Synchronization of the circannual reproductive rhythm of the ewe by discrete photoperiodic signals

Although many species display endogenous circannual rhythms of biological activity that are synchronized by day length, the specific photoperiodic requirements for synchronizing such rhythms are not established for any species. We tested the hypothesis that the circannual reproductive rhythm of sheep can be synchronized by exposure to just one or two discrete blocks of photoperiodic information each year. Ewes were pinealectomized to prevent their ability to transduce photoperiodic information into altered reproductive neuroendocrine activity. During the 53/4 yr following pinealectomy, specific photoperiodic signals were restored for discrete periods of time via replacement of 24-h patterns of melatonin, the pineal hormone that transmits photic information to the reproductive neuroendocrine axis. The ewes were kept in a 12-mo photoycycle that alternated between short (8L:16D) and long (16L:8D) days every 6 mo and that was 6 mo out of phase with the geophysical year. Pineal-intact control ewes exhibited synchronous annual reproductive cycles. Noninfused pinealectomized control ewes did not exhibit synchronous cycles. Pinealectomized ewes infused with alternating 70-day blocks of short- and long-day patterns of melatonin every 6 mo for the first 21/2 yr of the experiment exhibited synchronous annual reproductive cycles that were 6 mo out of phase with those of ewes maintained outdoors. This synchrony persisted when the frequency of the melatonin treatment was reduced to just one 70-day block of a long-day pattern of melatonin each 365 days. Cycle period was 368 +/- 3 days; standard deviation of the date of onset of reproductive induction averaged only 3 days. Our study provides the first direct evidence that a single block of photoperiodic information a year can synchronize a circannual rhythm.     

Temperature-independence of circannual variations in circadian rhythms of golden-mantled ground squirrels

In golden-mantled ground squirrels, phase angles of entrainment of circadian locomotor activity to a fixed light-dark cycle differ markedly between subjective summer and winter. A change in ambient temperature affects entrainment only during subjective winter when it also produces pronounced effects on body temperature (Tb). It was previously proposed that variations in Tb are causally related to the circannual rhythm in circadian entrainment. To test this hypothesis, wheel-running activity and Tb were monitored for 12 to 14 months in castrated male ground squirrels housed in a 14:10 LD photocycle at 21 degrees C. Animals were treated with testosterone implants that eliminated hibernation and prevented the marked winter decline in Tb; these squirrels manifested circannual changes in circadian entrainment indistinguishable from those of untreated animals. Both groups exhibited pronounced changes in phase angle and alpha of circadian wheel-running and Tb rhythms. Seasonal variation in Tb is not necessary for circannual changes in circadian organization of golden-mantled ground squirrels.     

Pineal-independent regulation of photo-nonresponsiveness in the Siberian hamster (Phodopus sungorus)

The pineal hormone melatonin influences circadian rhythms and also mediates reproductive responses to photoperiod. The authors tested whether pinealectomy influences circadian oscillators responsible for induction of nonresponsiveness to short day lengths by preventing normal short-day patterns of circadian entrainment. Adult male Siberian hamsters were pinealectomized or sham operated, maintained in either 18 h light per day (18L) or 15L for 10 weeks, and then tested for responsiveness to 10L. Because pinealectomized hamsters do not show gonadal regression in short day lengths, responsiveness was assessed by measuring phase angle of entrainment and the length of the nightly activity period following transfer to 10L. The incidence of nonresponsiveness was significantly higher in 18L hamsters than in 15L hamsters but was unaffected by pineal status. Fully 88% of 18L hamsters failed to entrain to 10L in the normal short-day manner; the duration of nightly activity remained compressed, and the phase angle of entrainment was large and negative relative to lights off. The 15L hamsters entrained normally to 10L. Exposure to constant light after 10L treatment was equally effective in inducing arrhythmicity in pinealectomized and intact hamsters. Changes in the period of morning and evening circadian oscillators subsequent to 18L treatment did not predict circadian responsiveness to short photoperiod. Long-day induction of photo-nonresponsiveness, which prevents winter responses to short day lengths, occurs independently of pineal melatonin feedback on the circadian system.     

