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1.
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A number of recent studies have debated the existence and nature of clocks outside the suprachiasmatic nucleus that may underlie circadian rhythms in conditions of food entrainment or methamphetamine administration. These papers claim that either the canonical clock genes, or the circuitry in the dorsomedial nucleus of the hypothalamus, may not be necessary for these forms of entrainment. In this paper, we review the evidence necessary to make these claims. In particular, we point out that it is necessary to remove classical conditioning stimuli and interval timer (homeostatic) effects to insure that the remaining entrainment is due to a circadian oscillator. None of these studies appears to meet these criteria for demonstrating circadian entrainment under these conditions. Our own studies, which were discussed in detail by a recent Review in these pages by Mistlberger and colleagues, came to an opposite conclusion. However, our studies were designed to meet these criteria, and we believe that these methodological differences explain why we find that canonical clock gene Bmal1 and the integrity of the dorsomedial nucleus are both required to produce true circadian entrainment under conditions of restricted feeding.  相似文献   

3.
Every physiological function in the human body exhibits some form of circadian rhythmicity. Under pathological conditions, however, circadian rhythmicity may be dusrupted. Patients infected with HIV or addicted to drugs of abuse often suffer from sleep disorders and altered circadian rhythms. Early studies in Drosophila suggested that drug seeking behavior might be related to the expression of certain circadian clock genes. Our previous research showed that conditioned place preference with morphine treatment was altered in mice lacking the Period-1 (mPer1) circadian clock gene. Thus, we sought to investigate whether morphine treatment could alter the expression of mPer1, especially in brain regions outside the SCN and in peripheral tissues. Our results using Western blot analysis showed that the mPER1 immunoreactivity exhibited a strong circadian rhythm in the brains of the control (Con), morphine-dependent (MD), and morphine-withdrawal (MW) mice. However, the phase of the circadian rhythm of mPER1 expression in the brains of MD mice significantly differed from that of the Con mice (p < 0.05). In contrast to mPER1 expression in the brain, the circadian rhythm of mPER1 immunoreactivity in the kidneys was abolished after morphine administration, whereas the Con mice maintained robust circadian rhythmicity of mPER1 in the kidney. Therefore, the effect of morphine on the circadian clock gene mPer1 may vary among different organs, resulting in desynchronization of circadian function between the SCN and peripheral organs.  相似文献   

4.
5.

Background

The Magel2 gene is most highly expressed in the suprachiasmatic nucleus of the hypothalamus, where its expression cycles in a circadian pattern comparable to that of clock-controlled genes. Mice lacking the Magel2 gene have hypothalamic dysfunction, including circadian defects that include reduced and fragmented total activity, excessive activity during the subjective day, but they have a normal circadian period. Magel2 is a member of the MAGE family of proteins that have various roles in cellular function, but the specific function of Magel2 is unknown.

Methods

We used a variety of cell-based assays to determine whether Magel2 modifies the properties of core circadian rhythm proteins.

Results

Magel2 represses the activity of the Clock:Bmal1 heterodimer in a Per2-luciferase assay. Magel2 interacts with Bmal1 and with Per2 as measured by co-immunoprecipitation in co-transfected cells, and exhibits a subcellular distribution consistent with these interactions when visualized by immunofluorescence. As well, Magel2 induces the redistribution of the subcellular localization of Clock towards the cytoplasm, in contrast to the nucleus-directed effect of Bmal1 on Clock subcellular localization.

Conclusion

Consistent with the blunted circadian rhythm observed in Magel2-null mice, these data suggest that Magel2 normally promotes negative feedback regulation of the cellular circadian cycle, through interactions with key core circadian rhythm proteins.  相似文献   

6.

Background

An endogenous circadian clock controls locomotor activity in common spiny mice (Acomys cahirinus). However, little is known about the effects of constant light (LL) on this activity or about the existence of an additional food entrainable clock. A series of experiments were performed to investigate the effects of LL and DD on tau and activity levels.

Methods

Spiny mice were housed individually and their running wheel activity monitored. One group of mice was exposed to LD, DD and several intensities of LL. Another group was exposed to a restricted feeding (RF) paradigm in light: dark (LD) during one hour before the L to D transition. Significance of rhythmicity was assessed using Lomb-Scargle periodograms.

