Basic concepts and unique features of human circadian rhythms : implications for human health

Most physiological functions and behaviors exhibit a robust approximately 24-hour rhythmicity (circadian rhythm) in the real world. These rhythms persist under constant conditions, but the period is slightly longer than 24 hours, suggesting that circadian rhythms are endogenously driven by an internal, self-sustained oscillator. In mammals, including humans, the central circadian pacemaker is located in the hypothalamic suprachiasmatic nucleus. The primary zeitgeber for this pacemaker is bright sunlight, but nonphotic time cues also affect circadian rhythms. The human circadian system uniquely exhibits spontaneous internal desynchronization between the sleep-wake cycle and core body temperature rhythm under constant conditions and partial entrainment of the sleep-wake cycle in response to nonphotic time cues. Experimental and clinical studies of human circadian rhythms must take into account these unique features. This review covers the basic concepts and unique features of the human circadian system, the mechanisms underlying phase adjustment of the circadian rhythms by light and nonphotic time cues (eg, physical exercise), and the effects of eating behavior (eg, chewing frequency) on the circadian rhythm of glucose metabolism.Figure legendsの番号訂正: Figure 2→Figure 3、Figure 3→Figure 4Figure legendsの追補: Figure 2　Light phase-response curve. A light phase-response curve produced by a single 3-hour pulse of bright light (∼5000 lx). Subjects were housed in an isolation facility under free-running conditions. The phase-advance portion coincides with late subjective night and early subjective morning. The phase-delay portion coincides with early subjective night, and the middle of the subjective day is a dead-zone when bright light does not produce a significant phase shift (dead-zone). Reproduced from Honma and Honma (1988)16 and Minors et al (1991),17 with permission

Cardiovascular autonomic nervous response to postural change in 610 healthy Japanese subjects in relation to age

To determine the effect of aging on the cardiovascular response to postural change, we examined the cardiovascular sympathetic and parasympathetic response to active standing in 610 healthy Japanese subject (6–83 years) measuring the initial heart rate (HR) response for 3 min in the supine and standing position, we also measured the coefficient of variation of R–R interval (CV R–R). As a result, the cardiovascular response to active standing demonstrated a different change with aging between sympathetic and parasympathetic. Sympathetic function was in a sthenia state in young subjects, and that this function declined with age increasing. Whereas, parasympathetic function was immature enough to inhibit the sympathetic tone in young subjects and matured at 20 years of age, and had an ability to inhibit sympathetic tone. CV R–R show a linear change that decline with age increasing. These results indicated that the cardiovascular parasympathetic response to active standing shows a characteristic change with aging that differs from cardiovascular parasympathetic at rest represented by CV R–R. The present study is the first report to demonstrate the cardiovascular response to standing in relation to aging in large population. These results suggested that the cardiovascular response to postural change is dependent on subject's age

Scheduled exposures to a novel environment with a running-wheel differentially accelerate re-entrainment of mice peripheral clocks to new light-dark cycles

Effects of scheduled exposures to novel environment with a running-wheel were examined on re-entrainment to 8 h shifted light-dark (LD) cycles of mouse circadian rhythms in locomotor activity and clock gene, Per1, expression in the suprachiasmatic nucleus (SCN) and peripheral tissues. Per1 expression was monitored by a bioluminescence reporter introduced into mice. The animals were exposed to the novel environment for 3 h from the shifted dark onset for four cycles and released into constant darkness. In the phase-advance shift, the circadian rhythm in locomotor activity fully re-entrained in the exposed group, whereas it was in transients in the control. On the other hand, the circadian rhythm of Per1 expression in the SCN almost completely re-entrained in both the control and exposed groups. In the skeletal muscle and lung, the circadian rhythm fully re-entrained in the exposed group, whereas the rhythms in the control did not. In the phase-delay shift, the circadian rhythms in locomotor activity and Per1 expression almost completely re-entrained in both groups. These findings indicate that the scheduled exposures to novel environment with a running-wheel differentially accelerate the re-entrainment of the mouse peripheral clocks to 8 h phase-advanced LD cycles

Cryptochrome deficiency enhances transcription but reduces protein levels of pineal Aanat

Cryptochrome (Cry) 1 and 2 are essential for circadian rhythm generation, not only in the suprachiasmatic nucleus, the site of the mammalian master circadian clock, but also in peripheral organs throughout the body. CRY is also known as a repressor of arylalkylamine-N-acetyltransferase (Aanat) transcription; therefore, Cry deficiency is expected to induce constantly high pineal melatonin content. Nevertheless, we previously found that the content was consistently low in melatonin-proficient Cry1 and Cry2 double-deficient mice (Cry1(-/-)/Cry2(-/-)) on C3H background. This study aims to clarify the mechanism underlying this discrepancy. In the Cry1(-/-)/Cry2(-/-) pineal, expression levels of Aanat and clock gene Per1 were consistently high with no circadian fluctuation on the first day in constant darkness, demonstrating that CRY acts in vivo as a repressor of the pineal circadian clock and AANAT. In contrast, the enzyme activity and protein levels of AANAT remained low throughout the day, supporting our previous observation of continuously low melatonin. Thus, effects of Cry deficiency on the responses of beta-adrenergic receptors were examined in cultured pineal glands. Isoproterenol, a beta-adrenergic stimulant, significantly increased melatonin content, although the increase was smaller in Cry1(-/-)/Cry2(-/-) than in WT mice, during both the day and night. However, the increase in cAMP in response to forskolin was similar in both genotypes, indicating that CRY deficiency does not affect the pathway downstream of the beta-adrenergic receptor. These results suggest that a lack of circadian adrenergic input due to CRY deficiency decreases beta-receptor activity and cAMP levels, resulting in consistently low AANAT levels despite abundant Aanat mRNA

Effects of physical exercise on human circadian rhythms

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

Effects of Lactococcus lactis subsp. cremoris YRC3780 daily intake on the HPA axis response to acute psychological stress in healthy Japanese men

Background: Lactococcus lactis subsp. cremoris (YRC3780), which is isolated from kefir, has been associated with anti-allergic effects in humans. However, it remains unknown whether daily intake of YRC3780 attenuates the response to psychological stress in humans in parallel with changes to the gut microbiome. We examined the fundamental role of YRC3780 in the gut microbiome, stress response, sleep, and mental health in humans. Methods: Effects of daily intake of YRC3780 on the hypothalamic-pituitary-adrenal (HPA) axis response to acute psychological stress were investigated in a double-blind, placebo-controlled clinical trial involving 27 healthy young men (mean age and body mass index: 23.5 years and 21.5 kg/m(2)) who were randomly assigned to placebo (n = 13) or YRC3780 (n = 14) groups. The HPA axis response to acute psychological stress, the diurnal rhythm of HPA axis activity, and gut microbiome were assessed and compared between the two groups. Results: The results showed that daily intake of YRC3780 significantly lowered morning salivary cortisol levels compared with placebo. In addition, salivary cortisol levels following a social stress test significantly decreased +40 min after beginning the TSST in the YRC3780-treated group compared to placebo. There were no significant differences between the two groups in terms of actigraphy-based sleep quality, but the subjective sleep quality and mental health were significantly improved in the YRC3780-treated group compared to placebo. Conclusions: Our study suggests that daily intake of YRC3780 improves the HPA axis response to acute psychological stress, which might be associated with a decrease in morning cortisol levels