Strain differences in the pattern and intensity of wheel running activity in laboratory rats

Wheel running activity rhythms of three inbred rat strains, ACI/Ztm, BH/Ztm, and LEW/Ztm, were compared in order to evaluate the effect of genetic differences on circadian rhythm parameters. Significant strain differences were found in the general pattern of the activity rhythms and their characteristic periodicities as well as in the amount and duration of wheel running activity and the timing of activity onsets and offsets. The results suggest that genetic differences exist in the coupling of the multiple circadian oscillators that generate the overall pattern of wheel running activity.     

Single-cell recordings from chick pineal glands in vitro reveal ultradian and circadian oscillations

Evidence is clear that each melatonin-producing cell in the chick pineal gland contains a circadian oscillator that continues to function in vitro, resulting in a prominent day/night rhythm of melatonin secretion. The aim of the present investigation was to examine whether the circadian organization of the gland has an electrophysiological correlate. To this end, single-cell recordings were made from isolated chick pineal glands kept in vitro under a light/dark cycle of 12:12 h, identical to that of the donors, or under continuous light or darkness. In all the glands investigated, a very small percentage of cells exhibited sodium-dependent spontaneous spike activity with a mean frequency below 10 Hz. The cells revealed rhythms with periods in the 15- to 60-min range and, additionally, exhibited ultradian and circadian rhythms in firing, with periods of 10.75+/-1.06 h and 26.25+/-1.26 h (mean +/- standard deviation), respectively. Most of the cells exhibited circadian rhythms with higher activity during daytime than at night, showing that the electrical activity and melatonin rhythm were out of phase. Under constant light or darkness, the circadian rhythm persisted. When the light/dark cycle of the donors was phase-advanced by 5 h, the cells revealed complete entrainment. We discuss whether the cells, albeit small in number, could function as a secondary ultradian/circadian oscillator contributing to the ultradian/circadian organization of the gland.     

Chronobiology of sleep in humans

Periodic circadian (24-h) cycles play an important role in daily hormonal and behavioural rhythms. Usually our sleep/wake cycle, temperature and melatonin rhythms are internally synchronized with a stable phase relationship. When there is a desynchrony between the sleep/wake cycle and circadian rhythm, sleep disorders such as advanced and delayed sleep phase syndrome can arise as well as transient chronobiologic disturbances, for example from jet lag and shift work. Appropriately timed bright light is effective in re-timing the circadian rhythm and sleep pattern to a more desired time, ameliorating these disturbances. Other less potent retiming effects may also be obtained from the judicious use of melatonin and exercise.     

Entrainment of human circadian rhythms by artificial bright light cycles

Summary Artificial bright light cycles (LD 816) of about 5000 lux during the light period were applied to two subjects in a temporal isolation unit, who had shown free-running circadian rhythms in sleep-wakefulness and rectal temperature. The circadian rhythms were successfully entrained by the artificial light cycle, but the phase relation of the rhythms to the light cycle was substantially different between the two subjects. The result indicated that the artificial bright lights are able to reset human circadian rhythms.     

Sex differences in human circadian rhythms: Intrinsic periods and sleep fractions

Summary The period of freerunning circadian rhythms is significantly shorter and the fraction of sleep is significantly larger in human females than in males, as long as the rhythms run internally synchronized. The sex difference in the period could be a property either of the whole circadian system or of only one of the oscillators in a multi-oscillator system. The sex difference in the sleep fraction could be a fixed property of the sleep-wake rhythm or could depend on interactions in the multi-oscillator system. To investigate these questions, a sample of 33 long-term experiments, in which the rhythms ran internally synchronized in one section and internally desynchronized in another section, were analyzed. The periods of rhythms in rectal temperature were different in females and males during internal synchronization, but became identical during internal desynchronization. In contrast, sex differences in sleep-wake periods were more pronounced when the rhythms were desynchronized than when they were internally synchronized. This result provides evidence that the sex difference in periodicity is a property only of the sleep-wake rhythm; the intrinsic periods of temperature rhythms are identical in females and males, whereas those of sleep-wake rhythms are distinctly shorter in females than in males. In the state of internal synchronization, the joint period is a compromise between the intrinsic periods of the rhythms involved, and therefore it shows a small but significant sex difference. Moreover, the transition from internally synchronized to desynchronized rhythms is combined with a highly significant reduction in the sleep fraction, which is considerably greater in females than in males. These results suggest that the occurrence of internal desynchronization strongly affects the sleep-wake rhythm, and that the influence of rhythm disorders is considerably greater in females than in males.     

