Maximising survival by shifting the daily timing of activity.

Maximising survival requires animals to balance the competing demands of maintaining energy balance and avoiding predation. Here, quantitative modelling shows that optimising the daily timing of activity and rest based on the encountered environmental conditions enables small mammals to maximise survival. Our model shows that nocturnality is typically beneficial when predation risk is higher during the day than during the night, but this is reversed by the energetic benefit of diurnality when food becomes scarce. Empirical testing under semi-natural conditions revealed that the daily timing of activity and rest in mice exposed to manipulations in energy availability and perceived predation risk is in line with the model's predictions. Low food availability and decreased perceived daytime predation risk promote diurnal activity patterns. Overall, our results identify temporal niche switching in small mammals as a strategy to maximise survival in response to environmental changes in food availability and perceived predation risk.

Revealing Oft-cited but Unpublished Papers of Colin Pittendrigh and Coworkers.

Among the scientific resources that Colin Pittendrigh passed on to his colleagues after his death in 1996 were two unpublished papers. These manuscripts, developed first in the mid-1960s and continually updated and refined through the late 1970s, centered on the development and experimental exploration of a model of circadian entrainment combining aspects of the well-known parametric (continuous) and nonparametric (discrete) models of entrainment. These texts reveal the experimental work surrounding Pittendrigh's determination of the limits of entrainment and the explanation of the bistability phenomenon. These manuscripts are being made publicly available in their final format (February 1978) as supplementary material to this introduction.

Plasticity in the Period of the Circadian Pacemaker Induced by Phase Dispersion of Its Constituent Cellular Clocks.

The mammalian circadian pacemaker is commonly thought to be a rigid oscillator that generates output under a variety of circumstances that differ only in phase, period, and/or amplitude. Yet the pacemaker is composed of many cells that each can respond to varying circumstances in different ways. Computer simulations demonstrate that networks of such pacemaker cells behave differently under a light-dark cycle compared with constant darkness. The differences demonstrate that the circadian pacemaker is plastic: The pacemaker shapes its properties in response to the circumstances. A consequence is that properties of a pacemaker under a light-dark cycle cannot be derived from studies of the same system in constant darkness. In this paper we show that the dispersion of phase in a network of coupled oscillators can influence ensemble period: For the considered type of coupling, it is demonstrated that the more synchronous the cells are, the longer is the ensemble period. This is consistent with various data sets obtained in mammals, and even with a data set from fruit flies, in which circadian variation in behavior is regulated in a distinctly differently way from that in mammals. We conclude that environmental circumstances such as photoperiod and exposure to light pulses in otherwise darkness modify the phase distribution of the network and, thereby, the period of the ensemble. Our study supports the view that such properties as circadian period are not solely determined by clock genes but are also determined by the genes that regulate the communication in cellular networks.

Hell on earth? Equatorial peaks of heat, poverty, and aggression.

Van Lange et al.'s global CLASH model overemphasizes climatic origins and underemphasizes economic origins of aggression. Our 167-country analysis of latitudinal gradients of heat, poverty, and aggression finds that heat-induced aggression is mediated by poverty and that heat tempers rather than fuels poverty-induced aggression. More importantly, the CLASH model hints at latitudinal, equatorial, and hemispheric upgradings of climato-economic modeling of human behavior.

Melatonin and Sleep-Wake Rhythms before and after Ocular Lens Replacement in Elderly Humans.

Light of short wavelengths has been shown to play a key role in non-image forming responses. Due to aging, the ocular lens becomes more yellow reducing the transmission of short wavelengths in the elderly. In the present study, we make use of cataract surgery to investigate the effects of a relative increase of short wavelength transmission on melatonin- and sleep-wake rhythms (N = 14). We observed, on average, a delay of the sleep-wake and the nocturnal melatonin rhythms after cataract surgery. This delay is tentatively attributed to a relatively large increase of light transmittance in the evening hours more than an increase of the already relatively high light intensities found in the daytime. The later phase that we observed after cataract surgery (clear lens) as compared to the earlier phase observed before cataract (yellowish lens) is in agreement with the general later phase reported in the young (clear lens) population.

The two-process model of sleep regulation: a reappraisal.

