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.     

Circadian phase,circadian period and chronotype are reproducible over months

The timing of the circadian clock, circadian period and chronotype varies among individuals. To date, not much is known about how these parameters vary over time in an individual. We performed an analysis of the following five common circadian clock and chronotype measures: 1) the dim light melatonin onset (DLMO, a measure of circadian phase), 2) phase angle of entrainment (the phase the circadian clock assumes within the 24-h day, measured here as the interval between DLMO and bedtime/dark onset), 3) free-running circadian period (tau) from an ultradian forced desynchrony protocol (tau influences circadian phase and phase angle of entrainment), 4) mid-sleep on work-free days (MSF from the Munich ChronoType Questionnaire; MCTQ) and 5) the score from the Morningness–Eveningness Questionnaire (MEQ). The first three are objective physiological measures, and the last two are measures of chronotype obtained from questionnaires. These data were collected from 18 individuals (10 men, eight women, ages 21–44 years) who participated in two studies with identical protocols for the first 10 days. We show how much these circadian rhythm and chronotype measures changed from the first to the second study. The time between the two studies ranged from 9 months to almost 3 years, depending on the individual. Since the full experiment required living in the laboratory for 14 days, participants were unemployed, had part-time jobs or were freelance workers with flexible hours. Thus, they did not have many constraints on their sleep schedules before the studies. The DLMO was measured on the first night in the lab, after free-sleeping at home and also after sleeping in the lab on fixed 8-h sleep schedules (loosely tailored to their sleep times before entering the laboratory) for four nights. Graphs with lines of unity (when the value from the first study is identical to the value from the second study) showed how much each variable changed from the first to the second study. The DLMO did not change more than 2 h from the first to the second study, except for two participants whose sleep schedules changed the most between studies, a change in sleep times of 3 h. Phase angle did not change by more than 2 h regardless of changes in the sleep schedule. Circadian period did not change more than 0.2 h, except for one participant. MSF did not change more than 1 h, except for two participants. MEQ did not change more than 10 points and the categories (e.g. M-type) did not change. Pearson’s correlations for the DLMO between the first and second studies increased after participants slept in the lab on their individually timed fixed 8-h sleep schedules for four nights. A longer time between the two studies did not increase the difference between any of the variables from the first to the second study. This analysis shows that the circadian clock and chronotype measures were fairly reproducible, even after many months between the two studies.     

Intrinsic period and light intensity determine the phase relationship between melatonin and sleep in humans

The internal circadian clock and sleep-wake homeostasis regulate the timing of human brain function, physiology, and behavior so that wakefulness and its associated functions are optimal during the solar day and that sleep and its related functions are optimal at night. The maintenance of a normal phase relationship between the internal circadian clock, sleep-wake homeostasis, and the light-dark cycle is crucial for optimal neurobehavioral and physiological function. Here, the authors show that the phase relationship between these factors-the phase angle of entrainment (psi)-is strongly determined by the intrinsic period (tau) of the master circadian clock and the strength of the circadian synchronizer. Melatonin was used as a marker of internal biological time, and circadian period was estimated during a forced desynchrony protocol. The authors observed relationships between the phase angle of entrainment and intrinsic period after exposure to scheduled habitual wakefulness-sleep light-dark cycle conditions inside and outside of the laboratory. Individuals with shorter circadian periods initiated sleep and awakened at a later biological time than did individuals with longer circadian periods. The authors also observed that light exposure history influenced the phase angle of entrainment such that phase angle was shorter following exposure to a moderate bright light (approximately 450 lux)-dark/wakefulness-sleep schedule for 5 days than exposure to the equivalent of an indoor daytime light (approximately 150 lux)-dark/wakefulness-sleep schedule for 2 days. These findings demonstrate that neurobiological and environmental factors interact to regulate the phase angle of entrainment in humans. This finding has important implications for understanding physiological organization by the brain's master circadian clock and may have implications for understanding mechanisms underlying circadian sleep disorders.     