Seasonal changes in entrainment cues for the circadian rhythm of the supratidal amphipod Talorchestia longicornis

The supratidal amphipod Talorchestia longicornis Say has a circadian rhythm in activity, in which it is active on the substrate surface at night and inactive in burrows during the day. The present study determined: (1) the circadian rhythms in individual versus groups of amphipods; (2) the range of temperature cycles that entrain the circadian rhythm; (3) entrainment by high-temperature cycles versus light?:?dark cycles, and (4) seasonal substrate temperature cycles. The circadian rhythm was determined by monitoring temporal changes in surface activity using a video system. Individual and groups of amphipods have similar circadian rhythms. Entrainment occurred only to temperature cycles that included temperatures below 20°C (10–20, 15–20, 17–19, 15–25°C) but not to temperatures above 20°C (20–25, 20–30°C), and required only a 2°C temperature cycle (17–19°C). Diel substrate temperatures were above 20°C in the summer and below 20°C during the winter. Upon simultaneous exposure to a diel high-temperature cycle (20–30°C) and a light?:?dark cycle phased differently, amphipods entrained to the light?:?dark cycle. Past studies found that a temperature cycle below 20°C overrode the light?:?dark cycle for entrainment. The functional significance of this change in entrainment cues may be that while buried during the winter, the activity rhythm remains in phase with the day?:?night cycle by the substrate temperature cycles. During the summer, T. longicornis switches to the light?:?dark cycle for entrainment, perhaps as a mechanism to phase activity precisely to the short summer nights.     

Photic entrainment of circannual rhythms in golden-mantled ground squirrels: role of the pineal gland

Entrainment of circannual rhythms of body mass and reproduction was monitored for 3 years in female golden-mantled ground squirrels maintained in a simulated natural photoperiod. Both pinealectomized and pineal-intact squirrels generated circannual rhythms of body mass and estrus, but only the intact animals entrained these rhythms to a period of 365 days. In the second and third years after treatment, the period of the body mass rhythm was significantly shorter than 365 days for pinealectomized squirrels, and variance in tau among these animals was significantly greater than for intact squirrels. A similar pattern was evident in the rhythm of reproduction, which was phase-disrupted in pinealectomized squirrels but entrained in intacts. Seasonal changes in duration of nocturnal melatonin secretion by the pineal appear to be necessary to produce phase-delays required to entrain the circannual clock to a period of 12 months.     

Does seasonal reproductive state affect the neuroendocrine response of the ewe to a long-day pattern of melatonin?

This study examined whether or not the reproductive response of female sheep to photoperiod varies with seasonal reproductive state. The specific objective was to test the hypothesis that the reproductive response to a long-day pattern of melatonin varies with the reproductive state of the ewe. The response examined was the synchronization of reproductive neuroendocrine induction (rise in serum luteinizing hormone, or LH) following nocturnal infusion of melatonin into pinealectomized ewes for 35 consecutive nights. This infusion restored a pattern of circulating melatonin similar to that in pineal-intact ewes maintained in a long photoperiod (LD 16:8). The ewes had been pinealectomized and without melatonin replacement for 16-25 months prior to the study. They were in differing reproductive states at the start of the infusion, as their endogenous reproductive rhythm had become desynchronized among individuals and with respect to time of year. Noninfused pinealectomized ewes served as controls. Regardless of the reproductive state at the start of the 35-day infusion of the long-day pattern of melatonin, all treated ewes exhibited the same reproductive neuroendocrine response after the infusion was ended. This consisted of a synchronized rise in LH some 6-8 weeks after the infusion was terminated, the maintenance of a high level of serum LH for some 15 weeks, and a subsequent precipitous fall in LH to a very low level. These results provide evidence that a long-day pattern of melatonin can synchronize reproductive neuroendocrine induction in the ewe, regardless of reproductive condition, and thus do not support the hypothesis that this response differs with seasonal reproductive state.     

Entrainment of the circadian locomotor activity rhythm in the Japanese newt by melatonin injections

We examined whether melatonin can act as a synchronizing agent within the circadian system of amphibians by testing the ability of melatonin injections to entrain the circadian locomotor activity rhythm of a newt (Cynops pyrrhogaster). Under constant darkness, all newts (13 cases) showing the free-running rhythms were subcutaneously injected with 10 g melatonin at the same time every other day for at least 30 days. Subsequently, they were injected with vehicle (1% ethanolic saline) instead of melatonin for at least another 30 days. In 10 of the 13 newts, the locomotor activity rhythms could be entrained to a period of 24 h by melatonin injections but not by vehicle injections. During the entrained steady-state, the active phase of an activity-rest cycle preceded the time of melatonin injections as previously reported in other diurnal species. These results suggest that the endogenous circadian rhythm of melatonin concentration may be involved in synchronizing circadian oscillator(s) within the newt's circadian system.     

