Circadian Organization Research Articles

Differences in Photic Entrainment of Circadian Locomotor Activity Between Lean and Obese Volcano Mice (Neotomodon alstoni).

Obesity is a growing problem worldwide with a clear impact on health status. It is also a condition that negatively affects circadian rhythms. When the mouse Neotomodon alstoni is fed a regular rodent chow, some individuals develop obesity, representing an opportunity to compare the effects of spontaneous obesity upon the circadian organization in this species with that observed in other rodents with induced obesity. We report differences in the free running circadian locomotor activity rhythm and in the effects of light pulses between lean and obese mice. Also, the photo-induced expression of the c-Fos protein and vasoactive intestinal peptide (VIP) in the suprachiasmatic nucleus (SCN) were examined at circadian time (CT) 14 and 22. We show that obese mice have a larger dispersion of the period of circadian locomotor rhythm in constant darkness. Photic induced phase shifts are nearly 50% shorter at CT 14, and 50% larger at CT 22 than in lean mice. The photoinduction of VIP in the SCN at CT 22 was larger in obese mice, which may be related to the differences observed in photic phase shifting. Our work indicates that the obesity in Neotomodon has effects on the neural mechanisms that regulate the circadian system.

NEWBORNS POSTHYPOXIC CARDIOPATHY: NEW TREATMENT OPTIONS

Objective of the research – to assess efficacy and safety of drug Elkar® 100 mg/ml for intravenous and intramuscular injection in treatment of newborns with posthypoxic cardiopathy. Patients were randomized into 2 groups, comparable in age, gestational age, severity of cerebral ischemia. The main group (n=43) in addition to standard therapy received Elkar® intravenously at a dose of 50–100 mg/kg/day, the comparison group (n=40) received only standard therapy for posthypoxic cardiopathy. The control group consisted of 20 children without clinically significant CNS and cardiovascular system (CVS) lesions. Elkar® contributed to a significant improvement in clinical status and optimization of postnatal CVS adjustment, manifesting as effective reduction of electrical instability and myocardial ischemia, heart rate recovery, systolic and diastolic function normalization, size of right heart chambers, reduced the diameter and hemodynamic significance of fetal functioning communications, restored vegetative regulation of heart rate and its circadian organization, helped to reduce rhythm pauses duration and arrhythmias representation. Elkar® intravenous use was satisfactorily tolerated by newborns and had no clinically significant adverse effects. The most rapid and complete regression of posthypoxic cardiopathy manifestations revealed after intravenous drug use at a dose of 80–100 mg/kg/day and continuing oral administration up to 1 month.

Circadian behavior of adult mice exposed to stress and fluoxetine during development.

Women of child-bearing age are the population at greatest risk for depression. The stress experienced during pregnancy and the associated antidepressant treatments can both affect fetal development. Fluoxetine (FLX) is among the most common antidepressants used by pregnant women. We have previously demonstrated that perinatal exposure to FLX can alter expression of circadian rhythms in adulthood. Here, we examine the combined effects of maternal stress during pregnancy and perinatal exposure to the antidepressant FLX on the circadian behavior of mice as adults. Mouse dams were exposed to chronic unpredictable stress (embryonic (E) day 7 to E18), FLX (E15 to postnatal day 12), a combination of both stress and FLX, or were left untreated. At 2months of age, male offspring were placed in recording chambers and circadian organization of wheel running rhythms and phase shifts to photic and non-photic stimuli were assessed. Mice exposed to prenatal stress (PS) had smaller light-induced phase delays. Mice exposed to perinatal FLX required more days to re-entrainment to an 8-h phase advance of their light-dark cycle. Mice subjected to either perinatal FLX or to PS had larger light-induced phase advances and smaller phase advances to 8-OH-DPAT. FLX treatment partially reversed the effect of PS on phase shifts to late-night light exposure and to 8-OH-DPAT. Our results suggest that, in mice, perinatal exposure to either FLX, or PS, or their combination, leads to discernible, persistent changes in their circadian systems as adults.

Development of Circadian Sleep Regulation in the Rat: A Longitudinal Study Under Constant Conditions.

