Direction Of Phase Shift Research Articles

Complementary phase responses via functional differentiation of dual negative feedback loops.

Multiple feedback loops are often found in gene regulations for various cellular functions. In mammalian circadian clocks, oscillations of Period1 (Per1) and Period2 (Per2) expression are caused by interacting negative feedback loops (NFLs) whose protein products with similar molecular functions repress each other. However, Per1 expression peaks earlier than Per2 in the pacemaker tissue, raising the question of whether the peak time difference reflects their different dynamical functions. Here, we address this question by analyzing phase responses of the circadian clock caused by light-induced transcription of both Per1 and Per2 mRNAs. Through mathematical analyses of dual NFLs, we show that phase advance is mainly driven by light inputs to the repressor with an earlier expression peak as Per1, whereas phase delay is driven by the other repressor with a later peak as Per2. Due to the complementary contributions to phase responses, the ratio of light-induced transcription rates between Per1 and Per2 determines the magnitude and direction of phase shifts at each time of day. Specifically, stronger Per1 light induction than Per2 results in a phase response curve (PRC) with a larger phase advance zone than delay zone as observed in rats and hamsters, whereas stronger Per2 induction causes a larger delay zone as observed in mice. Furthermore, the ratio of light-induced transcription rates required for entrainment is determined by the relation between the circadian and light-dark periods. Namely, if the autonomous period of a circadian clock is longer than the light-dark period, a larger light-induced transcription rate of Per1 than Per2 is required for entrainment, and vice versa. In short, the time difference between Per1 and Per2 expression peaks can differentiate their dynamical functions. The resultant complementary contributions to phase responses can determine entrainability of the circadian clock to the light-dark cycle.

Human circadian phase-response curves for exercise.

Key points Exercise elicits circadian phase‐shifting effects, but additional information is needed.The phase–response curve describing the magnitude and direction of circadian rhythm phase shifts, depending on the time of the zeigeber (time cue) stimulus, is the most fundamental chronobiological tool for alleviating circadian misalignment and related morbidity.Fifty‐one older and 48 young adults followed a circadian rhythms measurement protocol for up to 5.5 days, and performed 1 h of moderate treadmill exercise for 3 consecutive days at one of eight times of the day/night.Temporal changes in the phase of 6‐sulphatoxymelatonin (aMT6s) were measured from evening onset, cosine acrophase, morning offset and duration of excretion. Significant phase–response curves were established for aMT6 onset and acrophase with large phase delays from 7:00 pm to 10:00 pm and large phase advances at both 7:00 am and from 1:00 pm to 4:00 pm. Delays or advances would be desired, for example, for adjustment to westward or eastward air travel, respectively.Along with known synergism with bright light, the above PRCs with a second phase advance region (afternoon) could support both practical and clinical applications. Although bright light is regarded as the primary circadian zeitgeber, its limitations support exploring alternative zeitgebers. Exercise elicits significant circadian phase‐shifting effects, but fundamental information regarding these effects is needed. The primary aim of the present study was to establish phase–response curves (PRCs) documenting the size and direction of phase shifts in relation to the circadian time of exercise. Aerobically fit older (n = 51; 59–75 years) and young adults (n = 48; 18–30 years) followed a 90 min laboratory ultrashort sleep–wake cycle (60 min wake/30 min sleep) for up to 5½ days. At the same clock time on three consecutive days, each participant performed 60 min of moderate treadmill exercise (65–75% of heart rate reserve) at one of eight times of day/night. To describe PRCs, phase shifts were measured for the cosine‐fitted acrophase of urinary 6‐sulphatoxymelatonin (aMT6s), as well as for the evening rise, morning decline and change in duration of aMT6s excretion. Significant PRCs were found for aMT6s acrophase, onset and duration, with peak phase advances corresponding to clock times of 7:00 am and from 1:00 pm to 4:00 pm, delays from 7:00 pm to 10:00 pm, and minimal shifts around 4:00 pm and 2:00 am. There were no significant age or sex differences. The amplitudes of the aMT6s onset and acrophase PRCs are comparable to expectations for bright light of equal duration. The phase advance to afternoon exercise and the exercise‐induced PRC for change in aMT6s duration are novel findings. The results support further research exploring additive phase‐shifting effects of bright light and exercise and health benefits.