Pentobarbital-induced phase shifts of circadian rhythms of locomotor activity are not mediated through stimulated activity in mice

The possibility that phase shifts of circadian rhythms of locomotor activity induced by pentobarbital injections are mediated through hyperactivity after recovery from the sedative condition was tested in DBA/2 mice. The mice were restrained for 3 h in a tube immediately after injections of pentobarbital at either CT 9 or CT 0. The results indicated that immobilization did not block the phase shifts, suggesting that pentobarbital-induced phase shifts are not due to increasing the level of activity.     

Entrainment of human circadian rhythms by artificial bright light cycles

Artificial bright light cycles (LD 8:16) of about 5000 lux during the light period were applied to two subjects in a temporal isolation unit, who had shown free-running circadian rhythms in sleep-wakefulness and rectal temperature. The circadian rhythms were successfully entrained by the artificial light cycle, but the phase relation of the rhythms to the light cycle was substantially different between the two subjects. The result indicated that the artificial bright lights are able to reset human circadian rhythms.     

Pentobarbital-induced phase shifts of circadian rhythms of locomotor activity are not mediated through stimulated activity in mice

Summary The possibility that phase shifts of circadian rhythms of locomotor activity induced by pentobarbital injections are mediated through hyperactivity after recovery from the sedative condition was tested in DBA/2 mice. The mice were restrained for 3 h in a tube immediately after injections of pentobarbital at either CT 9 or CT 0. The results indicated that immobilization did not block the phase shifts, suggesting that pentobarbital-induced phase shifts are not due to increasing the level of activity.     

Aging alters resynchronization of the circadian system in rats after a shift of the light-dark cycle

Four days following an 8-h advance of the light-dark cycle, the circadian rhythms in the pineal N-acetyltransferase activity and melatonin content reappeared in 7-week-old rats, but were still abolished in 24-month-old animals.     

Aging alters resynchronization of the circadian system in rats after a shift of the light-dark cycle

Summary Four days following an 8-h advance of the light-dark cycle, the circadian rhythms in the pineal N-acetyltransferase activity and melatonin content reappeared in 7-week-old rats, but were still abolished in 24-month-old animals.     

The design of intracellular oscillators that interact with metabolism

Biological oscillations such as circadian rhythms are ubiquitous in nature and have attracted significant attention because of their intriguing dynamics and important biological roles. Understanding of such sophisticated and robust oscillators requires more than the traditional reductionist approach. Recently, a synthetic approach similar to the design of engineering machinery has provided a valuable alternative for testing hypothetical operating principles. These man-made genetic circuits and gene-metabolic circuits are designed based on physical concepts, guided by mathematical models, and constrained by biological and chemical reality. While still primitive compared with the natural circuits, the designed gene-metabolic oscillator has begun to show hallmarks of circadian rhythms such as temperature compensation and close interaction with metabolism. Received 29 December 2005; received after revision 12 February 2006; accepted 16 March 2006     

Antidepressant drugs can slow or dissociate circadian rhythms

Summary The circadian rest-activity cycle of female hamsters was lengthened by chronic administration of the monoamineoxidase inhibitor antidepressant drug clorgyline. Chronic treatment with clorgyline or the tricyclic antidepressant drug imipramine also induced dissociation of circadian activity rhythm components. Thus these drugs may be added to the very small group of substances (including the prophylactic antidepressant and antimanic drug lithium) that modify circadian frequency and/or coupling between circadian rhythms.A preliminary analysis of these results was presented at the 18th Annual Meeting of the American College of Neuropsychopharmacology, Puerto Rico 1979²⁸.Neuropharmacology Branch, National Institute of Mental Health.     

Structures and molecules involved in generation and regulation of biological rhythms in vertebrates and invertebrates

Melatonin from the retina and the pineal gland functions in neuroendocrine hierarchies. Photoreceptors — eyes and extraretinal — detect light. Oscillators — pineal and suprachiasmatic nuclei — act as pacemakers. Driven neuroendocrine rhythms carry temporal hormone signals throughout the body. Light controls melatonin: light sets the phase of the melatonin rhythm and determines the duration of melatonin synthesis. By these means, circadian rhythms (e.g. in locomotor activity and body temperature) and seasonal rhythms (e.g. in reproduction) are controlled.     

Interdependence between locomotor activity and duration of wakefulness in humans during isolation

Locomotor activity was recorded in 14 subjects who lived singly in an isolation unit for 16 to 88 days. Their free-running circadian rhythms had a mean period of 25.9 h, with individual means in the duration of wakefulness (alpha) ranging from 12.1 to 22.9 h. Intraindividually, the hourly means of activity were negatively correlated with alpha to such a degree that the total amount of activity per 'day' remained constant irrespective of large variations in alpha.     