Biological rhythms during residence in polar regions

At Arctic and Antarctic latitudes, personnel are deprived of natural sunlight in winter and have continuous daylight in summer: light of sufficient intensity and suitable spectral composition is the main factor that maintains the 24-h period of human circadian rhythms. Thus, the status of the circadian system is of interest. Moreover, the relatively controlled artificial light conditions in winter are conducive to experimentation with different types of light treatment. The hormone melatonin and/or its metabolite 6-sulfatoxymelatonin (aMT6s) provide probably the best index of circadian (and seasonal) timing. A frequent observation has been a delay of the circadian system in winter. A skeleton photoperiod (2 × 1-h, bright white light, morning and evening) can restore summer timing. A single 1-h pulse of light in the morning may be sufficient. A few people desynchronize from the 24-h day (free-run) and show their intrinsic circadian period, usually >24 h. With regard to general health in polar regions, intermittent reports describe abnormalities in various physiological processes from the point of view of daily and seasonal rhythms, but positive health outcomes are also published. True winter depression (SAD) appears to be rare, although subsyndromal SAD is reported. Probably of most concern are the numerous reports of sleep problems. These have prompted investigations of the underlying mechanisms and treatment interventions. A delay of the circadian system with "normal" working hours implies sleep is attempted at a suboptimal phase. Decrements in sleep efficiency, latency, duration, and quality are also seen in winter. Increasing the intensity of ambient light exposure throughout the day advanced circadian phase and was associated with benefits for sleep: blue-enriched light was slightly more effective than standard white light. Effects on performance remain to be fully investigated. At 75°S, base personnel adapt the circadian system to night work within a week, in contrast to temperate zones where complete adaptation rarely occurs. A similar situation occurs on high-latitude North Sea oil installations, especially when working 18:00-06:00 h. Lack of conflicting light exposure (and "social obligations") is the probable explanation. Many have problems returning to day work, showing circadian desynchrony. Timed light treatment again has helped to restore normal phase/sleep in a small number of people. Postprandial response to meals is compromised during periods of desynchrony with evidence of insulin resistance and elevated triglycerides, risk factors for heart disease. Only small numbers of subjects have been studied intensively in polar regions; however, these observations suggest that suboptimal light conditions are deleterious to health. They apply equally to people living in temperate zones with insufficient light exposure.     

A phase dynamics model of human circadian rhythms

Nonphotic entrainment of an overt sleep-wake rhythm and a circadian pacemaker-driving temperature/melatonin rhythm suggests existence of feedback mechanisms in the human circadian system. In this study, the authors constructed a phase dynamics model that consisted of two oscillators driving temperature/melatonin and sleep-wake rhythms, and an additional oscillator generating an overt sleep-wake rhythm. The feedback mechanism was implemented by modifying couplings between the constituent oscillators according to the history of correlations between them. The model successfully simulated the behavior of human circadian rhythms in response to forced rest-activity schedules under free-run situations: the sleep-wake rhythm is reentrained with the circadian pacemaker after release from the schedule, there is a critical period for the schedule to fully entrain the sleep-wake rhythm, and the forced rest-activity schedule can entrain the circadian pacemaker with the aid of exercise. The behavior of human circadian rhythms was reproduced with variations in only a few model parameters. Because conventional models are unable to reproduce the experimental results concerned here, it was suggested that the feedback mechanisms included in this model underlie nonphotic entrainment of human circadian rhythms.     

Entrainment of the master circadian clock by scheduled feeding

The master circadian clock, located in the mammalian suprachiasmatic nuclei (SCN), generates and coordinates circadian rhythmicity, i.e., internal organization of physiological and behavioral rhythms that cycle with a near 24-h period. Light is the most powerful synchronizer of the SCN. Although other nonphotic cues also have the potential to influence the circadian clock, their effects can be masked by photic cues. The purpose of this study was to investigate the ability of scheduled feeding to entrain the SCN in the absence of photic cues in four lines of house mouse (Mus domesticus). Mice were initially housed in 12:12-h light/dark cycle with ad libitum access to food for 6 h during the light period followed by 4-6 mo of constant dark under the same feeding schedule. Wheel running behavior suggested and circadian PER2 protein expression profiles in the SCN confirmed entrainment of the master circadian clock to the onset of food availability in 100% (49/49) of the line 2 mice in contrast to only 4% (1/24) in line 3 mice. Mice from line 1 and line 4 showed intermediate levels of entrainment, 57% (8/14) and 39% (7/18), respectively. The predictability of entrainment vs. nonentrainment in line 2 and line 3 and the novel entrainment process provide a powerful tool with which to further elucidate mechanisms involved in entrainment of the SCN by scheduled feeding.     

