numerical Organizing Centers * 17 Electrical Singular Filaments in the Heart Wall * 18 Pattern Formation in the Fungi * 19 Circadian Rhythms in General * 20 The Circadian Clocks of Insect Eclosion * 21 The Flower of Kalanchoe * 22 The Cell Mitotic Cycle * 23 The Female Cycle * References * Index of Names * Index of Subjects

https://www.cambridge.org/core/services/aop-cambridge-core/content/view/596B270197FE27DE5FABB598B6210622/S0025557200150892a.pdf/div-class-title-span-class-italic-the-geometry-of-biological-time-span-by-a-t-winfree-pp-544-dm68-corrected-second-printing-1990-isbn-3-540-52528-9-springer-div.pdf

The geometry of biological time , by A. T. Winfree. Pp 544. DM68. Corrected Second Printing 1990. ISBN 3-540-52528-9 (Springer)

Light synchronizes mammalian circadian rhythms with environmental time by modulating retinal input to the circadian pacemaker-the suprachiasmatic nucleus (SCN) of the hypothalamus. Such photic entrainment requires neither rods nor cones, the only known retinal photoreceptors. Here, we show that retinal ganglion cells innervating the SCN are intrinsically photosensitive. Unlike other ganglion cells, they depolarized in response to light even when all synaptic input from rods and cones was blocked. The sensitivity, spectral tuning, and slow kinetics of this light response matched those of the photic entrainment mechanism, suggesting that these ganglion cells may be the primary photoreceptors for this system.

http://science.sciencemag.org/content/sci/295/5557/1070.full.pdf

Phototransduction by retinal ganglion cells that set the circadian clock.

Molecular Bases for Circadian Clocks

▪ Abstract The peroxisome proliferator-activated receptors (PPARs) are a group of three nuclear receptor isoforms, PPARγ, PPARα, and PPARδ, encoded by different genes. PPARs are ligand-regulated transcription factors that control gene expression by binding to specific response elements (PPREs) within promoters. PPARs bind as heterodimers with a retinoid X receptor and, upon binding agonist, interact with cofactors such that the rate of transcription initiation is increased. The PPARs play a critical physiological role as lipid sensors and regulators of lipid metabolism. Fatty acids and eicosanoids have been identified as natural ligands for the PPARs. More potent synthetic PPAR ligands, including the fibrates and thiazolidinediones, have proven effective in the treatment of dyslipidemia and diabetes. Use of such ligands has allowed researchers to unveil many potential roles for the PPARs in pathological states including atherosclerosis, inflammation, cancer, infertility, and demyelination. Here, we presen...

The Mechanisms of Action of PPARs

The present experiments were designed to evaluate whether the intraventricular administration of excitatory amino acid (EAA) receptor antagonists would prevent light-induced phase shifts of the circadian rhythm of wheel-running activity in the hamster. Administration of the non-N-methyl-D-aspartate (non-NMDA) antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX) blocked light-induced phase advances and delays. Similarly, administration of the competitive NMDA receptor antagonist, 3(2-carboxypiperazin-4-yl)-propyl-l-phosphonic acid (CPP), prevented light-induced phase advances and delays. Neither drug by itself caused any consistent effect on the phase of the rhythm. These data provide further evidence that EAA receptors mediate the effects of light on the circadian system, and suggest that both NMDA and non-NMDA receptor types may be involved.

NMDA as well as non-NMDA receptor antagonists can prevent the phase-shifting effects of light on the circadian system of the golden hamster.

A small but convincing body of literature indicates the existence of photoreception by nervous tissue which is not obviously specialized for this function. Among the invertebrates, perhaps the most thoroughly studied case is the caudal ganglion of the crayfish, which possesses two neurons that respond electrically to light stimuli.' The pineal organs of fish, amphibians, and reptiles, though not of birds and mammals, have been shown to be light-sensitive.2 Sunlight penetrates to the hypothalamus of several mammalian species ;3 however, the only indication that light may exert a physiological effect directly on the mammalian brain comes from the work of Lisk and Kannwischer,4 who showed that selective illumination of several areas of the hypothalamus affected the estrous cycle in blinded rats. An elegant series of studies by Benoit and co-workers5 has established that testis growth, a system under partial photoperiodic control, can be effected by light impinging directly on the hypothalamic area of the brains of blinded ducks. Benoit's results have not stimulated other workers to perform similar experiments, probably because of the great difficulty encountered in keeping blinded birds of most species alive, and remain the only published evidence for light sensitivity of the avian brain. Circadian rhythms of locomotor activity have been extensively studied in many species of passerine birds7 as well as in rodents, insects, and a variety of other animals. In constant darkness or constant dim light, such rhythms universally exhibit free-running periods, characteristic of both the species and the individual animals studied and generally different from 24 hours. Without exception, free-running rhythms can be entrained (synchronized) by exposing the organism to light-dark cycles with periods of exactly 24 hours. The entrained rhythm has a period of exactly 24 hours as well as a determinate phase relationship to the light cycle. Entrainment to a light cycle can thus serve as a definitive and easily obtainable assay of light perception. Several workers have studied circadian rhythms of blinded mammals in the presence of light cycles and have reported that the rhythms were free-running, as if the animals were in constant darkness.8 It therefore appears that in mammals retinal light perception may provide the only route by which information about the environmental light regimen reaches the centers that control circadian rhythms. There are no previous reports of experiments with circadian rhythms of blinded birds. The present paper reports on experiments which demonstrate that the house sparrow (Passer domesticus) possesses an extraretinal photoreceptor(s) which is coupled to the \"clock\" system controlling the overt circadian rhythm of locomotor activity. The sensitivity of this receptor and the response of the free-running period of the rhythm of blinded birds to constant light of various intensities are also discussed.