Melatonin and circadian control in mammals

Summary Although pinealectomy has little influence on the circadian locomotor rhythms of laboratory rats, administration of the pineal hormone melatonin has profound effects. Evidence for this comes from studies in which pharmacological doses of melatonin are administered under conditions of external desynchronization, internal desynchronization, steady state light-dark conditions, and phase shifts of the zeitgeber. Taken together with recent findings on melatonin receptor concentration in the rat hypothalamus, particularly at the level of the suprachiasmatic nuclei, these results suggest that melatonin is a potent synchronizer of rat circadian rhythms and has a direct action on the circadian pacemaker. It is possible, therefore, that the natural role of endogenous melatonin is to act as an internal zeitgeber for the total circadian structure of mammals at the level of cell, tissue, organ, whole organism and interaction of that organism with environmental photoperiod changes.     

Melatonin and circadian control in mammals

Although pinealectomy has little influence on the circadian locomotor rhythms of laboratory rats, administration of the pineal hormone melatonin has profound effects. Evidence for this comes from studies in which pharmacological doses of melatonin are administered under conditions of external desynchronization, internal desynchronization, steady state light-dark conditions, and phase shifts of the zeitgeber. Taken together with recent findings on melatonin receptor concentration in the rat hypothalamus, particularly at the level of the suprachiasmatic nuclei, these results suggest that melatonin is a potent synchronizer of rat circadian rhythms and has a direct action on the circadian pacemaker. It is possible, therefore, that the natural role of endogenous melatonin is to act as an internal zeitgeber for the total circadian structure of mammals at the level of cell, tissue, organ, whole organism and interaction of that organism with environmental photoperiod changes.     

Phase-dependent shift of free-running human circadian rhythms in response to a single bright light pulse

Responsiveness of free-running human circadian rhythms to a single pulse of bright light was examined in a temporal isolation unit. Bright light (5000 lx) of either 3 or 6 h duration, applied during the early subjective day, produced phase-advance shifts in both the sleep-wake cycle and the rhythm of rectal temperature; the light pulse had essentially no effect on the phase of the circadian rhythms, when it was introduced during the late subjective day or the early subjective night. The results indicate that bright light can reset the human circadian pacemaker.     

Circadian variation in urinary melatonin in clinically healthy women in Japan and the United States of America.

Urinary melatonin excretion is lower in East-Asian (Japanese) than in North-American (whites of mixed ethnic origin) women. Moreover, a statistically significant circadian rhythm is demonstrated by population-mean cosinor in the data pool from both groups of women. Furthermore, statistical significance characterizes interactions of effects from geographic differences (between ethnic groups) with temporal factors. Such spatio-temporal interactions await further scrutiny with a view inter alia of carcinogenesis as it is influenced by a spectrum of intermodulating rhythms.     

Persistent 24-h variations of urinary 6-hydroxy melatonin sulphate and cortisol in Antarctica

Bright light (2000-3000 lux) of sufficient intensity to suppress human melatonin secretion, acts as a strong zeitgeber in the entrainment of circadian rhythms in man. In polar conditions, light of this intensity is not experienced for several weeks during the winter. The entrainment of human circadian rhythms, in particular that of melatonin, is clearly of interest in these circumstances. Urinary 6-hydroxy melatonin sulphate (aMT6s) is a good index of melatonin secretion in man. In a limited study of seven male volunteers living on an Antarctic base the overall 24-h rhythm of aMT6s excretion was maintained at four different times of year (spring, summer, autumn and winter) and no significant seasonal effects were noted. Cortisol excretion, appeared to be markedly affected by the season although other factors such as social and environmental stress cannot be discounted. These observations suggest that in the absence of a strong light-dark cycle melatonin production may be entrained by other factors.     

Zeitgeber-schedule dependent resynchronization of circadian rhythms in nocturnal mammals (Primates and Chiroptera)

Summary Changing the L: D time ratio of an entraining light-dark regime leads to characteristic alterations of the resynchronization behaviour of the circadian activity rhythms in night monkeys (Aotus trivirgatus) and African fruit bats (Rousettus aegyptiacus) after 8 h advance and delay shifts of the LD-Zeitgeber. Reduced speed of re-entrainment and occurrence of antidromic resynchronization point to a lower Zeitgeber strength of 24-h LD-cycles with a prolonged D-phase.Supported by the Deutsche Forschungsgemeinschaft (Er 59/8).