Circadian rhythms of sleep and wakefulness in mice: analysis using long-term automated recording of sleep

1985 ◽  
Vol 248 (3) ◽  
pp. R320-R330 ◽  
Author(s):  
G. S. Richardson ◽  
M. C. Moore-Ede ◽  
C. A. Czeisler ◽  
W. C. Dement
Keyword(s):  
Circadian Rhythms ◽  
Rem Sleep ◽  
Wheel Running ◽  
Nrem Sleep ◽  
Sleep State ◽  
Continuous Darkness ◽  
Running Activity ◽  
Wheel Running Activity ◽  
Significant Difference ◽  
Wake State

Circadian rhythms of wheel-running activity and polygraphically defined wakefulness, rapid-eye-movement (REM) sleep and non-REM (NREM) sleep were continuously observed in ten mice (Mus musculus) under both alternating light-dark (LD 12:12) and continuous darkness (DD) conditions. Sleep-wake state was determined automatically using a computer-based method that allowed continuous recordings of from 60 to 280 days in duration. The sleep-wake state percentages (of the circadian cycle) thus obtained were in substantial agreement with other estimates for this or similar strains and showed no significant difference between LD 12:12 (wake 54.3%, NREM sleep 38.1%, REM sleep 7.6%) and DD (wake 53.1%, NREM sleep 39.9%, REM sleep 7.0%) conditions. All 10 mice exhibited clear circadian rhythms in each of the three states and wheel-running activity under both lighting conditions for the entire duration of observation. Probability functions, computed using stationary sections of data from all 10 mice, showed distinct waveforms for all three states and wheel running. These waveforms were remarkably similar under entrained and free-running conditions. This documentation of sustained circadian rhythmicity in sleep-wake state throughout observations of unprecedented length contradicts the currently common assertion that circadian control of sleep state is weaker than that of activity.

Altered sleep and behavioral activity phenotypes in PER3-deficient mice

2011 ◽  
Vol 301 (6) ◽  
pp. R1821-R1830 ◽  
Author(s):  
Sibah Hasan ◽  
Daan R. van der Veen ◽  
Raphaelle Winsky-Sommerer ◽  
Derk-Jan Dijk ◽  
Simon N. Archer
Keyword(s):  
Rem Sleep ◽  
Wheel Running ◽  
Nrem Sleep ◽  
Light Period ◽  
Behavioral Activity ◽  
Dark Phase ◽  
Running Activity ◽  
Sleep Homeostasis ◽  
Wheel Running Activity ◽  
Delta Activity

Sleep homeostasis and circadian rhythmicity interact to determine the timing of behavioral activity. Circadian clock genes contribute to circadian rhythmicity centrally and in the periphery, but some also have roles within sleep regulation. The clock gene Period3 ( Per3) has a redundant function within the circadian system and is associated with sleep homeostasis in humans. This study investigated the role of PER3 in sleep/wake activity and sleep homeostasis in mice by recording wheel-running activity under baseline conditions in wild-type (WT; n = 54) and in PER3-deficient ( Per3−/−; n = 53) mice, as well as EEG-assessed sleep before and after 6 h of sleep deprivation in WT ( n = 7) and Per3−/− ( n = 8) mice. Whereas total activity and vigilance states did not differ between the genotypes, the temporal distribution of wheel-running activity, vigilance states, and EEG delta activity was affected by genotype. In Per3−/− mice, running wheel activity was increased, and REM sleep and NREM sleep were reduced in the middle of the dark phase, and delta activity was enhanced at the end of the dark phase. At the beginning of the baseline light period, there was less wakefulness and more REM and NREM sleep in Per3−/− mice. Per3−/− mice spent less time in wakefulness and more time in NREM sleep in the light period immediately after sleep deprivation, and REM sleep accumulated more slowly during the recovery dark phase. These data confirm a role for PER3 in sleep-wake timing and sleep homeostasis.

The effects of androgen deprivation therapy and radiation therapy on cancer-related fatigue.

