Melatonin: an internal signal for daily and seasonal timing

See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/262581135 Melatonin: An internal signal for daily and seasonal timing Article in Indian journal of experimental biology · May 2014 Source: PubMed CITATIONS READS 10 299 2 authors: Amit Trivedi Vinod Kumar 23 PUBLICATIONS 197 CITATIONS 160 PUBLICATIONS 1,966 CITATIONS Mizoram University SEE PROFILE All content following this page was uploaded by Amit Trivedi on 10 June 2014. The user has requested enhancement of the downloaded file. University of Delhi SEE PROFILE Indian Journal of Experimental Biology Vol. 52, May 2014, pp. 425-437 Review Article Melatonin: An internal signal for daily and seasonal timing Amit Kumar Trivedi & Vinod Kumar* DST-IRHPA Center for Excellence, Department of Zoology, University of Delhi, Delhi 110 007, India Melatonin is secreted only during night, irrespective of the habitat of an organism and the site of its synthesis and secretion, and hence known as “darkness hormone”. Elevated melatonin levels reflect the nighttime. In vertebrates, the main site of melatonin production is the pineal gland. Species in which melatonin is also secreted from sources other than the pineal, as in some birds, relative contributions of different melatonin producing tissues to the blood melatonin level can vary from species to species. Melatonin acts through its receptors, which are members of the G protein-coupled (GPCR) superfamily. Three melatonin receptors subtypes MT1 (mel1a), MT2 (mel1b), and MT3 (mel1c) have been identified in different brain areas and other body organs of vertebrates. Melatonin synthesis and secretion are circadianly rhythmic. Changes and differences in specific features of melatonin signal can vary among species, and under a variety of natural environmental conditions. Two major physiological roles of melatonin are established in vertebrates. First, melatonin is involved in the circadian system regulated behavioural and physiological functions. Second, it is critical for the photoperiodic system. Besides, melatonin has been implicated in various ways both directly and indirectly to human health, including jet lag, sleep, immune system and cancer. Keywords: Bird, Clock, Melatonin, Photoperiod, Sleep Aron Lerner and collaborators discovered melatonin (N-acetyl-5-methoxytryptamine) in the vertebrate pineal gland, which is an unpaired appendage of the brain (called epiphysis) in most vertebrates. It is an indoleamine molecule named after its effects on amphibian melanophores. The presence of melatonin has been widely reported from plants and protozoa to humans2. One of the potential reasons for the presence of melatonin across the living systems appears to be its chemical nature. It is a lipophilic molecule and therefore can diffuse into all kinds of cell types without facing any biological barrier. During the course of evolution, melatonin is presumed to have mediated the adaptation to the daynight (light-dark, LD) cycle of the environment. Melatonin is secreted only during night, irrespective of the habitat of an organism and the site of its synthesis and secretion, and hence known as “darkness hormone”. Elevated melatonin levels reflect night time andpromote sleep at night; thus aptly called “nature’s sleeping pill”. Because of its importance in the regulation of circadian (circa = about; dian = day) and circannual (circa = about; annum = year) functions, melatonin is also referred as “circadian glue”. __________ *Correspondent author Telephone: 011-27667725; Ext. 212 E-mail: [email protected] As in other vertebrates, especially in mammals, the main site of melatonin production is the pineal gland, which in most species is situated within the recess formed by the two cerebral hemispheres and the cerebellum. Each pineal cell (pinealocyte) synthesizes and secretes melatonin, as evidenced by in vitro experiments. Cultured pineal cells exhibit significant rhythm in the melatonin production, similar to that exhibited by the pineal gland3,4. Several reports show significant amount of melatonin production by retinae of the lateral eyes, harderian gland, and gastrointestinal tract2. In principle, circulating melatonin levels faithfully reflect total melatonin production by an organism. Relative contributions of different melatonin producing tissues to the blood melatonin level can vary from species to species. In this aspect, the roles of the eyes and the pineal have been investigated in a few species. In the House sparrows (Passer domesticus) most, if not all, blood melatonin is secreted by the pineal gland; surgical removal of pineal gland renders sparrows with undetectable levels of melatonin5,6. In Japanese quail (Coturnix coturnix japonica) and pigeon (Columba livia), on the other hand, only a little over than half of blood melatonin comes from the pineal gland; the remaining, a little less than half of blood