Does the precision of a biological clock depend upon its period? Effects of the duper and tau mutations in Syrian hamsters

Mutations which alter the feedback loops that generate circadian rhythms may provide insight into their insensitivity to perturbation robustness) and their consistency of period (precision). I examined relationships between endogenous period, activity and rest (τ(DD), α and ρ) in Syrian hamsters using two different mutations, duper and tau, both of which speed up the circadian clock. I generated 8 strains of hamsters that are homozygous or heterozygous for the tau, duper, and wild type alleles in all combinations. The endogenous period of activity onsets among these strains ranged from 17.94+0.04 to 24.13 ± 0.04 h. Contrary to predictions, the variability of period was unrelated to its absolute value: all strains showed similar variability of τ(DD) when activity onsets and acrophase were used as phase markers. The τ(DD) of activity offsets was more variable than onsets but also differed little between genotypes. Cycle variation and precision were not correlated with τ(DD) within any strain, and only weakly correlated when all strains are considered together. Only in animals homozygous for both mutations (super duper hamsters) were cycle variation and precision reduced. Rhythm amplitude differed between strains and was positively correlated with τ(DD) and precision. All genotypes showed negative correlations between α and ρ. This confirms the expectation that deviations in the duration of subjective day and night should offset one another in order to conserve circadian period, even though homeostatic maintenance of energy reserves predicts that longer intervals of activity or rest would be followed by longer durations of rest or activity. Females consistently showed greater variability of the period of activity onset and acrophase, and of α, but variability of the period of offset differed between sexes only in super duper hamsters. Despite the differences between genotypes in τ(DD), ρ was consistently more strongly correlated with the preceding than the succeeding α.     

Entrainment of split circadian activity rhythms in hamsters

Hamsters that showed splitting of their circadian rhythms of wheel-running activity following long-term exposure to constant illumination (LL) were exposed to light-dark (LD) cycles with 2-hr dark segments, and with periods of 24.00, 24.23 or 24.72 hr. For comparison, hamsters showing nonsplit rhythms were also studied. In all cases of split rhythms, at least one of the two split components entrained to the LD cycles. In some animals, the second component continued to free-run until it merged with the entrained component, while in others, the second component also entrained to the LD cycle but maintained a stable phase angle of 6-14.5 hr relative to dark onset. These results were obtained in cases where the period of the LD cycle was shorter than that of the split rhythms and in cases where it was longer, implying that split components can be phase-advanced as well as phase-delayed by 2 hr of darkness. Three hamsters that showed stable entrainment of split rhythms were allowed to free-run in LL. The LD cycles were then reinstated, but instead of overlapping with the first component, as it did before, the dark segment was timed to overlap with the second. The entrainment patterns that ensued were similar to the ones obtained during the first LD exposure, indicating that the two split components respond to darkness in a qualitatively similar fashion. These results are further evidence that the pacemaker system underlying split circadian activity rhythms in hamsters is composed of two mutually coupled populations of oscillators that have similar properties, including a bidirectional phase response curve. Such a dual-oscillator organization may also underlie normal, or nonsplit, activity rhythms, as suggested by Pittendrigh and Daan (1976c), but the data are also compatible with the alternative view that the circadian pacemaker consists of a large number of coupled oscillators, which only dissociate into two separate populations in some animals under conditions of moderate LL intensity.     

Splitting of circadian rhythms in the rat

Summary Patterns of splitting of circadian rhythms into two or more components are described in rats. The patterns were always the same when two or three behaviors were recorded concurrently from the same animal (drinking, feeding, and electrical brain self-stimulation).Several characteristics of the split rhythms were similar to those described for hamster locomotor activity (Pittendrigh and Daan, 1976): 1. The period of the split components was shorter than that of the pre-split free-running rhythm; 2. in cases of splitting of rhythms into two components, synchronization occurred when the components reached a 180° phase-relation; and 3. refusion of the split components followed a reduction in light intensity.In one case, a complete lesion of the suprachias-matic nuclei was made in a rat showing split rhythms. The lesion abolished both of the split components, although one remained visible for about a week following the lesion.The results suggest control of the three behavioral rhythms by a common pacemaker which may consist of two coupled populations of oscillators, as described by Pittendrigh and Daan (1976) for circadian locomotor activity rhythms in nocturnal rodents.Abbreviations EBSS electrical brain self-stimulation - SCN suprachiasmatic nuclei Research supported by PHS Grants MH27442 and RR07143. We are grateful to D. Logothetis, G. Ruben, and J.S. Terman for assistance with data analysis, and to L. Thorington (Duro-Test Corp.) for contribution of Vita-Lite sources     