Authors' response

At Arctic and Antarctic latitudes, personnel are deprived of natural sunlight in winter and have continuous daylight in summer: light of sufficient intensity and suitable spectral composition is the main factor that maintains the 24-h period of human circadian rhythms. Thus, the status of the circadian system is of interest. Moreover, the relatively controlled artificial light conditions in winter are conducive to experimentation with different types of light treatment. The hormone melatonin and/or its metabolite 6-sulfatoxymelatonin (aMT6s) provide probably the best index of circadian (and seasonal) timing. A frequent observation has been a delay of the circadian system in winter. A skeleton photoperiod (2?×?1-h, bright white light, morning and evening) can restore summer timing. A single 1-h pulse of light in the morning may be sufficient. A few people desynchronize from the 24-h day (free-run) and show their intrinsic circadian period, usually >24?h. With regard to general health in polar regions, intermittent reports describe abnormalities in various physiological processes from the point of view of daily and seasonal rhythms, but positive health outcomes are also published. True winter depression (SAD) appears to be rare, although subsyndromal SAD is reported. Probably of most concern are the numerous reports of sleep problems. These have prompted investigations of the underlying mechanisms and treatment interventions. A delay of the circadian system with “normal” working hours implies sleep is attempted at a suboptimal phase. Decrements in sleep efficiency, latency, duration, and quality are also seen in winter. Increasing the intensity of ambient light exposure throughout the day advanced circadian phase and was associated with benefits for sleep: blue-enriched light was slightly more effective than standard white light. Effects on performance remain to be fully investigated. At 75°S, base personnel adapt the circadian system to night work within a week, in contrast to temperate zones where complete adaptation rarely occurs. A similar situation occurs on high-latitude North Sea oil installations, especially when working 18:00–06:00?h. Lack of conflicting light exposure (and “social obligations”) is the probable explanation. Many have problems returning to day work, showing circadian desynchrony. Timed light treatment again has helped to restore normal phase/sleep in a small number of people. Postprandial response to meals is compromised during periods of desynchrony with evidence of insulin resistance and elevated triglycerides, risk factors for heart disease. Only small numbers of subjects have been studied intensively in polar regions; however, these observations suggest that suboptimal light conditions are deleterious to health. They apply equally to people living in temperate zones with insufficient light exposure. (Author correspondence: arendtjo@gmail.com)     

Chronic Artificial Blue-Enriched White Light Is an Effective Countermeasure to Delayed Circadian Phase and Neurobehavioral Decrements

Studies in Polar Base stations, where personnel have no access to sunlight during winter, have reported circadian misalignment, free-running of the sleep-wake rhythm, and sleep problems. Here we tested light as a countermeasure to circadian misalignment in personnel of the Concordia Polar Base station during the polar winter. We hypothesized that entrainment of the circadian pacemaker to a 24-h light-dark schedule would not occur in all crew members (n = 10) exposed to 100–300 lux of standard fluorescent white (SW) light during the daytime, and that chronic non-time restricted daytime exposure to melanopsin-optimized blue-enriched white (BE) light would establish an a stable circadian phase, in participants, together with increased cognitive performance and mood levels. The lighting schedule consisted of an alternation between SW lighting (2 weeks), followed by a BE lighting (2 weeks) for a total of 9 weeks. Rest-activity cycles assessed by actigraphy showed a stable rest-activity pattern under both SW and BE light. No difference was found between light conditions on the intra-daily stability, variability and amplitude of activity, as assessed by non-parametric circadian analysis. As hypothesized, a significant delay of about 30 minutes in the onset of melatonin secretion occurred with SW, but not with BE light. BE light significantly enhanced well being and alertness compared to SW light. We propose that the superior efficacy of blue-enriched white light versus standard white light involves melanopsin-based mechanisms in the activation of the non-visual functions studied, and that their responses do not dampen with time (over 9-weeks). This work could lead to practical applications of light exposure in working environment where background light intensity is chronically low to moderate (polar base stations, power plants, space missions, etc.), and may help design lighting strategies to maintain health, productivity, and personnel safety.     

