Satoko Hashimoto

Midday exposure to bright light changes the circadian organization of plasma melatonin rhythm in humans

Effects of bright light exposure at midday were examined on plasma melatonin rhythm in humans under controlled living conditions. Bright light of 5000 1x was provided from the ceiling at midday (1100-1700 h) for 3 consecutive days and the circadian rhythm in plasma melatonin was determined from the fourth to fifth day. The control study was performed in the same subjects who spend four days under dim light conditions (less than 200 1x). The subjects were allowed to sleep from 2400 to 0800 h. The onset phase, but not the end phase, of plasma melatonin rhythm was significantly phase-advanced by bright light exposure. Furthermore, the area under the curve of nocturnal melatonin rise was significantly larger under bright light exposure than under dim light. These findings indicate that midday exposure to bright light for 3 consecutive days changes the circadian organization of plasma melatonin rhythm in humans.

Seasonal changes of human circadian rhythms in Antarctica

The human circadian rhythms in sleep, activity, plasma melatonin, and rectal temperature were explored under two conflicting time cues in Antarctica: an extreme photoperiod and a strict work schedule. The nine healthy male subjects stayed at the Antarctic zone (latitude 66.5-90° south) for 15 mo including a 13-mo wintering at the Dome station (latitude 77° south). Neither the phases nor the amounts of sleep and daily activity underwent a seasonal change. On the other hand, the peak phase of melatonin rhythm was phase delayed by 4.1 h in winter compared with summer. When the analysis is limited to the Dome data, the seasonal difference was reduced to 1.3 h. Similarly the trough phase of rectal temperature rhythm in two of three subjects was phase delayed by ∼2 h in winter. From these findings, the sleep or activity rhythm is concluded to be reset predominantly by the work schedule, whereas the circadian rhythm in plasma melatonin and rectal temperature is substantially influenced by the photoperiod.The human circadian rhythms in sleep, activity, plasma melatonin, and rectal temperature were explored under two conflicting time cues in Antarctica: an extreme photoperiod and a strict work schedule. The nine healthy male subjects stayed at the Antarctic zone (latitude 66.5-90 degrees south) for 15 mo including a 13-mo wintering at the Dome station (latitude 77 degrees south). Neither the phases nor the amounts of sleep and daily activity underwent a seasonal change. On the other hand, the peak phase of melatonin rhythm was phase delayed by 4.1 h in winter compared with summer. When the analysis is limited to the Dome data, the seasonal difference was reduced to 1.3 h. Similarly the trough phase of rectal temperature rhythm in two of three subjects was phase delayed by approximately 2 h in winter. From these findings, the sleep or activity rhythm is concluded to be reset predominantly by the work schedule, whereas the circadian rhythm in plasma melatonin and rectal temperature is substantially influenced by the photoperiod.

Physical exercise accelerates reentrainment of human sleep-wake cycle but not of plasma melatonin rhythm to 8-h phase-advanced sleep schedule

Effects of timed physical exercise were examined on the reentrainment of sleep-wake cycle and circadian rhythms to an 8-h phase-advanced sleep schedule. Seventeen male adults spent 12 days in a temporal isolation facility with dim light conditions (<10 lux). The sleep schedule was phase-advanced by 8 h from their habitual sleep times for 4 days, which was followed by a free-run session for 6 days, during which the subjects were deprived of time cues. During the shift schedule, the exercise group (n = 9) performed physical exercise with a bicycle ergometer in the early and middle waking period for 2 h each. The control group (n = 8) sat on a chair at those times. Their sleep-wake cycles were monitored every day by polysomnography and/or weight sensor equipped with a bed. The circadian rhythm in plasma melatonin was measured on the baseline day before phase shift: on the 4th day of shift schedule and the 5th day of free-run. As a result, the sleep-onset on the first day of free-run in the exercise group was significantly phase-advanced from that in the control and from the baseline. On the other hand, the circadian melatonin rhythm was significantly phase-delayed in the both groups, showing internal desynchronization of the circadian rhythms. The sleep-wake cycle resynchronized to the melatonin rhythm by either phase-advance or phase-delay shifts in the free-run session. These findings indicate that the reentrainment of the sleep-wake cycle to a phase-advanced schedule occurs independent of the circadian pacemaker and is accelerated by timed physical exercise.

