Human time production under constant routine

Abstract Previous reports have suggested that human time production of several seconds fluctuates across the day. In order to test whether human time production was controlled by the circadian process or by the homeostatic process, we investigate diurnal fluctuation of human time production under constant routine conditions. We found a common circadian feature in time production tests of 10 s by calculating Z-score for each subject; afternoon troughs and morning peaks. These results may suggest that human time production was modulated by the circadian process.     

Dim light melatonin onset and circadian temperature during a constant routine in hypersomnic winter depression

The onset of melatonin secretion under dim light conditions (DLMO) and the circadian temperature rhythm during a constant routine were assessed in 6 female controls and 6 female patients with winter depression (seasonal affective disorder, SAD) before and after bright light treatment. After sleep was standardized for 6 days, the subjects were sleep-deprived and at bedrest for 27 h while core temperature and evening melatonin levels were determined. The DLMO of the SAD patients was phase-delayed compared with controls (2310 vs 2138); with bright light treatment, the DLMO advanced (2310 to 2135). The minimum of the fitted rectal temperature rhythm was phase-delayed in the SAD group compared with the controls (0542 vs 0316); with bright light treatment, the minimum advanced (0542 vs 0336).     

Loss of circadian behavioural rhythms in rats kept in constant darkness

Ten male Sprague-Dawley rats were exposed to 1-h light and 1-h dark (LD 1 : 1) cycles for 50 days. They were then released into constant darkness (DD) for 104 days. Exposure to LD 1 : 1 caused gradual disruption of circadian rhythms in their ambulatory and drinking activities until, finally, all the animals lost their circadian behavioural rhythms. After their release into DD, eight rats showed free-running circadian behavioural rhythms, whereas the remaining two rats showed circadian arrhythmicity for approximately 50 days in DD before they restored their free-running rhythms spontaneously.     

Nocturnal melatonin profiles before and one year after beginning shift-work

Abstract Nocturnal serum melatonin profiles were determined twice for seven single women, during their time of employment as nurses (baseline), and after one year (follow up), in order to investigate the effects of shift-work on nocturnal melatonin secretion. All subjects were working in the same hospital under an irregularly rotating three-shift system. Five (5) mL blood samples were drawn six times at 2 h intervals between 20:00–06:00 hours under dim light conditions (< 50 lux). The same sampling procedures were repeated the following year. The results showed pronounced inter-individual differences in melatonin concentrations. There was a trend towards increasing maximum melatonin concentration (MAX melatonin) at follow up, with a similar tendency seen in summed melatonin (the sum of six measured melatonin concentrations). A trend was also seen towards increasing melatonin ratio at 06:00 hours (the percentage of melatonin concentration at 06:00 hours by summed melatonin) at follow up. Melatonin concentration at 06:00 hours was significantly higher at follow up, and a significant correlation between Morningness-Eveningness score (M-E score) at baseline and increased summed melatonin at follow up was also seen. These results suggest that: nocturnal melatonin secretion does not significantly increase after beginning shift-work; and that greater increases in melatonin secretion at follow up are found in subjects with higher M-E scones (increased morning type). With more subjects, however, there may be significant increase in MAX melatonin and/or summed melatonin in the follow-up study.     

The effects of constant light and constant darkness on daily changes in the morphology of the pineal organ in the goldfish,Carassius auratus

Summary The fine structure of photoreceptor cells in the pineal organ of the goldfish was found to vary quantitatively over a 24-hour period. Stereological analysis revealed significant daily changes in the volume of the cell and inner segment, nuclear volume and nucleolar diameter, volume of endo-plasmic reticulum and Golgi bodies, area of both rough and smooth endo-plasmic reticulum, and number of vesicles associated with each Golgi body. Peak values of these variables occurred either during the dark phase or latter part of the light phase. These findings agree closely with those reported in higher vertebrates, and suggest that metabolic activities, and possible secretory functions, of the pineal organ of fishes are synchronized to the light: dark cycle. Daily changes in these variables generally persisted in fish exposed to constant darkness for seven days, with the peaks in these rhythms coinciding closely with those observed in fish exposed to a light: dark cycle. In contrast, the rhythms in all variables were abolished in fish kept in continual light for seven days. Photoreceptor cells from fish exposed to continuous light had larger nucleoli and greater amounts of rough endoplasmic reticulum indicating a further effect of light on pineal metabolism in lower vertebrates.     

