Adjustment of the human melatonin and cortisol rhythms to shortening of the natural summer photoperiod

Fifteen human subjects were exposed to natural outdoor summer light from 0415 h until 2000 h for 4 days and then from 0800 h until 1600 h for another 4 days. Following shortening of the natural summer photoperiod, times of the morning salivary melatonin decline and cortisol rise did not change whereas the time of the evening melatonin rise phase advanced by about 1.5 h within 1 day and further did not change significantly. Consequently, the melatonin signal duration extended markedly within 1 day. The data show that the compressed melatonin rhythm waveform in humans experiencing a long natural summer photoperiod from sunrise until sunset may change rapidly following a shortening of the photoperiod.     

Daily and seasonal variations in the concentration of melatonin in the human pineal gland

To elucidate whether pineal melatonin secretion is affected by changes in day length, we determined the concentration of melatonin in human pineal glands obtained at autopsy from 66 male subjects, aged 16–84 years over a period of 12 consecutive months. Based on the time of death, a day–night difference in pineal melatonin levels was evident only in the long photoperiod (April–September) with significantly higher melatonin concentrations occurring at night (2200–1000 h). Nighttime values in the long photoperiod were significantly higher than the nighttime values during the short photoperiod (October–March). During the short photoperiod, the data suggested a possible phase-delay in melatonin secretion. Day–night difference was evident in young subjects (30–60 years), but not in elderly subjects (61–84 years). Elderly subjects had lower total melatonin levels (day and night values) although statistically not significant. Therefore, melatonin levels did not decline with age and when the data were analyzed by age there was no significant day–night difference in melatonin levels. These data indicate that the concentration of melatonin in the human pineal is augmented only during the long photoperiod. The results suggest a partial effect of photoperiod on melatonin secretion in humans. This may result from living in an artificial light environment or due to other nonphotic signals involved in generating melatonin rhythm.     

The circadian rhythm of Per1 gene product in the rat suprachiasmatic nucleus and its modulation by seasonal changes in daylength

The suprachiasmatic nucleus (SCN) of rats maintained under a 12-h light, 12-h dark cycle (LD12:12) as well as of those released into darkness exhibited the rhythm of a clock gene Per1 product, PER1 protein, with the maximum late in the subjective day and early night and minimum in the morning. The rhythm was phase delayed by 6-8 h compared with the reported rhythm of Per1 mRNA in the rat SCN [L. Yan et al. Neuroscience 94 (1999) 141]. Under a long, LD16:8, artificial photoperiod, the interval of elevated PER1-immunoreactivity was at least 4 h longer than that under a short, LD 8:16 photoperiod, due mainly to an earlier PER1 day-time rise under the long photoperiod. Under a natural photoperiod, profiles of the PER1 rhythm in summer and in winter resembled those under corresponding artificial photoperiods; therefore, twilight did not affect the rhythm in a substantial way. Under all photoperiods, when PER1 immunoreactivity was elevated, immunopositive cells were localized in the dorsomedial rather than in the ventrolateral part of the SCN. As the Per1 gene is a part of a molecular clockwork and as the rhythm of its product is modulated by the photoperiod, it appears that the whole molecular clockwork in the rat SCN is photoperiod-dependent and thus shaped by the season of the year.     

Phototherapy of seasonal affective disorder. Time of day and suppression of melatonin are not critical for antidepressant effects

Seasonal affective disorder is characterized by recurring cycles of fall-winter depression and spring-summer hypomania (or euthymia). In winter, depressed patients with seasonal affective disorder respond to daily treatments with five to six hours of bright artificial light in two to three days. They relapse two to three days after light is withdrawn. In this study carefully controlled experimental conditions were used to determine whether phototherapy acts via a photoperiodic mechanism in which the timing of light is critical for its therapeutic effect. Photoperiodism is a common regulatory mechanism in animal seasonal rhythms and depends for its effect on light-induced changes in the pattern of nocturnal melatonin secretion. The results reported herein of "skeleton photoperiod" experiments indicate that the efficacy of phototherapy may not depend on its timing or its effect on melatonin secretion.     