melatonin, comes from the retinae and other undefined tissues7-9. Melatonin acts through its receptors, which are members of the G protein-coupled receptor (GPCR) 426 INDIAN J EXP BIOL, MAY 2014 superfamily10. Three melatonin receptors subtypes have been identified in vertebrates: MT1 (mel1a), MT2 (mel1b), and MT3 (mel1c)11. MT1 and MT2 have been identified in all vertebrates, which have been investigated, but MT3 has been found only in non-mammalian species11,12. These receptors have been identified in different brain areas and other body organs13. In mammals, a high density of melatonin receptors has been found in the suprachiasmatic nuclei (SCN), which is the principal site of the biological clock in vertebrates14,15 and pars tuberalis (PT) of the anterior pituitary, which is involved in the photoperiodic regulation of reproduction in both birds and mammals16-18. In mammals, there is a peculiar orphan melatoninrelated receptor (GPR50), to which melatonin does not bind under in vitro expression assays and remains a puzzle from a functional perspective19. Recently, by analysis of Mel1c synteny, GPR50 is shown to be the mammalian orthologue of Mel1c20. Levoye et al.21 believed that GPR50 acts as a dimerization partner for mammalian melatonin receptors, thereby modulates melatonin signal transduction in the ligandindependent manner. A difficulty with this proposition is rather limited overlap between melatonin receptor and GPR50 expression, the former being concentrated in the pars tuberalis (PT) and the latter showing a strongest expression in the brain where melatonin receptor expression is weak or absent22,23. In the hypothalamus, GPR50 is expressed in areas linked with energy homeostasis [e.g. dorsomedial hypothalamus (DMH) and paraventricular nucleus (PVN)]22. Intriguingly, GPR50 in rodents is also expressed in the ependymal cell layer lining the third ventricle, and thus overlaps with distribution of Dio2 and Dio3 mRNA expression. In Siberian hamsters (Phodopus sungorus), exposure to short photoperiods leads to a loss of body fat as well as a reproductive switch off, along with reduced GPR50 expression levels in the MBH24. GPR50 knockedout mice show a lean phenotype, with an unusual tendency to express torpor in response to food restriction25. Taken together the results from several findings, GPR50 appears to be linked with the metabolic regulation, rather than directly to the photoperiodic response, which could be important in finding insights into its ligand search. The literature on pineal and melatonin is vast, and so it may not be possible to review it in a single review, like the present one. Therefore, because of our own bias and limitation, the present review is restricted mainly to birds with relevant information on mammals, for the sake of comparison, with focus on the role of melatonin in circadian and seasonal events in birds. Regulation of melatonin synthesis and secretion The regulation of melatonin synthesis and secretion has been studied in the avian pineal gland. Several studies have established that day-night cycle of the environment controls the time and duration of melatonin synthesis and secretion. Briefly, during the day, amino acid tryptophan is taken up from the bloodstream and hydrolyzed to 5-hydroxytryptophan (5-HTRP) in presence of the enzyme tryptophan hydroxylase (TRH). Then, it is converted to 5-hydroxytryptamine (5HT, serotonin) by the action of the enzyme, aromatic amino acid decarboxylase (AAADC). During the night, serotonin is acted upon by the enzyme arylalkylamine N-acetyltransferase (AANAT) forming N-acetylserotonin. The latter undergoes O-methylation by the action of the enzyme hydroxyindole-O-methyltransferase (HIOMT) producing melatonin, the final product of the biosynthesis. All melatonin synthesized is released into the circulation since it is a lipophilic molecule. But at any given time, the concentration of melatonin within the pineal gland is several folds higher than that of the blood suggesting that there may be some mechanism, hitherto unidentified, involved in the release of melatonin. Microarray studies of the pineal gland show the presence of genes encoding hormonebinding proteins, like transthyretin4,26. Neuronally, norepinephrine is shown to be involved in the regulation of melatonin biosynthesis but its role appears to be different in birds than what is known from the biosynthesis of melatonin from the mammalian pineal gland. In birds, norepinephrine inhibits cAMP accumulation via alpha-2 adrenergic receptors and, in turn, inhibits AANAT activity and melatonin production during daytime. By contrast, in mammals norepinephrine activates melatonin production by the pinealocytes during night. Melatonin secretion is a circadian rhythmMelatonin is produced rhythmically: circulating levels are low during the day and high during the night. The rhythmicity continues both in vivo and in vitro under constant conditions