2019 ◽  
Vol 37 (31_suppl) ◽  
pp. 10-10
Author(s):  
Leorey Saligan
Keyword(s):  
Prostate Cancer ◽  
Androgen Deprivation Therapy ◽  
Wheel Running ◽  
Androgen Deprivation ◽  
Common Symptom ◽  
Cancer Related Fatigue ◽  
Running Activity ◽  
Fatigue Development ◽  
Wheel Running Activity ◽  
Significant Difference

10 Background: Fatigue is a common symptom characterized by incapacitating tiredness. Androgen deprivation therapy (ADT) in combination with radiotherapy (RT) is one of the standard treatments for prostate cancer. Fatigue often worsens during RT with concomitant ADT and it persists long after treatment completion. The purpose of this study is to examine the effects of combined ADT and RT on fatigue in prostate cancer men and in a fatigue mouse model. Methods: 64 participants were recruited and followed at baseline, midpoint, completion, and 1 year post-RT. Two cohorts of men: +ADT cotinued after RT (n=27), +ADT during RT only (n=20), and -ADT (n=17). Fatigue was measured using FACT-F. Male C57BI/6 mice (n=55) were randomly placed into 2 groups: +ADT and –ADT (control). Mice were further subdivided into +RT and –RT (sham) groups. Voluntary Wheel Running Activity (VWRA) data from all mice were recorded for 6 days post-irradiation and the total average of all 6 days was used for analysis. Results: Fatigue (n=64) worsened during RT ( p=.02 at midpoint, p=.04 at completion). ADT significantly affected fatigue development over time (F3,42 = 3.80, p=.02) with the most significant difference occurring at midpoint ( p<.001) and completion of RT ( p<0.001). VWRA significantly decreased in mice that received the combination of ADT and irradiation, compared to those that received only ADT + sham radiation ( p=.001) and no ADT + sham radiation ( p=.004). Transcription factor A, mitochondrial (TFAM) in brain cortical samples was significantly reduced in irradiated mice compared to control mice ( p=.014). Glucose transported type 4 (GLUT4) in brain cortices was significantly reduced in irradiated mice compared to non-irradiated mice ( p=.0057). GLUT4 was also significantly reduced in irradiated mice receiving ADT compared to control mice receiving sham RT ( p=.043). Conclusions: There is a significant combined effect of ADT and RT on fatigue in both humans and mice. Mitochondrial function/neuronal bioenergetic markers were altered in the cortices of irradiated mice that received concomitant ADT. These findings suggest that fatigue experienced by subjects who receive ADT + RT could be attributable to impaired cortical energy production.

scholarly journals Chronic stimulation of the hypothalamic vasoactive intestinal peptide receptor lengthens circadian period in mice and hamsters

2010 ◽  
Vol 299 (1) ◽  
pp. R379-R385 ◽  
Author(s):  
Harry Pantazopoulos ◽  
Hamid Dolatshad ◽  
Fred C. Davis
Keyword(s):  
Circadian Rhythms ◽  
Vasoactive Intestinal Peptide ◽  
Wheel Running ◽  
Third Ventricle ◽  
Luciferase Expression ◽  
Activity Levels ◽  
Circadian Period ◽  
Running Activity ◽  
Wheel Running Activity

Evidence suggests that circadian rhythms are regulated through diffusible signals generated by the suprachiasmatic nucleus (SCN). Vasoactive intestinal peptide (VIP) is located in SCN neurons positioned to receive photic input from the retinohypothalamic tract and transmit information to other SCN cells and adjacent hypothalamic areas. Studies using knockout mice indicate that VIP is essential for synchrony among SCN cells and for the expression of normal circadian rhythms. To test the hypothesis that VIP is also an SCN output signal, we recorded wheel-running activity rhythms in hamsters and continuously infused the VIP receptor agonist BAY 55-9837 in the third ventricle for 28 days. Unlike other candidate output signals, infusion of BAY 55-9837 did not affect activity levels. Instead, BAY 55-9837 lengthened the circadian period by 0.69 ± 0.04 h ( P < 0.0002 compared with controls). Period returned to baseline after infusions. We analyzed the effect of BAY 55-9837 on cultured SCN from PER2::LUC mice to determine if lengthening of the period by BAY 55-9837 is a direct effect on the SCN. Application of 10 μM BAY 55-9837 to SCN in culture lengthened the period of PER2 luciferase expression (24.73 ± 0.24 h) compared with control SCN (23.57 ± 0.26, P = 0.01). In addition, rhythm amplitude was significantly increased, consistent with increased synchronization of SCN neurons. The effect of BAY 55-9837 in vivo on period is similar to the effect of constant light. The present results suggest that VIP-VPAC2 signaling in the SCN may play two roles, synchronizing SCN neurons and setting the period of the SCN as a whole.

