Glucocorticosteroid injection is a circadian zeitgeber in the laboratory rat

Intraperitoneal temperatures were monitored by radiotelemetry to observe the thermoregulatory rhythm of male laboratory rats (Rattus norvegicus albinus) Rats received single injections of dexamethasone (as dexamethasone sodium phosphate) during constant darkness (0.1 lx) with food freely available or no food available. No phase shifts occurred following saline injection or dexamethasone at 1 mg/kg body wt. Depending on the phase of injection relative to the circadian cycle, dexamethasone at 10 mg/kg caused thermoregulatory peaks to be either delayed or advanced on the 4th and 5th day after injection. There was an insensitive interval which corresponded to subjective day. Phase shifts induced by dexamethasone during ad libitum feeding were of less magnitude than those induced during starvation. The determination of phase-shifting parameters (i.e., a phase-response curve) for hormonal substances represents a rigorous and broadly applicable technique for determining endogenous mechanisms for circadian phase control and entrainment.

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PDF neuron firing phase-shifts key circadian activity neurons in Drosophila

eLife ◽

10.7554/elife.02780 ◽

2014 ◽

Vol 3 ◽

Cited By ~ 55

Author(s):

Fang Guo ◽

Isadora Cerullo ◽

Xiao Chen ◽

Michael Rosbash

Keyword(s):

Response Curve ◽

Phase Response Curve ◽

Receptor Expression ◽

Phase Shifting ◽

Constant Darkness ◽

Behavioral Rhythms ◽

Circadian Phase ◽

Phase Adjustment ◽

Drosophila Brain ◽

A Cell

Our experiments address two long-standing models for the function of the Drosophila brain circadian network: a dual oscillator model, which emphasizes the primacy of PDF-containing neurons, and a cell-autonomous model for circadian phase adjustment. We identify five different circadian (E) neurons that are a major source of rhythmicity and locomotor activity. Brief firing of PDF cells at different times of day generates a phase response curve (PRC), which mimics a light-mediated PRC and requires PDF receptor expression in the five E neurons. Firing also resembles light by causing TIM degradation in downstream neurons. Unlike light however, firing-mediated phase-shifting is CRY-independent and exploits the E3 ligase component CUL-3 in the early night to degrade TIM. Our results suggest that PDF neurons integrate light information and then modulate the phase of E cell oscillations and behavioral rhythms. The results also explain how fly brain rhythms persist in constant darkness and without CRY.

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Exercise elicits phase shifts and acute alterations of melatonin that vary with circadian phase

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00355.2002 ◽

2003 ◽

Vol 284 (3) ◽

pp. R714-R724 ◽

Cited By ~ 156

Author(s):

Orfeu M. Buxton ◽

Calvin W. Lee ◽

Mireille L'Hermite-Balériaux ◽

Fred W. Turek ◽

Eve Van Cauter

Keyword(s):

High Intensity ◽

Phase Response Curve ◽

Phase Shifts ◽

Exercise Group ◽

Time Of Day ◽

Circadian System ◽

Phase Shifting ◽

Circadian Phase ◽

First Onset ◽

Nonphotic Entrainment

To examine the immediate phase-shifting effects of high-intensity exercise of a practical duration (1 h) on human circadian phase, five groups of healthy men 20–30 yr of age participated in studies involving no exercise or exposure to morning, afternoon, evening, or nocturnal exercise. Except during scheduled sleep/dark and exercise periods, subjects remained under modified constant routine conditions allowing a sleep period and including constant posture, knowledge of clock time, and exposure to dim light intensities averaging (±SD) 42 ± 19 lx. The nocturnal onset of plasma melatonin secretion was used as a marker of circadian phase. A phase response curve was used to summarize the phase-shifting effects of exercise as a function of the timing of exercise. A significant effect of time of day on circadian phase shifts was observed ( P < 0.004). Over the interval from the melatonin onset before exercise to the first onset after exercise, circadian phase was significantly advanced in the evening exercise group by 30 ± 15 min (SE) compared with the phase delays observed in the no-exercise group (−25 ± 14 min, P < 0.05). Phase shifts in response to evening exercise exposure were attenuated on the second day after exercise exposure and no longer significantly different from phase shifts observed in the absence of exercise. Unanticipated transient elevations of melatonin levels were observed in response to nocturnal exercise and in some evening exercise subjects. Taken together with the results from previous studies in humans and diurnal rodents, the current results suggest that 1) a longer duration of exercise exposure and/or repeated daily exposure to exercise may be necessary for reliable phase-shifting of the human circadian system and that 2) early evening exercise of high intensity may induce phase advances relevant for nonphotic entrainment of the human circadian system.