of darkness (DD) or dim light (LLdim) with a period close to 24 h27-29. Further, an advance or a delay of the Zeitgeber (zeit = time; geber = giver) conditions (e.g. TRIVEDI & KUMAR: MELATONINE & SEASONAL TIMING LD-cycle) produces corresponding phase shifts of the melatonin rhythm, and this phase shift is seen even when the animal is subjected to constant conditions, suggesting that the underlying circadian melatonin oscillator was entrained30,31. A further confirmation that the properties of the melatonin rhythm are consistent with the melatonin oscillator comes from T-experiments. Exposure to T-photocycles (LD cycle with varying periods, e.g. 22, 24, 26 h etc.) produces changes in the phase of melatonin rhythm27,32 as one would predict from the oscillatory theory. This is not surprising as the biochemical pathway involved in the synthesis of melatonin appears to be regulated by the circadian clock, which resides within each pinealocyte. This clock is clearly seen operating both at the transcriptional level (as seen in the rhythmic expression of mRNAs of TRH, AANAT and HIOMT) and posttranscriptional level (AANAT protein activity parallels the presence and absence of AANAT mRNA expression)4,33,34. At molecular level, pinealocytes appear to be equipped with all those genes, which are implicated in the generation of circadian rhythmicity in other tissues including the hypothalamic clock. However, the degree of persistence of circadian rhythmicity could vary between species28,30,31,35,36. Role of melatonin in the regulation of physiology Two major physiological roles of melatonin are established in vertebrates. First, melatonin is involved in the circadian system. Second, melatonin is critical for the photoperiodic system to sense the environment and operate accordingly. Organisms use daily melatonin rhythm to decipher the photoperiodic message (LD cycle) of the environment. Melatonin in the circadian systemA circadian system is conceptualized as comprising three components: an input pathway, a central clock with an intrinsic capacity of generating precise oscillations, and an output pathway. In mammals, the SCN of the anterior hypothalamus contains central circadian pacemaker and coordinates overt circadian rhythms14,15. In birds the circadian system is highly complex, as it comprises several independent clocks. Each clock has its own input and output pathways. Thus, birds perceive light by the retinae of the lateral eyes, by the pineal gland, and by the photoreceptors in the hypothalamus. Circadian oscillators are present at all the three levels, each having independent outputs. Unlike mammals, avian SCN is recognized in two sets of structures, medial (mSCN) and visual SCN (vSCN). Further, in birds these three central clocks 427 interact with eachother before producing the final output. Melatonin is a known output of at least two of them, the pineal gland and the eyes. In the circadian clock system, melatonin performs at least two roles, although their relative importance may be species-specific. (1) Melatonin is a potential clock component. The retinal and pineal clocks control their circadian outputs via melatonin rhythm. Therefore, the absence of melatonin rhythm leads to arrhythmicity. (2) Melatonin acts as a coupling agent. It affects either the frequency of one or more oscillators or the strength of coupling among different oscillators, or both37-39. Any change that occurs in melatonin profile will, therefore, induce changes in the circadian system functions. A high-amplitude melatonin will strengthen the mutual coupling, resulting in an increase of the selfsustainment of clocks and hence decreases their susceptibility to the photoperiodic noise. The reduced melatonin amplitude will weaken the mutual coupling, resulting in a decrease of the self-sustainment of clocks and hence facilitating the adjustment of the circadian system to changing Zeitgeber conditions. Most studies have measured the effects of pineal melatonin on circadian system regulated behavioural rhythms, especially locomotion and feeding activities. Surgical removal of the pineal (pinealectomy) disrupts circadian rhythmicity of locomotor activity40, body temperature41, and feeding38 in House Sparrows. However, the same effect is not achieved by neural disconnection of the pineal gland or by chemical sympathectomy42, which suggests that some humoral substance (melatonin) is involved. The pineal (melatonin) contains the circadian information since arrhythmic pinealectomized House Sparrow becomes rhythmic when the pineal gland from another bird is transplanted in its eye43. Periodically applied exogenous melatonin by infusion or by drinking water also restores rhythmicity in arrhythmic pinealectomized House Sparrows and Pigeons44-46, confirming that the clock properties of the pineal are achieved through the secretion of melatonin. The effect of pineal removal on circadian activity rhythms in the Indian Weaverbird (Ploceus philippinus) was studied. When Weaver birds were exposed to a 12L:12D Zeitgeber conditions, all of them showed good entrainment. Half of them were pinealectomized and the other half were sham-operated. Pineal removal led to the gradual loss of circadian rhythmicity in Indian Weaverbirds47, similar to that reported in House Sparrow. 