Twenty-four hour pattern of childhood febrile seizures substantiated by time series meta-analysis: Circadian medicine perspectives

Major objectives of this work were to: (1) substantiate the 24-hour pattern in the occurrence of childhood febrile seizures (CFSs) by a novel time series meta-analysis of past reported time-of-day data and (2) discuss its potential circadian rhythm-dependencies. Comprehensive search of the published literature retrieved eight articles that met inclusion criteria. Three investigations were conducted in Iran, two in Japan, and one each in Finland, Italy, and South Korea, representing a total of 2461 mostly simple febrile seizures of children who were on average about 2 years of age. Population-mean cosinor analysis validated (p < .001) a 24-hour pattern in the onset of CFSs, with an approximate four-fold difference in the proportion of children expressing seizures at its peak at 18:04 h (95% confidence interval: 16:40–19:07 h) vs trough at 06:00 h, in the absence of meaningful time-of-day differences in mean body temeprarure. The CFS time-of-day pattern likely derives from the actions of multiple circadian rhythms, particularly the cytokines that comprise the pyrogenic inflammatory pathway and melatonin that influences the excitation level of central neurons and helps regulate body temperature. Past laboratory animal and patient investigations document that the vulnerability to a seizure by a provoking trigger of the same intensity is not the same but different in a predictable-in-time manner during the 24 h as a circadian susceptibility/resistance rhythm. Knowledge of the marked disparity in the time-of-day risk of CFSs can be translated into improved prevention, particularly during the late afternoon and early evening when highest, through proper timing of prophylactic interventions.     

持续光照或摘除松果腺对仓鼠视交叉上核神经元褪黑素敏感性的影响

为探讨视交叉上核 (SCN)神经元对褪黑素敏感性的昼夜节律改变的机制 ,先对仓鼠进行持续光照或摘除松果腺 ,然后制成下丘脑薄片 ,记录昼夜周期中 SCN神经元的自发单位放电 ,并观察其对褪黑素的反应。结果表明 ,取自正常光照动物的脑薄片 ,SCN对外源性褪黑素产生抑制反应的单位数量有昼多夜少的节律性。取自持续光照条件下或摘除松果腺动物的 SCN,对外源性褪黑素反应的昼夜节律性消失。持续光照条件下 ,起抑制反应的单位数量增加 ,引起反应的阈值无明显改变 ;在摘除松果腺后 ,起抑制反应的单位数量减少 ,引起反应的阈值升高。实验结果提示 ,SCN神经元对外源性褪黑素敏感性 ,与内源性褪黑素水平和褪黑素受体的适应性调制有关 ,还可能与松果腺和内源性褪黑素的其他神经生化作用有关。     

Diurnal secretion profiles of growth hormone, thyrotrophin and prolactin in Parkinson's disease

Recently, a massive loss of both hypocretin and melanin‐concentrating hormone (MCH) neurones was found in the hypothalamus of Parkinson’s disease (PD) patients. Because both hypocretin and MCH play a key role in the regulation of sleep, energy homeostasis and autonomic function, partly by modulation of the somatotrophic, thyrotrophic and lactotrophic axes, neuroendocrine dysregulation may contribute to some of the non‐motor features of PD. In eight de novo, medication‐free PD patients and eight age‐, sex‐ and body mass index‐matched controls, we measured serum levels of growth hormone (GH), thyroid‐stimulating hormone (TSH) and prolactin every 10 min for 24 h. Auto‐deconvolution, cosinor and approximate entropy analysis were applied to quantify GH, TSH and prolactin secretion rates, diurnal rhythmicity, as well as regularity of hormone release. Sleep was polygraphically‐recorded throughout the night. Total 24‐h secretion of GH (191 ± 31 versus 130 ± 39 mU/l/24 h), TSH (38 ± 9 versus 36 ± 2 mU/l/24 h) and prolactin (102 ± 14 versus 116 ± 17 μg/l/24 h), as well as their diurnal rhythmicity and regularity of release, were not significantly different between PD patients and controls (all P ≥ 0.12). Fasting levels of insulin‐like growth factor‐1 were also unaltered in PD patients. However, free thyroxine (T₄) levels were significantly higher in PD patients compared to controls (16.19 ± 0.80 versus 13.88 ± 0.40 pmol/l; P = 0.031). In PD patients, prolactin levels were related to disease duration (r = 0.76, P = 0.028), whereas both GH (r = ?0.91, P = 0.002) and free T₄ (r = ?0.71, P = 0.050) levels correlated inversely with body fat content. Apart from a mild increase in free T₄ levels, we found no indications for altered somatotrophic, thyrotrophic and lactotrophic axes activity in early‐stage PD patients.     