Results

In LD all animals exhibited nocturnal activity rhythms that persisted in DD. When animals were exposed to RF (during L), all of these animals (n?=?11) demonstrated significant food anticipatory activity as well as an increase in diurnal activity. This increase in diurnal activity persisted in 4/11 animals during subsequent ad libitum conditions. Under LL conditions, the locomotor rhythms of 2/11 animals appeared to entrain to RF. When animals were exposed to sequentially increasing LL intensities, rhythmicity persisted and, while activity decreased significantly, the free-running period was relatively unaffected. In addition, the period in LL was significantly longer than the period in DD. Exposure to LL also induced long-term changes (after-effects) on period and activity when animals were again exposed to DD.

Conclusions

Overall these studies demonstrate clear and robust circadian rhythms of wheel-running in A. cahirinus. In addition, LL clearly inhibited activity in this species and induced after-effects. The results also confirm the presence of a food entrainable oscillator in this species.  相似文献   

7.
Circadian rhythms are daily oscillations of multiple biological processes directed by endogenous clocks. The circadian timing system comprises peripheral oscillators located in most tissues of the body and a central pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Circadian genes and the proteins produced by these genes constitute the molecular components of the circadian oscillator which form positive/negative feedback loops and generate circadian rhythms. The circadian regulation extends beyond clock genes to involve various clock-controlled genes (CCGs) including various cell cycle genes. Aberrant expression of circadian clock genes could have important consequences on the transactivation of downstream targets that control the cell cycle and on the ability of cells to undergo apoptosis. This may lead to genomic instability and accelerated cellular proliferation potentially promoting carcinogenesis. Different lines of evidence in mice and humans suggest that cancer may be a circadian-related disorder. The genetic or functional disruption of the molecular circadian clock has been found in various cancers including breast, ovarian, endometrial, prostate and hematological cancers. The acquisition of current data in circadian clock mechanism may help chronotherapy, which takes into consideration the biological time to improve treatments by devising new therapeutic approaches for treating circadian-related disorders, especially cancer.  相似文献   

8.

Background  

It is reported that the circadian rhythms of female mating activity differ among Drosophila species and are controlled by an endogenous circadian clock. Here, we found that the mating rhythm of D. ananassae differed from that of D. melanogaster. Moreover, to evaluate the effect of clock gene products on mating activities, we examined the mating activity of D. melanogaster timeless (tim 01) transgenic fly harboring heat-shock promotor driven-D. ananassae timeless (tim) gene (hs-AT tim 01).  相似文献   

9.

Background  

Recent advances in sociogenomics allow for comparative analyses of molecular mechanisms regulating the development of social behavior. In eusocial insects, one key aspect of their sociality, the division of labor, has received the most attention. Age-related polyethism, a derived form of division of labor in ants and bees where colony tasks are allocated among distinct behavioral phenotypes, has traditionally been assumed to be a product of convergent evolution. Previous work has shown that the circadian clock is associated with the development of behavior and division of labor in honeybee societies. We cloned the ortholog of the clock gene, period, from a harvester ant (Pogonomyrmex occidentalis) and examined circadian rhythms and daily activity patterns in a species that represents an evolutionary origin of eusociality independent of the honeybee.  相似文献   

10.
ABSTRACT: BACKGROUND: An endogenous circadian clock controls locomotor activity in common spiny mice (Acomys cahirinus). However, little is known about the effects of constant light (LL) on this activity or about the existence of an additional food entrainable clock. A series of experiments were performed to investigate the effects of LL and DD on tau and activity levels. METHODS: Spiny mice were housed individually and their running wheel activity monitored. One group of mice was exposed to LD, DD and several intensities of LL. Another group was exposed to a restricted feeding (RF) paradigm in light: dark (LD) during one hour before the L to D transition. Significance of rhythmicity was assessed using Lomb-Scargle periodograms. RESULTS: In LD all animals exhibited nocturnal activity rhythms that persisted in DD. When animals were exposed to RF (during L), all of these animals (n = 11) demonstrated significant food anticipatory activity as well as an increase in diurnal activity. This increase in diurnal activity persisted in 4/11 animals during subsequent ad libitum conditions. Under LL conditions, the locomotor rhythms of 2/11 animals appeared to entrain to RF. When animals were exposed to sequentially increasing LL intensities, rhythmicity persisted and, while activity decreased significantly, the free-running period was relatively unaffected. In addition, the period in LL was significantly longer than the period in DD. Exposure to LL also induced long-term changes (after-effects) on period and activity when animals were again exposed to DD. CONCLUSIONS: Overall these studies demonstrate clear and robust circadian rhythms of wheel-running in A. cahirinus. In addition, LL clearly inhibited activity in this species and induced after-effects. The results also confirm the presence of a food entrainable oscillator in this species.  相似文献   