Two coupled neural oscillators as a model of the circadian pacemaker

Pittendrigh first found that the circadian rhythm of locomotor activity in nocturnal rodents split into two components. Hoffman then reported that the splitting phenomenon was even more reproducible in the small diurnal primate Tupaia. These “splitting” experiments and many other experiments suggest that two coupled oscillators may constitute the circadian pacemaker system. Pittendrigh proposed a phenomenological two-oscillator model. Daan and Berde developed a quantitative model assuming that the interaction between the two constituent oscillators is by instantaneous resets. Their model system can simulate several qualitative features in the experimental data. As the assumption of instantaneous resets seems to be unnatural, we study two limit cycle oscillators, which are coupled continuously to each other, as a model of the circadian pacemaker. We assume the following points, (i) One oscillator in a resting state does not affect another oscillator, (ii) Two oscillators are identical, (iii) The coupling is symmetrical. By the theory of Hopf bifurcation it is found that the general two-oscillator system has two stable periodic solutions. One is the in-phase solution where the two constituent oscillators oscillate in phase synchrony. Another is the anti-phase solution where the two oscillators oscillate 180 ° out of phase. The former corresponds to a single pattern of locomotor activity and the latter corresponds to a splitting pattern. Furthermore, we study specific two-neural oscillators, which are linearly coupled to each other. By the method of secondary bifurcation we find that the model shows simultaneous stability of the two alternative phase relationships and the hysteresis phenomena found in Tupaia. A natural period of the uncoupled constituent oscillator is longer than that of the in-phase solution but it is shorter than that of the anti-phase solution. This is in agreement with the data of Tupaia.     

Temporal organisation of hibernation in wild-type and tau mutant Syrian hamsters

The temporal pattern of hibernation was studied in three genotypes of Syrian hamsters with different circadian periodicity to assess a potential circadian control of alternating torpor and euthermy. We recorded the pattern of hibernation by measuring activity in continuous dim light and constant environmental temperature (6 +/- 1 degrees C). In spite of differences in the endogenous circadian period of three genotypes (tau +/+: approximately equals 24 h, tau +/-: approximately equals 22 h, and tau -/-: approximately equals 20 h) torpor bout duration was statistically indistinguishable (tau +/+: 86.9+/-5.3 h; tau +/-: 94.2+/-3.3 h; tau -/-: 88.8+/-6.2 h). The time between two consecutive arousals from torpor showed unimodal distributions not significantly different between genotypes. The first entry into torpor occurred within the active phase of the circadian cycle in all genotypes whereas the first arousal from torpor appeared to be timed randomly with respect to the prior circadian cycle. The amplitude of the activity rhythm was lower after hibernation compared with the amplitude before hibernation. The results suggest that in the Syrian hamster the circadian system does not control periodicity of torpor and arousal onsets in prolonged hibernation at 6 degrees C.     

Circadian complexes: Circadian rhythms under common gene control

Summary Circadian rhythms for food and water consumption were measured in five inbred strains of mice under a photoperiod of 16 h light and 8 h dark (16:8 LD), and under constant light (LL).Significant strain differences were observed which indicate that a common gene difference, or set of differences inMus musculus influences both the phase angle () associating the rhythms with the light-dark cycle, and the periods (_LL) of circadian rhythms for food and water consumption. The biological clock mechanism influenced by this genetic variance is common to both food and water circadian rhythms, and differs among the five inbred strains. A positive genetic correlation was observed between the phase angle () and the period (_LL) of each rhythm. This observation can be understood in terms of a functional relationship between phase and period proposed by Pittendrigh and Daan (1976b) for the entrainment of a circadian oscillator by a light-dark cycle in nocturnal rodents.These results suggest that circadian rhythms for food and water consumption in mice are regulated by a common physiological mechanism, and would respond to natural selection as a single circadian complex under common gene control.     