scholarly journals Age-related changes in circadian responses to dark pulses

2000 ◽  
Vol 279 (2) ◽  
pp. R586-R590 ◽  
Author(s):  
Marilyn J. Duncan ◽  
Anthony W. Deveraux
Keyword(s):  
Wheel Running ◽  
Activity Rhythm ◽  
Circadian Pacemaker ◽  
Running Activity ◽  
Age Related ◽  
Wheel Running Activity ◽  
Significant Difference ◽  
Time Signals ◽  
Dark Pulse ◽  
Age Related Changes

Aging involves many alterations in circadian rhythms, including a loss of sensitivity to both photic and nonphotic time signals. This study investigated the sensitivity of young and old hamsters to the phase advancing effect of a 6-h dark pulse on the locomotor activity rhythm. Each hamster was tested four times during a period of ∼9 mo; periods of exposure to a 14-h photoperiod were alternated with the periods of exposure to constant light (20–80 lx), during which the dark pulses were administered. There was no significant difference in the phase shifts exhibited by the young (4–10 mo) and old hamsters (19–25 mo) or in the amount of wheel running activity displayed during each dark pulse. However, young hamsters had a significantly greater propensity to exhibit split rhythms immediately after the dark pulses. These results suggest that, although aging does not reduce the sensitivity of the circadian pacemaker to this nonphotic signal, it alters one property of the pacemaker, i.e., the flexibility of the coupling of its component oscillators.

Failure of pinealectomy or melatonin to alter circadian activity rhythm of the rat

1982 ◽  
Vol 242 (3) ◽  
pp. R261-R264 ◽  
Author(s):  
P. W. Cheung ◽  
C. E. McCormack
Keyword(s):  
Wheel Running ◽  
Activity Rhythm ◽  
Physiological Mechanism ◽  
Continuous Darkness ◽  
Running Activity ◽  
Melatonin Administration ◽  
Wheel Running Activity ◽  
Free Running ◽  
Dim Light ◽  
Free Running Period

These experiments were undertaken to determine if the pineal gland is involved in the physiological mechanism by which the rat alters its free-running period (tau) in response to changes in illuminance. Spontaneous wheel-running activity was recorded from pinealectomized or sham-operated female Charles River rats. The tau of running activity was determined in continuous darkness (DD) or in continuous dim light (LL). Pinealectomized rats and sham-operated rats lengthened their tau's to approximately the same extent when shifted from DD to LL and shortened their tau's when shifted back to DD. Continuous melatonin administration via Silastic capsules failed to alter tau of rats kept in dim LL. These results indicate that the pineal is not primarily involved in the mechanism by which the rat alters tau in response to changes in illuminance.

Temporal phasing of locomotor activity, heart rate rhythmicity, and core body temperature is disrupted in VIP receptor 2-deficient mice

2011 ◽  
Vol 300 (3) ◽  
pp. R519-R530 ◽  
Author(s):  
Jens Hannibal ◽  
Hansen M. Hsiung ◽  
Jan Fahrenkrug
Keyword(s):  
Heart Rate ◽  
Locomotor Activity ◽  
Body Temperature ◽  
Circadian Rhythms ◽  
Wheel Running ◽  
Core Body Temperature ◽  
Running Activity ◽  
Wheel Running Activity ◽  
Core Body ◽  
Deficient Mice