In the last three decades the two-process model of sleep regulation has served as a major conceptual framework in sleep research. It has been applied widely in studies on fatigue and performance and to dissect individual differences in sleep regulation. The model posits that a homeostatic process (Process S) interacts with a process controlled by the circadian pacemaker (Process C), with time-courses derived from physiological and behavioural variables. The model simulates successfully the timing and intensity of sleep in diverse experimental protocols. Electrophysiological recordings from the suprachiasmatic nuclei (SCN) suggest that S and C interact continuously. Oscillators outside the SCN that are linked to energy metabolism are evident in SCN-lesioned arrhythmic animals subjected to restricted feeding or methamphetamine administration, as well as in human subjects during internal desynchronization. In intact animals these peripheral oscillators may dissociate from the central pacemaker rhythm. A sleep/fast and wake/feed phase segregate antagonistic anabolic and catabolic metabolic processes in peripheral tissues. A deficiency of Process S was proposed to account for both depressive sleep disturbances and the antidepressant effect of sleep deprivation. The model supported the development of novel non-pharmacological treatment paradigms in psychiatry, based on manipulating circadian phase, sleep and light exposure. In conclusion, the model remains conceptually useful for promoting the integration of sleep and circadian rhythm research. Sleep appears to have not only a short-term, use-dependent function; it also serves to enforce rest and fasting, thereby supporting the optimization of metabolic processes at the appropriate phase of the 24-h cycle.

Natural selection against a circadian clock gene mutation in mice.

Circadian rhythms with an endogenous period close to or equal to the natural light-dark cycle are considered evolutionarily adaptive ("circadian resonance hypothesis"). Despite remarkable insight into the molecular mechanisms driving circadian cycles, this hypothesis has not been tested under natural conditions for any eukaryotic organism. We tested this hypothesis in mice bearing a short-period mutation in the enzyme casein kinase 1ε (tau mutation), which accelerates free-running circadian cycles. We compared daily activity (feeding) rhythms, survivorship, and reproduction in six replicate populations in outdoor experimental enclosures, established with wild-type, heterozygous, and homozygous mice in a Mendelian ratio. In the release cohort, survival was reduced in the homozygote mutant mice, revealing strong selection against short-period genotypes. Over the course of 14 mo, the relative frequency of the tau allele dropped from initial parity to 20%. Adult survival and recruitment of juveniles into the population contributed approximately equally to the selection for wild-type alleles. The expression of activity during daytime varied throughout the experiment and was significantly increased by the tau mutation. The strong selection against the short-period tau allele observed here contrasts with earlier studies showing absence of selection against a Period 2 (Per2) mutation, which disrupts internal clock function, but does not change period length. These findings are consistent with, and predicted by the theory that resonance of the circadian system plays an important role in individual fitness.

Cold and hunger induce diurnality in a nocturnal mammal.

The mammalian circadian system synchronizes daily timing of activity and rest with the environmental light-dark cycle. Although the underlying molecular oscillatory mechanism is well studied, factors that influence phenotypic plasticity in daily activity patterns (temporal niche switching, chronotype) are presently unknown. Molecular evidence suggests that metabolism may influence the circadian molecular clock, but evidence at the level of the organism is lacking. Here we show that a metabolic challenge by cold and hunger induces diurnality in otherwise nocturnal mice. Lowering ambient temperature changes the phase of circadian light-dark entrainment in mice by increasing daytime and decreasing nighttime activity. This effect is further enhanced by simulated food shortage, which identifies metabolic balance as the underlying common factor influencing circadian organization. Clock gene expression analysis shows that the underlying neuronal mechanism is downstream from or parallel to the main circadian pacemaker (the hypothalamic suprachiasmatic nucleus) and that the behavioral phenotype is accompanied by phase adjustment of peripheral tissues. These findings indicate that nocturnal mammals can display considerable plasticity in circadian organization and may adopt a diurnal phenotype when energetically challenged. Our previously defined circadian thermoenergetics hypothesis proposes that such circadian plasticity, which naturally occurs in nocturnal mammals, reflects adaptive maintenance of energy balance. Quantification of energy expenditure shows that diurnality under natural conditions reduces thermoregulatory costs in small burrowing mammals like mice. Metabolic feedback on circadian organization thus provides functional benefits by reducing energy expenditure. Our findings may help to clarify relationships between sleep-wake patterns and metabolic phenotypes in humans.