Activity feedback to the mammalian circadian pacemaker: influence on observed measures of rhythm period length.

In the mouse, activity is precisely timed by the circadian clock and is normally most intense in the early subjective night. Since vigorous activity (e.g., wheel running) is thought to induce phase shifts in rodents, the temporal placement of daily exercise/activity could be a determinant of observed circadian rhythm period. The relationship between spontaneous running-wheel activity and the circadian period of free-running rhythms was studied to assess this possibility. With ad libitum access to a running wheel, mice exhibited a free-running period (tau) of 23.43 +/- 0.08 hr (mean +/- SEM). When running wheels were locked, tau increased (23.88 +/- 0.04 hr, p less than 0.03), and restoration of ad libitum wheel running again produced a shorter period (tau = 23.56 +/- 0.06 hr, p less than 0.05). A survey of free-running activity patterns in a population of 100 mice revealed a significant correlation between the observed circadian period and the time of day in which spontaneous wheel running occurred (r = 0.7314, p less than 0.0001). Significantly shorter periods were observed when running was concentrated at the beginning of the subjective night (tau = 23.23 +/- 0.04), and longer periods were observed if mice ran late in the subjective night (tau = 23.89 +/- 0.04), F (1, 99) = 34.96, p less than 0.0001. It was previously believed that the period of the circadian clock was primarily responsive to externally imposed tonic or phasic events. Systematic influences of spontaneous exercise on tau demonstrate that physiological and/or behavioral determinants of circadian timekeeping exist as well.     

Unilateral lesions of the hamster suprachiasmatic nuclei: evidence for redundant control of circadian rhythms

Summary Several properties of vertebrate circadian rhythms can be attributed to the behavior of an underlying pacemaker system which is composed of two separate but mutually interacting circadian oscillators. As originally formulated, the model for such a pacemaker system proposed that two oscillators or populations of oscillators have different properties, specifically in their responses to light (Pittendrigh 1974; Pittendrigh and Daan 1976b). We have tested the proposition that the right and left suprachiasmatic nuclei (SCN) of the golden hamster contribute in different ways to the regulation of circadian rhythmicity by measuring the wheel-running activity rhythms of hamsters with lesions to either the right or left SCN. Although effects of unilateral or other partial SCN lesions on pacemaker properties were observed, these effects were not different in hamsters receiving right- or left-side lesions. More specifically: (1) free-running period () in constant light was shorter in lesioned hamsters irrespective of the side lesioned (Fig. 3a), and the total amount of SCN destruction was found to correlate with (Fig. 4). (2) Phase-angle difference () of some lesioned hamsters (both right- and left-side) during entrainment to LD, 1410 was significantly more positive than that of controls (Fig. 3b). (3) The rate of phase-shift following a shift of the light/dark cycle was not different in hamsters with right- or left-side lesions (Fig. 3c). And (4) the simultaneous expression of different circadian periods, similar to splitting, was observed in hamsters with unilateral lesions (Fig. 5). It is concluded that the right and left SCN are similar in their contributions to the control of circadian rhythmicity and that there is as yet no evidence for the permanent loss of multioscillator properties resulting from the destruction of only one of the two SCN.Abbreviations SCN suprachiasmatic nuclei or nucleus - LD light/dark cycle - LL constant light - DD constant dark - circadian period - activity time - rest time - phase angle - phase-angle difference - SD standard deviation - SE standard error - ANOVA analysis of variance     