Relationship between burnout and circadian typology and sleep habits in Japanese nursery school and kindergarten teachers

ABSTRACTThere have been few studies on the relationship between diurnal rhythms & sleep habits and the burnout of teachers of young children attending nursery schools and kindergarten. This study aims to clarify this relationship with a questionnaire. Integrated questionnaire was given to 272 teachers who worked at 10 nursery schools founded by Kochi city and one kindergarten affiliated with the Facuty of Education, Kochi University. Responses were recieved from 220 teachers (response rate: 80.8%). The integrated questionnaire included Diurnal Type Scale (DTS), questions on sleep hatits, questions on lighting conditions, and the Maslach Burnout Inventory (MBI). There was no correlative relationship between MBI and DTS. However, the total score for three questions on morning phase ("morning scores") among the DTS was significantly negatively correlated with MBI (waking up later related to higher burnout score; p=0.001). A significantly positive correlation was observed between MBI and three questions scores related to evening phase ("evening scores") (earlier bed time related higher burnout scores; p=0.001). This opposite direction of phase shift at night and in the morning can increase sleep hours. As a physiological view point, a high level of burnout may result in a longer duration of sleep as one homeostatic response.

Circadian rhythm phase shifts and endogenous free-running circadian period differ between African-Americans and European-Americans.

Successful adaptation to modern civilization requires the internal circadian clock to make large phase shifts in response to circumstances (e.g., jet travel and shift work) that were not encountered during most of our evolution. We found that the magnitude and direction of the circadian clock's phase shift after the light/dark and sleep/wake/meal schedule was phase-advanced (made earlier) by 9 hours differed in European-Americans compared to African-Americans. European-Americans had larger phase shifts, but were more likely to phase-delay after the 9-hour advance (to phase shift in the wrong direction). The magnitude and direction of the phase shift was related to the free-running circadian period, and European-Americans had a longer circadian period than African-Americans. Circadian period was related to the percent Sub-Saharan African and European ancestry from DNA samples. We speculate that a short circadian period was advantageous during our evolution in Africa and lengthened with northern migrations out of Africa. The differences in circadian rhythms remaining today are relevant for understanding and treating the modern circadian-rhythm-based disorders which are due to a misalignment between the internal circadian rhythms and the times for sleep, work, school and meals.

Phase‐shifting response to light in older adults

Age-related changes in circadian rhythms may contribute to the sleep disruption observed in older adults. A reduction in responsiveness to photic stimuli in the circadian timing system has been hypothesized as a possible reason for the advanced circadian phase in older adults. This project compared phase-shifting responses to 2 h of broad-spectrum white light at moderate and high intensities in younger and older adults. Subjects included 29 healthy young (25.1 ± 4.1 years; male to female ratio: 8: 21) and 16 healthy older (66.5 ± 6.0 years; male to female ratio: 5: 11) subjects, who participated in two 4-night and 3-day laboratory stays, separated by at least 3 weeks. Subjects were randomly assigned to one of three different time-points, 8 h before (-8), 3 h before (-3) or 3 h after (+3) the core body temperature minimum (CBTmin) measured on the baseline night. For each condition, subjects were exposed in a randomized order to 2 h light pulses of two intensities (2000 lux and 8000 lux) during the two different laboratory stays. Phase shifts were analysed according to the time of melatonin midpoint on the nights before and after light exposure. Older subjects in this study showed an earlier baseline phase and lower amplitude of melatonin rhythm compared to younger subjects, but there was no evidence of age-related changes in the magnitude or direction of phase shifts of melatonin midpoint in response to 2 h of light at either 2000 lux or 8000 lux. These results indicate that the acute phase-shifting response to moderate- or high-intensity broad spectrum light is not significantly affected by age.