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Cycloheximide-induced phase shifting of circadian clock of Neurospora

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1981.241.1.r31 ◽

1981 ◽

Vol 241 (1) ◽

pp. R31-R35 ◽

Cited By ~ 1

Author(s):

H. Nakashima ◽

J. Perlman ◽

J. F. Feldman

Keyword(s):

Protein Synthesis ◽

Circadian Clock ◽

Response Curve ◽

Phase Response Curve ◽

Phase Shifts ◽

Phase Shifting ◽

Normal Operation ◽

Circadian Cycle ◽

Response Curves ◽

Inhibition Of Protein Synthesis

Cycloheximide (CHX), an inhibitor of cytosolic (80S) protein synthesis in eucaryotes, causes phase shifts of the circadian clock of Neurospora crassa when administered as 4-h pulses to cultures in liquid medium. Differential effects of the pulses at different phases of the circadian cycle were observed and plotted as a phase-response curve (PRC). Nearly all phase shifts observed were phase advances, with maximum sensitivity in the middle of the subjective day. Inhibition of protein synthesis by CHX was the same at both phases of the cycle. The PRC was the same at 20 and 25 degrees C. Dose-response curves for the effects of CHX on phase shifting and inhibition of protein synthesis were determined and showed a striking parallel in the responses of these two phenomena to CHX. These results support the view that synthesis of one or more proteins at specific phases of the circadian cycle is necessary for the normal operation of the circadian clock of Neurospora.

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Inhibitor of DNA binding 2 (Id2) Regulates Photic Entrainment Responses in Mice: Differential Responses of the Id2-/- Mouse Circadian System Are Dependent on Circadian Phase and on Duration and Intensity of Light

Journal of Biological Rhythms ◽

10.1177/0748730420957504 ◽

2020 ◽

Vol 35 (6) ◽

pp. 555-575

Author(s):

Giles E. Duffield ◽

Sung Han ◽

Tim Y. Hou ◽

Horacio O. de la Iglesia ◽

Kathleen A. McDonald ◽

...

Keyword(s):

Clock Genes ◽

Phase Response Curve ◽

Continuous Light ◽

Phase Shifts ◽

Constant Darkness ◽

Genotypic Differences ◽

State Variables ◽

Similar Treatment ◽

Central Pacemaker

ID2 is a rhythmically expressed helix–loop–helix transcriptional repressor, and its deletion results in abnormal properties of photoentrainment. By examining parametric and nonparametric models of entrainment, we have started to explore the mechanism underlying this circadian phenotype. Id2-/- mice were exposed to differing photoperiods, and the phase angle of entrainment under short days was delayed 2 h as compared with controls. When exposed to long durations of continuous light, enhanced entrainment responses were observed after a delay of the clock but not with phase advances. However, the magnitude of phase shifts was not different in Id2-/- mice tested in constant darkness using a discrete pulse of saturating light. No differences were observed in the speed of clock resetting when challenged by a series of discrete pulses interspaced by varying time intervals. A photic phase-response curve was constructed, although no genotypic differences were observed. Although phase shifts produced by discrete saturating light pulses at CT16 were similar, treatment with a subsaturating pulse revealed a ~2-fold increase in the magnitude of the Id2-/- shift. A corresponding elevation of light-induced per1 expression was observed in the Id2-/- suprachiasmatic nucleus (SCN). To test whether the phenotype is based on a sensitivity change at the level of the retina, pupil constriction responses were measured. No differences were observed in responses or in retinal histology, suggesting that the phenotype occurs downstream of the retina and retinal hypothalamic tract. To test whether the phenotype is due to a reduced amplitude of state variables of the clock, the expression of clock genes per1 and per2 was assessed in vivo and in SCN tissue explants. Amplitude, phase, and period length were normal in Id2-/- mice. These findings suggest that ID2 contributes to a photoregulatory mechanism at the level of the SCN central pacemaker through control of the photic induction of negative elements of the clock.