11.
Although out-of-lab investigation of the human circadian clock at the clock gene expression level remains difficult, a recent method using hair follicle cells might be useful. While exercise may function as an entrainment cue for circadian rhythms, it remains unclear whether exercise affects human circadian clock gene expression. Efforts to observe apparent effects of exercise on clock gene expression require that several specific conditions be met: intense exercise should be habitually performed at a relatively uncommon time of day over an extended period; and any relative phase shift thereby observed should be validated by comparison of exercise and no-exercise periods. Wake-up and meal times should be kept almost constant over the experimental period. The present study was conducted using a professional fighter who met these strict criteria as subject. Facial hair samples were collected at 4-h intervals around the clock to ascertain rhythms of clock gene expression. During a period in which nighttime training (from 20:00 to 22:00) was habitually performed, circadian clock gene expression was phase-delayed by 2 to 4 h compared with that during a no-exercise period. Maximum level and circadian amplitude of clock gene expression were not affected by the nighttime training. Our trial observations illustrate the possibility that heavy physical exercise might strongly affect the circadian phase of clock gene expression. Exercise might be therefore effective for the clinical care of circadian disorders. The results also suggest that athletes may require careful scheduling of heavy physical exercise to maintain normal circadian phase and ensure optimal athletic performance.  相似文献   

12.
Seasonal timing is assumed to involve the circadian clock, an endogenous mechanism to track time and measure day length. Some debate persists, however, and aphids were among the first organisms for which circadian clock involvement was questioned. Inferences about links to phenology are problematic, as the clock itself is little investigated in aphids. For instance, it is unknown whether aphids possess diurnal rhythms at all. Possibly, the close interaction with host plants prevents independent measurements of rhythmicity. We reared the pea aphid Acyrthosiphon pisum (Harris) on an artificial diet, and recorded survival, moulting, and honeydew excretion. Despite their plant-dependent life style, aphids were independently rhythmic under light–dark conditions. This first demonstration of diurnal aphid rhythms shows that aphids do not simply track the host plant’s rhythmicity.  相似文献   

13.

Background  

Recent evidence suggests a two-way interaction between the immune and circadian systems. Circadian control of immune factors, as well as the effect of immunological variables on circadian rhythms, might be key elements in both physiological and pathological responses to the environment. Among these relevant factors, galectin-1 is a member of a family of evolutionarily-conserved glycan-binding proteins with both extracellular and intracellular effects, playing important roles in immune cell processes and inflammatory responses. Many of these actions have been studied through the use of mice with a null mutation in the galectin-1 (Lgals1) gene. To further analyze the role of endogenous galectin-1 in vivo, we aimed to characterize the circadian behavior of galectin-1 null (Lgals1 -/-) mice.  相似文献   

14.

Background  

Depression and alcohol abuse or dependence (AUD) co-occur in the general population more frequently than expected by chance. Alcohol use influences the circadian rhythms generated by the central pacemaker in the suprachiasmatic nucleus, and circadian rhythm alterations in turn are common in depressive disorders as well as among persons addicted to alcohol.  相似文献   

15.

Background  

The central circadian pacemaker is a remarkably robust regulator of daily rhythmic variations of cardiovascular, endocrine, and neural physiology. Environmental lighting conditions are powerful modulators of circadian rhythms, but regulation of circadian rhythms by disease states is less clear. Here, we examine the effect of ischemic stroke on circadian rhythms in rats using high-resolution pineal microdialysis.  相似文献   

16.

Background  

Rapid displacement across multiple time zones results in a conflict between the new cycle of light and dark and the previously entrained program of the internal circadian clock, a phenomenon known as jet lag. In humans, jet lag is often characterized by malaise, appetite loss, fatigue, disturbed sleep and performance deficit, the consequences of which are of particular concern to athletes hoping to perform optimally at an international destination. As a species renowned for its capacity for athletic performance, the consequences of jet lag are also relevant for the horse. However, the duration and severity of jet lag related circadian disruption is presently unknown in this species. We investigated the rates of re-entrainment of serum melatonin and core body temperature (BT) rhythms following an abrupt 6-h phase advance of the LD cycle in the horse.  相似文献   

17.