Potential animal models of seasonal affective disorder

Seasonal affective disorder (SAD) is characterized by depressive episodes during winter that are alleviated during summer and by morning bright light treatment. Currently, there is no animal model of SAD. However, it may be possible to use rodents that respond to day length (photoperiod) to understand how photoperiod can shape the brain and behavior in humans. As nights lengthen in the autumn, the duration of the nightly elevation of melatonin increase; seasonally breeding animals use this information to orchestrate seasonal changes in physiology and behavior. SAD may originate from the extended duration of nightly melatonin secretion during fall and winter. These similarities between humans and rodents in melatonin secretion allows for comparisons with rodents that express more depressive-like responses when exposed to short day lengths. For instance, Siberian hamsters, fat sand rats, Nile grass rats, and Wistar rats display a depressive-like phenotype when exposed to short days. Current research in depression and animal models of depression suggests that hippocampal plasticity may underlie the symptoms of depression and depressive-like behaviors, respectively. It is also possible that day length induces structural changes in human brains. Many seasonally breeding rodents undergo changes in whole brain and hippocampal volume in short days. Based on strict validity criteria, there is no animal model of SAD, but rodents that respond to reduced day lengths may be useful to approximate the neurobiological phenomena that occur in people with SAD, leading to greater understanding of the etiology of the disorder as well as novel therapeutic interventions.     

Testosterone and photoperiod interact to affect spatial learning and memory in adult male white-footed mice (Peromyscus leucopus)

Gonadal hormones affect spatial learning and memory in mammals and circulating gonadal hormone concentrations fluctuate by season. Most nontropical rodents are spring/summer breeders and males display higher testosterone concentrations during the breeding season compared with the nonbreeding season (fall/winter). Seasonal patterns of testosterone concentration (as well as many other seasonal modifications of physiology, morphology, and behaviour) are induced by manipulation of photoperiod (day length; i.e. short or long days) in the laboratory. Coincident with reducing testosterone concentration, short days also impair spatial learning and memory performance in male white-footed mice (Peromyscus leucopus) compared with long days. We hypothesized that short-day-induced reduction of testosterone concentrations inhibits spatial learning and memory performance compared with long days. Adult male white-footed mice were maintained in long (16 h light/day) or short (8 h light/day) days for 14 weeks following sham-castration, castration plus saline implant, or castration plus testosterone implant treatment. Spatial learning and memory was assessed using a water maze, and photoperiod-evoked changes in gene expression of sex steroid receptors within the hippocampus were also examined. Castrated, short-day mice with testosterone replacement displayed enhanced water maze performance compared with other short-day mice, but no differences among testosterone treatments were observed in long-day mice. Photoperiod did not affect hippocampal androgen, oestrogen alpha, or oestrogen beta receptor gene expression. These results suggest that photoperiod modulates the effects of testosterone on spatial learning performance by mechanisms indirect of the hippocampus.     

Tissue-specific abolition of Per1 expression in the pars tuberalis by pinealectomy in the Syrian hamster

Melatonin secretion by the pineal gland transduces photoperiod into a neuroendocrine signal. In the pars tuberalis (PT), we have shown that photoperiod modifies the amplitude of the clock gene Per1. The aim of this study was to test whether the endogenous melatonin signal is required for rhythmic expression of Per1 in the PT. Male Syrian hamsters housed in long days (LD, 16:8h light:dark) were pinealectomized and Per1 mRNA expression studied by in situ hybridization. Pinealectomy abolished the rhythm of Per1 expression in the PT, but had no effect on Per1 expression in the suprachiasmatic nucleus (SCN), or the ventromedial nucleus (VMH) of the hypothalamus. Interestingly, a single night-time injection of melatonin (25 microg), given to pinealectomized animals, failed to restore Per1 expression in the PT. These data demonstrate that Per1 expression in the PT is driven by melatonin, and that the features of the endogenous signal through which the Per1 expression is achieved cannot be reproduced by a single melatonin injection.     