Body temperature predicts the direction of internal desynchronization in humans isolated from time cues.

This publication presents a new analysis of experiments that were carried out in human subjects in isolation from time cues, under supervision of Jürgen Aschoff and Rütger Wever at the Max Planck Institute for Behavioural Physiology (Erling-Andechs, Germany, 1964-1974). Mean rectal temperatures (tb) were compared between subjects who showed internal desynchronization (ID) and internal synchronization (IS) of the endogenous rhythms of sleep-wakefulness and of body temperature. The results showed that tb was reduced in long ID (circadian sleep-wake cycle length [τ(SW)] > 27 h) and increased in short ID (τ(SW) < 22 h) relative to IS. In subjects with both ID and IS sections in the complete record, these differences were also found when comparing only the IS sections: Low tb during IS predicts the later occurrence of long ID, and high tb predicts the incidence of short ID. While this association is associated with sex differences in tb, it also occurs within each sex. To the extent that the variation in tb reflects the variation in heat production (metabolic rate), the results are consistent with the proposition that the spontaneous frequency of the human sleep-wake oscillator is associated with the metabolic rate, as suggested on the basis of the proportionality of meal frequency and sleep-wake frequency. The finding thus has implications for our views on spontaneous sleep timing.

Latitudinal clines: an evolutionary view on biological rhythms.

Properties of the circadian and annual timing systems are expected to vary systematically with latitude on the basis of different annual light and temperature patterns at higher latitudes, creating specific selection pressures. We review literature with respect to latitudinal clines in circadian phenotypes as well as in polymorphisms of circadian clock genes and their possible association with annual timing. The use of latitudinal (and altitudinal) clines in identifying selective forces acting on biological rhythms is discussed, and we evaluate how these studies can reveal novel molecular and physiological components of these rhythms.

Working for food shifts nocturnal mouse activity into the day.

Nocturnal rodents show diurnal food anticipatory activity when food access is restricted to a few hours in daytime. Timed food access also results in reduced food intake, but the role of food intake in circadian organization per se has not been described. By simulating natural food shortage in mice that work for food we show that reduced food intake alone shifts the activity phase from the night into the day and eventually causes nocturnal torpor (natural hypothermia). Release into continuous darkness with ad libitum food, elicits immediate reversal of activity to the previous nocturnal phase, indicating that the classical circadian pacemaker maintained its phase to the light-dark cycle. This flexibility in behavioral timing would allow mice to exploit the diurnal temporal niche while minimizing energy expenditure under poor feeding conditions in nature. This study reveals an intimate link between metabolism and mammalian circadian organization.

Lab mice in the field: unorthodox daily activity and effects of a dysfunctional circadian clock allele.

Daily patterns of animal behavior are potentially of vast functional importance. Fitness benefits have been identified in nature by the association between individual timing and survival or by the fate of individuals after experimental deletion of their circadian pacemaker. The recent advances in unraveling the molecular basis of circadian timing enable new approaches to natural selection on timing. The investigators report on the effect and fate of the mutant Per2(Brdm1) allele in 4 replicate populations of house mice in a seminatural outside environment over 2 years. This allele is known to compromise circadian organization and entrainment and to cause multiple physiological disturbances. Mice (N=250) bred from Per2(Brdm1) heterozygotes were implanted subcutaneously with transponders and released in approximately Mendelian ratios in four 400 m(2) pens. An electronic system stored the times of all visits to feeders of each individual. The study first demonstrates that mice are not explicitly nocturnal in this natural environment. Feeding activity was predominantly and sometimes exclusively diurnal and spread nearly equally over day and night under the protective snow cover in winter. The effect of Per2(Brdm1) on activity timing is negligible compared to seasonal changes in all genotypes. Second, the Per2(Brdm1) allele did not have persistent negative effects on fitness. In the first year, the allele gradually became less frequent by reducing survival. New cohorts captured had the same Per2(Brdm1) frequency as the survivors from previous cohorts, consistent with an absence of an effect on reproduction. In the second year, the allele recovered to about its initial frequency (0.54). These changes in selective advantage were primarily due to female mice, as females lived longer and the sex ratio dropped to about 25% males in the population. While it is unknown which selective advantage led to the recovery, the results caution against inferences from laboratory experiments on fitness consequences in the natural environment. It also demonstrates that the activity of mice, while strictly nocturnal in the laboratory, may be partially or completely diurnal in the field. The new method allows assessment of natural selection on specific alleles on a day-today basis.