Background  

Light and dark patterns are the major synchronizer of circadian rhythms to the 24-hour solar day. Disruption of circadian rhythms has been associated with a variety of maladies. Ecological studies of human exposures to light are virtually nonexistent, however, making it difficult to determine if, in fact, light-induced circadian disruption directly affects human health.  相似文献   

18.
In humans, chronic ethanol consumption leads to a characteristic set of changes to the metabolism of lipids in the liver that is referred to as an "alcoholic fatty liver (AFL)". In severe cases, these metabolic changes result in the enlargement and fibrillization of the liver and are considered risk factors for cirrhosis and liver cancer. Clock-mutant mice have been shown to display abnormal lipid metabolism and alcohol preferences. To further understand the potential interactions between ethanol consumption, lipid metabolism, and the circadian clock, we investigated the effect of chronic ethanol intake on the lipid metabolism of Clock-mutant mice. We found that ethanol treatment produced a number of changes in the liver of Clock-mutant mice without impacting the wild-type controls. First, we found that 8 weeks of exposure to ethanol in the drinking water increased the weight of the liver in Clock-mutant mice. Ethanol treatment also increased triglyceride content of liver in Clock-mutant and wild-type mice. This increase was larger in the mutant mice. Finally, ethanol treatment altered the expression of a number of genes related to lipid metabolism in the Clock-mutant mice. Interestingly, this treatment did not impact circadian clock gene expression in the liver of either genotype. Thus, ethanol produces a number of changes in the liver of Clock-mutant mice that are not seen in the wild-type mice. These changes are consistent with the possibility that disturbance of circadian rhythmicity associated with the Clock mutation could be a risk factor for the development of an alcoholic fatty liver.  相似文献   

19.

Background

Variation in circadian rhythms and nocturnality may, hypothetically, be related to or independent of genetic variation in photoperiodic mediation of seasonal changes in physiology and behavior. We hypothesized that strain variation in photoperiodism between photoperiodic F344 rats and nonphotoperiodic Harlan Sprague Dawley (HSD) rats might be caused by underlying variation in clock function. We predicted that HSD rats would have more activity during the day or subjective day, longer free-running rhythms, poor entrainment to short day length, and shorter duration of activity, traits that have been associated with nonphotoperiodism in other laboratory rodent species, relative to F344 rats. An alternative hypothesis, that differences are due to variation in melatonin secretion or responses to melatonin, predicts either no such differences or inconsistent combinations of differences.

Methods

We tested these predictions by examining activity rhythms of young male F344 and HSD rats given access to running wheels in constant dark (DD), short day length (L8:D16; SD), and long day length (L16:D8; LD). We compared nocturnality (the proportion of activity during night or subjective night), duration of activity (alpha), activity onset and offset, phase angle of entrainment, and free running rhythms (tau) of F344 and HSD rats.

Results

HSD rats had significantly greater activity during the day, were sometimes arrhythmic in DD, and had significantly longer tau than F344 rats, consistent with predictions. However, HSD rats had significantly longer alpha than F344 rats and both strains entrained to SD, inconsistent with predictions.

Conclusion

The ability of HSD rats to entrain to SD, combined with longer alpha than F344 rats, suggests that the circadian system of HSD rats responds correctly to SD. These data offer best support for the alternative hypothesis, that differences in photoresponsiveness between F344 and HSD rats are caused by non-circadian differences in melatonin secretion or the response to melatonin.  相似文献   

20.

Background  

Bipolar disorder (BPD) is a widespread condition characterized by recurring states of mania and depression. Lithium, a direct inhibitor of glycogen synthase kinase 3 (GSK3) activity, and a mainstay in BPD therapeutics, has been proposed to target GSK3 as a mechanism of mood stabilization. In addition to mood imbalances, patients with BPD often suffer from circadian disturbances. GSK3, an essential kinase with widespread roles in development, cell survival, and metabolism has been demonstrated to be an essential component of the Drosophila circadian clock. We sought to investigate the role of GSK3 in the mammalian clock mechanism, as a possible mediator of lithium's therapeutic effects.  相似文献   

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