Neurons of the brain's biological clock located in the hypothalamic suprachiasmatic nucleus (SCN) generate circadian rhythms of physiology (core body temperature, hormone secretion, locomotor activity, sleep/wake, and heart rate) with distinct temporal phasing when entrained by the light/dark (LD) cycle. The neuropeptide vasoactive intestinal polypetide (VIP) and its receptor (VPAC2) are highly expressed in the SCN. Recent studies indicate that VIPergic signaling plays an essential role in the maintenance of ongoing circadian rhythmicity by synchronizing SCN cells and by maintaining rhythmicity within individual neurons. To further increase the understanding of the role of VPAC2 signaling in circadian regulation, we implanted telemetric devices and simultaneously measured core body temperature, spontaneous activity, and heart rate in a strain of VPAC2-deficient mice and compared these observations with observations made from mice examined by wheel-running activity. The study demonstrates that VPAC2 signaling is necessary for a functional circadian clock driving locomotor activity, core body temperature, and heart rate rhythmicity, since VPAC2-deficient mice lose the rhythms in all three parameters when placed under constant conditions (of either light or darkness). Furthermore, although 24-h rhythms for three parameters are retained in VPAC2-deficient mice during the LD cycle, the temperature rhythm displays markedly altered time course and profile, rising earlier and peaking ∼4–6 h prior to that of wild-type mice. The use of telemetric devices to measure circadian locomotor activity, temperature, and heart rate, together with the classical determination of circadian rhythms of wheel-running activity, raises questions about how representative wheel-running activity may be of other behavioral parameters, especially when animals have altered circadian phenotype.

Behavioral characterization and modulation of circadian rhythms by light and melatonin in C3H/HeN mice homozygous for the RORβ knockout

2007 ◽  
Vol 292 (6) ◽  
pp. R2357-R2367 ◽  
Author(s):  
Monica I. Masana ◽  
Isabel C. Sumaya ◽  
Michael Becker-Andre ◽  
Margarita L. Dubocovich
Keyword(s):  
Circadian Rhythms ◽  
Light Pulse ◽  
Learned Helplessness ◽  
Wheel Running ◽  
Receptor Gene ◽  
Activity Rhythms ◽  
Pineal Melatonin ◽  
Running Activity ◽  
Melatonin Administration ◽  
Wheel Running Activity

This study reports for the first time the effects of retinoid-related orphan receptors [RORβ; receptor gene deletion RORβ(C3H)−/−] in C3H/HeN mice on behavioral and circadian phenotypes. Pineal melatonin levels showed a robust diurnal rhythm with high levels at night in wild-type (+/+), heterozygous (+/−), and knockout (−/−) mice. The RORβ(C3H)−/− mice displayed motor (“duck gait,” hind paw clasping reflex) and olfactory deficits, and reduced anxiety and learned helplessness-related behaviors. Circadian rhythms of wheel-running activity in all genotypes showed entrainment to the light-dark (LD) cycle, and free running in constant dark, with RORβ(C3H)−/− mice showing a significant increase in circadian period ( tau). Melatonin administration (90 μg/mouse sc for 3 days) at circadian time (CT) 10 induced phase advances, while exposure to a light pulse (300 lux) at CT 14 induced phase delays of circadian activity rhythms of the same magnitude in all genotypes. In RORβ(C3H)−/− mice a light pulse at CT 22 elicited a larger phase advance in activity rhythms and a slower rate of reentrainment after a 6-h advance in the LD cycle compared with (+/+) mice. Yet, the rate of reentrainment was significantly advanced by melatonin administration at the new dark onset in both (+/+) and (−/−) mice. We conclude that the RORβ nuclear receptor is not involved in either the rhythmic production of pineal melatonin or in mediating phase shifts of circadian rhythms by melatonin, but it may regulate clock responses to photic stimuli at certain time domains.