To better understand the development of sleep, we characterized the development of circadian rhythms in sleep and wakefulness in the artificially-reared, isolated rat pup using an experimental design that minimized the effects of maternal separation. Neonatal rats were reared in constant conditions (dim red light) while electroencephalographic and electromyographic signals were continuously recorded for up to 3 weeks. This time period spanned the preweaned and weaned ages. The distribution of sleep-wake states was analyzed to estimate the emergence of circadian rhythms. Overt ~24-hour rhythms in time spent awake and asleep appear by postnatal day (P)17. A marked bi-modal sleep-wake pattern was also observed, evidenced by the appearance of a pronounced ~12-hour component in the periodogram over the subsequent 3 days (P17-P21). This suggested the presence of two ~24-hour components consistent with the dual-oscillator concept. During this 3-day time window, waking bouts became longer resulting in a repartition of the duration of intervals without non-rapid-eye movement (NREM) sleep into short (<30 minutes) and longer inter-NREM sleep episodes. These longer waking bouts did not immediately result in an increase in NREM sleep delta (0.5-4.0 Hz) power, which is an index of sleep homeostasis in adult mammals. The sleep homeostatic response did not fully mature until P25. These results demonstrate that the maturation of circadian organization of sleep-wake behavior precedes the expression of mature sleep homeostasis.

Interplay between the endocrine and circadian systems in fishes.

The circadian system is responsible for the temporal organisation of physiological functions which, in part, involves daily cycles of hormonal activity. In this review, we analyse the interplay between the circadian and endocrine systems in fishes. We first describe the current model of fish circadian system organisation and the basis of the molecular clockwork that enables different tissues to act as internal pacemakers. This system consists of a net of central and peripherally located oscillators and can be synchronised by the light-darkness and feeding-fasting cycles. We then focus on two central neuroendocrine transducers (melatonin and orexin) and three peripheral hormones (leptin, ghrelin and cortisol), which are involved in the synchronisation of the circadian system in mammals and/or energy status signalling. We review the role of each of these as overt rhythms (i.e. outputs of the circadian system) and, for the first time, as key internal temporal messengers that act as inputs for other endogenous oscillators. Based on acute changes in clock gene expression, we describe the currently accepted model of endogenous oscillator entrainment by the light-darkness cycle and propose a new model for non-photic (endocrine) entrainment, highlighting the importance of the bidirectional cross-talking between the endocrine and circadian systems in fishes. The flexibility of the fish circadian system combined with the absence of a master clock makes these vertebrates a very attractive model for studying communication among oscillators to drive functionally coordinated outputs.

Circadian rhythms accelerate wound healing in female Siberian hamsters

Circadian rhythms (CRs) provide temporal regulation and coordination of numerous physiological traits, including immune function. CRs in multiple aspects of immune function are impaired in rodents that have been rendered circadian-arrhythmic through various methods. In Siberian hamsters, circadian arrhythmia can be induced by disruptive light treatments (DPS). Here we examined CRs in wound healing, and the effects of circadian disruption on wound healing in DPS-arrhythmic hamsters. Circadian entrained/rhythmic (RHYTH) and behaviorally-arrhythmic (ARR) female hamsters were administered a cutaneous wound either 3h after light onset (ZT03) or 2h after dark onset (ZT18); wound size was quantified daily using image analyses. Among RHYTH hamsters, ZT03 wounds healed faster than ZT18 wounds, whereas in ARR hamsters, circadian phase did not affect wound healing. In addition, wounds healed slower in ARR hamsters. The results document a clear CR in wound healing, and indicate that the mere presence of organismal circadian organization enhances this aspect of immune function. Faster wound healing in CR-competent hamsters may be mediated by CR-driven coordination of the temporal order of mechanisms (inflammation, leukocyte trafficking, tissue remodeling) underlying cutaneous wound healing.

Dim light at night prior to adolescence increases adult anxiety-like behaviors

ABSTRACTDim light at night (dLAN) disrupts circadian organization and influences adult behavior. We examined early dLAN exposure on adult affective responses. Beginning 3 (juvenile) or 5 weeks (adolescent) of age, mice were maintained in standard light–dark cycles or exposed to nightly dLAN (5 lx) for 5 weeks, then anxiety-like and fear responses were assessed. Hypothalami were collected around the clock to assess core clock genes. Exposure to dLAN at either age increased anxiety-like responses in adults. Clock and Rev-ERB expression were altered by exposure to dLAN. In contrast to adults, dLAN exposure during early life increases anxiety and fear behavior.

Effects of Photoperiod Extension on Clock Gene and Neuropeptide RNA Expression in the SCN of the Soay Sheep.