Free-running rhythms of pineal circadian output

Circadian rhythms are self-sustaining oscillations that free-run in constant conditions with a period close to 24 h. Overt circadian rhythms have been studied mostly using onset phase as the marker for the underlying pacemaker. Using in vivo online pineal microdialysis, the authors have performed detailed analysis of free-running profiles of rat pineal secretory products, including N-acetylserotonin (NAS) and melatonin that have precisely defined onsets and offsets. When rats entrained in LD 12:12 were released into constant darkness (DD), both onset and offset phases of melatonin and NAS free-run. However, while onsets free-run with a period closer to a day (FRP(on) = 24-24.17 h) at the beginning, offset phases free-run with significantly larger FRPs (free-running periods) (FRP(off) = 24.24-24.42 h). This asymmetric free-running of onset and offset of NAS and melatonin in DD resulted in a 60- to 120-min increase of secretion duration of both NAS and melatonin. The rate of expansion of melatonin duration was 10 to 15 min per circadian cycle. The expansion of melatonin secretion duration ended for some within 4 days, while others were still expanding by the end of 10th day in DD. These results revealed that upon release into DD, the pacemaker's oscillation is initially driven by 2 forces, free running and decompression, before reaching a stable state of free running, and suggest that the circadian pacemaker may be an elastic structure that can decompress and compress under varying photic conditions. They also illustrate the importance of using both onset and offset of a given rhythm as phase markers, as compression/decompression, and transient disparity between FRP(on) and FRP(off) may be a common phenomenon of the circadian pacemaker.     

The temporal ‘structure’ and function of the insect photoperiodic clock: a tribute to Colin S. Pittendrigh

In 1936, Erwin Bünning suggested that photoperiodic time measurement was a function of the circadian system. Colin Pittendrigh became an ardent supporter of Bünning's hypothesis, drawing parallels between photoperiodism and his own group's investigations of adult eclosion rhythmicity in the fruit fly Drosophila pseudoobscura. They developed several more modern versions of Bünning's general hypothesis based on the entrainment of circadian oscillations to the light cycle, including ‘external coincidence’, which is a derivation of Bünning's original model, and ‘internal coincidence’, which relied upon seasonal changes in the mutual phase relationship of oscillators within a multi‐oscillator circadian system. This review considers the experimental evidence for the central role of the circadian system in photoperiodic timing and, in some species, for both external and internal coincidence. Pittendrigh, however, pursued the idea of internal coincidence further with his analysis of the pacemaker–slave organization of eclosion rhythmicity in D. pseudoobscura and proposed a similar theoretical model for photoperiodism comprising a group of slave oscillators driven by a light‐sensitive pacemaker. In this model, the phase relationships of the slaves to the pacemaker were affected by (i) the relative periods of the pacemaker and slave(s); (ii) the strength(s) of the coupling between the two; and (iii) the dampening coefficients of the various slaves. Manipulation of these variables showed that the slaves adopted different internal phase relationships (both to each other and to the pacemaker) under the influence of changes in daily photophase, the period of the Zeitgeber and phase shifts of the entraining light cycle.     

A change in the pattern in circadian running‐wheel activity after lesions of the intergeniculate leaflet and ventral lateral geniculate nucleus in the Syrian hamster

Abstract

The suprachiasmatic nuclei (SCN) contain the endogenous mammalian circadian pacemaker, which generates the circadian rhythm in locomotor activity. In Syrian hamsters with free‐running rhythms, the onset of running‐wheel activity is very precise and predictable while the end (offset) is more variable. From the thalamic intergeniculate leaflet (IGL) and the ventral lateral geniculate nucleus (vLGN) a projection to the SCN originates. Animals with a lesion aimed at the IGL/vLGN and sham‐and unoperated controls were kept in continuous darkness. With linear regression, lines were fitted through 10 successive onsets and offsets of activity and the mean deviation of the onsets and offsets from the fitted lines was determined. Animals with a complete or partial lesion of the IGL/vLGN had a smaller mean deviation of the circadian activity offset from the fitted regression line (0.313 h) compared with the grouped control animals (0.678 h). To test the difference statistically, we compared the sum of the square residuals of the circadian offsets between the groups. This difference was highly significant (F(69,64)=4.16, p<0.0001), which indicates that animals with a lesion of the IGL/ vLGN have a less variable circadian offset of running‐wheel activity. No differences were observed in the variability in the circadian onset of locomotor activity between experimental and control animals. It is concluded that the IGL/vLGN influence the variability of the offset of the circadian running‐wheel activity.     