Dueling Hypotheses: Circatidal Versus Circalunidian Battle Basics–Second Engagement

The daily rhythm in body temperature is thought to be the result of the direct effects of activity and the effects of an endogenous circadian clock. Forced desynchrony (FD) is a tool used in human circadian rhythm research to disentangle endogenous and activity-related effects on daily rhythms. In the present study, we applied an FD protocol to rats. We subjected 8 rats for 5 days to a 20h forced activity cycle consisting of lOh of forced wakefulness and lOh for rest and sleep. The procedure aimed to introduce a lOh sleep/ lOh wake cycle, which period was different from the endogenous circadian (about 24h) rhythm. Of the variation in the raw body temperature data, 68–77% could be explained by a summation of estimated endogenous circadian cycle and forced activity cycle components of body temperature. Free-running circadian periods of body temperature during FD were similar to free-running periods measured in constant conditions. The applied forced activity cycle reduced clock-related circadian modulation of activity. This reduction of circadian modulation of activity did not affect body temperature. Also, the effects of the forced activity on body temperature were remarkably small.     

Forced Desynchrony of Orcadian Rhythms of Body Temperature and Activity in Rats

The daily rhythm in body temperature is thought to be the result of the direct effects of activity and the effects of an endogenous circadian clock. Forced desynchrony (FD) is a tool used in human circadian rhythm research to disentangle endogenous and activity-related effects on daily rhythms. In the present study, we applied an FD protocol to rats. We subjected 8 rats for 5 days to a 20h forced activity cycle consisting of lOh of forced wakefulness and lOh for rest and sleep. The procedure aimed to introduce a lOh sleep/ lOh wake cycle, which period was different from the endogenous circadian (about 24h) rhythm. Of the variation in the raw body temperature data, 68-77% could be explained by a summation of estimated endogenous circadian cycle and forced activity cycle components of body temperature. Free-running circadian periods of body temperature during FD were similar to free-running periods measured in constant conditions. The applied forced activity cycle reduced clock-related circadian modulation of activity. This reduction of circadian modulation of activity did not affect body temperature. Also, the effects of the forced activity on body temperature were remarkably small.     

A forced desynchrony study of circadian pacemaker characteristics in seasonal affective disorder

The circadian pacemaker is an endogenous clock that regulates oscillations in most physiological and psychological processes with a near 24-h period. In many species, this pacemaker triggers seasonal changes in behavior. The seasonality of symptoms and the efficacy of light therapy suggest involvement of the circadian pacemaker in seasonal affective disorder (SAD), winter type. In this study, circadian pacemaker characteristics of SAD patients were compared with those of controls. Seven SAD patients and matched controls were subjected to a 120-h forced desynchrony protocol, in which core body temperature and melatonin secretion profiles were measured for the characterization of circadian pacemaker parameters. During this protocol, which enables the study of unmasked circadian pacemaker characteristics, subjects were exposed to six 20-h days in time isolation. Patients participated twice in winter (while depressed and while remitted after light therapy) and once in summer. Controls participated once in winter and once in summer. Between the SAD patients and controls, no significant differences were observed in the melatonin-derived period or in the phase of the endogenous circadian temperature rhythm. The amplitude of this rhythm was significantly smaller in depressed and remitted SAD patients than in controls. No abnormalities of the circadian pacemaker were observed in SAD patients. A disturbance in thermoregulatory processes might explain the smaller circadian temperature amplitude in SAD patients during winter.     