428 INDIAN J EXP BIOL, MAY 2014 The effect of pineal removal though is not uniform in the avian world. In European Starlings (Sturnus vulgaris), the role of pineal gland in the control of circadian behavioural rhythms is only partial. Pinealectomy impairs activity, but not feeding rhythms48. In Chicken (Gallus domestics)49 and Japanese Quail50, the removal of pineal has no effect on circadian activity rhythms. Rather, removal of the eye (enucleation) impairs circadian rhythmicity in Quails. Since enucleation in Quail, achieved by sectioning the optic nerve, leaves rhythm in melatonin secretion intact9,51, the melatonin is not responsible for enucleation-induced arrhythmicity in Quails. In pigeons, pinealectomy and blinding together produces arrhythmicity, but none of them alone could achieve this. Cyclic melatonin infusions restored rhythmicity in arrhythmic individuals52. The other evidence of melatonin being part of the avian circadian system comes from studies, which have manipulated the rhythm of melatonin. A change in the amplitude of melatonin, for example, will have consequential effects on the properties of avian circadian system, as one would predict from the general principles of an oscillator theory53. The persistence of circadian rhythms under constant conditions, the range of entrainment (i.e. the range of Zeitgeber periods to which rhythmicity can be synchronized), and the time required to resynchronize following phase shifts of the Zeitgeber should change in absence of melatonin rhythm. Several recent studies clearly support this idea. In House Sparrows, the elimination of rhythm in plasma melatonin by pinealectomy which removed the elevated nighttime melatonin levels, or by melatonin implants which enhanced both the daytime and nighttime levels to supraphysiological levels, resulted in (i) loss of the circadian rhythmicity in locomotion and feeding38,54, (ii) an increase in the range of entrainment55,56, and (iii) a decrease in the duration required for resynchronization following phase shifts 6,57,58. Changes and differences in specific features of melatonin signal can also be found to vary under a variety of natural environmental conditions. For example, pinealectomy abolished circadian rhythmicity in House Sparrows when kept under constant conditions and free-ran, but not when they were kept under LD and synchronized. Further, there was always a residual rhythmicity for-a-while in pinealectomized Sarrows40. On the other hand, lesions of the hypothalamic pacemaker resulted in severe impairment of rhythmicity in Sparrows although they had their pineals intact59. Collectively, this means that melatonin interacts with at least one oscillator other than its source to regulate avian circadian rhythmicity. In absence of melatonin signal, hypothalamic oscillator functions as a damped oscillator. In presence of light, however, hypothalamic oscillator continues to function as a self-sustained pacemaker even if the melatonin signal is absent. Pineal gland and clock genes expressionTime is generated at molecular level within a clock structure by interlocking transcriptiontranslation negative feedback loops, comprising positive and negative limbs. Each limb is formed by a set of core genes (called clock genes). In vertebrates, core clock genes of the positive limb are bmal (brain and muscle ARNT-like) and clock (circadian locomotor output cycles kaput), while that of negative limb are periods and cryptochromes. Pineal gland and melatonin have been shown to influence the expression of these clock genes in some but not in other species. In rat, pineal gland is not essential for circadian expression of rper2 mRNA in SCN and peripheral tissues60 and in limbic forebrain system61. However, in PT of the rat rcry1 expression is directly induced by melatonin62. House Sparrow vSCN contains melatonin receptor binding sites63. In Japanese Quail, constant exogenous melatonin administration caused arrhythmicity or period changes in body temperature and activity rhythms64, and rhythmic melatonin administration entrained feeding rhythm65, but melatonin did not alter the expression of clock genes in mSCN66. Also, pinealectomy failed to abolish the rhythmic expressionof period2 gene in House Sparrows67. Also, a differential effect of pinealectomy on rhythmic expression of bmal1, period3 and cryptochrome1in different brain areas was found in Chicken68. Because in these studies, gene expression was studied within three days of exposure to constant conditions, when birds were still behaviourally rhythmic40, the