A two process model of sleep regulation.

Molecular Bases for Circadian Clocks

Three mutants have been isolated in which the normal 24-hour rhythm is drastically changed. One mutant is arrhythmic; another has a period of 19 hr; a third has a period of 28 hr. Both the eclosion rhythm of a population and the locomotor activity of individual flies are affected. All these mutations appear to involve the same functional gene on the X chromosome.

https://www.pnas.org/content/pnas/68/9/2112.full.pdf

Clock Mutants of Drosophila melanogaster

1. In the first part of the paper, the model of non-parametric entrainment of circadian pacemakers is tested for the case of nocturnal rodents. The model makes use of the available data on freerunning period (τ) in constant darkness and on phase response curves (PRC) for short light pulses. It is tested in experiments using 1 or 2 light pulses per cycle. 2. Mesocricetus auratus and Peromyscus leucopus entrain to Zeitgebers involving 1 pulse (15' or 60') per cycle. The phase angle differences between rhythm and light cycle depends on the periods (τ and T) as predicted by the model. Entrainment of P. leucopus is unstable due to the after effects on τ created by the light pulse. 3. The limiting values of Zeitgeber period to which the animals entrain are much closer to 24 h than in Drosophila pseudoobscura, as the model predicts. However, frequent failures to entrain to T = 23 and T = 25 h are only explained if we take considerable interindividual variation in both τ and PRC into account. 4. With 2 pulses per cycle, the model predicts that entrainment will be more stable when activity is in the longer interval between the pulses than when it is in the shorter interval. This is true in the experimental data, where the phase relationships match predictions for skeleton photoperiods up to ca. 14 h. Increasing asymmetry forces animals into a "phase jump", so that activity shifts from the shorter to the longer interval. These ψ-jumps are accurately predicted in the hamster, but they occur at much longer photoperiods than predicted in P. leucopus. 5. Thus, the unqualified model, using a rigidly fixed species τ and PRC, is surely inadequate to explain entrainment. The extent to which variations in τ and PRC-shape, both "spontaneous" and induced by the entrainment process, can be known or inferred restricts the validity of the predictions. Yet we conclude, from a good deal of agreement between experiment and prediction (i), from the close correspondence between complete and skeleton photoperiods (ii), and on behavioural grounds (iii), that non-parametric entrainment by short light signals has a major share in the entrainment of nocturnal rodent rhythms in nature. 6. With these restrictions in mind, we analyse in the second part of the paper how the empirical regularities concerning τ and PRC contribute to the stabilization of the phase angle difference (ψ) between the pacemaker and the external world. Use is made of computer simulations of artificial pacemakers with variable τ and PRC. 7. ψ is most sensitive to instabilities in τ when ¯τ is close to 24 h. Thus the very circadian nature of these pacemakers helps to conserve ψ. Selection pressure for homeostasis of τ has been large in a species (M. auratus) where ¯τ = 24 h. The effect of ψ-instability is further reduced by entrainment with 2 pulses (dawn and dusk), made possible by the PRC's having both an advance and a delay section. 8. To analyze the contributions to ψ-conservation with seasonally changing photoperiod, we have assumed that it is of functional significance to conserve the phase of activity with respect to dusk (nocturnal animals) or to dawn (diurnal animals). We distinguish three contributions of nocturnal pacemaker behaviour to this type of ψ-conservation: increased amplitude of the PRC (i), asymmetry in the PRC, such that the slope of the delay-part is steeper than the slope of the advance-part (ii), and a short freerunning period in DD (iii). 9. A further contribution must derive from parametric effects of light, which are not traceable by the model, but certainly effective in preventing in complete photoperiods the ψ-jump which is seen in skeleton photoperiods. The existence of parametric effects is further demonstrated by the change of τ with light intensity in LL, described by Aschoffs Rule, which presumably reflects differences in PRC-shape between nocturnal and diurnal animals. 10. The paper concludes with an attempt to distinguish the features of circadian clocks that are analytically necessary for entrainment to occur (i), or have functional meaning, either in the measurement of the lapse of time (ii) or in the identification of local time (iii).

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A Functional Analysis of Circadian Pacemakers in Nocturnal Rodents. I. The Stability and Lability of Spontaneous Frequency

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.