A phase response curve for circannual rhythm in the varied carpet beetle <Emphasis Type="Italic">Anthrenus verbasci</Emphasis>

We know that entrainment, a stable phase relationship with an environmental cycle, must be established for a biological clock to function properly. Phase response curves (PRCs), which are plots of phase shifts that result as a function of the phase of a stimulus, have been created to examine the mode of entrainment. In circadian rhythms, single-light pulse PRCs have been obtained by giving a light pulse to various phases of a free-running rhythm under continuous darkness. This successfully explains the entrainment to light-dark cycles. Some organisms show circannual rhythms. In some of these, changes in photoperiod entrain the circannual rhythms. However, no single-pulse PRCs have been created. Here we show the PRC to a long-day pulse superimposed for 4 weeks over constant short days in the circannual pupation rhythm in the varied carpet beetle Anthrenus verbasci. Because the shape of that PRC closely resembles that of the Type 0 PRC with large phase shifts in circadian rhythms, we suggest that an oscillator having a common feature in the phase response with the circadian clock, produces a circannual rhythm.     

A phase dynamics model of human circadian rhythms

Nonphotic entrainment of an overt sleep-wake rhythm and a circadian pacemaker-driving temperature/melatonin rhythm suggests existence of feedback mechanisms in the human circadian system. In this study, the authors constructed a phase dynamics model that consisted of two oscillators driving temperature/melatonin and sleep-wake rhythms, and an additional oscillator generating an overt sleep-wake rhythm. The feedback mechanism was implemented by modifying couplings between the constituent oscillators according to the history of correlations between them. The model successfully simulated the behavior of human circadian rhythms in response to forced rest-activity schedules under free-run situations: the sleep-wake rhythm is reentrained with the circadian pacemaker after release from the schedule, there is a critical period for the schedule to fully entrain the sleep-wake rhythm, and the forced rest-activity schedule can entrain the circadian pacemaker with the aid of exercise. The behavior of human circadian rhythms was reproduced with variations in only a few model parameters. Because conventional models are unable to reproduce the experimental results concerned here, it was suggested that the feedback mechanisms included in this model underlie nonphotic entrainment of human circadian rhythms.     

Circadian rhythm of locomotor activity in the Japanese honeybee, Apis cerana japonica

Abstract.  To reveal circadian characteristics and entrainment mechanisms in the Japanese honeybee Apis cerana japonica , the locomotor-activity rhythm of foragers is investigated under programmed light and temperature conditions. After entrainment to an LD 12 : 12 h photoperiodic regime, free-running rhythms are released in constant dark (DD) or light (LL) conditions with different free-running periods. Under the LD 12 : 12 h regime, activity offset occurs approximately 0.4 h after lights-off transition, assigned to circadian time (Ct) 12.4 h. The phase of activity onset, peak and offset, and activity duration depends on the photoperiodic regimes. The circadian rhythm can be entrained to a 24-h period by exposure to submultiple cycles of LD 6 : 6 h, as if the locomotive rhythm is entrained to LD 18 : 6 h. Phase shifts of delay and advance are observed when perturbing single light pulses are presented during free-running under DD conditions. Temperature compensation of the free-running period is demonstrated under DD and LL conditions. Steady-state entrainment of the locomotor rhythm is achieved with square-wave temperature cycles of 10 °C amplitude, but a 5 °C amplitude fails to entrain.     

The effects of low-dose 0.5-mg melatonin on the free-running circadian rhythms of blind subjects