In mammals, changing daylength (photoperiod) is the main synchronizer of seasonal functions. The photoperiodic information is transmitted through the retino-hypothalamic tract to the suprachiasmatic nuclei (SCN), site of the master circadian clock. To investigate effects of day length change on the sheep SCN, we used in-situ hybridization to assess the daily temporal organization of expression of circadian clock genes (Per1, Per2, Bmal1 and Fbxl21) and neuropeptides (Vip, Grp and Avp) in animals acclimated to a short photoperiod (SP; 8h of light) and at 3 or 15 days following transfer to a long photoperiod (LP3, LP15, respectively; 16h of light), achieved by an acute 8-h delay of lights off. We found that waveforms of SCN gene expression conformed to those previously seen in LP acclimated animals within 3 days of transfer to LP. Mean levels of expression for Per1-2 and Fbxl21 were nearly 2-fold higher in the LP15 than in the SP group. The expression of Vip was arrhythmic and unaffected by photoperiod, while, in contrast to rodents, Grp expression was not detectable within the sheep SCN. Expression of the circadian output gene Avp cycled robustly in all photoperiod groups with no detectable change in phasing. Overall these data suggest that synchronizing effects of light on SCN circadian organisation proceed similarly in ungulates and in rodents, despite differences in neuropeptide gene expression.

Participation of the Olfactory Bulb in Circadian Organization during Early Postnatal Life in Rabbits.

Experimental evidence indicates that during pre-visual stages of development in mammals, circadian regulation is still not under the control of the light-entrainable hypothalamic pacemaker, raising the possibility that the circadian rhythmicity that occurs during postnatal development is under the control of peripheral oscillators, such as the main olfactory bulb (MOB). We evaluated the outcome of olfactory bulbectomy on the temporal pattern of core body temperature and gross locomotor activity in newborn rabbits. From postnatal day 1 (P1), pups were randomly assigned to one of the following conditions: intact pups (INT), intact pups fed by enteral gavage (INT+ENT), sham operated pups (SHAM), pups with unilateral lesions of the olfactory bulb (OBx-UNI), and pups with bilateral lesions of the olfactory bulb (OBx-BI). At the beginning of the experiment, from P1-8, the animals in all groups were fed at 11:00, from P9-13 the feeding schedule was delayed 6 h (17:00), and finally, from P14-15 the animals were subjected to fasting conditions. The rabbit pups of the INT, INT+ENT, SHAM and OBx-UNI groups exhibited a clear circadian rhythmicity in body temperature and locomotor activity, with a conspicuous anticipatory rise hours prior to the nursing or feeding schedule, which persisted even during fasting conditions. In addition, phase delays in the nursing or feeding schedule induced a clear phase shift in both parameters. In contrast, the OBx-BI group exhibited atypical rhythmicity in both parameters under entrained conditions that altered the anticipatory component, as well as deficient phase control of both rhythms. The present results demonstrate that the expression of circadian rhythmicity at behavioral and physiological levels during early stages of rabbit development largely depends on the integrity of the main olfactory bulb.

Nutrition and the circadian system

The human circadian system anticipates and adapts to daily environmental changes to optimise behaviour according to time of day and temporally partitions incompatible physiological processes. At the helm of this system is a master clock in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus. The SCN are primarily synchronised to the 24-h day by the light/dark cycle; however, feeding/fasting cycles are the primary time cues for clocks in peripheral tissues. Aligning feeding/fasting cycles with clock-regulated metabolic changes optimises metabolism, and studies of other animals suggest that feeding at inappropriate times disrupts circadian system organisation, and thereby contributes to adverse metabolic consequences and chronic disease development. 'High-fat diets' (HFD) produce particularly deleterious effects on circadian system organisation in rodents by blunting feeding/fasting cycles. Time-of-day-restricted feeding, where food availability is restricted to a period of several hours, offsets many adverse consequences of HFD in these animals; however, further evidence is required to assess whether the same is true in humans. Several nutritional compounds have robust effects on the circadian system. Caffeine, for example, can speed synchronisation to new time zones after jetlag. An appreciation of the circadian system has many implications for nutritional science and may ultimately help reduce the burden of chronic diseases.