Entrainment concepts revisited.

The traditional approaches to predict entrainment of circadian clocks by light are based on 2 concepts that were never successfully unified: the non-parametric approach assumes that entrainment occurs via discrete daily phase shifts while the parametric approach assumes that entrainment involves changes of the clock's velocity. Here the authors suggest a new approach to predict and model entrainment. Unlike the traditional approaches, it does not assume a priori the mechanism of how the internal and external cycle lengths are matched (via phase shifts, velocity changes, or even other mechanisms). It is based on a circadian integrated response characteristic (CIRC) that describes how the circadian system integrates light signals at different circadian phases, without specifying exactly when and how fast its progression is affected. Light around subjective dawn compresses the internal cycle; light around subjective dusk expands it. While the phase response curve (PRC) describes the results of experiments using light stimuli (of specified duration and intensity), the CIRC reflects how the system integrates any given light profile, be it single pulses or any form of light-dark cycle (from skeleton photoperiods to natural light profiles). CIRCs are characterized by their shape (determining the extent of their dead zone) and their asymmetry (the ratio of its compressing and expanding portions). They are dimensionless (time/time), and their maximum is by definition 1. To make predictions about entrainment, the CIRC is multiplied with the light intensity/sensitivity at any given time point. Unlike the PRC and the velocity response curve, the CIRC can be assessed on the basis of entrained steady states, by modeling experimental results. The CIRC approach makes several predictions that can be tested experimentally.

An adaptive annual rhythm in the sex of first pigeon eggs.

When the reproductive value of male and female offspring varies differentially, parents are predicted to adjust the sex ratio of their offspring to maximize their fitness (Trivers and Willard, Science 179:90-92, 1973). Two factors have been repeatedly linked to skews in avian offspring sex ratio. First, laying date can affect offspring sex ratio when the sexes differ in age of first reproduction, such that the more slowly maturing sex is overproduced early in the season. Second, position of the egg in the laying sequence of a clutch may affect sex ratio bias since manipulating the sex of the first eggs may be least costly to the mother. We studied both factors in two non-domesticated pigeon species. Both the Wood pigeon (Columba palumbus) and the Rock pigeon (Columba livia) have long breeding seasons and lay two-egg clutches. In the field, we determined the sex of Wood pigeon nestlings. In Rock pigeons, housed in captivity outdoors, we determined embryo sex after 3 days of incubation. On the basis of their sex-specific age of first reproduction, we predicted that males, maturing at older age than females, should be produced in majority early and females later in the year. This was confirmed for both species. The bias was restricted to first eggs. Rock pigeons produced clutches throughout the year and show that the sex of the first egg followed an annual cycle. To our knowledge, this study presents the first evidence of a full annual rhythm in adaptive sex allocation in birds. We suggest that this reflects an endogenous seasonal program in primary sex ratio controlled by a preovulatory mechanism.

Exercising for life? Energy metabolism, body composition, and longevity in mice exercising at different intensities.

Studies that have found a positive influence of moderate, nonexhaustive exercise on life expectancy contradict the rate-of-living theory, which predicts that high energy expenditure in exercising animals should shorten life. We investigated effects of exercise on energy metabolism and life span in male mice from lines that had been selectively bred for high voluntary wheel-running activity and from the nonselected control lines. Mice were divided into the following three groups (n = 100 per group): active high-runner mice (housed with wheels; HR+), sedentary high-runner mice (no wheels provided; HR-), and active control mice (C+). Sixty animals from each group were left undisturbed throughout their lives to create survival curves. In the remaining 40 animals in each group, energy metabolism and body composition was measured at 2, 10, 18, or 26 mo of age. Wheel-running activity was increased by approximately 50% throughout life in HR+ mice compared with C+ mice, and mass-specific daily energy expenditure was increased by approximately 30% in HR+ mice compared with both C+ mice and HR- mice. Median life span was similar in HR+ mice and HR- mice (740 and 733 d, respectively), and it was significantly shorter in these mice than it was in C+ mice (828 d). Thus, increasing the amount of voluntary aerobic exercise (as a result of selective breeding or housing with wheels) did not result in extended life span in mice, and we found no evidence for a direct link between energy expenditure and life span.