Circadian rhythm of plasma melatonin in endogenous depression

1. The circadian rhythm of plasma melatonin was investigated in normal men 18–30 years (N=5), normal men 50–70 years (N=5) and in six patients with endogenous depression.

2. The environmental photoperiod was 11 hours.

3. The subjects and patients were indoors with lights on from 07:00 until 23:00 hours.

4. Blood samples were obtained every 4 hours over a 24 hour period, with additional sampling at 22:00 and 02:00 hours.

5. Plasma melatonin was estimated by radioimmunoassay compared to both groups of controls.

6. In the depressed patients, the levels of melatonin were low throughout the 24 hour period.

7. The depressives had a delayed onset of the dark phase of the rhythm.

8. The patients also showed peak melatonin levels occurring earlier than in the controls.

9. Circadian rhythm of melatonin and therefore of its pacemaker may be altered in endogenous depression.     

Melatonin: Generation and Modulation of Avian Circadian Rhythms

The pineal organ and its hormone melatonin are significant components of avian circadian pacemaking systems. In songbirds, pinealectomy results in the abolition or destabilization of overt circadian rhythms such as the rhythm of locomotor activity, feeding, or body temperature. A stable rhythmicity can be restored either by reimplanting a pineal organ, by periodic injections or infusions of melatonin, or by applying melatonin rhythmically through the drinking water. Several results suggest that the pineal melatonin rhythm acts on at least one other oscillator within the circadian pacemaking system, presumably the SCN, which in turn, feeds back to the pineal. As described by the “Neuroendocrine Loop” and “Internal Resonance” models, overall pacemaker output thus depends on the relative strengths of the oscillations in the pineal and the SCN. Investigations on migratory birds have shown that the amplitude of the 24-h plasma melatonin rhythm is reduced during the migratory seasons compared with the nonmigratory seasons. According to the models mentioned above, such a reduced melatonin amplitude should result in a reduction in the degree of self-sustainment of the pacemaker as a whole. This, in turn, should facilitate adjustment to the altered Zeitgeber conditions encountered by these birds as a result of their own migratory flights. A seasonal reduction in melatonin amplitude also occurs in some high-latitude birds during midsummer and midwinter. Under such conditions a less self-sustained circadian pacemaker may enhance entrainability to weak zeitgeber conditions. These examples suggest that the properties of the circadian system may be adjusted to match the changing requirements for synchronization, and that this is achieved by altering the melatonin amplitude.     

Thyroid hormone activation of retinoic acid synthesis in hypothalamic tanycytes

Thyroid hormone (TH) is essential for adult brain function and its actions include several key roles in the hypothalamus. Although TH controls gene expression via specific TH receptors of the nuclear receptor class, surprisingly few genes have been demonstrated to be directly regulated by TH in the hypothalamus, or the adult brain as a whole. This study explored the rapid induction by TH of retinaldehyde dehydrogenase 1 (Raldh1), encoding a retinoic acid (RA)‐synthesizing enzyme, as a gene specifically expressed in hypothalamic tanycytes, cells that mediate a number of actions of TH in the hypothalamus. The resulting increase in RA may then regulate gene expression via the RA receptors, also of the nuclear receptor class. In vivo exposure of the rat to TH led to a significant and rapid increase in hypothalamic Raldh1 within 4 hours. That this may lead to an in vivo increase in RA is suggested by the later induction by TH of the RA‐responsive gene Cyp26b1. To explore the actions of RA in the hypothalamus as a potential mediator of TH control of gene regulation, an ex vivo hypothalamic rat slice culture method was developed in which the Raldh1‐expressing tanycytes were maintained. These slice cultures confirmed that TH did not act on genes regulating energy balance but could induce Raldh1. RA has the potential to upregulate expression of genes involved in growth and appetite, Ghrh and Agrp. This regulation is acutely sensitive to epigenetic changes, as has been shown for TH action in vivo. These results indicate that sequential triggering of two nuclear receptor signalling systems has the capability to mediate some of the functions of TH in the hypothalamus. GLIA 2016;64:425–439     

Somatostatin release as measured by in vivo microdialysis: circadian variation and effect of prolonged food deprivation