Evidence that Melatonin Acts in the Pituitary Gland through a Dopamine-independent Mechanism to Mediate Effects of Daylength on the Secretion of Prolactin in the Ram

A previous study provided evidence that melatonin acts in the pituitary gland to mediate the effects of daylength on the secretion of prolactin in sheep. This was based on the observation that hypothalamo-pituitary disconnected (HPD) Soay rams showed normal patterns in the changes in the peripheral blood concentrations of prolactin in response to alterations in photoperiod (10-fold higher concentrations under long than short days), and in response to exogenous melatonin (rapid decline following the administration of a constant-release implant of melatonin). The purpose of this study was to establish whether dopamine (DA) might be involved in mediating the effects of melatonin on the secretion of prolactin. Groups of HPD (n = 7) and control Soay rams (n = 8) were treated with vehicle (control, 2.0 ml 0.1 M tartaric acid/saline sc), bromocriptine (DA agonist, 0.06 mg/kg sc) or sulpiride (DA antagonist, 0.6 mg/kg sc), and the acute prolactin responses were measured over the next 4 h. Treatments were carried out under short days (8L:16D, low prolactin), long days (16L:8D, high prolactin), and under long days in the presence of a constant-release implant of melatonin (low prolactin). The prolactin response to TRH (1.25μg/kg iv) was also measured. Bromocriptine caused a decrease in the plasma concentrations of prolactin in both HPD and control rams under short and long days. Sulpiride had no effect in the HPD rams on any occasion, but caused a very marked increase in the plasma concentrations of prolactin in the control rams under short days, long days, and under long days + melatonin. TRH caused an acute increase in the plasma concentrations of prolactin in the HPD rams under both long and short days although the responses were notably reduced compared with the controls especially under long days + melatonin. Overall, the inhibitory response to the DA agonist in HPD rams indicates the presence of DA D₂ receptors linked to functional lactotrophs in the isolated pituitary gland. However, the total lack of a response to the DA antagonist indicates the absence of endogenous DA mechanisms regulating the secretion of prolactin in the HPD rams. The conclusion is that melatonin acts directly on the pituitary gland to mediate effects of photoperiod through a DA-independent mechanism.     

Short photoperiods attenuate central responses to an inflammogen

In most parts of the world, environmental conditions vary in a predictable seasonal manner. Thus, seasonal variation in reproductive timing and immune function has emerged in some species to cope with disparate seasonal demands. During the long days of spring and summer when food availability is high and thermoregulatory demands low, Siberian hamsters invest in reproduction, whereas during the harsh short days of winter hamsters divert energy away from reproductive activities and modify immune capabilities. Many seasonal adaptations can be recapitulated in a laboratory setting by adjusting day length (photoperiod). Early-life photoperiods are important sources of seasonal information and can establish an individual's developmental trajectory. Siberian hamsters housed under short days (SD; 8 h light/day) recover more rapidly than long-day (LD; 16 h light/day) hamsters from immune activation with lipopolysaccharide (LPS). SD hamsters attenuate fever response, reduce cytokine production, and abrogate behavioral responses following LPS injection. The mechanism by which SD Siberian hamsters attenuate febrile response remains unspecified. It is possible that periphery-to-brain communication of inflammatory signals is altered by exposure to photoperiod. Rather than testing photoperiod effects on each of the multiple routes by which immunological cues are communicated to the CNS, we administered LPS intracerebroventricularly (i.c.v.) following adolescent exposure to either 6 weeks of SD or LD. Injection of LPS i.c.v. led to a similar immune reaction in SD hamsters as previously reported with intraperitoneal injection. Short days attenuated the response to LPS with diminished fever spike and duration, as well as decreased locomotor inactivity. Furthermore, only LD hamsters demonstrated anhedonic-like behavior following LPS injection as evaluated by decreased preference for a milk solution. These results suggest that photoperiodic differences in response to infection are due in part to changes in central immune activation.     