Melatonin and activity rhythm responses to light pulses in mice with the Clock mutation

2003 ◽  
Vol 284 (5) ◽  
pp. R1231-R1240 ◽  
Author(s):  
David J. Kennaway ◽  
Athena Voultsios ◽  
Tamara J. Varcoe ◽  
Robert W. Moyer
Keyword(s):  
Wheel Running ◽  
Activity Rhythm ◽  
Mutant Mice ◽  
Constant Darkness ◽  
Wild Type ◽  
Continuous Darkness ◽  
Light Pulses ◽  
Essentially Normal ◽  
Running Activity ◽  
Wheel Running Activity

Melatonin and wheel-running rhythmicity and the effects of acute and chronic light pulses on these rhythms were studied in Clock Δ19 mutant mice selectively bred to synthesize melatonin. Homozygous melatonin-proficient Clock Δ19 mutant mice ( Clock Δ19/Δ19 -MEL) produced melatonin rhythmically, with peak production 2 h later than the wild-type controls (i.e., just before lights on). By contrast, the time of onset of wheel-running activity occurred within a 20-min period around lights off, irrespective of the genotype. Melatonin production in the mutants spontaneously decreased within 1 h of the expected time of lights on. On placement of the mice in continuous darkness, the melatonin rhythm persisted, and the peak occurred 2 h later in each cycle over the first two cycles, consistent with the endogenous period of the mutant. This contrasted with the onset of wheel-running activity, which did not shift for several days in constant darkness. A light pulse around the time of expected lights on followed by constant darkness reduced the expected 2-h delay of the melatonin peak of the mutants to ∼1 h and advanced the time of the melatonin peak in the wild-type mice. When the Clock Δ19/Δ19 -MEL mice were maintained in a skeleton photoperiod of daily 15-min light pulses, a higher proportion entrained to the schedule (57%) than melatonin-deficient mutants (9%). These results provide compelling evidence that mice with the Clock Δ19 mutation express essentially normal rhythmicity, albeit with an underlying endogenous period of 26–27 h, and they can be entrained by brief exposure to light. They also raise important questions about the role of Clock in rhythmicity and the usefulness of monitoring behavioral rhythms compared with hormonal rhythms.

scholarly journals The Dorsal Medial Habenula Minimally Impacts Circadian Regulation of Locomotor Activity and Sleep

2017 ◽  
Vol 32 (5) ◽  
pp. 444-455 ◽  
Author(s):  
Yun-Wei A. Hsu ◽  
Jennifer J. Gile ◽  
Jazmine G. Perez ◽  
Glenn Morton ◽  
Miriam Ben-Hamo ◽  
...  
Keyword(s):  
Rem Sleep ◽  
Clock Genes ◽  
Wheel Running ◽  
Circadian System ◽  
Sleep Stages ◽  
Constant Darkness ◽  
Running Activity ◽  
Medial Habenula ◽  
Wheel Running Activity ◽  
Central Pacemaker

In nocturnal rodents, voluntary wheel-running activity (WRA) represents a self-reinforcing behavior. We have previously demonstrated that WRA is markedly reduced in mice with a region-specific deletion of the transcription factor Pou4f1 (Brn3a), which leads to an ablation of the dorsal medial habenula (dMHb). The decrease in WRA in these dMHb-lesioned (dMHbCKO) mice suggests that the dMHb constitutes a critical center for conveying reinforcement by exercise. However, WRA also represents a prominent output of the circadian system, and the possibility remains that the dMHb is a source of input to the master circadian pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus. To test this hypothesis, we assessed the integrity of the circadian system in dMHbCKO mice. Here we show that the developmental lesion of the dMHb reduces WRA under both a light-dark cycle and constant darkness, increases the circadian period of WRA, but has no effect on the circadian amplitude or period of home cage activity or the daily amplitude of sleep stages, suggesting that the lengthening of period is a result of the decreased WRA in the mutant mice. Polysomnographic sleep recordings show that dMHbCKO mice have an overall unaltered daily amplitude of sleep stages but have fragmented sleep and an overall increase in total rapid eye movement (REM) sleep. Photoresponsiveness is intact in dMHbCKO mice, but compared with control animals, they reentrain faster to a 6-h abrupt phase delay protocol. Circadian changes in WRA of dMHbCKO mice do not appear to emerge within the central pacemaker, as circadian expression of the clock genes Per1 and Per2 within the SCN is normal. We do find some evidence for fragmented sleep and an overall increase in total REM sleep, supporting a model in which the dMHb is part of the neural circuitry encoding motivation and involved in the manifestation of some of the symptoms of depression.

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