Chromatic input to cells of the magnocellular pathway: Mean chromaticity and the relative phase of modulated lights

If the relative phase of red and green modulated lights is changed, at low temporal frequencies the response of cells of the magnocellular (MC) pathway has been found to be minimal not to counterphase, chromatic modulation (as expected of a luminance mechanism) but shifted to some phase intermediate between luminance and chromatic modulation. The results could only be modeled by assuming interaction between achromatic and chromatic inputs to MC cells. The 'phase shift' resembled that seen with psychophysical threshold measurements using the same stimuli. Psychophysical results also showed that the phase shift is dependent on the chromaticity of a background. The results reported here show that the direction of the phase shift in MC cells is reversed by changing the background from long to short wavelengths and is consistent with psychophysical observations. Cell behavior was again modeled by assuming vector summation of achromatic and chromatic inputs. The reversal of phase-shift direction requires a reversal in polarity of the chromatic input. The underlying physiological mechanism may involve summation of chromatic signals of opposite polarity; if the relative size of these signals depends on the background, this may determine the direction of phase shift.

Phase-shifting human circadian rhythms: influence of sleep timing, social contact and light exposure.

1. Both the timing of behavioural events (activity, sleep and social interactions) and the environmental light-dark cycle have been reported to contribute to entrainment of human circadian rhythms to the 24 h day. Yet, the relative contribution of those putative behavioural synchronizers to that of light exposure remains unclear. 2. To investigate this, we inverted the schedule of rest, sedentary activity and social contact of thirty-two young men either with or without exposure to bright light. 3. On this inverted schedule, the endogenous component of the core temperature rhythm of subjects who were exposed to bright light showed a significant phase shift, demonstrating that they were adapting to the new schedule. In contrast, the core temperature rhythm of subjects who were not exposed to bright light moved on average 0.2 h later per day and after 10 days had not significantly adapted to the new schedule. 4. The direction of phase shift in the groups exposed to bright light was dependent on the time of bright light exposure, while control subjects drifted to a later hour regardless of the timing of their schedule of sleep timing, social contact and meals. 5. These results support the concept that the light-dark cycle is the most important synchronizer of the human circadian system. They suggest that inversion of the sleep-wake, rest-activity and social contact cycles provides relatively minimal drive for resetting the human circadian pacemaker. 6. These data indicate that interventions designed to phase shift human circadian rhythms for adjustment to time zone changes or altered work schedules should focus on properly timed light exposure.

Phase response curves to neuropeptide Y in wildtype and tau mutant hamsters.

Neuropeptide Y (NPY)-containing fibers project from the intergeniculate leaflet to the suprachiasmatic nucleus. NPY has been shown to phase shift the circadian locomotor activity rhythm of wildtype hamsters, producing large phase advances in the subjective day and small delays in the subjective night. Previous studies have implicated this pathway in the mediation of activity-induced resetting of the circadian clock. Homozygous tau mutant and wildtype hamsters respond very differently to pulses of activity. Not only is the amplitude of the phase response curve exaggerated in the mutants with shifts of up to 7 h, but the stimuli are effective at different times during the cycle. Homozygous tau mutant hamsters and wildtype controls were implanted with guide cannulas aimed at the suprachiasmatic nucleus and injected with NPY at various times during the circadian cycle. The responses of homozygous tau mutant hamsters to NPY resembled their responses to nonphotic stimuli in both timing and direction of phase shift. This finding provides correlational evidence that NPY is involved in the effects of nonphotic behavioral events on the circadian system.

Demonstration of rapid light-induced advances and delays of the human circadian clock using hormonal phase markers.

To determine the magnitude and direction of phase shifts of human circadian rhythms occurring within 1 day after a single exposure to bright light, plasma thyrotropin, melatonin, and cortisol levels and body temperature were monitored for 38 h in 17 men who were each studied two times, once during continuous dim light conditions and once with light exposure. After a period of entrainment to a fixed sleep-wake cycle, a 3-h light pulse (5,000 lux) was presented under constant routine conditions, and the resultant phase shifts were measured, also under constant routine conditions, on the 1st day after pulse presentation. The phase shifts in response to light occurred within 24 h and were in the delaying direction for most of the nocturnal period, with the crossover to phase advances occurring approximately 1 h after the temperature minimum. Phase shifts averaged 1 h, with delays being larger than advances, and were achieved without significant changes in rhythm amplitude. The immediate response of the human circadian clock to a single 3-h light pulse is thus characteristic of "type 1" resetting.