Exogenous melatonin (0.5-10 mg) has been shown to entrain the free-running circadian rhythms of some blind subjects. The aim of this study was to assess further the entraining effects of a daily dose of 0.5 mg melatonin on the cortisol rhythm and its acute effects on subjective sleep in blind subjects with free-running 6-sulphatoxymelatonin (aMT6s) rhythms (circadian period [tau] 24.23-24.95 h). Ten subjects (9 males) were studied, aged 32 to 65 years, with no conscious light perception (NPL). In a placebo-controlled, single-blind design, subjects received 0.5 mg melatonin or placebo p.o. daily at 2100 h (treatment duration 26-81 days depending on individuals' circadian period). Subjective sleep was assessed from daily sleep and nap diaries. Urinary cortisol and aMT6s were assessed for 24 to 48 h weekly and measured by radioimmunoassay. Seven subjects exhibited an entrained or shortened cortisol period during melatonin treatment. Of these, 4 subjects entrained with a period indistinguishable from 24 h, 2 subjects continued to free run for up to 25 days during melatonin treatment before their cortisol rhythm became entrained, and 1 subject appeared to exhibit a shortened cortisol period throughout melatonin treatment. The subjects who entrained within 7 days did so when melatonin treatment commenced in the phase advance portion of the melatonin PRC (CT6-18). When melatonin treatment ceased, cortisol and aMT6s rhythms free ran at a similar period to before treatment. Three subjects failed to entrain with initial melatonin treatment commencing in the phase delay portion of the PRC. During melatonin treatment, there was a significant increase in nighttime sleep duration and a reduction in the number and duration of daytime naps. The positive effect of melatonin on sleep may be partly due to its acute soporific properties. The findings demonstrate that a daily dose of 0.5 mg melatonin is effective at entraining the free-running circadian systems in most of the blind subjects studied, and that circadian time (CT) of administration of melatonin may be important in determining whether a subject entrains to melatonin treatment. Optimal treatment with melatonin for this non-24-h sleep disorder should correct the underlying circadian disorder (to entrain the sleep-wake cycle) in addition to improving sleep acutely.     

Temperature entrainment of the circadian cuticle deposition rhythm in Drosophila melanogaster

The cuticle deposition rhythm, which is observed in the apodeme of the furca in the thorax, is controlled by a peripheral circadian clock in the epidermal cells and entrained to light-dark (LD) cycles via CRYPTOCHROME (CRY) in Drosophila melanogaster. In the present study, we examined the effects of temperature (TC) cycles and the combination of LD and TC cycles on entrainment of the cuticle deposition rhythm. The rhythm was entrained to TC cycles, whose period was 28 h. In T = 21 and 24 h, the rhythm was entrained to TC cycles in some individuals. CRY is not necessary for temperature entrainment of the cuticle deposition rhythm because the rhythm in cry(b) (lacking functional CRY) was entrained to TC cycles. Temperature entrainment of the rhythm was achieved even when the thoraxes or furcae were cultured in vitro, suggesting that the mechanism for temperature entrainment is independent of the central clock in the brain and the site of the thermoreception resides in the epidermal cells. When LD and TC cycles with different periods were applied, the rhythm was entrained to LD cycles with a slight influence of TC cycles. Thus, the LD cycle is a stronger zeitgeber than the TC cycle. The variance of the number of the cuticle layers decreased in the flies kept under LD and TC cycles with the same period in which the thermophase coincided with the photophase. Therefore, we conclude that LD and TC cycles synergistically entrain the rhythm. Synergistic effects of LD and TC cycles on entrainment were also observed even when the thoraxes were cultured in vitro, suggesting that the light and temperature information is integrated within the peripheral circadian system.     

Circannual rhythms of ground squirrels: a test of the frequency demultiplication hypothesis

The frequency demultiplication hypothesis (FDH) posits that circannual rhythms are generated from circadian cycles by frequency transformation to the lower-frequency rhythm. To test the FDH, we determined the periods of the circannual body mass and estrous cycles of golden-mantled ground squirrels with circadian locomotor activity rhythms entrained to 23-, 24-, or 25-hr days (T-cycles). Circannual period length did not differ among squirrels entrained to the different T-cycles; intergroup ranges were 298-314 days and 303-312 days, respectively, for body mass and estrus. These results are not consistent with the FDH and suggest instead that separate mechanisms generate circadian and circannual rhythms. In ground squirrels the circannual system influences circadian organization, but a reciprocal influence of circadian on circannual rhythms has yet to be demonstrated.     

