Importance of regular lifestyle with daytime bright light exposure on circadian rhythm sleep–wake disorders in pervasive developmental disorders

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

In vivo monitoring of multi-unit neural activity in the suprachiasmatic nucleus reveals robust circadian rhythms in Period1⁻/⁻ mice.

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 vivo monitoring of multi-unit neural activity in the suprachiasmatic nucleus reveals robust circadian rhythms in Period1⁻/⁻ mice.

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

Recovery from Age-Related Infertility under Environmental Light-Dark Cycles Adjusted to the Intrinsic Circadian Period.

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

Recovery from Age-Related Infertility under Environmental Light-Dark Cycles Adjusted to the Intrinsic Circadian Period.

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

Histological examination of recording sites in the ventral and dorsal SCN.

<p>Representative serial coronal sections (25 µm, every other section shown) of a wild-type (A) and <i>Per1^−/−</i> (B) SCN following MUA recording. Sections were stained with neutral-red and blue spots of deposited iron are the recording sites. Recording sites were present in the ventral and dorsal SCN. The anterior to posterior orientation of the sections is indicated. Scale bar represents 200 µm. The data in A and B correspond to the data shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0064333#pone-0064333-g002" target="_blank">Fig. 2A and B</a>, respectively.</p

Circadian Regulation of Food-Anticipatory Activity in Molecular Clock–Deficient Mice

<div><p>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. <em>Cry1^−/−</em> mice, which are known to be a “short-period mutant,” entrained to a shorter period of feeding cycles than did <em>Cry2^−/−</em> mice. This result indicated that the intrinsic periods of FAA rhythms are also affected by <em>Cry</em> deficiency. <em>Bmal1</em>^−/− 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 <em>Cry1</em>, <em>Cry2</em> and <em>Bmal1</em> play essential roles in regulating FAA in a circadian oscillatory manner.</p> </div

Behavioral and SCN responses to light.

<p>Representative double-plotted actograms of wheel-running activity (left panels) and multi-unit neural activity in the SCN (right panels) of wild-type (A) and <i>Per1</i>^−/− (D) mice. Each line represents two consecutive days (48 hr), with time in 6-min bins plotted left to right. Consecutive days are aligned vertically. The mice were maintained in constant darkness (indicated by the black bars above actograms) and a 15-min light pulse (100 lux) was administered 3 hr after activity onset (CT15; open inverted triangle). Open circles indicate the respective phase markers: activity onset for wheel-running activity and acrophase for MUA. The magnitudes of phase shifts were determined by measuring the phase differences between least-squares fitted regression lines through the respective phase markers before and after the light pulse [locomotor: −2.20 h, MUA: −1.94 h in (A); locomotor: −3.24 h, MUA:−2.60 h in (D)]. To show the acute response of the SCN to light, MUA data (plotted in 1-min bins) surrounding the light pulse in (A) and (D) are magnified in (B) and (E), respectively. The time of the light pulse is indicated by the open bars at the tops of the figures and dark is indicated by gray shading. Mean (±SD) MUA responses in wild-type (C; n = 4) and <i>Per1^−/−</i> (F; n = 4) SCN are shown relative to baseline (baseline determined from the mean counts 15 min before the light pulse and set to 100% in wild-type and <i>Per1</i>^−/− mice).</p