Neuroendocrine control of photoperiodic changes in immune function

Seasonal variation in immune function putatively maximizes survival and reproductive success. Day length (photoperiod) is the most potent signal for time of year. Animals typically organize breeding, growth, and behavior to adapt to spatial and temporal niches. Outside the tropics individuals monitor photoperiod to support adaptations favoring survival and reproductive success. Changes in day length allow anticipation of seasonal changes in temperature and food availability that are critical for reproductive success. Immune function is typically bolstered during winter, whereas reproduction and growth are favored during summer. We provide an overview of how photoperiod influences neuronal function and melatonin secretion, how melatonin acts directly and indirectly to govern seasonal changes in immune function, and the manner by which other neuroendocrine effectors such as glucocorticoids, prolactin, thyroid, and sex steroid hormones modulate seasonal variations in immune function. Potential future research avenues include commensal gut microbiota and light pollution influences on photoperiodic responses.     

Short-day stimulation of testicular activity and immunoreactivity of the hypothalamic GnRH system in mink following deafferentation of the pineal body by bilateral superior cervical ganglionectomy and melatonin replacement.

The effects of superior cervical ganglionectomy on testicular function (testis volume and plasma testosterone levels) and the immunocytochemical activity of the GnRH hypothalamic system were studied in the mink, a short-day breeder. Animals reared in a natural photoperiod were (i) ganglionectomized at four different times during the period extending from the end of summer to the end of autumn (September 15, October 20, October 28, and December 1), and (ii) reared for 50 days in a short gonadostimulatory photoperiod (4L:20D). Lastly, an attempt was made to overcome the effects of superior cervical ganglion removal by administering melatonin to mink reared in a natural photoperiod. In mink reared in a natural photoperiod, deafferentation of the pineal on September 15 (L = 12.5 h) or October 20 (L = 10.5 h) resulted in consistently low values of testicular volume and plasma testosterone until the end of the experiment (February). When the operation was performed on October 28 (L = 10 h) testicular activity was initiated but only lasted a short time and did not allow maximal gonadal development. When superior cervical ganglionectomy was carried out on December 1 (L = 8.5 h), during the phase of renewed testicular activity, the increases in testicular volume and testosterone levels were not affected by the operation and the subsequent variation of these parameters was identical to that observed in intact animals. Similarly, in mink reared for 50 days in a photoperiod of 4L:20D before superior cervical ganglionectomy, deafferentation of the pineal did not prevent gonadostimulation induced by short days.(ABSTRACT TRUNCATED AT 250 WORDS)     

The Effect of Photoperiod on Plasma Levels of Melanin-Concentrating Hormone in the Trout

The neurohypophysial melanin-concentrating hormone, MCH, plays a role in adaptive colour change in teleost fishes, inducing pallor when the fish is placed in pale-coloured surroundings. The present study shows that its plasma concentration, measured in groups of white-adapted fish, is not uniformly high throughout the day but follows a clear diurnal pattern. Over a 24 h cycle, plasma concentrations rise gradually during the morning to reach peak values around the middle of the photophase, after which they decline significantly before night. Lowest concentrations are observed during the dark period. This pattern was observed under a long photoperiod in summer and a short photoperiod in winter. The peak was shifted within a week of changing the onset of either light or dark. When dawn was delayed by 6 h for fish held on a long photoperiod, the usual morning rise in hormone titres was suppressed but, with the advent of light, hormone concentrations rose more rapidly than usual to reach peak values at about the normal time. If the dawn was advanced by 6 h for fish held under short photoperiod conditions, then peak concentrations were attained 6 h precociously. Fish from a long photoperiod placed in constant light showed a pattern of MCH release which approximated to the normal over the first 24 h period but plasma values then became raised and periodicity was no longer discernible. Plasma hormone concentrations were much reduced in trout kept in black coloured tanks in which nocturnal and daytime values differed, but significant differences during the photophase were not demonstrable. The results suggest that an illuminated white background can initiate the early morning release of MCH, and that an endogenous pacemaker underlies the pattern of MCH secretion.     