Clock-controlled endogenous melatonin rhythms in Nile tilapia (Oreochromis niloticus niloticus) and African catfish (Clarias gariepinus)

The purpose of this work was to investigate the circadian melatonin system in two tropical teleost species characterized by different behavioral habits, Nile tilapia (diurnal) and African catfish (nocturnal). To do so, fish were subjected to either a control photoperiod (12L:12D), continuous light (LL) or darkness (DD), or a 6L:6D photoperiod. Under 12L:12D, plasma melatonin levels were typically low during the photophase and high during the scotophase in both species. Interestingly, in both species, melatonin levels significantly decreased prior to the onset of light, which in catfish reached similar basal levels to those during the day, demonstrating that melatonin production can anticipate photic changes probably through circadian clocks. Further evidence for the existence of such pacemaker activity was obtained when fish were exposed to DD, as a strong circadian melatonin rhythm was maintained. Such an endogenous rhythm was sustained for at least 18 days in Nile tilapia. A similar rhythm was shown in catfish, although DD was only tested for four days. Under LL, the results confirmed the inhibitory effect of light on melatonin synthesis already reported in other species. Finally, when acclimatized to a short photo-cycle (6L:6D), no endogenous melatonin rhythm was observed in tilapia under DD, with melatonin levels remaining high. This could suggest that the circadian clocks cannot entrain to such a short photocycle. Additional research is clearly needed to further characterize the circadian axis in teleost species, identify and localize the circadian clocks, and better understand the environmental entrainment of fish physiology.     

Entrainment of the larval release rhythm of the crab Rhithropanopeus harrisii (Brachyura: Xanthidae) by cycles in hydrostatic pressure

This study investigated the entrainment of a larval release rhythm by determining whether a tidal cycle in hydrostatic pressure could entrain the circatidal rhythm in larval release by the crab Rhithropanopeus harrisii (Gould). Ovigerous females were collected from a non-tidal estuary. The time of larval release by individual crabs was monitored under constant conditions with a time-lapse video system. Crabs with mature embryos at the time of collection had a pronounced circadian rhythm in larval release with a free running period of 25.1 h. Crabs with immature embryos that were maintained under constant conditions from the time of collection until larval release retained a weak circadian rhythm. Other crabs with immature embryos were exposed to a tidal cycle in step changes in hydrostatic pressure equivalent to 1 m of water. This cycle entrained a circatidal rhythm in larval release. The free-running period was 12.1 h and larvae were released at the time of the transition from low to high pressure. Although past studies demonstrated that a tidal cycle in hydrostatic pressure could entrain activity rhythms in crustaceans, this is the first study to show that pressure can entrain a larval release rhythm.     

The circadian timing system and reproduction in mammals.

Circadian systems in a wide variety of organisms all appear to include three basic components: 1) biological oscillators that maintain a self-sustained circadian periodicity in the absence of environmental time cues; 2) input pathways that convey environmental information, especially light cues, that can entrain the circadian oscillations to local time; and 3) output pathways that drive overt circadian rhythms, such as the rhythms of locomotor activity and a variety of endocrine rhythms. In mammals, the circadian system is employed in the regulation of reproductive physiology and behavior in two very important ways. 1) In some species, there is a strong circadian component in the timing of ovulation and reproductive behavior, ensuring that these events will occur at a time when the animal is most likely to encounter a potential mate. 2) Many mammals exhibit seasonal reproductive rhythms that are largely under photoperiod regulation; in these species, the circadian system and the pineal gland are crucial components of the mechanism that is used to measure day length. The rhythm of pineal melatonin secretion is driven by a neural pathway that includes the circadian oscillator(s) in the suprachiasmatic nuclei. Melatonin is secreted at night in all mammals, and the duration of each nocturnal episode of melatonin secretion is inversely related to day length. The pineal melatonin rhythm appears to serve as an internal signal that represents day length and that is capable of regulating a variety of seasonal variations in physiology and behavior.     

Biorhythms and pineal gland

Endocrine biorhythms are classified according to the period time, as one of the most characteristic properties of biorhythms. Each endocrine organ has parallel more than one biorhythms with different period time (e. g. circadian and circannual rhythms). The time of acrophase of the biorhythms at the different endocrine organs is fairly variant. This review summarizes the rhythmic function of the THS-thyroid, gonadotrophic-gonadal and ACTH-adrenocortical systems. Pineal gland plays an integrative role in the regulation of rhythmic function of the endocrine system. The melatonin secretion of this gland also reveals conspicuous circadian and circannual rhythms both in mammals and in birds. Mammalian pineal is functional only if its peripheral sympathetic innervation from the superior cervical ganglion is intact. In contrast, melatonin secretion and its circadian rhythm is also maintained in birds under isolated conditions (explanted into an in vitro superfusion system). The 24 hours period time of melatonin circadian rhythm can not be changed by light impulses. The phases of the circadian rhythm, however, can be turned by changing the time of environmental light-dark phases. The wavelength of the artificial light used for reversal of circadian rhythm is an important factor. The development of the entrainment and synchronization of the circadian melatonin rhythm in birds is independent of the rhythmic day-night changes in environmental lighting condition. The differences in the main elements of the biological clock between mammals and birds are discussed.     

