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The circadian rhythms of physiology and behavior are based on molecular systems at the cellular level, which are regulated by clock genes, including cryptochrome genes, Cry1 and Cry2. In mammals, the circadian pacemaker in the suprachiasmatic nucleus (SCN) of the hypothalamus maintains the circadian rhythms throughout the body. Cry1 and Cry2 play distinct roles in regulating the circadian rhythm. However, the different effects of manipulating clock genes in heterozygous and homozygous alleles, Cry1 and Cry2, remain unclear. Therefore, this study aimed to understand the haplosufficiency of cryptochrome genes in regulating the circadian system. We examined wheel-running activity rhythms and PER2::LUC expression rhythms in SCN slices and pituitary explants in mice. Compared with wild-type mice, Cry1

Salivary secretion displays day-night variations that are controlled by the circadian clock. The central clock in the suprachiasmatic nucleus (SCN) regulates daily physiological rhythms by prompting peripheral oscillators to adjust to changing environments. Aquaporin 5 (Aqp5) is known to play a key role in salivary secretion, but the association between Aqp5 and the circadian rhythm is poorly understood. The aim of our study was to evaluate whether Aqp5 expression in submandibular glands (SMGs) is driven by the central clock in the SCN or by autonomous oscillations. We observed circadian oscillations in the activity of period circadian protein homolog 2 and luciferase fusion protein (PER2::LUC) in cultured SMGs with periodicity depending on core clock genes. A daily rhythm was detected in the expression profiles of Aqp5 in SMGs in vivo. In cultured SMGs ex vivo, clock genes showed distinct circadian rhythms, whereas Aqp5 expression did not. These data indicate that daily Aqp5 expression in the mouse SMG is driven by the central clock in the SCN.

Aging is associated with changes in sleep duration and quality, as well as increased rates of pathologic/disordered sleep. While several factors contribute to these changes, emerging research suggests that age-related changes in the mammalian central circadian clock within the suprachiasmatic nucleus (SCN) may be a key factor. Prior work from our group suggests that circadian output from the SCN declines because of aging. Furthermore, we have previously observed age-related infertility in female mice, caused by a mismatch between environmental light-dark cycles and the intrinsic, internal biological clocks. In this review, we address regulatory mechanisms underlying circadian rhythms in mammals and summarize recent literature describing the effects of aging on the circadian system.

© 2015 The Authors. Female reproductive function changes during aging with the estrous cycle becoming more irregular during the transition to menopause. We found that intermittent shifts of the light-dark cycle disrupted regularity of estrous cycles in middle-aged female mice, whose estrous cycles were regular under unperturbed 24-hr light-dark cycles. Although female mice deficient in Cry1 or Cry2, the core components of the molecular circadian clock, exhibited regular estrous cycles during youth, they showed accelerated senescence characterized by irregular and unstable estrous cycles and resultant infertility in middle age. Notably, tuning the period length of the environmental light-dark cycles closely to the endogenous one inherent in the Cry-deficient females restored the regularity of the estrous cycles and, consequently, improved fertility in middle age. These results suggest that reproductive potential can be strongly influenced by age-related changes in the circadian system and normal reproductive functioning can be rescued by the manipulation of environmental timing signals. Takasu et al. show that weekly perturbation of the light-dark cycle disrupts estrous cycles in middle-aged female mice, and early infertility evident in female mice deficient in core circadian clock genes is improved by coordinating environmental and endogenous circadian rhythms. These findings suggest that an age-related decline in fertility may be rescued by control of environmental timing signals.

The present study examined the effects of regularizing sleep-wake schedules on sleep, autonomic function and mood/emotional and personality states in 14 habitually irregular sleepers. During the experiment, sleep monitoring and regularized sleep-wake schedules were conducted at home. First, the subjects’ habitual sleep-wake patterns were strictly monitored for 6 days (Session 1); second, subjects’ irregular sleep-wake patterns were regularized for 6 days (Session 2); and finally, subjects reverted from their regularized sleep-wake schedules to their original, habitual sleep-wake schedules and were monitored for 6 days (Session 3). Assessments in the laboratory, which were conducted in the daytime, were repeated four times. The first three assessments were carried out on the days following Sessions 1, 2, and 3. The fourth measurement (Session 4), which was conducted under the original irregular sleep-wake pattern condition, was performed approximately 6 months after initiation of the second irregular sleep-wake schedule. In results, significant reductions in daytime parasympathetic activity and negative mood, i.e. tensionanxiety, angerhostility, and fatigue, were observed after the 6-day regularized sleep-wake schedule and extending through Session 3. However, the parasympathetic activity, as well as negative mood manifestations, returned to their initial levels when measured 6 months later. On the other hand, sleep and personality states did not change in response to alternations in sleep-wake regularity. However, the reduction of daytime fatigue level suggests a possibility that further sleep improvements might be difficult to detect under the regularized sleep-wake schedule because the subjects were healthy university students without sleep disorders.