http://www.pnas.org/content/59/2/414.full.pdf

Extraretinal light perception in the sparrow. I. Entrainment of the biological clock.

Food-anticipatory activity (FAA) is the increase in locomotion and core body temperature that precedes a daily scheduled meal. It is driven by a circadian oscillator but is independent of the suprachiasmatic nuclei. Recent results that reveal meal-entrained clock gene expression in rat and mouse peripheral organs raise the intriguing possibility that the digestive system is the site of the feeding-entrained oscillator (FEO) that underlies FAA. We tested this possibility by comparing FAA and Per1 rhythmicity in the digestive system of the Per1-luciferase transgenic rat. First, rats were entrained to daytime restricted feeding (RF, 10 days), then fed ad libitum (AL, 10 days), then food deprived (FD, 2 days). As expected FAA was evident during RF and disappeared during subsequent AL feeding, but returned at the correct phase during deprivation. The phase of Per1 in liver, stomach and colon shifted from a nocturnal to a diurnal peak during RF, but shifted back to nocturnal phase during the subsequent AL and remained nocturnal during food deprivation periods. Second, rats were entrained to two daily meals at zeitgeber time (ZT) 0400 and ZT 1600. FAA to both meals emerged after about 10days of dual RF. However, all tissues studied (all five liver lobes, esophagus, antral stomach, body of stomach, colon) showed entrainment consistent with only the night-time meal. These two results are inconsistent with the hypothesis that FAA arises as an output of rhythms in the gastrointestinal (GI) system. The results also highlight an interesting diversity among peripheral oscillators in their ability to entrain to meals and the direction of the phase shift after RF ends.

https://onlinelibrary.wiley.com/doi/pdf/10.1034/j.1601-183X.2003.00005.x

Is the food-entrainable circadian oscillator in the digestive system?

The continuous administration of low levels of melatonin via intraperitoneally placed Silastic capsules either (i) shortened the free-running period of activity or (ii) induced continuous activity in house sparrows (Passer domesticus) maintained in constant darkness. After the melatonin-filled capsules were removed, the period of the circadian rhythm of activity lengthened in rhythmic birds and normal rhythmicity was restored in continuously active birds. The results suggest that melatonin is involved in the physiological control of circadian rhythmicity in sparrows.

https://science.sciencemag.org/content/sci/194/4272/1441.full.pdf

Melatonin: Effects on the circadian locomotor rhythm of sparrows

Both dopamine and melatonin are important for the regulation of retinal rhythmicity, and substantial evidence suggests that these two substances are mutually inhibitory factors that act as chemical analogs of day and night. A circadian oscillator in the mammalian retina regulates melatonin synthesis. Here we show a circadian rhythm of retinal dopamine content in the mouse retina, and examine the role of melatonin in its control. Using high-performance liquid chromatography (HPLC), we measured levels of dopamine and its two major metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in retinas of C3H+/+ mice (which make melatonin) and C57BL/6J mice that are genetically incapable of melatonin synthesis. In a light/dark cycle both strains of mice exhibited daily rhythms of retinal dopamine, DOPAC, and HVA content. However, after 10 days in constant darkness (DD), a circadian rhythm in dopamine levels was present in C3H, but not in C57 mice. C57 mice given ten daily injections of melatonin in DD exhibited a robust circadian rhythm of retinal dopamine content whereas no such rhythm was present in saline-injected controls. Our results demonstrate that (1) a circadian clock generates rhythms of dopamine content in the C3H mouse retina, (2) mice lacking melatonin also lack circadian rhythms of dopamine content, and (3) dopamine rhythms can be generated in these mice by cyclic administration of exogenous melatonin. Our results also indicate that circadian rhythms of retinal dopamine depend upon the rhythmic presence of melatonin, but that cyclic light can drive dopamine rhythms in the absence of melatonin.

https://www.cambridge.org/core/services/aop-cambridge-core/content/view/S0952523802195058

Michael Menaker

Papers

NMDA as well as non-NMDA receptor antagonists can prevent the phase-shifting effects of light on the circadian system of the golden hamster.

Extraretinal light perception in the sparrow. I. Entrainment of the biological clock.

Is the food-entrainable circadian oscillator in the digestive system?

Melatonin: Effects on the circadian locomotor rhythm of sparrows

Circadian rhythms of dopamine in mouse retina: the role of melatonin.