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)

Most physiology and behavior of mammalian organisms follow daily oscillations. These rhythmic processes are governed by environmental cues (e.g., fluctuations in light intensity and temperature), an internal circadian timing system, and the interaction between this timekeeping system and environmental signals. In mammals, the circadian timekeeping system has a complex architecture, composed of a central pacemaker in the brain's suprachiasmatic nuclei (SCN) and subsidiary clocks in nearly every body cell. The central clock is synchronized to geophysical time mainly via photic cues perceived by the retina and transmitted by electrical signals to SCN neurons. In turn, the SCN influences circadian physiology and behavior via neuronal and humoral cues and via the synchronization of local oscillators that are operative in the cells of most organs and tissues. Thus, some of the SCN output pathways serve as input pathways for peripheral tissues. Here we discuss knowledge acquired during the past few years on the complex structure and function of the mammalian circadian timing system.

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The mammalian circadian timing system: organization and coordination of central and peripheral clocks.

Over more than a century of research has established the fact that sleep benefits the retention of memory. In this review we aim to comprehensively cover the field of "sleep and memory" research by providing a historical perspective on concepts and a discussion of more recent key findings. Whereas initial theories posed a passive role for sleep enhancing memories by protecting them from interfering stimuli, current theories highlight an active role for sleep in which memories undergo a process of system consolidation during sleep. Whereas older research concentrated on the role of rapid-eye-movement (REM) sleep, recent work has revealed the importance of slow-wave sleep (SWS) for memory consolidation and also enlightened some of the underlying electrophysiological, neurochemical, and genetic mechanisms, as well as developmental aspects in these processes. Specifically, newer findings characterize sleep as a brain state optimizing memory consolidation, in opposition to the waking brain being optimized for encoding of memories. Consolidation originates from reactivation of recently encoded neuronal memory representations, which occur during SWS and transform respective representations for integration into long-term memory. Ensuing REM sleep may stabilize transformed memories. While elaborated with respect to hippocampus-dependent memories, the concept of an active redistribution of memory representations from networks serving as temporary store into long-term stores might hold also for non-hippocampus-dependent memory, and even for nonneuronal, i.e., immunological memories, giving rise to the idea that the offline consolidation of memory during sleep represents a principle of long-term memory formation established in quite different physiological systems.

https://www.zora.uzh.ch/id/eprint/77770/1/physiol_rev_93.pdf

About sleep's role in memory

The circadian system of mammals is composed of a hierarchy of oscillators that function at the cellular, tissue, and systems levels. A common molecular mechanism underlies the cell-autonomous circadian oscillator throughout the body, yet this clock system is adapted to different functional contexts. In the central suprachiasmatic nucleus (SCN) of the hypothalamus, a coupled population of neuronal circadian oscillators acts as a master pacemaker for the organism to drive rhythms in activity and rest, feeding, body temperature, and hormones. Coupling within the SCN network confers robustness to the SCN pacemaker, which in turn provides stability to the overall temporal architecture of the organism. Throughout the majority of the cells in the body, cell-autonomous circadian clocks are intimately enmeshed within metabolic pathways. Thus, an emerging view for the adaptive significance of circadian clocks is their fundamental role in orchestrating metabolism.

/pdf/central-and-peripheral-circadian-clocks-in-mammals-2qtn9mbv5i.pdf

Central and Peripheral Circadian Clocks in Mammals

The organization of biological activities into daily cycles is universal in organisms as diverse as cyanobacteria, fungi, algae, plants, flies, birds and man. Comparisons of circadian clocks in unicellular and multicellular organisms using molecular genetics and genomics have provided new insights into the mechanisms and complexity of clock systems. Whereas unicellular organisms require stand-alone clocks that can generate 24-hour rhythms for diverse processes, organisms with differentiated tissues can partition clock function to generate and coordinate different rhythms. In both cases, the temporal coordination of a multi-oscillator system is essential for producing robust circadian rhythms of gene expression and biological activity.