Variation in the timing of the reproductive season among breeds of sheep in relation to differences in photoperiodic synchronization of an endogenous rhythm.

Photoperiod may regulate seasonal reproduction either by providing the primary driving force for the reproductive transitions or by synchronizing an endogenous reproductive rhythm. This study evaluated whether breed differences in timing of the reproductive seasons of Finnish Landrace (Finn) and Galway ewes are due to differences in photoperiodic drive of the reproductive transitions or to differences in photoperiodic synchronization of the endogenous rhythm of reproductive activity. The importance of decreasing photoperiod after the summer solstice in determining the onset and duration of the breeding season was tested by housing ewes from the summer solstice in either a simulated natural photoperiod or a fixed summer-solstice photoperiod (18 h light:6 h dark; summer-solstice hold). Onset of the breeding season within each breed did not differ between these photoperiodic treatments, but Galway ewes began and ended their breeding season earlier than Finn ewes. The duration of the breeding season was shorter in Galway ewes on summer-solstice hold than on simulated natural photoperiod; duration did not differ between photoperiodic treatments in Finn ewes. The requirement for increasing photoperiod after the winter solstice for initiation of anoestrus was tested by exposing ewes from the winter solstice to either a simulated natural photoperiod or a winter-solstice hold photoperiod (8.5 h light:15.5 h dark). Onset of anoestrus within each breed did not differ between these photoperiodic treatments, but the time of this transition differed between breeds. These observations suggest that genetic differences in timing of the breeding season in Galway and Finn ewes do not reflect differences in the extent to which photoperiod drives the reproductive transitions, because neither breed requires shortening days to enter the breeding season or lengthening days to end it at appropriate times. These findings are consistent with the hypothesis that photoperiod synchronizes an endogenous rhythm of reproductive activity in both breeds and that genetic differences in timing of the breeding season reflect differences in photoperiodic synchronization of this rhythm.     

S20098 AFFECTS THE FREE-RUNNING RHYTHMS OF BODY TEMPERATURE AND ACTIVITY AND DECREASES LIGHT-INDUCED PHASE DELAYS OF CIRCADIAN RHYTHMS OF THE RAT

Mammalian endogenous circadian rhythms are entrained to the environmental day-night cycle by light exposure. Melatonin is involved in this entrainment by signaling the day-night information to the endogenous circadian pacemaker. Furthermore, melatonin is known to affect the circadian rhythm of body temperature directly. A striking property of the endogenous melatonin signal is its synthesis pattern, characterized by long-term elevated melatonin levels throughout the night. In the present study, the influence of prolonged treatment with the melatonin agonist S20098 during the activity phase of free-running rats was examined. This was achieved by giving S20098 in the food. The free-running body temperature and activity rhythms were studied. The present study shows that enhancement of the melatonin signal, using S20098, affected the free-running rhythm by gradual phase advances of the start of the activity phase, consequently causing an increase in length of the activity phase. A well-known feature of circadian rhythms is its time-dependent sensitivity for light. Light pulse exposure of an animal housed under continuous dark conditions can cause a phase shift of the circadian pacemaker. Therefore, in a second experiment, the influence of melatonin receptor stimulation on the sensitivity of the pacemaker to light was examined by giving the melatonin agonist S20098 in the food during 1 day prior to exposure to a 60-min light pulse of 0, 1.5, 15, or 150 lux given at circadian time (CT) 14. S20098 pretreatment caused a diminished lightpulse- induced phase shift when a light pulse of low light intensity (1.5 lux) was given. S20098 treatment via the food was sufficient to exert chronobiotic activity, and S20098 treatment resulting in prolonged overstimulation of melatonin receptors is able to attenuate the effect of light on the circadian timing system. (Chronobiology International, 18(5), 781-799, 2001)