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Transmitterlike action of serotonin in phase shifting a rhythm from the Aplysia eye

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1982.242.3.r333 ◽

1982 ◽

Vol 242 (3) ◽

pp. R333-R338

Author(s):

G. Corrent ◽

A. Eskin

Keyword(s):

Phase Response Curve ◽

Membrane Conductance ◽

Phase Shifts ◽

Phase Shifting ◽

Circadian Pacemaker ◽

Pacemaker Cell ◽

Monoamine Neurotransmitters ◽

Hydroxyindoleacetic Acid ◽

High Degree

The presence of serotonin (5-HT) and the characteristics of the phase-response curve for 5-HT indicate that 5-HT acts as a transmitter of circadian information in the Aplysia eye. Additional evidence for such a neurotransmitter role of 5-HT in the eye is presented. The isolated eye has the capacity to synthesize 5-HT from exogenous tryptophan. The receptors mediating the phase-shifting effect of 5-HT have a high affinity for 5-HT (threshold for phase shifting is less than or equal to 10(-7) M). Also these receptors demonstrate a high degree of structural specificity for 5-HT. Some structurally similar indoles to 5-HT do not cause phase shifts (5-hydroxytryptophan, 5-hydroxyindoleacetic acid), whereas others (bufotenine, tryptamine, LSD) do cause phase shifts but are less effective than 5-HT. Furthermore phase shifts in the rhythm are not produced by other monoamine neurotransmitters (dopamine, octopamine) or acetylcholine. Changes in membrane conductance to Na+, Cl-, or Ca2+ do not appear to be involved in phase shifting by 5-HT. Since large reductions in extracellular Ca2+ did not affect phase shifting by 5-HT, 5-HT is acting either directly on the circadian pacemaker cell(s) or on cells electronically coupled to the pacemaker cell(s).

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Isolation and Analysis of Six timeless Alleles That Cause Short- or Long-Period Circadian Rhythms in Drosophila

Genetics ◽

10.1093/genetics/156.2.665 ◽

2000 ◽

Vol 156 (2) ◽

pp. 665-675

Author(s):

Adrian Rothenfluh ◽

Marla Abodeely ◽

Jeffrey L Price ◽

Michael W Young

Keyword(s):

Nuclear Translocation ◽

Phase Response Curve ◽

Fixed Number ◽

Constant Darkness ◽

Genetic Screens ◽

Protein Levels ◽

Long Period ◽

Short Period ◽

Molecular Oscillation ◽

New Alleles

Abstract In genetic screens for Drosophila mutations affecting circadian locomotion rhythms, we have isolated six new alleles of the timeless (tim) gene. Two of these mutations cause short-period rhythms of 21–22 hr in constant darkness, and four result in long-period cycles of 26–28 hr. All alleles are semidominant. Studies of the genetic interactions of some of the tim alleles with period-altering period (per) mutations indicate that these interactions are close to multiplicative; a given allele changes the period length of the genetic background by a fixed percentage, rather than by a fixed number of hours. The timL1 allele was studied in molecular detail. The long behavioral period of timL1 is reflected in a lengthened molecular oscillation of per and tim RNA and protein levels. The lengthened period is partly caused by delayed nuclear translocation of TIML1 protein, shown directly by immunocytochemistry and indirectly by an analysis of the phase response curve of timL1 flies.

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