Asymmetric control of short day response in European hamsters

The European hamster (Cricetus cricetus) is a circannual species in which the synchronization of the circannual cycle to the natural year occurs during 2 annual phases of sensitivity. Around the summer solstice, the animals are sensitive to a shortening of photoperiod. During this sensitive phase, pronounced changes in circadian output parameters are observed, indicating a different functional state of the circadian system. This special state is assumed to be necessary to develop the extreme sensitivity to short day length in European hamsters during this phase. In natural conditions, the animals are able to recognize the shortening of photoperiod already in mid-July, when the photoperiod is reduced only by 30 min. To investigate the short-day response in sensitive European hamsters on the basis of the 2-coupled oscillator model of Pittendrigh and Daan (1976), daily activity and the reproductive state of European hamsters were recorded after an asymmetrical reduction of photoperiod from long (LD 16:08) to short (LD 08:16) photoperiods. The activity pattern of the animals showed an immediate response to the short photoperiod at the day of transfer when the night was extended only into the evening, but there was a significant delay in the response time when the night was extended into the morning. Thus, the evening oscillator E is more important in inducing the photoperiodic response than the morning oscillator M. Moreover, the broad intragroup variation in the latter conditions strongly suggests that the changes in the activity pattern were endogenously induced and that the animals were not able to recognize a lengthening of the night into the morning. Gonadal regression started in both groups 3 weeks after the change in the activity pattern, indicating that this process is initiated when the circadian system has received the short-day signal either through changes in photoperiod or through the circannual clock.     

Taking the Lag out of Jet Lag through Model-Based Schedule Design

Travel across multiple time zones results in desynchronization of environmental time cues and the sleep–wake schedule from their normal phase relationships with the endogenous circadian system. Circadian misalignment can result in poor neurobehavioral performance, decreased sleep efficiency, and inappropriately timed physiological signals including gastrointestinal activity and hormone release. Frequent and repeated transmeridian travel is associated with long-term cognitive deficits, and rodents experimentally exposed to repeated schedule shifts have increased death rates. One approach to reduce the short-term circadian, sleep–wake, and performance problems is to use mathematical models of the circadian pacemaker to design countermeasures that rapidly shift the circadian pacemaker to align with the new schedule. In this paper, the use of mathematical models to design sleep–wake and countermeasure schedules for improved performance is demonstrated. We present an approach to designing interventions that combines an algorithm for optimal placement of countermeasures with a novel mode of schedule representation. With these methods, rapid circadian resynchrony and the resulting improvement in neurobehavioral performance can be quickly achieved even after moderate to large shifts in the sleep–wake schedule. The key schedule design inputs are endogenous circadian period length, desired sleep–wake schedule, length of intervention, background light level, and countermeasure strength. The new schedule representation facilitates schedule design, simulation studies, and experiment design and significantly decreases the amount of time to design an appropriate intervention. The method presented in this paper has direct implications for designing jet lag, shift-work, and non-24-hour schedules, including scheduling for extreme environments, such as in space, undersea, or in polar regions.     

Plasticity of the intrinsic period of the human circadian timing system

Human expeditions to Mars will require adaptation to the 24.65-h Martian solar day-night cycle (sol), which is outside the range of entrainment of the human circadian pacemaker under lighting intensities to which astronauts are typically exposed. Failure to entrain the circadian time-keeping system to the desired rest-activity cycle disturbs sleep and impairs cognitive function. Furthermore, differences between the intrinsic circadian period and Earth's 24-h light-dark cycle underlie human circadian rhythm sleep disorders, such as advanced sleep phase disorder and non-24-hour sleep-wake disorders. Therefore, first, we tested whether exposure to a model-based lighting regimen would entrain the human circadian pacemaker at a normal phase angle to the 24.65-h Martian sol and to the 23.5-h day length often required of astronauts during short duration space exploration. Second, we tested here whether such prior entrainment to non-24-h light-dark cycles would lead to subsequent modification of the intrinsic period of the human circadian timing system. Here we show that exposure to moderately bright light ( approximately 450 lux; approximately 1.2 W/m(2)) for the second or first half of the scheduled wake episode is effective for entraining individuals to the 24.65-h Martian sol and a 23.5-h day length, respectively. Estimations of the circadian periods of plasma melatonin, plasma cortisol, and core body temperature rhythms collected under forced desynchrony protocols revealed that the intrinsic circadian period of the human circadian pacemaker was significantly longer following entrainment to the Martian sol as compared to following entrainment to the 23.5-h day. The latter finding of after-effects of entrainment reveals for the first time plasticity of the period of the human circadian timing system. Both findings have important implications for the treatment of circadian rhythm sleep disorders and human space exploration.     