Sleep deficits in the High Arctic summer in relation to light exposure and behaviour: use of melatonin as a countermeasure

BackgroundThere are conflicting reports regarding seasonal sleep difficulties in polar regions. Herein we report differences in actigraphic sleep measures between two summer trials (collected at Canadian Forces Station Alert, 82.5°N, in 2012 and 2014) and evaluate exogenous melatonin for preventing/treating circadian phase delay due to nocturnal light exposure.MethodsSubjects wore actigraphs continuously to obtain sleep data. Following seven days of actigraphic recording the subjects filled out questionnaires regarding sleep difficulty and psychosocial parameters and subsequently remained in dim light conditions for 24 hours, during which saliva was collected bihourly to measure melatonin. During Trial 2, individuals who reported difficulty sleeping were prescribed melatonin, and a second saliva collection was conducted to evaluate the effect of melatonin on the circadian system.ResultsTrial 1 subjects collectively had late dim light melatonin onsets and difficulty sleeping; however, the Trial 2 subjects had normally timed melatonin rhythms, and obtained a good quantity of high-quality sleep. Nocturnal light exposure was significantly different between the trials, with Trial 1 subjects exposed to significantly more light between 2200 and 0200h. Melatonin treatment during Trial 2 led to an improvement in the subjective sleep difficulty between the pre- and post-treatment surveys; however there were no significant differences in the objective measures of sleep.ConclusionsThe difference in sleep and melatonin rhythms between research participants in June 2012 and June 2014 is attributed to the higher levels of nocturnal light exposure in 2012. The avoidance of nocturnal light is likely to improve sleep during the Arctic summer.     

Treatment of a patient with seasonal premenstrual syndrome

The authors identified a patient who had premenstrual syndrome (late luteal phase dysphoric disorder) only in the fall and winter and was virtually asymptomatic during the spring and summer. On the basis of previous experience with seasonal affective disorder, they treated the patient with bright artificial light, which reversed her symptoms. On subsequent occasions they reversed this treatment effect with oral melatonin administration and found that propranolol and atenolol, beta-antagonists that inhibit the production of melatonin, had a therapeutic effect similar to that of light. They discuss the implications of these findings in relation to the importance of melatonin as a mediator of seasonal rhythms in biology.     

Testicular and somatic growth in Siberian hamsters depend on the melatonin-free interval between twice daily melatonin signals

In Siberian hamsters, day length is encoded by the duration of the nocturnal melatonin signal; short and long melatonin signals over the course of several weeks stimulate and inhibit somatic and gonadal development, respectively, in prepubertal males. We sought to determine whether juvenile male Siberian hamsters respond to multiple melatonin signals each day and the manner in which the sequence of melatonin signals and the duration of the melatonin-free interval between signals affects development. Twenty-one day old male Siberian hamsters, gestated and maintained in a short-day photoperiod of 10 h light/day (10 L), were transferred to constant light to suppress endogenous melatonin secretion and received s.c. infusions of melatonin or saline for 12 days. Hamsters infused with saline retained small testes, whereas one short melatonin infusion each day resulted in significant testicular growth. Other hamsters were provided with two melatonin signals each day, one long (9 h) and one short (4 or 5 h); the order in which these signals was administered and the duration of the melatonin-free interval after each signal varied between groups. In asymmetrical melatonin infusions, the first and second daily infusions were followed by 3-h and 7-h melatonin-free intervals, respectively, whereas in symmetrical infusions, each melatonin signal was followed by a 5-h melatonin-free interval. In the asymmetrical sequence, the melatonin signal that immediately preceded the longer melatonin-free interval determined the rate gonadal growth. Equal melatonin-free intervals after each of the long and short daily melatonin infusions produced intermediate increases in gonadal and somatic development. The hypothalamic-pituitary-gonadal axis of Siberian hamsters can respond to multiple melatonin signals each day, with the rate of testicular growth determined primarily by the duration of the melatonin-free interval following each infusion.     