In vivo microdialysis was used to determine SRIF release from the hypothalamus in unanesthetized male rats over a period of 24 h and in rats deprived of food for 72 h, in relation to changes in plasma GH levels. Before the experiment, a microdialysis probe was inserted into the anterior pituitary gland of the rats with an indwelling right atrial cannula. Dialysates and blood samples were collected serially, after normal feeding or 72-h deprivation of food. Normal rats implanted with the microdialysis probe showed an episodical pattern of GH secretion at intervals of 3 h. SRIF was secreted in a pulsatile fashion in the dark period in a similar manner to the light period. Mean SRIF pulse amplitude and mean SRIF level were significantly increased in the dark period. There was no significant correlation between the SRIF and GH pulses in the light period. SRIF levels in dialysates obtained from fed rats and food-deprived rats showed a pulsatile pattern. Food deprivation resulted in significant increases in mean SRIF level and mean SRIF pulse amplitude. These results suggest that the existence of circadian rhythm in SRIF release and the increase in SRIF release play an important role in suppressing GH secretion during prolonged food deprivation.     

Circadian photic regulation of melatonin receptor density in rat suprachiasmatic nuclei: Comparison with light induction of fos-related protein

High-affinity melatonin receptors are present in rat suprachiasmatic nuclei (SCN), and their density exhibits a daily rhythm regulated by the light/dark cycle. In this study we demonstrate that the light regulation of these receptors depends on a circadian mechanism. Pinealectomized rats kept in constant darkness were subjected to 1-hr light pulses delivered across the circadian cycle. The density of melatonin receptors was significantly increased when photic exposure was performed during subjective night, and not different from control animals kept in darkness when the light pulse was applied during subjective day. The protein product (Fos) of the immediate early gene c-fos studied in the same paradigm showed globally the same circadian sensitivity phase. These results clearly show that, although the rhythmic appearance of melatonin receptor density in SCN follows and is directly regulated by the standard light/dark cycle, this light regulation is not passive. As is the case with Fos-like protein, it is only during a precise phase of the circadian cycle that light is able to regulate the density of melatonin receptors in SCN. © 1996 Wiley-Liss,Inc.     

Hormone release in depressed patients before and after recovery.

(1) In 19 deeply depressed patients suffering from primary affective disorders, the thyroid stimulating hormone (TSH) and prolactin (hPRL) responses to thyrotrophin releasing hormone (TRH) were measured. In ten of them, the growth hormone (hGH) and cortisol responses to hypoglycaemia (ITT) were also determined. (2) In the depressed state, TSH secretion was extremely low or non-existent and hPRL was below normal. Half of the tested patients had zero or subnormal hGH secretion in response to hypoglycaemia. (3) After recovery, 16 of these patients were retested by TRH injection. TSH responses showed a fourfold increase and hPRL showed an increase of 45%. In the seven retested by ITT, the mean hGH response was not different, but the three previous non responders, herein included, were normalized. In all seven, the fall in glycaemia was more marked and the cortisol discharge was more sustained. (4) These findings draw attention to (a) the high frequency of alterations in the functional endocrine tests in depressed patients, (b) the discrepancy between these observations and the absence of any overt clinical signs of endocrine disease in these subjects, (c) the interest in using the patient as his own control, (d) the reversible nature of these alterations after recovery.     

Changes in circadian rhythm for mRNA expression of melatonin 1A and 1B receptors in the hypothalamus under a neuropathic pain‐like state

Several clinical reports on neuropathic pain of various etiologies have shown that it significantly interferes with sleep. Inadequate sleep due to neuropathic pain may contribute to the stressful negative consequences of living with pain. It is generally recognized that melatonin (MT) system in the hypothalmus is crusial for circadian rhythm and sleep‐wake transition. However, little, if any, is known about whether neuropathic pain could affect the MT system associated with sleep disturbance. In this study, we investigated the possible changes in circadian rhythm for the expression of MT receptors, especially MT1A and MT1B receptors, in the hypothalamus of mice with sciatic nerve ligation. The samples for real‐time RT‐PCR assay were prepared at 8:00, 14:00, 20:00, and 2:00 on day 7 after sciatic nerve ligation or sham operation. The mRNA expression of MT1A and MT1B receptors at 2:00 in sciatic nerve‐ligated mice, which exhibited thermal hyperalgesia along with an increase in wakefulness and a decrease in nonrapid eye movement sleep, was significantly greater than those in sham‐operated mice, whereas the levels of both MT1A and MT1B receptors at 8:00 in sciatic nerve‐ligated mice were significantly lower than those in sham‐operated mice. These findings suggest that neuropathic pain‐like stimuli lead to sleep disturbance in parallel with changes in circadian rhythm for mRNA expression of MT 1A and 1B receptors in the hypothalamus of mice. Synapse 68:153–158, 2014. © 2014 Wiley Periodicals, Inc.     