This essay was prompted by the Editor’s invitation to illustrate the excitement and adventure inherent in scientific work while reflecting on my own preoccupation, as an evolutionary biologist, with biological clocks. In considering the challenge, the first adventure that came to mind occurred one evening 30 years ago when a drunken graduate student, frustrated by an unwanted experimental result, attempted to throw me out of a second story window in Princeton. He didn’t succeed. That seemed a good Indiana Jones start, but nothing as exciting occurred in later years, and all the adventures I can recount are less spectacular--the excitement of experiment and the hazardous fate of observation and ideas in the pursuit of understanding. While circadian periodicities have been the immediate object of my research for 40 years, that “view of life,” which Darwin so eloquently summarized in the last paragraph of “The Origin of Species,” has so dominated and guided my approach that it gets substantial attention in these reflections and hopefully ties together much of what I have to say about biological clocks. This Darwinian approach to behavioral and physiological interests traces to the accidental way I became a biologist. At 15 I kicked a soccer ball through a very large window in the Town Hall where I lived in the north of England. The only foreseeable source of the 13 shillings needed to replace it was a prize offered to local Boy Scouts for the best wild flower collection. In winning that prize, I got more money than was needed for the window and was seduced into a lasting love affair with plant

/pdf/temporal-organization-reflections-of-a-darwinian-clock-10xd1l5n2x.pdf

TEMPORAL ORGANIZATION: Reflections of a Darwinian Clock -Watcher

Bunning's general proposition, that circadian rhythmicity underlies the photoperiodic time-measurement, is, in our view, correct. In the first place the proposition seems highly plausible, a priori, in view of the diversity of other chronometric functions such rhythms subserve. In the second place there is a large body of experimental fact that cannot reasonably be interpreted in any other way. A "Coincidence Model" for photoperiodic induction is outlined; it is essentially Bunning's original scheme given in somewhat more explicit terms. It may yet prove true that the "coincidence-device" type of model will prove inadequate; but that would not necessarily render Bunning's more general proposition invalid-that the circadian system somehow executes the time-measurement. In any event we note that any general theory of circadian oscillations as photoperiodic clocks must go well beyond the terms in which the proposition was first stated; and specifically it must incorporate a general theory of the entrainment ...

The Entrainment of Circadian Oscillations by Light and Their Role as Photoperiodic Clocks

The nerve growth-stimulating effects of the intact tumor, when growing in close proximity to a sensory ganglion, are compared in Plate II, Figures 5-8, with the growth-stimulating effects of extracts obtained from these tumors. Our investigations are now directed toward (a) the further elucidation of the nature of the active material, (b) the duplication of the effect of the growing tumor in the living embryo with the active material isolated from the tumors, and (c) an examination of the metabolic response of the nerve cells under the influence of the growth-promoting agent.

https://www.pnas.org/content/pnas/40/10/1018.full.pdf

On temperature independence in the clock system controlling emergence time in drosophila.

The circadian rhythmicity of eukaroytic organisms is dictated by an innate program that specifies the time course through the day of many aspects of metabolism and behavior. The programmed sequence of events in each cycle of the rhythm has been evolved to parallel the sequence of predictable change (physical and biological) in the course of the day-outside: it constitutes an appropriate day-within. It is a characteristic, almost defining, feature of these circadian programs that their time course is stabilized with almost clocklike precision to parallel the stable time course of the environmental day. There is equally clear functional significance to the program’s being driven by a self-sustaining oscillator; thus, the program is subject to entrainment by one or more of the external cycles whose period it closely approximates. It is this entrainability that provides for proper phasing of the program to the sequence of external changes that it has been evolved to cope with and exploit.

Colin S. Pittendrigh

Papers

A Functional Analysis of Circadian Pacemakers in Nocturnal Rodents. I. The Stability and Lability of Spontaneous Frequency

TEMPORAL ORGANIZATION: Reflections of a Darwinian Clock -Watcher

The Entrainment of Circadian Oscillations by Light and Their Role as Photoperiodic Clocks

On temperature independence in the clock system controlling emergence time in drosophila.

Circadian Systems: Entrainment