Circadian Clock in a Mouse Colon Tumor Regulates Intracellular Iron Levels to Promote Tumor Progression

Iron is an important biological catalyst and is critical for DNA synthesis during cell proliferation. Cellular iron uptake is enhanced in tumor cells to support increased DNA synthesis. Circadian variations in DNA synthesis and proliferation have been identified in tumor cells, but their relationship with intracellular iron levels is unclear. In this study, we identified a 24-h rhythm in iron regulatory protein 2 (IRP2) levels in colon-26 tumors implanted in mice. Our findings suggest that IRP2 regulates the 24-h rhythm of transferrin receptor 1 (Tfr1) mRNA expression post-transcriptionally, by binding to RNA stem-loop structures known as iron-response elements. We also found thatIrp2mRNA transcription is promoted by circadian clock genes, including brain and muscle Arnt-like 1 (BMAL1) and the circadian locomotor output cycles kaput (CLOCK) heterodimer. Moreover, growth in colon-26(Δ19) tumors expressing the clock-mutant protein (CLOCK(Δ19)) was low compared with that in wild-type colon-26 tumor. The time-dependent variation of cellular iron levels, and the proliferation rate in wild-type colon-26 tumor was decreased by CLOCK(Δ19)expression. Our findings suggest that circadian organization contributes to tumor cell proliferation by regulating iron metabolism in the tumor.

Decreased emotional reactivity of rats exposed to repeated phase shifts of light–dark cycle

Disturbed light–dark (LD) cycles are associated with circadian disruption of physiological and behavioural rhythms and in turn with an increased risk of disease development. However, direct causal links and underlying mechanisms leading to negative health consequences still need to be revealed. In the present study, we exposed male Wistar rats to repeated phase shifts of LD cycle and analysed their ability to cope with mild emotional stressors. In experiment 1, rats were submitted to either a regular 12:12 LD cycle (CTRL rats) or 8-h phase delay shifts applied every 2days for 5weeks (SHIFT rats). Subsequently, the behaviour was examined in the open-field, black–white box and elevated plus maze tests. In experiment 2, changes in blood pressure (BP), heart rate (HR) as well as the activity of autonomic nervous system were measured in telemeterised rats in response to open-field and black–white box tests before and after 5-week exposure to shifted LD regime. Locomotor activity was consistently higher in SHIFT than CTRL rats in in the open-field and black–white box tests. Interestingly, in the elevated plus maze, SHIFT rats displayed increased risk assessment and decreased grooming compared to CTRL rats. Anxiety measures were affected only in the black–white box, where SHIFT rats displayed reduced anxiety-like behaviour compared to CTRL rats. Differences in behavioural reactivity between SHIFT and CTRL rats did not correspond with BP and HR changes. However, exposure to phase shifts increased the sympathovagal reactivity in the black–white box. Together, our results demonstrated that disturbed LD conditions decreased emotional reactivity of rats and affected their ability to cope with emotional stressors denoting an additional risk mechanism linking disrupted circadian organisation to adverse health effects.

Temporal tuning of daily rhythms helps advanced cancer patients and cancer survivors feel better, live better, and live longer

There is now little doubt that disrupted day/night (circadian) time structures are involved in the initiation and promotion of neoplastic disease. It has been established that the incidence of breast cancer, colorectal cancer, and prostate cancer is increased as a result of nocturnal exposure to light and circadian function disruption and that cancer patient survival is diminished. So the question is: what public health measures can be implemented to minimize these health hazards? In addition, untreated cancer patients experience the symptom cluster of brief, interrupted, and poor nighttime sleep; depressed mood/anxiety; daytime fatigue/lethargy; and anorexia/early satiety/diminished taste sensation - each of which is virtually pathognomonic of a disrupted circadian temporal organization. Direct measurements of patients' activities and their timing and intensity using actigraphy reveal that untreated cancer patients experience severe deterioration in the robustness (amplitude) and day-to-day phase stability of their daily rest/ activity rhythms - and one of the most personal and socially destructive results of such circadian disorientation is unplanned, unwanted, and avoidable temporal isolation from family, friends, and society. Thus, therapeutic manipulation of the circadian clock is a powerful tool for improving cancer patients' quality of life (QOL), making life more worth living and perhaps prolonging higher quality survival. We herein take what we have learned to design and execute strategies shown to be beneficial and carefully measure cancer patient benefits. Outcome measures include indices that describe our ability to enhance/maintain circadian organization and orientation, diminish the above-mentioned symptoms, and improve QOL and survival prolongation. We herein implement a suite of noninvasive, riskless and costless, largely behavior-based circadian rhythm entrainment and disturbance avoidance techniques for widespread everyday use by cancer patients and survivors together with real-time actigraphic monitoring, continuous electronic feedback, and positive reinforcement of these simple temporal tuning interventions.

