Circadian Rhythms In Mice Research Articles

Alterations of Circadian Rhythms in Mice Induced by Anti-Cancer Drugs

Carboplatinum was injected into four groups of mice for 5 successive days at one out of four daily equidistant hours. Upon the cessation of these injections, granulocyte colony stimulating factor was injected into half of these mice for 2 days at the same times. The stimulating factor was also injected into groups of untreated mice for 2 days at the same times. In each experiment the rhythms of four variables were monitored after the cessation of all injections: peripheral WBC count, bone marrow and sperm stem cells DNA synthesis, and sperm ribosomal RNA content. The results indicated that in the course of repeated drug administrations, variables' rhythm parameters (phases and periods) were altered. These changes have to be considered in chronotherapeutic schedules when variables which serve for toxicity diagnosis or as drug target are rhythmic in nature.

Temporal expression of rat per homologue in the brain

Haploinsufficiency of RAI1 results in Smith-Magenis syndrome (SMS), a disorder characterized by intellectual disability, multiple congenital anomalies, obesity, neurobehavioral abnormalities, and a disrupted circadian sleep-wake pattern. An inverted melatonin rhythm (i.e., melatonin peaks during the day instead of at night) and associated sleep-phase disturbances in individuals with SMS, as well as a short-period circadian rhythm in mice with a chromosomal deletion of Rai1, support SMS as a circadian-rhythm-dysfunction disorder. However, the molecular cause of the circadian defect in SMS has not been described. The circadian oscillator temporally orchestrates metabolism, physiology, and behavior largely through transcriptional modulation. Data support RAI1 as a transcriptional regulator, but the genes it might regulate are largely unknown. Investigation into the role that RAI1 plays in the regulation of gene transcription and circadian maintenance revealed that RAI1 regulates the transcription of circadian locomotor output cycles kaput (CLOCK), a key component of the mammalian circadian oscillator that transcriptionally regulates many critical circadian genes. Data further show that haploinsufficiency of RAI1 and Rai1 in SMS fibroblasts and the mouse hypothalamus, respectively, results in the transcriptional dysregulation of the circadian clock and causes altered expression and regulation of multiple circadian genes, including PER2, PER3, CRY1, BMAL1, and others. These data suggest that heterozygous mutation of RAI1 and Rai1 leads to a disrupted circadian rhythm and thus results in an abnormal sleep-wake cycle, which can contribute to an abnormal feeding pattern and dependent cognitive performance. Finally, we conclude that RAI1 is a positive transcriptional regulator of CLOCK, pinpointing a novel and important role for this gene in the circadian oscillator.

Both Neuropeptide Y and Serotonin Are Necessary for Entrainment of Circadian Rhythms in Mice by Daily Treadmill Running Schedules

This study investigated the role of the suprachiasmatic nucleus (SCN) circadian pacemaker and its neuropeptide Y (NPY) and serotonin (5-HT) afferents in entrainment (synchronization) of mouse circadian rhythms by treadmill running. Blind C57BL/6j mice were run in treadmills for 3 hr/d for 3-10 weeks after receiving radio-frequency lesions of the SCN or the intergeniculate leaflet (IGL, the source of SCN NPY) or infusions of the 5-HT neurotoxin 5,7-DHT into the SCN area. Of 25 intact mice, 22 entrained and three showed period (tau, the mean duration of the circadian cycle) modulations to scheduled running. Arrhythmic SCN-ablated mice did not synchronize to scheduled running in a way suggestive of circadian pacemaker mediation. Of 15 mice with IGL lesions, only two with partial lesions entrained. Mice with complete IGL lesions (five), confirmed by immunocytochemistry, showed no entrainment or tau changes. Of 19 mice with 5-HT lesions, only two with partial lesions entrained. All but two mice with complete (10) or nearly complete (4) 5-HT denervation, confirmed by immunocytochemistry, showed tau modulations during the treadmill schedule. Failure to entrain was not explained by group differences in tau before the treadmill schedules. The results indicate that the SCN and both NPY and 5-HT are necessary for entrainment to 24 hr schedules of forced running but that complete loss of 5-HT does not prevent modulations of pacemaker motion by behavioral stimuli. Treadmill entrainment in mice may involve synergistic interactions between 5-HT and NPY afferents at some site within the circadian system.