Effects of light and sleep stages on heart rate variability in humans

Effects of light intensity and sleep stages on heart rate variability (HRV) were investigated in young healthy subjects. The low‐frequency (LF)/high‐frequency (HF) ratio was significantly increased by exposing either to bright lights of 10 000 lx or to extreme darkness (< 0.01 lx), while HF and LF components of HRV were not changed, when compared with those under dim light (100 lx). However, LF was significantly increased at REM sleep, when compared with that at the pre‐sleep wake. In contrast, HF was increased at all stages of sleep, and the LF/HF ratio was decreased at slow wave sleep during the baseline night.

Melatonin Receptors in the Spinal Cord

The pineal hormone, melatonin, plays an important role in the regulation of diurnal and seasonal rhythms in animals. In addition to the well established actions on the brain, the possibility of a direct melatonin action on the spinal cord has to be considered. In our laboratory, we have obtained data suggesting that melatonin receptors are present in the spinal cords of birds and mammals. Using radioreceptor binding and quantitative autoradiography assays with 2-[125I]iodomelatonin as the specific melatonin agonist, melatonin binding sites have been demonstrated in the rabbit and chicken spinal cords. These sites are saturable, reversible, specific, guanosine nucleotide-sensitive, of picomolar affinity and femtomolar density. The linearity of Scatchard plots of saturation data and the unity of Hill coefficients indicate that a single class of melatonin binding sites is present in the spinal cord membranes studied. The picomolar affinity of these sites is in line with the circulating levels of melatonin in these animals suggesting that these sites are physiologically relevant. Autoradiography studies in the rabbit spinal cord show that melatonin binding sites are localized in the central gray substance (lamina X). In the chicken spinal cord, these binding sites are localized in dorsal gray horns (laminae I-V) and lamina X. As lamina X and laminae I-II have similar functions, melatonin may have comparable roles in the chicken and rabbit spinal cords. Moreover, in the chicken spinal cord, the density of 2-[125I]iodomelatonin binding in the lumbar segment was significantly higher than those of the cervical and thoracic segments. The densities of these binding sites changed with environmental manipulations. When chickens were adapted to a 12L/12D photoperiod and sacrificed at mid-light and mid-dark, there was a significant diurnal variation in the density (maximum number of binding sites; Bmax) of melatonin binding sites in the spinal cord. After constant light treatment or pinealectomy, the Bmax of melatonin receptors in the chicken spinal cord increased significantly in the subjective mid-dark period. Moreover, there was an age-related decrease in the 2-[125I]iodomelatonin binding to the chicken spinal cord. Our results suggest that melatonin receptors in the chicken spinal cord are regulated by environmental lighting and change with development. These receptors may play an important role in the chronobiology of spinal cord function. The biological responses of melatonin on spinal cords have also been demonstrated in vitro. Melatonin decreased the forskolin-stimulated cAMP production in the chicken spinal cord explant. Preincubation with pertussis toxin blocked the melatonin effect. Our results suggest that melatonin receptors in the chicken spinal cord are linked to the adenylate cyclase via a pertussis toxin-sensitive G protein and that melatonin binding sites in spinal cords are melatonin receptors with biological functions. These receptors may be involved in the regulation of spinal cord functions related to sensory transmission, visceral reflexes and autonomic activities.

Period and Phase Adjustments of Human Circadian Rhythms in the Real World

Entrainment of the circadian rhythm has 2 aspects, period and phase adjustments, which are established simultaneously in most nonhuman circadian systems. The human circadian system is unique in its functional structure in which 2 different subsystems are involved; one is the circadian pacemaker analogous to that located in the suprachiasmatic nucleus, and the other is the oscillatory system of unknown nature that drives the rest-activity cycle. The human circadian system shows the endogenous period very close to 24 h under entrainment and less sensitive to photic stimuli than under free running, which may explain stable entrainment in the real word where natural sun lights are unpredictable in terms of the intensity and time of appearance. On the other hand, nonphotic entrainment seems to play a significant role in phase adjustment of the human circadian system. Nonphotic zeitgebers initially directed to the rest-activity cycle may affect the circadian pacemaker through feedback and/or associated LD cycles.