Circadian PER2::LUC rhythms in the olfactory bulb of freely moving mice depend on the suprachiasmatic nucleus but not on behaviour rhythms

The temporal order of physiology and behaviour in mammals is regulated by the coordination of the master circadian clock in the suprachiasmatic nucleus (SCN) and peripheral clocks in various tissues outside the SCN. Because the circadian oscillator(s) in the olfactory bulb (OB) is regarded as SCN independent, we examined the relationship between the SCN master clock and the circadian clock in the OB. We also examined the role of vasoactive intestinal peptide receptor 2 in the circadian organization of the OB. We continuously monitored the circadian rhythms of a clock gene product PER2 in the SCN and OB of freely moving mice by means of a bioluminescence reporter and an optical fibre implanted in the brain. Robust circadian rhythms were detected in the OB and SCN for up to 19 days. Bilateral SCN lesions abolished the circadian behaviour rhythms and disorganized the PER2 rhythms in the OB. The PER2 rhythms in the OB showed more than one oscillatory component of a similar circadian period, suggesting internal desynchronization of constituent oscillators. By contrast, significant circadian PER2 rhythms were detected in the vasoactive intestinal peptide receptor 2-deficient mice, despite the substantial deterioration or abolition of circadian behavioural rhythms. These findings indicate that the circadian clock in the OB of freely moving mice depends on the SCN master clock but not on the circadian behavioural rhythms. The circadian PER2::LUC rhythm in the cultured OB was as robust as that in the cultured SCN but reset by slice preparation, suggesting that culturing of the slice reinforces the circadian rhythm.

Diurnality as an energy-saving strategy: energetic consequences of temporal niche switching in small mammals.

Endogenous daily (circadian) rhythms allow organisms to anticipate daily changes in the environment. Most mammals are specialized to be active during the night (nocturnal) or day (diurnal). However, typically nocturnal mammals become diurnal when energetically challenged by cold or hunger. The circadian thermo-energetics (CTE) hypothesis predicts that diurnal activity patterns reduce daily energy expenditure (DEE) compared with nocturnal activity patterns. Here, we tested the CTE hypothesis by quantifying the energetic consequences of relevant environmental factors in mice. Under natural conditions, diurnality reduces DEE by 6-10% in energetically challenged mice. Combined with night-time torpor, as observed in mice under prolonged food scarcity, DEE can be reduced by ∼20%. The dominant factor determining the energetic benefit of diurnality is thermal buffering provided by a sheltered resting location. Compared with nocturnal animals, diurnal animals encounter higher ambient temperatures during both day and night, leading to reduced thermogenesis costs in temperate climates. Analysis of weather station data shows that diurnality is energetically beneficial on almost all days of the year in a temperate climate region. Furthermore, diurnality provides energetic benefits at all investigated geographical locations on European longitudinal and latitudinal transects. The reduction of DEE by diurnality provides an ultimate explanation for temporal niche switching observed in typically nocturnal small mammals under energetically challenging conditions. Diurnality allows mammals to compensate for reductions in food availability and temperature as it reduces energetic needs. The optimal circadian organization of an animal ultimately depends on the balance between energetic consequences and other fitness consequences of the selected temporal niche.

Endocrine Effects of Circadian Disruption.

Disruption of circadian rhythms, provoked by artificial lighting at night, inconsistent sleep-wake schedules, and transmeridian air travel, is increasingly prevalent in modern society. Desynchrony of biological rhythms from environmental light cycles has dramatic consequences for human health. In particular, disrupting homeostatic oscillations in endocrine tissues and the hormones that these tissues regulate can have cascading effects on physiology and behavior. Accumulating evidence suggests that chronic disruption of circadian organization of endocrine function may lead to metabolic, reproductive, sleep, and mood disorders. This review discusses circadian control of endocrine systems and the consequences of distorting rhythmicity of these systems.

Photoperiodic and circadian bifurcation theories of depression and mania.

Seasonal effects on mood have been observed throughout much of human history. Seasonal changes in animals and plants are largely mediated through the changing photoperiod (i.e., the photophase or duration of daylight). We review that in mammals, daylight specifically regulates SCN (suprachiasmatic nucleus) circadian organization and its control of melatonin secretion. The timing of melatonin secretion interacts with gene transcription in the pituitary pars tuberalis to modulate production of TSH (thyrotropin), hypothalamic T3 (triiodothyronine), and tuberalin peptides which modulate pituitary production of regulatory gonadotropins and other hormones. Pituitary hormones largely mediate seasonal physiologic and behavioral variations. As a result of long winter nights or inadequate illumination, we propose that delayed morning offset of nocturnal melatonin secretion, suppressing pars tuberalis function, could be the main cause for winter depression and even cause depressions at other times of year. Irregularities of circadian sleep timing and thyroid homeostasis contribute to depression. Bright light and sleep restriction are antidepressant and conversely, sometimes trigger mania. We propose that internal desynchronization or bifurcation of SCN circadian rhythms may underlie rapid-cycling manic-depressive disorders and perhaps most mania. Much further research will be needed to add substance to these theories.