possibility remained that there was still residual melatonin effect on gene expression. It needs further investigation. Melatonin rhythm encodes photoperiodic informationThe duration of nocturnal melatonin production reflects night length, and hence day length27. On the other hand, the peak amplitude melatonin levels also appear to reflect the seasons. In House Sparrows, these levels are high in summer, low in winter and intermediate in spring29. Similarly, the TRIVEDI & KUMAR: MELATONINE & SEASONAL TIMING amplitude of plasma melatonin rhythm is significantly reduced during migratory seasons in migratory Garden Warblers (Sylvia borin)69, and during summer months in Adelie Penguin (Pygoscelis adeliae)70,71 and Arctic Svalbard Ptarmigan (Lagopus mutus hyperboreus)72. A study on House Sparrows also suggested that the pineal gland could store and retain the photoperiodic information28. Implication of all these findings is that melatonin rhythm provides the birds a calendar based on the photoperiodic information of the environment. The capacity of storing biologically meaningful information about time by the pineal may enable birds to compare and measure the day length, as season progresses, and to buffer the effects of adverse environmental conditions, when photoperiodic measurement may be tampered temporarily. This is supported by a recent study showing season-linked differences in the genes expression pattern at the transcript levels that encode enzymes of melatonin biosynthesis in Chicken pineal73. Melatonin and photoperiodic control of reproduction in birdsBecause melatonin is a part of avian circadian system, it is assumed to be involved in the regulation of the photoperiodic effects at one or the other level. However, melatonin signal appears to be redundant in many bird species as far as photoperiodic effects on gonadal growth and development is concerned. The list of birds include European Starling (Sturnus vulgaris)74, Spotted Munia (Lonchura punctulata)75, American Tree Sparrow (Spizella arborea)76, Japanese Quail (Coturnix c. japonica)27, Blackheaded Bunting (Emberiza melanocephala)77 and Redheaded Bunting (Emberiza bruniceps)78. The absence of role of melatonin in photoperiodic induction of gonadal growth and development in birds could be explained by a study of Saldanha et al.79 on Ring Doves (Streptopelia roesogrisea). They showed direct innervation of GnRH neurons by deep brain photoreceptors (DBPs). This might mean that DBPs, which are necessary and sufficient for the detection of changes in day length that regulates avian reproduction, are not linked to the reproductive axis via the circadian system. Alternatively, these brain photoreceptors also contain clock, a speculation that needs to be investigated further. The effects of pinealectomy or melatonin injections are shown nonetheless in some birds, including Domestic Duck (Anas platyrhynchos)80, Indian Weaverbird (Ploceus philippinus)81, Indian Jungle 429 Bush Quail (Perdicula asiatica)82, Rose-ringed Parakeets (Psittacula krameri)83 and Lal 84 Munia(Estrilda amandava) . However, Kumar et al.78 reported absence of melatonin effects in certain phases of the gonadal growth and development cycle The effect of melatonin as a modulator of testicular growth and development is also shown in Blackheaded Bunting. Buntings were implanted with melatonin-filled or empty silastic capsules subcutaneously and subjected to 11.75 h light per day (11.75L:12.25D) of long (red) or neutral (white) light wavelengths. Those exposed to long light wavelengths and melatonin-filled capsules had grown significantly larger testes85. These results are consistent with the hypothesis that elimination of melatonin rhythm probably altered the perception of the day length. Trivedi et al.86 have also shown themodulatory effect of melatonin on photoperiodic induction of testicular growth in the Redheaded Buntings, in which exogenous injections of prolactin attenuated long day induction of the photoperiodic response87. However, in Japanese Quail, mediobasal hypothalamus (MBH) controls photoperiodic time measurement for reproductive function88. As lesioning of MBH leads in the blocking of testicular recrudescence in response to increasing photoperiods and light illumination of this area resulted in testicular recrudescence89,90. Rhythmic expression of the clock genes in the MBH led them to hypothesize that MBH containsa circadian pacemaker associated with the photoperiodic time measurement17,91. Melatonin and GnIHIn vertebrate system, gonadotropin secretion is under the control of hypothalamic peptide gonadotropin-releasing hormone (GnRH)92. This gonadotropin secretion could be inhibited by another hypothalamic neuropeptide gonadotropin-inhibitory hormone (GnIH)93. So far, these GnIH releasing neurons have been identified only in the PVN of birds93-96. However, GnIH fibers are distributed throughout the hypothalamus and also inthe