Twenty‐four hour rhythm of melatonin in patients with a history of pineal and/or hypothalamo‐neurohypophyseal germinoma

Abstract: Melatonin deficiency after a pinealectomy has been investigated in animals; however, in humans, this status can be assessed solely by investigating patients with a tumor originating in the pineal gland. This study analyzes secretion of melatonin and pituitary hormones in 14 patients with germinoma originating in the pineal or the hypothalamic‐neurohypophyseal region. Thirteen patients had been successfully treated prior to this study. One patient was included in this study before the initiation of treatments. Plasma sampling was performed every 2 hr for 24 hr and melatonin concentrations were measured by radioimmunoassay. Melatonin secretion was nearly absent in the patients with pineal germinoma regardless of treatment option, even in the patient who had been untreated. In contrast, melatonin secretion and its circadian rhythms were not affected in patients with a hypothalamo‐neurohypophyseal germinoma. The circadian rhythms of growth hormone and adrenocorticotropic hormone were not dysregulated in patients with the melatonin deficiency. We conclude that germinoma cells originating the pineal gland impair the production of melatonin by pineocytes and consequently induce a permanent melatonin deficiency in those patients. Since melatonin exerts multiple physiological functions, once a clinical concept of “melatonin deficiency syndrome” is established, melatonin replacement therapy could be investigated in patients who have a pineal germinoma or who have undergone a neurosurgical pinealectomy.

Light and Plasma Melatonin Rhythm in Humans

Plasma melatonin rhythm in humans was investigated: its stability, relationship to the sleep-wake rhythm, and response to light. The so-called day-to-day variation of reference phases of plasma melatonin rhythm was within 1.4 h when blood was sampled at 1-hour intervals. Therefore, a change in phase beyond this value is regarded as a phase shift of melatonin rhythm in individuals. Plasma melatonin rhythm was spontaneously desynchronized from the sleep-wake rhythm and probably regulated by the common circadian pacemaker which drives the rhythm in rectal temperature. When a bright-light pulse was applied, the melatonin rhythm produced a phase shift, but the amount of phase shift seems to be different for the ascending and descending phases of nocturnal melatonin rise. Finally, a partial entrainment was observed in a subject who developed a non-24-hour sleep-wake syndrome later, in which the plasma melatonin rhythm was free-running whereas the sleep-wake rhythm was apparently entrained by a 24-hour day-night alternation. It is concluded that the plasma melatonin rhythm is the best marker of the human circadian pacemaker so far available.

Free-running circadian rhythm of melatonin in a sighted man despite a 24-hour sleep pattern : A non-24-hour circadian syndrome

Abstract Sleep and plasma melatonin rhythms were measured longitudinally in a sighted young man (21 years old) under a day‐night environment. At each measurement, the responsiveness of the melatonin rhythm to a single light pulse was examined in addition to the 24‐hour profile. In experiment 1, the timing of sleep was decided by the subject himself. Although most sleep episodes were observed between 21:02 h and 10:55 h, the plasma melatonin rhythm free‐ran for a period of 24.18 h. In experiment 2, the sleep‐wake schedule of the subject was strictly fixed. The subject was instructed to go to bed at 24:00 h and wake up, at the latest, before 8:00 h for 40 days. The melatonin rhythm, however, continued to free‐run for a period of 24.12 h. Nocturnal melatonin level could not be suppressed by a 3‐hour light pulse of 500 lx, but was suppressed by a pulse of 1000 lx. It is concluded that internal desynchronization occurred in this particular sighted subject where the sleep‐wake rhythm was entrained by the 24‐hour day‐night environment, whereas the plasma melatonin rhythm free ran, and that a forced sleep schedule did not act as a strong zeitgeber.

A sighted man with non-24-hour sleep-wake syndrome shows damped plasma melatonin rhythm

Abstract Twenty‐four‐hour profiles of plasma melatonin, cortisol and rectal temperature were measured longitudinally in a sighted man who has been suffering from sleep disorders for more than 10 years. The sleep‐wake rhythm of this subject free‐ran, despite his routine life, and occasionally showed a sign of internal desyn‐chronization, where sleep was lengthened up to 30 h. These states were classified into the non‐24‐hour sleep‐wake syndrome. Plasma melatonin concentrations in the subjective night remained at a low level and showed a damped circadian rhythm. At the same time, robust circadian rhythms were detected in plasma cortisol and rectal temperature, indicating that the circadian pacemaker was intact. The causal relationship between the damping of nocturnal melatonin rise and a failure of entrainment of the sleep‐wake cycle is discussed.