The circadian pacemaker in the suprachiasmatic nucleus (SCN) of the hypothalamus is responsible for controlling behavioral activity rhythms, such as a free running rhythm in constant darkness. Rodents have several circadian oscillators in other brain regions including the arcuate nucleus (ARC). In specific conditions such as food anticipatory activity rhythms in the context of timed restricted feeding, an alternative circadian pace-making system has been assumed by means of circadian oscillators like the SCN. Despite extensive lesion studies, the anatomic locations of extra-SCN circadian pacemakers responsible for regulating behavioral rhythms have not been found. In the present study, we investigated circadian rhythms in the SCN and extra-SCN region of the arcuate nucleus (ARC) by analyzing PER2::LUCIFERASE expression in specific regions from wild-type C57BL/6, Cry1(-/-), and Cry2(-/-) mice. Compared to wild-type animals, we observed period shortening in both the SCN and ARC of Cry1(-/-) mice and period lengthening in Cry2(-/-) mice. Interestingly, the periods in the ARC of both genotypes were identical to those in the SCN. Moreover, the amplitudes of PER2::LUC rhythms in the ARC of all animals were decreased compared to those in the SCN. These data suggest that the ARC is a candidate circadian pacemaker outside the SCN.

Effects of daily physical exercise in the morning or in the evening were examined on circadian rhythms in plasma melatonin and core body temperature of healthy young males who stayed in an experimental facility for 7 days under dim light conditions (

Effects of two different light intensities during daytime were examined on human circadian rhythms in plasma melatonin, core body temperature, and wrist activity under a fixed sleep schedule. Sleep qualities as indicated by polysomnography and subjective sleepiness were also measured. In the first week, under dim light conditions ( approximately 10 lx), the onset and peak of nocturnal melatonin rise were significantly delayed, whereas the end of melatonin rise was not changed. The peak level of melatonin rise was not affected. As a result, the width of nocturnal melatonin rise was significantly shortened. In the second week, under bright light conditions ( approximately 5,000 lx), the phases of nocturnal melatonin rise were not changed further, but the peak level was significantly increased. Core body temperature at the initial sleep phase was progressively elevated during the course of dim light exposure and reached the maximum level at the first night of bright light conditions. Subjective sleepiness gradually declined in the course of dim light exposure and reached the minimum level at the first day of bright light. These findings indicate that repeated exposures to daytime bright light are effective in controlling the circadian phase and increasing the peak level of nocturnal melatonin rise in plasma and suggest a close correlation between phase-delay shifts of the onset of nocturnal melatonin rise or body temperature rhythm and daytime sleepiness.

Bright light is the principal zeitgeber for the biological clock in mammals, including humans. But there is a line of evidence that non-photic stimuli such as physical activity play an important role in entrainment. Scheduled physical activity, such as wheel and forced treadmill running, has been reported to phase-shift and entrain the circadian rhythm in rodent species. In humans, several studies have reported the phase-shifting effects of physical exercise. A single bout of physical exercise at night was demonstrated to phase-delay the circadian rhythm in plasma melatonin. However, for the entrainment of human circadian rhythm, a phase-advance shift is needed. Previously, we demonstrated that scheduled physical exercise in the waking period facilitated the entrainment of plasma melatonin rhythm to the sleep/wake schedule of 23 h 40 min. This result suggested that timed physical exercise produced phase-advance shifts. A regular physical exercise also facilitated entrainment of the circadian rhythms associated with acute phase-delay shifts of the sleep/wake and light/dark schedule. These findings suggest that physical exercise is useful to adjust the circadian rhythm to external time cues, especially for totally blind people and elderly people.

The suprachiasmatic nuclei (SCNs) of the hypothalamus contain a circadian clock that exerts profound control over rhythmic physiology and behavior. The clock consists of multiple autonomous cellular pacemakers distributed throughout the rat SCN. In response to a shift in the light schedule, the SCN rapidly changes phase to achieve the appropriate phase relationship with the shifted light schedule. Through use of a transgenic rat in which rhythmicity in transcription of the Period 1 gene was measured with a luciferase reporter (Per1-luc), we have been successful in tracking the time course of molecular rhythm phase readjustments in different regions of the SCN that occur in response to a shift in the light schedule. We find that different regions of the SCN phase adjust at different rates, leading to transient internal desynchrony in Per1-luc expression among SCN regions. This desynchrony among regions is most pronounced and prolonged when the light schedule is advanced compared with light schedule delays. A similar asymmetry in the speed of phase resetting is observed with locomotor behavior, suggesting that phase shifting kinetics within the SCN may underlay the differences observed in behavioral resetting to advances or delays in the light schedule.