Postnatal growth rate and gonadal development in circadian tau mutant hamsters reared in constant dim red light

The role of the circadian clock in the reproductive development of Syrian hamsters (Mesocricetus auratus was examined in wild type and circadian tau mutant hamsters reared from birth to 26 weeks of age under constant dim red light. Testis diameter and body weights were determined at weekly intervals in male hamsters from 4 weeks of age. In both genotypes, testicular development, subsequent regression and recrudescence exhibited a similar time course. The age at which animals displayed reproductive photosensitivity, as exhibited by testicular regression, was unrelated to circadian genotype (mean +/- SEM: 54 +/- 3 days for wild type and 59 +/- 5 days for tau mutants). In contrast, our studies revealed a significant impact of the mutation on somatic growth, such that tau mutants weighed 18% less than wild types at the end of the experiment. Our study reveals that the juvenile onset of reproductive photoperiodism in Syrian hamsters is not timed by the circadian system.     

Integration of human sleep-wake regulation and circadian rhythmicity.

The human sleep-wake cycle is generated by a circadian process, originating from the suprachiasmatic nuclei, in interaction with a separate oscillatory process: the sleep homeostat. The sleep-wake cycle is normally timed to occur at a specific phase relative to the external cycle of light-dark exposure. It is also timed at a specific phase relative to internal circadian rhythms, such as the pineal melatonin rhythm, the circadian sleep-wake propensity rhythm, and the rhythm of responsiveness of the circadian pacemaker to light. Variations in these internal and external phase relationships, such as those that occur in blindness, aging, morning and evening, and advanced and delayed sleep-phase syndrome, lead to sleep disruptions and complaints. Changes in ocular circadian photoreception, interindividual variation in the near-24-h intrinsic period of the circadian pacemaker, and sleep homeostasis can contribute to variations in external and internal phase. Recent findings on the physiological and molecular-genetic correlates of circadian sleep disorders suggest that the timing of the sleep-wake cycle and circadian rhythms is closely integrated but is, in part, regulated differentially.     

Effects of photoperiod and aging on locomotor activity rhythms in the onion fly,Delia antiqua

At photoperiods longer than 8h per 24h, adults of the day-active onion fly Delia antiqua showed a major peak of locomotor activity in the late photophase and also bursts of activity induced by lights-on or lights-off. At shorter photoperiods the activity peaks fused. After transfer from long photoperiods to constant darkness (DD), the rhythm free-ran, but only the major peak persisted. This suggests that only the major peak is controlled by the circadian pacemaker. At long photoperiods, the daily phase of the major peak occurred progressively later with age. As a result, the activity at short photoperiods often shifted from photophase to scotophase in old flies. The free-running period (tau) also changed with age; tau was shorter than 24h until 14-20 days after eclosion and thereafter became longer, but a few individuals repeated changes in tau. The phase delay of locomotor activity with age in D. antiqua would be attributable to the increase in tau.     

Non-parametric photic entrainment of Djungarian hamsters with different rhythmic phenotypes