Entrainment of the rat circadian clock controlling the pineal N-acetyltransferase rhythm depends on photoperiod

Entrainment of the circadian clock as a function of time when a light stimulus is presented has been studied in detail while little attention has been paid to a role photoperiod may play in the resetting. To find out whether and how photoperiod affects the entrainment, resetting of the rat circadian pacemaker by delays in the evening light offset and by advances in the morning light onset, respectively, was studied in rats maintained either under a short photoperiod, with 8 h of light and 16 h of darkness per day (LD8:16) or under a long, LD18:6 photoperiod. To assess phase shifts of the clock, the suprachiasmatic nucleus controlled rhythm in the pineal N-acetyltransferase (NAT), namely the time of the evening NAT rise and the time of the morning decline, were followed. One day after a delay in lights off, on LD8:16 the NAT rhythm with a normal amplitude was retained following longer delays of the light offset and the maximum phase delay of the NAT rise was 3 times larger than on LD18:6. One day after an advance in lights on, the NAT decline was phase advanced under both photoperiods; on LD8:16 the maximum shift was 3 times as large as on LD18:6. On LD8:16, the NAT rise was not shifted after shorter advances in lights on and became phase delayed only when the light onset was brought forward to before midnight while on LD18:6 the NAT rise was phase delayed after any, even a mere 1 h, advance in lights on. The data show that magnitude and direction of phase shifts of the NAT rhythm depend not only on the time of light presentation but on photoperiod as well. Difference in resetting of the rhythm under various photoperiods may reflect photoperiod-dependent changes of an underlying pacemaker.

Cyclic nucleotides and circadian rhythm generation in Bulla gouldiana

1. 1. Phase shifts of the ocular circadian rhythm in isolated eyes of the marine snail, Bulla gouldiana were produced by 3- and 6-hr pulses of agents that increase or mimic cyclic AMP (cAMP) activity. 2. 2. The magnitude and direction of phase shifts depended upon the circadian phase of the rhythm, and the phase response curve was similar to that produced by membrane hyperpolarizing treatments in this species. 3. 3. Phase shifts induced by cAMP were eliminated by a depolarizing agent, tetraethylammonium, applied simultaneously to experimental and control eyes. 4. 4. As in other species, cAMP may regulate circadian rhythms in Bulla, possibly through effects on membrane potential.

Phase shifts and the square-wave illusion.

When observers view a vertical triangle-wave luminance profile, they often report a square-wave illusion with a depth component, resembling a corrugated surface. Alternate bars seem to be in front of or behind adjacent bars and the surface appears to be illuminated from the right or left. These perspectives alternate with continuous viewing. One explanation for this illusion stems from the notion of instability among phase-selective mechanisms. Two experiments (1 and 3) were designed to determine whether systematic phase shifts introduced between the fundamental and the odd harmonics of the waveform would lead to a systematic bias of the illusion. The results indicated that a significant bias occurred when a phase shift as small as 9 deg was introduced, and that the bias from the phase shifts was more powerful than previous reports of drift-induced bias. There was a highly significant effect of direction of phase shift and the corresponding perceived direction of illumination. Another experiment (2) was designed to determine if illusional cues within the phase-shifted profiles aided phase discrimination. The results indicated that experienced subjects, presumably using cues within the profiles, discriminated between the stimuli significantly better than did naive subjects. These data support the role of phase in the square-wave illusion, but they also raise questions about the role of contrast changes in local regions of the stimulus.

The jamming avoidance response in Rhamphichthys rostratus: an alternative principle of time domain analysis in electric fish.

A Jamming Avoidance Response was found in the weakly electric fish Rhamphichthys rostratus, a South American pulse-Gymnotid. The analysis of the response suggests that it requires a key stimulus which is fundamentally different from that in previously described harmonic Gymnotids. It relies on a sensitivity for the direction of phase shifts of stimulus pulses relative to the fish's own electric organ discharge rather than on a sensitivity for beating frequencies.

Two mechanisms of rephasal of circadian rhythms in response to a 180° phase shift (simulated 12‐hr time zone change)

A model developed by Wever (1966) is considered. The model describes the behavior of circadian rhythms in response to photoperiod phase shifts simulating time zone changes, as a function of endogenous periodicity, light intensity, and direction of phase shift. A description is given of an investigation conducted to test the model upon the deep body temperature rhythm in unrestrained subhuman primates. An evaluation is conducted regarding the applicability of the model in predicting the type and duration of desynchronization induced by simulated time zone changes as a function of endogenous periodicity.