http://www.ifc.unam.mx/curso_ritmos/capitulo8/Bell-Pedersen05.pdf

Circadian rhythms from multiple oscillators: lessons from diverse organisms

Time of day-dependent variations of immune system parameters are ubiquitous phenomena in immunology. The circadian clock has been attributed with coordinating these variations on multiple levels; however, their molecular basis is little understood. Here, we systematically investigated the link between the circadian clock and rhythmic immune functions. We show that spleen, lymph nodes, and peritoneal macrophages of mice contain intrinsic circadian clockworks that operate autonomously even ex vivo. These clocks regulate circadian rhythms in inflammatory innate immune functions: Isolated spleen cells stimulated with bacterial endotoxin at different circadian times display circadian rhythms in TNF-α and IL-6 secretion. Interestingly, we found that these rhythms are not driven by systemic glucocorticoid variations nor are they due to the detected circadian fluctuation in the cellular constitution of the spleen. Rather, a local circadian clock operative in splenic macrophages likely governs these oscillations as indicated by endotoxin stimulation experiments in rhythmic primary cell cultures. On the molecular level, we show that >8% of the macrophage transcriptome oscillates in a circadian fashion, including many important regulators for pathogen recognition and cytokine secretion. As such, understanding the cross-talk between the circadian clock and the immune system provides insights into the timing mechanism of physiological and pathophysiological immune functions.

https://www.pnas.org/content/pnas/106/50/21407.full.pdf

A circadian clock in macrophages controls inflammatory immune responses.

Circadian clocks are endogenous oscillators driving daily rhythms in physiology and behavior. Synchronization of these timers to environmental light–dark cycles (‘entrainment’) is crucial for an organism’s fitness. Little is known about which oscillator qualities determine entrainment, i.e., entrainment range, phase and amplitude. In a systematic theoretical and experimental study, we uncovered these qualities for circadian oscillators in the suprachiasmatic nucleus (SCN—the master clock in mammals) and the lung (a peripheral clock): (i) the ratio between stimulus (zeitgeber) strength and oscillator amplitude and (ii) the rigidity of the oscillatory system (relaxation rate upon perturbation) determine entrainment properties. Coupling among oscillators affects both qualities resulting in increased amplitude and rigidity. These principles explain our experimental findings that lung clocks entrain to extreme zeitgeber cycles, whereas SCN clocks do not. We confirmed our theoretical predictions by showing that pharmacological inhibition of coupling in the SCN leads to larger ranges of entrainment. These differences between master and the peripheral clocks suggest that coupling-induced rigidity in the SCN filters environmental noise to create a robust circadian system.

https://www.embopress.org/doi/pdf/10.1038/msb.2010.92

Coupling governs entrainment range of circadian clocks.

The suprachiasmatic nucleus (SCN) of the hypothalamus has been termed the master circadian pacemaker of mammals. Recent discoveries of damped circadian oscillators in other tissues have led to the hypothesis that the SCN synchronizes and sustains daily rhythms in these tissues. We studied the effects of constant lighting (LL) and of SCN lesions on behavioral rhythmicity and Period 1 (Per1) gene activity in the SCN and olfactory bulb (OB). We found that LL had similar effects on cyclic locomotor and feeding behaviors and Per1 expression in the SCN but had no effect on rhythmic Period 1 expression in the OB. LL lengthened the period of locomotor and SCN rhythms by approximately 1.6 hr. After 2 weeks in LL, nearly 35% of rats lost behavioral rhythmicity. Of these, 90% showed no rhythm in Per1-driven expression in their SCN. Returning the animals to constant darkness rapidly restored their daily cycles of running wheel activity and gene expression in the SCN. In contrast, the OB remained rhythmic with no significant change in period, even when cultured from animals that had been behaviorally arrhythmic for 1 month. Similarly, we found that lesions of the SCN abolished circadian rhythms in behavior but not in the OB. Together, these results suggest that LL causes the SCN to lose circadian rhythmicity and its ability to coordinate daily locomotor and feeding rhythms. The SCN, however, is not required to sustain all rhythms because the OB continues to oscillate in vivo when the SCN is arrhythmic or ablated.

https://www.jneurosci.org/content/jneuro/24/3/615.full.pdf

The suprachiasmatic nucleus entrains, but does not sustain, circadian rhythmicity in the olfactory bulb.