The master pacemaker in the suprachiasmatic nucleus (SCN) controls daily rhythms of behavior in mammals. C57BL/6J mice lacking Period1 (Per1−/−) are an anomaly because their SCN molecular rhythm is weak or absent in vitro even though their locomotor activity rhythm is robust. To resolve the contradiction between the in vitro and in vivo circadian phenotypes of Per1−/− mice, we measured the multi-unit activity (MUA) rhythm of the SCN neuronal population in freely-behaving mice. We found that in vivo Per1−/− SCN have high-amplitude MUA rhythms, demonstrating that the ensemble of neurons is driving robust locomotor activity in Per1−/− mice. Since the Per1−/− SCN electrical activity rhythm is indistinguishable from wild-types, in vivo physiological factors or coupling of the SCN to a known or unidentified circadian clock(s) may compensate for weak endogenous molecular rhythms in Per1−/− SCN. Consistent with the behavioral light responsiveness of Per1 −/− mice, in vivo MUA rhythms in Per1 −/− SCN exhibited large phase shifts in response to light. Since the acute response of the MUA rhythm to light in Per1−/− SCN is equivalent to wild-types, an unknown mechanism mediates enhanced light responsiveness of Per1−/− mice. Thus, Per1−/− mice are a unique model for investigating the component(s) of the in vivo environment that confers robust rhythmicity to the SCN as well as a novel mechanism of enhanced light responsiveness.

In the mammalian brain, the suprachiasmatic nucleus (SCN) of the anterior hypothalamus is considered to be the principal circadian pacemaker, keeping the rhythm of most physiological and behavioral processes on the basis of light/dark cycles. Because restriction of food availability to a certain time of day elicits anticipatory behavior even after ablation of the SCN, such behavior has been assumed to be under the control of another circadian oscillator. According to recent studies, however, mutant mice lacking circadian clock function exhibit normal food-anticipatory activity (FAA), a daily increase in locomotor activity preceding periodic feeding, suggesting that FAA is independent of the known circadian oscillator. To investigate the molecular basis of FAA, we examined oscillatory properties in mice lacking molecular clock components. Mice with SCN lesions or with mutant circadian periods were exposed to restricted feeding schedules at periods within and outside circadian range. Periodic feeding led to the entrainment of FAA rhythms only within a limited circadian range. Cry1(-/-) mice, which are known to be a "short-period mutant," entrained to a shorter period of feeding cycles than did Cry2(-/-) mice. This result indicated that the intrinsic periods of FAA rhythms are also affected by Cry deficiency. Bmal1(-/-) mice, deficient in another essential element of the molecular clock machinery, exhibited a pre-feeding increase of activity far from circadian range, indicating a deficit in circadian oscillation. We propose that mice possess a food-entrainable pacemaker outside the SCN in which canonical clock genes such as Cry1, Cry2 and Bmal1 play essential roles in regulating FAA in a circadian oscillatory manner.

Previous neuroimaging studies that examined cerebral blood flow during rapid eye movement (REM) sleep have reported inconsistent findings regarding the activity of the dorsolateral prefrontal cortex (DLPFC). Although most previous positron emission tomography (PET) studies failed to detect DLPFC activation during REM sleep, several studies have observed DLPFC activation, possibly reflecting transient prefrontal activities related to REM. More recently, an event-related functional magnetic resonance imaging (fMRI) study observed REM-locked activation of the DLPFC during REM sleep. The present study investigated hemodynamic changes of the DLPFC throughout the REM sleep period in 25 subjects using near-infrared spectroscopy. Continuous monitoring of changes in the hemoglobin (Hb) concentration and tissue oxygenation index (TOI, proportion of oxygenated-Hb to total-Hb) in the bilateral DLPFC was conducted every 0.5 s, simultaneously with polysomnographic recordings. Eight of the 25 subjects showed REM sleep, and all indicated a clear increase in both the oxygenated-Hb concentration and TOI from baseline at the occurrence of first REM, relative to prior stage 2 sleep. The results indicate that the appearance of the first REM that occurred just after onset of the REM sleep closely coincides with the activation of the DLPFC, which could play a role in cognitive activities during REM sleep in humans.

Summary Considerable attention has been paid to individuals showing social maladjustment as well as withdrawal from social situations and activity, a state referred to as “Hikikomori” in Japanese. Recently, social maladjustment and Hikikomori states have also been noted to be highly prevalent among individuals with pervasive developmental disorders (PDDs), which involve abnormalities in social interactions and communication. The individuals with PDDs report a tendency to sleep and wake at irregular or inappropriate times and to suffer from sleep disorders by nature, and they tend to sleep at extreme late night or during the day while experiencing social maladjustment and Hikikomori states. Therefore, it is probable that their oral hygiene might deteriorate due to a circadian rhythm disorder, such as an abnormal salivary secretion rhythm or refusals and noncooperation of dental care due to mood/emotional and social problems, underlying and caused by their sleep and wake patterns. In this review, we describe the importance of regular lifestyle, especially regular sleep–wake rhythm with appropriately timed bright light exposure during daytime, for management of oral health in PDDs via improving their circadian rhythm disorders.