Prognostic impact of sleep-time relative blood pressure decline for predicting the risk of developing chronic kidney disease

Some patients with hypertension exhibit disturbed circadian organization in the cardiovascular system. Hormone melatonin can synchronize circadian rhythms and its repeated administration can improve synchronization of rhythmicity in blood pressure (BP). In our study we measured endogenous melatonin production in patients with essential hypertension exhibiting a dipping and non-dipping BP profile. Blood pressure was monitored for at least 24-hr with an automatic ambulatory BP monitor and patients with no decline in BP were classified as non-dippers. Plasma melatonin was measured in the middle of the daytime and night-time by radioimmunoassay. As expected night-time systolic (P < 0.05), diastolic (P < 0.001) and mean arterial (P < 0.001) BP was higher in non-dippers than in dippers. No significant difference was found between both groups in BP during the day. Mean melatonin concentrations were higher during the night than during the day in both dippers and non-dippers. When patients were divided into dippers and non-dippers on the basis of mean arterial or diastolic BP a lower ratio of night/day concentration was determined in non-dippers than in dippers. Our study showed a blunted night/day difference in plasma melatonin concentrations in hypertensive patients with the non-dipping profile in diastolic BP indicating disturbances in the circadian system of these patients.

Circadian rhythms measured by actigraphy during oncological treatments: a systematic review

During oncological treatment patients often suffer from fatigue, insomnia, and daytime inactivity. This cluster of symptoms and overall survival are linked with circadian rhythm disruptions in rest-activity, which can be objectively characterized using actigraphy. We systematically reviewed the body of literature using actigraphy to characterize the circadian rhythm disruption in patients during oncological treatments and studies that introduced interventions to deal with this disruption. Thirteen observational and two interventional studies were included in this review. These mainly described patients with breast cancer undergoing chemotherapy, and the disruptions were persistent among these patients, and the disruptions peaked at the start of chemotherapy cycles and decreased during the periods in between. Light and behavioral therapy showed some alleviating effects in patients with breast cancer. We also found that circadian rhythm disruptions were prevalent in patients during other cancer therapies. Effective cancer therapy controls cancer growth and improves circadian organization. Cancer therapy itself, however, also contributes to cancer associated circadian dys-synchrony. Interrupting this vicious cycle represents an important opportunity for diminishing cancer patients’ suffering and improving or even prolonging their useful and enjoyable lives.

Phase resetting in duper hamsters: specificity to photic zeitgebers and circadian phase.

The duper mutation in Syrian hamsters shortens the free-running period of locomotor activity (τDD) to about 23 h and results in a type 0 phase-response curve (PRC) to 15-min light pulses. To determine whether exaggerated phase shifts are specific to photic cues and/or restricted to subjective night, we subjected hamsters to novel wheel confinements and dark pulses during subjective day. Small phase shifts elicited by the nonphotic cue were comparable in mutant and wild-type (WT) hamsters, but dark pulses triggered larger shifts in dupers. To assess further the effects of the duper mutation on light-dark transitions, we transferred hamsters between constant light (LL) and constant dark (DD) or between DD and LL at various circadian phases. Duper hamsters displayed significantly larger phase shifts than WT hamsters when transferred from LL to DD during subjective day and from DD to LL during subjective night. The variability of phase shifts in response to all light/dark transitions was significantly greater in duper hamsters at all time points. In addition, most duper hamsters, but none of the WTs, displayed transient ultradian wheel-running patterns for 5 to 12 days when transferred from light to dark at CT 18. The χ(2) periodogram and autocorrelation analyses indicate that these ultradian patterns differ from the disruption of rhythmicity by SCN lesions or exposure to constant bright light. We conclude that the duper mutation specifically amplifies phase shifts to photic cues and may destabilize coupling of circadian organization upon photic challenge due to weakened coupling among components of the circadian pacemaker. Mathematical modeling of the circadian pacemaker supports this hypothesis.