To investigate the role of non-parametric light effects in entrainment, Djungarian hamsters of two different circadian phenotypes were exposed to skeleton photoperiods, or to light pulses at different circadian times, to compile phase response curves (PRCs). Wild-type (WT) hamsters show daily rhythms of locomotor activity in accord with the ambient light/dark conditions, with activity onset and offset strongly coupled to light-off and light-on, respectively. Hamsters of the delayed activity onset (DAO) phenotype, in contrast, progressively delay their activity onset, whereas activity offset remains coupled to light-on. The present study was performed to better understand the underlying mechanisms of this phenomenon. Hamsters of DAO and WT phenotypes were kept first under standard housing conditions with a 14:10 h light–dark cycle, and then exposed to skeleton photoperiods (one or two 15-min light pulses of 100 lx at the times of the former light–dark and/or dark–light transitions). In a second experiment, hamsters of both phenotypes were transferred to constant darkness and allowed to free-run until the lengths of the active (α) and resting (ρ) periods were equal (α:ρ = 1). At this point, animals were then exposed to light pulses (100 lx, 15 min) at different circadian times (CTs). Phase and period changes were estimated separately for activity onset and offset. When exposed to skeleton-photoperiods with one or two light pulses, the daily activity patterns of DAO and WT hamsters were similar to those obtained under conditions of a complete 14:10 h light–dark cycle. However, in the case of giving only one light pulse at the time of the former light–dark transition, animals temporarily free-ran until activity offset coincided with the light pulse. These results show that photic entrainment of the circadian activity rhythm is attained primarily via non-parametric mechanisms, with the “morning” light pulse being the essential cue. In the second experiment, typical photic PRCs were obtained with phase delays in the first half of the subjective night, phase advances in the second half, and a dead zone during the subjective day. ANOVA indicated no significant differences between WT and DAO animals despite a significantly longer free-running period (tau) in DAO hamsters. Considering the phase shifts induced around CT0 and the different period lengths, it was possible to model the entrainment patterns of both phenotypes. It was shown that light-induced phase shifts of activity offset were sufficient to compensate for the long tau in WT and DAO hamsters, thus enabling a stable entrainment of their activity offsets to be achieved. With respect to activity onsets, phase shifts were sufficient only in WT animals; in DAO hamsters, activity onset showed increasing delays. The results of the present paper clearly demonstrate that, under laboratory conditions, the non-parametric component of light and dark leads to circadian entrainment in Djungarian hamsters. However, a stable entrainment of activity onset can be achieved only if the free-running period does not exceed a certain value. With longer tau values, hamsters reveal a DAO phenotype. Under field conditions, therefore, non-photic cues/zeitgebers must obviously be involved to enable a proper circadian entrainment.     

Assembling a clock for all seasons: are there M and E oscillators in the genes?

The hypothesis is advanced that the circadian pacemaker in the mammalian suprachiasmatic nucleus (SCN) is composed at the molecular level of a nonredundant double complex of circadian genes (per1, cry1, and per2, cry2). Each one of these sets would be sufficient for the maintenance of endogenous rhythmicity and thus constitute an oscillator. Each would have slightly different temporal dynamics and light responses. The per1/cry1 oscillator is accelerated by light and decelerated by darkness and thereby tracks dawn when day length changes. The per2 /cry2 oscillator is decelerated by light and accelerated by darkness and thereby tracks dusk. These M (morning) and E (evening) oscillators would give rise to the SCN's neuronal activity in an M and an E component. Suppression of behavioral activity by SCN activity in nocturnal mammals would give rise to adaptive tuning of the endogenous behavioral program to day length. The proposition-which is a specification of Pittendrigh and Daan's E-M oscillator model-yields specific nonintuitive predictions amenable to experimental testing in animals with mutations of circadian genes.     

Scheduled voluntary wheel running activity modulates free-running circadian body temperature rhythms in Octodon degus

Entrainment of the circadian pacemaker to nonphotic stimuli, such as scheduled wheel-running activity, is well characterized in nocturnal rodents, but little is known about activity-dependent entrainment in diurnal or crepuscular species. In the present study, effects of scheduled voluntary wheel-running activity on circadian timekeeping were investigated in Octodon degus, a hystricomorph rodent that exhibits robust crepuscular patterns of wakefulness. When housed in constant darkness, O. degus exhibited circadian rhythms in wheel-running activity and body temperature (Tb) with an average period length (tau) of 23.39 +/- 0.11 h. When wheel running was restricted to a fixed 2-h schedule every 24 h, tau increased on average 0.39 +/- 0.09 h but did not result in steady-state entrainment. Instead, relative coordination between the fixed running schedule and circadian timing was observed. Tau was greatest when scheduled wheel running occurred at CT 20.5 (0.4 h greater than DD baseline tau). Scheduled running activity also influenced Tb waveform symmetry, reflecting concomitant changes in the circadian activity-rest ratio (alpha:rho). Aftereffects of the scheduled wheel-running paradigm were also observed. In 2 animals, tau lengthened from 23.20 and 23.80 h to 24.14 and 24.15 h, respectively, and remained relatively stable for approximately 1 month during the wheel schedule. Although behavioral activity appears to be a weak zeitgeber in this species, these data suggest that nonphotic stimuli can phase delay the circadian pacemaker in O. degus at similar times of the day as in nocturnal hamsters and mice, and in humans.