Free-running of plasma melatonin rhythm prior to full manifestation of a non-24 hour sleep-wake syndrome

Abstract A long-term observation of a sighted man who developed a non-24 h sleep-wake syndrome is reported. A partial entrainment was observed first, whereby the sleep-wake rhythm was entrained by the day-night alternation whereas the circadian rhythm in plasma melatonin was free-running. Two years later, the sleep-wake rhythm of this subject started to free-run together with the melatonin rhythm. Oral administration of melatonin for 2 weeks improved the entrainability of both rhythms but failed to entrain the rhythms completely. It is concluded that the free-running of the circadian pacemaker preceded a full manifestation of a non-24 h sleep-wake syndrome in this particular subject.     

Neuronal projections from the mesencephalic raphe nuclear complex to the suprachiasmatic nucleus and the deep pineal gland of the golden hamster (Mesocricetus auratus)

Neuronal projections from the mesencephalic raphe system to the suprachiasmatic nucleus and the pineal complex were mapped in this study of the golden hamster, by use of the anterograde tracer Phaseolus vulgaris-leucoagglutinin and the retrograde tracer cholera toxin subunit B. From the median raphe nucleus, a rostral projection ascended in the ventral part of the mesencephalon to continue in the medial forebrain bundle of the forebrain. Nerve fibres from this bundle innervated the ventral and medial parts of the suprachiasmatic nucleus. At the level of the interpeduncular nucleus of the mesencephalon, fibres of the ventral bundle bent dorsally to reach the epithalamic area and to continue in the forebrain in a periventricular position. Some of these fibres innervated the dorsal tip of the suprachiasmatic nucleus. The dorsal raphe nucleus was the origin of a nerve fibre bundle, located in the periaqueductal gray of the mesencephalon, innervating the deep pineal gland and pineal stalk. Injection of cholera toxin B into the suprachiasmatic nucleus labelled cells in the median raphe. Combination of the retrograde tracing from the suprachiasmatic nucleus and serotonin transmitter immunohistochemistry showed that some of the cholera toxin B–immunoreactive nerve cells also contained serotonin. Thus, this study of the golden hamster shows a serotonergic projection from the median raphe nucleus to the suprachiasmatic nucleus and a projection from the dorsal raphe nucleus to the deep pineal gland supporting physiological indications of an influence of serotonin on the photoreceptive circadian system of the brain. J. Comp. Neurol. 399:73–93, 1998. © 1998 Wiley-Liss, Inc.     

Correlation between the circadian sleep propensity rhythm and hormonal rhythms under ultra-short sleep–wake cycle

The aim of this study was to clarify effects of hormonal and temperature rhythms on circadian fluctuations of sleep propensity. Ten healthy females underwent 24-h sleep deprivation and entered the circadian sleep propensity assessment setting under the ultra-short sleep-wake schedule. During the experiment, sleep propensity rhythm, rectal temperature, and 24-h serum hormone profiles (melatonin, cortisol and thyroid-stimulating hormone) were investigated. The circadian sleep propensity rhythms had two apparent peaks (afternoon and nocturnal peaks) and a trough (nocturnal sleep gate). The timings of the nocturnal sleep gate and the nocturnal peak were correlated exclusively with temperature and melatonin rhythms (P < 0.05), while that of the afternoon peak was significantly correlated with habitual wake time and melatonin rhythm. These results indicate that the circadian sleep propensity rhythm is influenced not only by the circadian pacemaker, but also by sleep habit.     

Effects of antidepressants on thyroid stimulating hormone release in rats under ether stress

Abstract We found inhibitory effects of antidepressants (clomipramine, maprotyline, mianserin and zimelidine) and 5-hydroxytryptophan (5-HTP) on thyroid stimulating hormone (TSH) release induced by ether stress in freely moving rats. We confirmed that ether stress suppressed the plasma TSH levels after 30 min. We then injected intravenously 250 ng thyrotropin releasing hormone (TRH), 0.1 mg/kg clomipramine, 2.5 mg/kg maprotyline, 2.5 mg/kg mianserin, 0.5 mg/kg zimelidine and 25 mg/kg 5-HTP simultaneously. These materials blocked the influences on plasma TSH levels by the ether stress. Serotonergic antidepressants (clomipramine, zimelidine) and 5-HTP (precursor of serotonin) had a higher potency against the ether stress. These results suggest that antagonizing effects against the ether stress may involve the serotonergic system in the pituitary gland.