Cyclic melatonin synchronizes the circadian rhythm of feeding activity in Japanese quail,Coturnix c. japonica

In Japanese quail, we can observe the circadian rhythm of feeding activity in constant conditions, especially in birds from selected lines. In order to try to test the importance of melatonin as hormonal output for the circadian system, we gave a 24-h period cycle of exogenous melatonin to some of these birds when they were free running. We used castrated males firstly in order to cancel the known effect of steroids on circadian organisation. Secondly, as castrated birds generally expressed a very short periodicity, it allowed us to check induced synchronisation more easily. We maintained ten castrated males in constant dim light. We divided the experiment into five successive phases. The birds received a 24-h period cycle of melatonin (M phase) or of control solution with only the alcoholic solvent (C phase) as a drink. Before and after each one of these two phases, we gave water continually to drink (W1, W2 and W3 phases). Thus, the successive phases were W1-M-W2-C-W3. We measured intake of liquids and plasma melatonin concentrations to check melatonin ingestion. We automatically recorded individual feeding activity by infrared detectors, and analysed this by spectral analysis. At the beginning of the experiment, eight birds showed a rhythmic feeding activity, with a mean period of 22.9 +/- 0.2 h, and the two others an arrhythmic circadian activity. During the 24-h period cycle of exogenous melatonin, for the rhythmic birds, the circadian period became approximately 24 h (23.9 +/- 0.2 h), the inactive phase corresponding to the period of melatonin availability. During the W2 and C phases, the circadian period was similar to that expressed during the W1 phase. Moreover, when birds only drink water, we found a significant positive relationship between the clarity of the circadian rhythm and the ratio, between the melatonin level of the inactive phase and that of the active phase. These facts support the hypothesis of the role of this hormone in the regulation of the circadian system, at least for feeding activity, in quail.     

History dependence of circadian pacemaker period in the cockroach

The freerunning period of circadian clocks in constant environmental conditions can be history-dependent, and one effect of entrainment of circadian clocks by light cycles is to cause long-lasting changes in the freerunning period that are termed after-effects. We have studied after-effects of entrainment to 22-h (LD 8:14) and 26-h (LD 8:18) light cycles in the cockroach Leucophaea maderae. We find that in cockroaches, the freerunning period of the locomotor activity rhythm, measured in constant darkness (DD), is 0.7h less after entrainment to T22 than after entrainment to T26. Induction of after-effects requires several days (>1 week) entrainment, and after induction, after-effects will persist in DD for over 40 days. Further after-effects are unaltered by phase-resetting of up to 12h caused by exposure to low-temperature pulses (7 degrees C) of 24 or 48h duration. After-effects also persist through re-entrainment for 2 weeks to 24-h light cycles. These results indicate that after-effects arise from stable changes in the circadian system that are likely to be independent of phase relationships among oscillators within the circadian system. We also show that entrainment to temperature cycles does not generate after-effects indicating that light may be unique in its ability to generate lasting changes in pacemaker period.     

Exercise distributed across day and night does not alter circadian period in humans

In rodents, increased activity due to running-wheel access is associated with a change in observed circadian period. In humans, exposure to exercise has failed to demonstrate similar effects on period. Methodological issues with prior studies such as light exposure during exercise, length of study, and method of measuring period confounded those evaluations of the effect of exercise on period in humans. In the present experiment, the authors examined the effect of exercise on period in 8 subjects using a 44-day within-subjects inpatient study. They used a 20-h forced desynchrony protocol, in which subjects were exposed to exercise across circadian phases under dim light conditions. Exercise consisted of three 45-min sessions per wake period on an ergometer. Target exercise intensity was ~65% of maximal heart rate. Intrinsic circadian period was measured using both core body temperature and hourly plasma melatonin samples. Consistent with previous reports, the authors find no effect of exercise on endogenous circadian period as measured by either core body temperature or melatonin. Exercise distributed across biological day and night does not appear to affect circadian period.     