Encoding time of day and time of year by the avian circadian system

The most important zeitgeber for seasonal rhythmicity of physiology and behaviour in birds is the annual cycle of photoperiod. Regulatory mechanisms are less well understood in birds than in mammals since photic information can be perceived by photoreceptors in the retina and the pineal gland, as well as in the brain, and photoperiodic time measurement might be performed with reference to at least three autonomous circadian systems, the retina, the pineal gland and a hypothalamic oscillator. In many bird species, the pineal melatonin rhythm plays a central role in circadian organization. Durations of elevated melatonin in the blood reflect night length when animals are kept under natural photoperiodic conditions, as well as under different light/dark schedules in the laboratory. In the house sparrow, time of year is encoded in a particular melatonin signal, being short in duration and high in amplitude in long photoperiods and being long in duration and low in amplitude in short photoperiods, independent of whether the light zeitgeber is natural or artificial or varies in strength. Specific features of the melatonin signal are retained in vivo as well as in vitro when birds or isolated pineal glands are transferred to constant conditions. To regulate daily and seasonal changes of behaviour and physiology, melatonin may act at various target sites, including a complex hypothalamic oscillator that, unlike that in mammals, is not confined to a single cell group in the house sparrow. There is increasing evidence that interactions between two or more components of the songbird circadian pacemaking system are essential to encode and store biologically meaningful information about time, and thus provide the basis for photoperiodic time measurements and after effects in birds.     

Effect of Photostimulation on Concentrations of Plasma Prolactin in Castrated Bantams (Gallus domesticus)

The annual breeding cycle of ‘unimproved’ breeds of domestic chicken, including the bantam, at temperate latitudes, is terminated by decreasing daylength in autumn and is initiated in late winter, while daylengths are still short. Observations on photoperiodic birds that terminate seasonal breeding by the development of long day photorefractoriness suggest that the photoinduced pattern of prolactin secretion is associated with the pattern of gonadal growth and regression. It was predicted that, if there is a causal relationship between photoinduced changes in prolactin secretion and gonadal function in birds then, in the bantam, the pattern of prolactin secretion observed after photostimulation would not be the same as in birds terminating breeding by the development of long day photorefractoriness. Experiments were carried out on surgically castrated bantams to avoid confounding the effects of photostimulation and the stimulatory actions of testicular hormones on prolactin secretion. Transfer of photosensitive castrated bantams from 8 to 14, 16, 18 or 20 h light/day initially stimulated prolactin release and, subsequently, after 20–30 days, concentrations of plasma prolactin progressively decreased. After 148 days of photostimulation, concentrations of plasma prolactin approached but were still higher than short day controls. Transfer of photosensitive castrated bantam cockerels from 8 to 12 h light/day stimulated a slower increase in plasma prolactin that subsequently remained higher than in other photostimulated groups. A further 4 h increase in photoperiod in the birds exposed for 148 days to 12 or 16 h light/day resulted, respectively, in a transitory increase and no increase in prolactin secretion. Recovery of photosensitivity for prolactin release was observed in the birds transferred to 18 or 20 h light/day for 148 days after treatment with 8 h light/day for 35 days. Attempts to obtain an independent hormonal correlate of the prolactin responses to photostimulation by measurement of plasma luteinizing hormone (LH) were unsuccessful. The concentration of plasma LH in castrated bantams did not change in response to a change in photoperiod. These observations show that the photoinduced pattern of prolactin release in the bantam, a species which terminates seasonal breeding in response to decreasing daylength, is the same as that in birds which terminate seasonal breeding by the development of long day photorefractoriness. It is concluded that the photoinduced pattern of prolactin secretion in birds can be dissociated from the neuroendocrine mechanisms controlling the termination of seasonal breeding.     

The circadian rhythm in plasma melatonin concentration of the urbanized man: the effect of summer and winter time

Plasma melatonin rhythms were measured in healthy urbanized persons between July 4 and 5 and between January 13 and 14. In contrast to findings in other mammals studied thus far, no difference in the duration of elevated night melatonin concentration was observed between summer and winter. In winter, melatonin rhythms were phase-delayed by about 1.5 h as compared with summer patterns.     

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).