Daily torpor in mice: high foraging costs trigger energy-saving hypothermia.

Many animal species employ natural hypothermia in seasonal (hibernation) and daily (torpor) strategies to save energy. Facultative daily torpor is a typical response to fluctuations in food availability, but the relationship between environmental quality, foraging behaviour and torpor responses is poorly understood. We studied body temperature responses of outbred ICR (CD-1) mice exposed to different food reward schedules, simulating variation in habitat quality. Our main comparison was between female mice exposed to low foraging-cost environments and high-cost environments. As controls, we pair-fed a group of inactive animals (no-cost treatment) the same amount of pellets as high-cost animals. Mice faced with high foraging costs were more likely to employ torpor than mice exposed to low foraging costs, or no-cost controls (100% versus 40% and 33% of animals, respectively). While resting-phase temperature showed a non-significant decrease in high-cost animals, torpor was not associated with depressions in active-phase body temperature. These results demonstrate (i) that mice show daily torpor in response to poor foraging conditions; (ii) that torpor incidence is not attributable to food restriction alone; and (iii) that high levels of nocturnal activity do not preclude the use of daily torpor as an energy-saving strategy. The finding that daily torpor is not restricted to conditions of severe starvation puts torpor in mice in a more fundamental ecological context.

Influence of photoperiod duration and light-dark transitions on entrainment of Per1 and Per2 gene and protein expression in subdivisions of the mouse suprachiasmatic nucleus.

The circadian clock located within the suprachiasmatic nuclei (SCN) of the hypothalamus responds to changes in the duration of day length, i.e. photoperiod. Recently, changes in phase relationships among the SCN cell subpopulations, especially between the rostral and caudal region, were implicated in the SCN photoperiodic modulation. To date, the effect of abrupt, rectangular, light-to-dark transitions have been studied while in nature organisms experience gradual dawn and twilight transitions. The aim of this study was to compare the effect of a long (18 h of light) and a short (6 h of light) photoperiod with twilight relative to that with rectangular light-to-dark transition on the daily profiles of Per1 and Per2 mRNA (in situ hybridization) and PER1 and PER2 protein (immunohistochemistry) levels within the rostral, middle and caudal regions of the mouse SCN. Under the short but not under the long photoperiod, Per1, Per2 and PER1, PER2 profiles were significantly phase-advanced under the twilight relative to rectangular light-to-dark transition in all SCN regions examined. Under the photoperiods with rectangular light-to-dark transition, Per1 and Per2 mRNA profiles in the caudal SCN were phase-advanced as compared with those in the rostral SCN. The phase differences between the SCN regions were reduced under the long, or completely abolished under the short, photoperiods with twilight. The data indicate that the twilight photoperiod provides stronger synchronization among the individual SCN cell subpopulations than the rectangular one, and the effect is more pronounced under the short than under the long photoperiod.

Maternal energy allocation to offspring increases with environmental quality in house mice.

Breeding success generally increases with environmental productivity, but little is known about underlying mechanisms, and such relationships are not quantitatively understood. We studied female mice reproducing across an experimental environmental-quality gradient defined by the amount of wheel running required to obtain a food reward. Measuring energy metabolism with doubly labeled water, we quantified how mice made two key decisions: how much food to earn and how to allocate the energy earned between self and offspring. As environmental quality declined, female foraging effort increased, but not sufficiently to compensate for the increase in foraging costs. In absolute terms, energy allocated to both self and offspring was lower in a poor-quality environment. Moreover, the proportion of gained energy that was allocated to offspring declined with decreasing environmental quality. Environmental effects on reproductive output (total litter mass produced) could be fully explained by energy allocated to milk. Thus, the efficiency with which offspring converted milk energy to tissue growth was independent of environmental quality. To the best of our knowledge, this is the first study to provide a quantitative explanation, via maternal energy allocation, of the link between foraging costs and reproductive output.