Behavioral and physiological circadian rhythms in mammals are controlled by a master pacemaker in the hypothalamic suprachiasmatic nuclei (SCN). Recently, circadian oscillations of hormone secretion, clock gene expression, and electrical activity have been demonstrated in explants of other brain regions. This suggests that some extra-SCN brain regions contain a functional, SCN-independent circadian clock, but in vivo evidence for intrinsic pacemaking is still lacking. We developed a novel method to image bioluminescence in vivo from the main olfactory bulbs (OB) of intact and SCN-lesioned (SCNX) Period1::luciferase rats for 2 d in constant darkness. The OBs expressed circadian rhythms in situ with a reliable twofold increase from day to night, similar to the phase and amplitude of ex vivo rhythms. In vivo cycling persisted for at least 1 month in the absence of the SCN. To assess indirectly in vivo rhythmicity of other brain areas, we measured the phase-dependence of their in vitro rhythms on the time of surgery. Surgery reliably reset the phase of the pineal gland and vascular organ of the lamina terminalis (VOLT) harvested from SCNX rats but had little effect on the phase of the OB. We deduce that the SCN and OB contain self-sustained circadian oscillators, whereas the pineal gland and VOLT are weak oscillators that require input from the SCN to show coordinated circadian rhythms. We conclude that the mammalian brain comprises a diverse set of SCN-dependent and SCN-independent circadian oscillators.

https://www.jneurosci.org/content/jneuro/25/38/8620.full.pdf

Independent Circadian Oscillations of Period1 in Specific Brain Areas In Vivo and In Vitro

Endogenous circadian rhythms have been described in a wide range of organisms from prokaryotes to man. Although basic circadian mechanisms at the molecular level are genetically fixed, certain properties of circadian rhythms at the organismic level can be modified by environmental conditions and subsequently retained for some time, even in organisms shielded from 24-hr environmental variations. To investigate the capacity of animals to acquire and store photoperiodic information, we examined activity and melatonin rhythms in house sparrows during synchronization to two different photoperiods and during subsequent prolonged darkness. Under constant environmental conditions, intact animals continued to have long feeding activity times when previously exposed to long days and short feeding activity times when previously exposed to short days. Correspondingly, significantly different durations of elevated melatonin in the plasma directly reflected the differences in night length during synchronization as well as during prolonged darkness. Additionally, we found a significant difference in the amplitude of the nocturnal melatonin signal, which also was conserved in prolonged darkness. To investigate whether the photoperiodic experience of an intact animal can be “memorized” by an isolated component of its circadian pacemaking system, we have investigated in vitro melatonin release during continuous darkness from explanted pineal glands of house sparrows after in vivo synchronization to two distinct photoperiods. Differences in the durations of elevated melatonin occurred during the first two cycles in culture and a difference in melatonin amplitude was detectable during the first night in culture. Our data indicate that photoperiodic patterns imposed on sparrows during in vivo synchronization can be maintained as an internal representation of time within the isolated pineal gland. Hence, the pineal gland, as one of the most significant components of the songbird circadian pacemaker, not only has the capacity to autonomously produce circadian rhythms of melatonin release but also is capable of storing biologically meaningful information experienced during previous cycles.

https://www.pnas.org/content/pnas/97/22/12324.full.pdf

Ute Abraham

Papers

A circadian clock in macrophages controls inflammatory immune responses.

Coupling governs entrainment range of circadian clocks.

The suprachiasmatic nucleus entrains, but does not sustain, circadian rhythmicity in the olfactory bulb.

Independent Circadian Oscillations of Period1 in Specific Brain Areas In Vivo and In Vitro

Photoperiodic information acquired and stored in vivo is retained in vitro by a circadian oscillator, the avian pineal gland.