Melatonin production and light exposure of rotating night workers

Decreased melatonin production, due to acute suppression of pineal melatonin secretion by light exposure during night work, has been suggested to underlie higher cancer risks associated with prolonged experience of night work. However, the association between light exposure and melatonin production has never been measured in the field. In this study, 24-h melatonin production and ambulatory light exposure were assessed during both night-shift and day/evening-shift periods in 13 full-time rotating shiftworkers. Melatonin production was estimated with the excretion of urinary 6-sulfatoxymelatonin (aMT6s), and light exposure was measured with an ambulatory photometer. There was no difference in total 24-h aMT6s excretion between the two work periods. The night-shift period was characterized by a desynchrony between melatonin and sleep-wake rhythms, as shown by higher melatonin production during work and lower melatonin production during sleep when working night shifts than when working day/evening shifts. Light exposure during night work showed no correlation with aMT6s excreted during the night of work (p?>?.5), or with the difference in 24-h aMT6s excretion between the two work periods (p >?.1). However, light exposure during night work was negatively correlated with total 24-h aMT6s excretion over the entire night-shift period (p?相似文献   

Amplitude reduction and phase shifts of melatonin, cortisol and other circadian rhythms after a gradual advance of sleep and light exposure in humans

Background

The phase and amplitude of rhythms in physiology and behavior are generated by circadian oscillators and entrained to the 24-h day by exposure to the light-dark cycle and feedback from the sleep-wake cycle. The extent to which the phase and amplitude of multiple rhythms are similarly affected during altered timing of light exposure and the sleep-wake cycle has not been fully characterized.

Methodology/Principal Findings

We assessed the phase and amplitude of the rhythms of melatonin, core body temperature, cortisol, alertness, performance and sleep after a perturbation of entrainment by a gradual advance of the sleep-wake schedule (10 h in 5 days) and associated light-dark cycle in 14 healthy men. The light-dark cycle consisted either of moderate intensity ‘room’ light (∼90–150 lux) or moderate light supplemented with bright light (∼10,000 lux) for 5 to 8 hours following sleep. After the advance of the sleep-wake schedule in moderate light, no significant advance of the melatonin rhythm was observed whereas, after bright light supplementation the phase advance was 8.1 h (SEM 0.7 h). Individual differences in phase shifts correlated across variables. The amplitude of the melatonin rhythm assessed under constant conditions was reduced after moderate light by 54% (17–94%) and after bright light by 52% (range 12–84%), as compared to the amplitude at baseline in the presence of a sleep-wake cycle. Individual differences in amplitude reduction of the melatonin rhythm correlated with the amplitude of body temperature, cortisol and alertness.

Conclusions/Significance

Alterations in the timing of the sleep-wake cycle and associated bright or moderate light exposure can lead to changes in phase and reduction of circadian amplitude which are consistent across multiple variables but differ between individuals. These data have implications for our understanding of circadian organization and the negative health outcomes associated with shift-work, jet-lag and exposure to artificial light.     

Robust entrainment of circadian oscillators requires specific phase response curves

The circadian clocks keeping time in many living organisms rely on self-sustained biochemical oscillations entrained by external cues, such as light, to the 24-h cycle induced by Earth's rotation. However, environmental cues are unreliable due to the variability of habitats, weather conditions, or cue-sensing mechanisms among individuals. A tempting hypothesis is that circadian clocks have evolved so as to be robust to fluctuations in the signal that entrains them. To support this hypothesis, we analyze the synchronization behavior of weakly and periodically forced oscillators in terms of their phase response curve (PRC), which measures phase changes induced by a perturbation applied at different times of the cycle. We establish a general relationship between the robustness of key entrainment properties, such as stability and oscillator phase, on the one hand, and the shape of the PRC as characterized by a specific curvature or the existence of a dead zone, on the other hand. The criteria obtained are applied to computational models of circadian clocks and account for the disparate robustness properties of various forcing schemes. Finally, the analysis of PRCs measured experimentally in several organisms strongly suggests a case of convergent evolution toward an optimal strategy for maintaining a clock that is accurate and robust to environmental fluctuations.     