Entrainment and phase shifting of circadian rhythms in mice by forced treadmill running

Daily schedules of spontaneous, drug-, or novelty-induced running can entrain circadian rhythms in rodents. Forced running, by contrast, has been reported to have weak or no effects, although a thorough comparative study in a single species is lacking. To fill this gap, drinking or activity rhythms were monitored in C57 mice subjected to daily, 3-h bouts of forced treadmill running or to 3-h daily access to home cage running wheels. Entrainment to treadmill running was observed in 17/27 mice, and to restricted wheel access in 11/20 mice. Entrainment was affected by availability of a home cage wheel (e.g., 14/16 mice with no wheel entrained to treadmill running). Phase angle of entrainment was related to prior circadian period (τ), and τ following entrainment exhibited aftereffects. No mice entrained to a 3-h daily schedule of water access, suggesting that entrainment to scheduled running was not related to water or associated food intake. Phase shifts in response to single 3-h bouts of treadmill running or wheel access were small and not reliably induced. The entrainment paradigm is thus recommended for further study of behavioral effects on the mouse circadian system; forced running, in particular, offers several methodological advantages. The results do not support prior suggestions that forced and voluntary activity differ in value as nonphotic zeitgebers.

Entrainment and Phase Shifting of Circadian Rhythms in Mice by Forced Treadmill Running

Entrainment and Phase Shifting of Circadian Rhythms in Mice by Forced Treadmill Running

Vitamin B 12 affects non-photic entrainment of circadian locomotor activity rhythms in mice

Administration of vitamin B 12 (VB12) has been reported to normalize human sleep-wake rhythm disorders such as non-24-h sleep-wake syndrome (HNS), delayed sleep phase syndrome (DSPS) or insomnia. However, the mechanisms of the action of VB 12 on the rhythm disorders are unknown. In the present study, therefore, effects of VB 12 on circadian rhythms of locomotor activity were examined in mice. In the first experiment, CBA/J mice were maintained under continuous light condition (LL) or blinded, and after free-running rhythms became stable, the mice were intraperitoneally injected with either VB12 or saline at a fixed time every day. In all the mice with τ > 24 h, saline injections resulted in entrainment of circadian rhythms, whereas not all the mice with τ < 24 h entrained to the injection. In contrast to saline injections, VB12 injections did not always induce entrainment and about half of the mice with τ > 24 h free-ran during the injection. In the second experiment, the amount of phase advances of circadian rhythms induced by a single injection of saline at circadian time (CT) 11 under LL was compared between the mice with and without VB 12 silastic tubes. The results showed that the amplitude of phase advances was smaller in the mice with VB 12 than those without V1312. In the third experiment, daily injections of saline were given to the mice with VB12 silastic tubes maintained under LL. In this chronic treatment of VB12 as well, attenuating effects of VB 12 on saline-induced entrainment were observed. These results suggest that VB 12 affects the mechanisms implicated in non-photic entrainment of circadian rhythms in mice.

Morphine phase-shifts circadian rhythms in mice: role of behavioural activation

The effect of morphine on circadial wheel-running rhythms of C57BL/6j mice was examined. Mice received morphine (25 mg kg−1, i.p.) or saline at eight different circadian phases in constant dark. Morphine injections in the middle of the inactive period induced significant advance phase shifts, whereas injections at other times induced small delay shifts or no responses. This phase–response relationship was not altered by optic enucleation. Morphine also induced hyperactivity. Restriction of activity prevented phase shifts. The results indicate that morphine shifts circadian rhythms by its effects on behaviour, rather than by a direct action on the circadian pacemaker. Morphine may represent a useful tool for further study of behaviourally induced phase-resetting in this species.

Morphine phase-shifts circadian rhythms in mice

The effect of morphine on circadial wheel-running rhythms of C57BL/6j mice was examined. Mice received morphine (25 mg kg-1, i.p.) or saline at eight different circadian phases in constant dark. Morphine injections in the middle of the inactive period induced significant advance phase shifts, whereas injections at other times induced small delay shifts or no responses. This phase-response relationship was not altered by optic enucleation. Morphine also induced hyperactivity. Restriction of activity prevented phase shifts. The results indicate that morphine shifts circadian rhythms by its effects on behaviour, rather than by a direct action on the circadian pacemaker. Morphine may represent a useful tool for further study of behaviourally induced phase-resetting in this species.