Significance of Nonparametric Light Effects in Entrainment of Circadian Rhythms in Owl Monkeys (Aotus Lemurinus Griseimembra) by Light-Dark Cycles

In a total of 12 adult Colombian owl monkeys, Aotus lemurinus griseimembra, the significance of nonparametric light effects for the entrainment of the circadian system by light-dark (LD) cycles was studied by carrying out (a) phase-response experiments testing the phase-shifting effect of 30-min light pulses (LPs) of 250 lx applied at various phases of the free-running circadian activity rhythm (LL 0.2 lx) and (b) synchronization experiments testing the entraining effect of 24-h single LP photoperiods consisting of 30-min L of 80 lx and 23.5-h D of 0.5 lx (sP 0.5) and skeleton photoperiods consisting of two 30-min LPs of 80 lx, given against a background illuminance of 0.5 lx either symmetrically at 12-h intervals (PP 12:12) or asymmetrically at 9- and 15-h intervals (PP 9:15). The phase-response characteristics in Aotus, as evidenced by the phase-response curve, generally correspond to those of nocturnal rodents, proving that this neotropical simian primate chronobiologically is a genuine nocturnal species. When free-running with a spontaneous period close to 24 h (24.3 ± 0.1 h), the PP 12:12 produced entrainment in only two of five owl monkeys, whereas the sP 0.5 entrained four of them. The PP 9:15, however, brought about stable entrainment of the circadian rhythms of locomotor activity, feeding activity, and core temperature in all animals tested (n = 8). Changes in phase position of the activity time with the endogenous rhythm entrained by a PP 12:12, by an sP 0.5, or by a PP 9:15 give evidence that both LPs of a skeleton photoperiod contribute to the phase setting of the circadian system. When free-running with a considerably lengthened spontaneous period (τ ≥ 25.5 h), even the sP 0.5 and the PP 9:15 failed to entrain the owl monkeys' circadian rhythms, whereas a 24-h photoperiod with a very long LP of 3 h caused entrainment. The results indicate that in Aotus lemurinus griseimembra, in addition to the nonparametric light effects, parametric light effects play a significant role in the entrainment of circadian rhythms by LD cycles.     

Melatonin facilitates synchronization of sparrow circadian rhythms to light

We recorded circadian locomotor activity rhythms of house sparrows (Passer domesticus) exposed to low-amplitude light-dark cycles (2∶1 lux) with periods of 22.5 or 24.5 h. Under these conditions the circadian rhythms of the majority of the birds were not synchronized by the light cycle but either free-ran or showed relative coordination. However, when melatonin was administered continuously via subcutaneous silastic implants the rhythms became synchronized. It is proposed that melatonin facilitates synchronization either by weakening the circadian oscillatory system thereby increasing its range of entrainment, or by enhancing circadian sensitivity to the light Zeitgeber. In general, the results suggest that melatonin, besides its well-known phasic effects on the circadian system also has important tonic effects modifying the ease with which circadian systems can be entrained.     

Dysregulation of circadian rhythms following prolactin-secreting pituitary microadenoma

A patient who developed an irregular sleep-wake pattern following prolactin-secreting pituitary microadenoma is described. The patient reported difficulties in sleep onset and awakening at the desired time, which caused major dysfunction in his daily life activities. Despite these difficulties, the sleep-related complaints of the patient remained unrecognized for as long as three yrs. Statistical analyses of the patient's rest-activity patterns revealed that the disruption of the sleep-wake circadian rhythm originated from a disharmony between ultradian (semicircadian) and circadian components. The circadian component displayed shorter than 24 h periodicity most of the time, but the semicircadian component fluctuated between longer and shorter than 12 h periods. Additionally, desynchrony in terms of period length was found in the tentative analyses of the rest-activity pattern, salivary melatonin, and oral temperature. While the salivary melatonin time series data could be characterized by a best-fit cosine curve of 24 h, the time series data of oral temperature was more compatible with 28 h best-fit curve. The rest-activity cycle during the simultaneous measurements, however, was best approximated by a best-fit curve of 21 h. The dysregulation of circadian rhythms occurred concomitantly, but not beforehand, with the onset of pituitary disease, thus suggesting an association between the two phenomena. This association may have interesting implications to the modeling of the circadian time-keeping system. This case also highlights the need to raise the awareness to circadian rhythm sleep disorders and to consider disruptions of sleep-wake cycle in patients with pituitary adenoma.