Circadian rhythms in mice can be regulated by photoreceptors with cone-like characteristics

In this report we have characterized the photopigments mediating circadian phase shifts in retinal degenerate (rd) mice. In aged rd rd mice, which lack detectable opsin, high performance liquid chromatography (HPLC) was used to quantify the photopigment chromophore 11- cis-retinaldehyde. This chromophore was photoisomerized in whole eyes, suggesting the presence of a functional opsin-based photopigment system. We also analyzed the spectral sensitivity of phase shifting circadian locomotor rhythms. Our data implicate a photopigment that is consistent with the involvement of the middle wavelength-sensitive cone photoreceptors (M-cones; Λ max = 511 nm) found in the mouse retina. In addition, discrete near-ultraviolet (UV-A) pulses were capable of eliciting large phase shifts in circadian locomotor activity rhythms. This result is consistent with the involvement of the short wavelength-sensitive cone photoreceptors (UV-cones; Λ max = 359 nm) in photoentrainment. Collectively, these data suggest that both cone classes of the mouse may mediate the photic regulation of circadian rhythms. If this is the case, circadian sensitivity can be maintained by very few degenerate cones. Alternatively, an unknown class of ocular photoreceptor may fulfill this function.

Whole body calorimetry, a measure of the circadian rhythm of mice

Whole body calorimetry, a measure of the circadian rhythm of mice

Spectral sensitivity of photoreceptor(s) mediating entrainment of circadian rhythms in mice

Spectral sensitivity of photoreceptor(s) mediating entrainment of circadian rhythms in mice

Circadian Rhythm in the Cerebral Resistance to Hypoxia in Mice

The cerebral resistance to hypoxia in mice was investigated by measuring the survival time under both hypobaric and normobaric hypoxic conditions. In the ad libitum fed mice, there was a circadian variation in the survival time that was longer during the light period than during the dark period under hypobaric hypoxic conditions. The survival time under normobaric hypoxic conditions also exhibited a similar circadian variation in the ad libitum fed mice, whereas the rhythm of the survival time was completely reversed by the restriction of food presentation (9:00-15:00). These findings suggest that there is a circadian rhythm in the cerebral resistance of mice to hypoxia, which can be shifted by the time of food presentation. Furthermore, regression analyses revealed a negative correlation between the survival time of mice exposed to hypoxia and body temperature, and blood glucose levels. These indicate that the cerebral resistance to hypoxia was intimately associated with body temperature and blood glucose that both show a circadian rhythm in mice.

Influence of running wheel activity on free-running sleep/wake and drinking circadian rhythms in mice

Previous studies have indicated that manipulation of activity levels can modify characteristics of sleep/wake and activity rhythms. The generality of these observations was evaluated by simultaneously measuring drinking and sleep/wake rhythms while mice had free or no access to a running wheel in constant conditions (DD). Robust circadian rhythms in all parameters were observed in the “wheel free” (unrestrited) condition. When wheels were locked, the peak amplitude of the sleep/wake circadian rhythm decreased by approximately 50% without affecting the amplitude of the drinking rhythm. Total wake time decreased 11% per circadian day when wheels were locked with increases in both NREM and REM sleep. Whereas the amplitude of the drinking waveform was unaffected, wheel restriction caused an equivalent increase in period length (τ) for both rhythms. These results indicate that, unlike the generalized effects of activity on τ, activity restriction influences on rhythm amplitude do not generalize to all behavioral and/or physiological variables. This work also supports the notion that activity influences on sleep/wake rhythm amplitude reflect behavioral “masking” rather than a fundamental change in the direct coupling mechanisms of the biological clock.

Hereditary nature of the pattern of the motor activity circadian rhythm in mice

The inherited nature of the pattern of the daily motor activity function (MAF) has been studied using different families of the same strain of mice. The motor activity of 6 male mice, belonging to two different families (A and B was recorded during 54 days in LD conditions (12L:12D) using six inductive units. The register began the day just after weaning. A Fourier analysis was applied to motor activity data corresponding to observation periods of 24 hours. The daily power spectrum, with 20 harmonics, was calculated by obtaining the power content of each harmonic expressed as a percentage of the total power content of the MAF. A discriminant function based on the first fifteen harmonics was created to distinguish between the males of the two families. Then, the same discriminant function was applied to the daily power spectra of the progeny. It was also possible to differentiate among the mice (males and females) coming from fathers of family A and the mice coming from fathers of family B ( p<0.02). This fact suggests that, in the power spectra of the progeny, there may be enough characteristic equal to that of their respective fathers and it further suggests that some characteristic of the MAF could have been inherited.

A Circadian Rhythm in Mice for the Susceptibility to Toluene

A Circadian Rhythm in Mice for the Susceptibility to Toluene

Opiate analgesia: Evidence for circadian rhythms in mice

The effects of a 12-12 h light-dark (L-D) cycle and of constant light (L-L) on nociceptive thresholds and morphine-induced analgesia were studied in two strains of mice: C57BL/6 and SEC/1Re. Under the L-D condition, a diurnal rhythm was observed in the responsivity of mice to nociceptive stimuli, and in the analgesic effects of morphine. Under the L-L schedule clear patterns of daily rhythmicity were evident in both strains for both nociceptive thresholds and responsivity to morphine. Finally, under the L-L schedule, the overall responsivity to pain and the antinociceptive effects of morphine were clearly increased in comparison to the patterns evident in the L-D condition. The administration of naloxone decreased the nociceptive thresholds, thus indicating an involvement of the endogenous opioid peptides. These phenomena are discussed in terms of the different pacemaker mechanisms involved in the expression of various patterns of daily behavioral and neurochemical rhythmicity in these strains, and of the effects of light in controlling the release of endogenous opioids.

Pigment mutations associated with altered circadian rhythms in mice

Mammalian albinism is known to alter neural pathways, reduce retinal pigment, and affect diverse behaviors. Mammalian circadian rhythms have been shown to depend on visual pathways, respond to light intensity and regulate many behaviors. Here we show that mice homozygous for the recessive albino or pinkeye-dilute mutations display shorter circadian rhythms than pigmented controls. We conclude that these pigment loci, or closely linked loci, influence the expression of circadian rhythms in mice.

Investigation of circadian rhythms in a genetically anophthalmic mouse strain: Correlation of activity patterns with suprachiasmatic nuclei hypogenesis

ZRDCT-An mice are anophthalmic mutants with varying degrees of hypogenesis of the mediobasal hypothalamus and suprachias-matic nuclei. Statistical analysis of the wheelrunning activity patterns of these animals showed that most mice had circadian activity rhythms unentrained to the light-dark cycle. However, four of 22 animals had random or non-circadian activity patterns. Of these four mice, three had fewer than one third the typical number of cells in the suprachiasmatic nuclei. The absence of detectable circadian rhythms in mice with genetically produced hypogenesis of the suprachiasmatic nuclei is reminiscent of the effects of partial electrolytic lesions of the same tissue.

Circadian Rhythms in Mice Fed a Single Daily Meal at Different Stages of Lighting Regimen

Circadian rhythms in systemic and cellular variables were studied in three groups of mice on different schedules of daily food accessibility: (1) only during the first 4 hours of the 12-hour light span; (2) only during the first 4 hours of the 12-hour dark span; and (3) at all times. The amplitudes of circadian variation in rectal temperature, serum corticosterone, and liver glycogen were increased by "meal-feeding" in either early light or early darkness. The overall averages of corticosterone and glycogen were also increased by meal-feeding at either stage of the lighting regimen. The time of peak values in temperature, corticosterone, and glycogen were determined by the time of food presentation, regardless of its relation to the lighting regimen. On the other hand, the interval between food presentation and peak values in the corneal mitotic index was greater when feeding was restricted to early darkness. These differences among the three groups of animals resulted in different relations among varibles at any given interval after feeding onset. Such effects concerning total bodily function, energy storage, hormonal regulation, and basic cellular processes indicate the pertinence of meal timing to nutritional research and practice.