median eminence (ME) suggesting GnIH to be involved in the regulation of anterior pituitary functions93,97. Melatonin is shown to induce GnIH expression in the Quail brain98. Decreased levels of GnIH precursor mRNA and peptide in pinealectomized and enucleated Quails have been to shown to be restored by melatonin administration in the dose-dependent manner98. Dosedependent effect of melatonin on GnIH release from 430 INDIAN J EXP BIOL, MAY 2014 hypothalamic explants in vitro has also been reported in Quail99. There is a diurnal variation in GnIH release from hypothalamic explants with higher levels during dark than during light period99. GnIH release was increased under short photoperiods, when the duration of night melatonin secretion was longer. In another study on European Starlings, melatonin was found to have a season dependent effect on testicular GnIH, with up-regulated mRNA levels during the pre breeding periods100. Melatonin and photoperiodic control of reproduction in mammals After the discovery of melatonin, most early research was focused on its role in the regulation of reproduction in seasonal breeding rodents and sheep. It is established that the photoperiodic information is relayed via rhythmic secretion of melatonin by the pineal gland101, and is used in the regulation of reproductive cycle in mammals. Pinealectomized male Hamsters did not gonadally regressunder nonstimulatory short photoperiods102, and infusion of melatonin led gonadal regression in Siberian hamsters on stimulatory long days103. Short day breeding sheepand goatalso use melatonin in timing their reproduction104, and melatonin can be used to advance or induce cyclicity in these seasonal breeders105. The effect of melatonin is at the central level, i.e. at the level of hypothalamic-hypophysial axis. In anoestrous ewes, melatonin treatment over about 10 weeks induces a significantly high GnRH and LH pulsatility106. Melatonin in the form of implants has been commonly used to alter the breeding season of short day seasonal breeders like ewes and goats107-109. Melatonin alone110 or combined withphotoperiodalters reproductive activity in anoestrous ewes111,112. A study on rabbits showed that melatonin treatment improved the quantity and quality of ejaculate traits and overall sexual activity and decreased gestation period and pre-weaning mortality113. Melatonin and secondary sexual characteristics One well-studied secondary sexual character in which the role of melatonin has been studied is the development of song system in Passeriformes birds, commonly called as songbirds. The avian vocalization can be broadly characterized in two major categoriesthe song and call. A song is typically complex, long, multisyllabic and mostly produced by adult male birds, and is species-specific and can bear the signature of an individual. Ausually short, monosyllabic call is also produced bymale and female as well as juvenile birds for general communications such as in alarm, food pleading, food availability and other social communications. However, adult male birds generally use its song to attract a mating partner and protect their territory. In captivity, these male songbirds sing both undirected and directed song to attract the females, but in some situation as in case of predator–prey, such songs may not necessarily address to a conspecific114. The avian vocalization is under control of complex circuit that includes a group of interconnected and well distinct nuclei115, collectively calledas song control nuclei. The circuit comprises motor nuclei, involved in auditory feedback essential for vocal learning and perception116. On the top of this pathway is a nucleus hyperstriatum ventrale, parscaudale (high vocal center, HVc) that leads to the nucleus robustus archistriatalis (RA). RA then leads to nucleus intercollicularis (ICo) and the XIIth cranial nerve in the brainstem, which connects to the syrinx. RA and ICo also communicate to the nucleus retroambigualis (RAm) and nucleus ambiguous (NA), both help in the integration of song production117,118. The HVc also communicates with RA through other pathway, which consists of a projection from HVc to Area X of the lobus parolfactorius (LPO) and medial portion of the dorsolateral nucleus of the anterior thalamus (DLM). DLM leads to lateral portion of the nucleus magnocellularis of the anterior neostriatum (IMAN) that finally connects to RA. Seasonal variation in the size of nuclei of the song control system largely depends on the circulating testosterone level119,120. Nonetheless, there is a testosterone independent seasonal variation in the size of song control nuclei121. Melatonin is a key player in the steroid-independent neuroplasticity of the song control nuclei induced by the photoperiod122. The distribution of melatonin binding sites has been well identified in different regions of avian brain including the song control system63,123,124. Whitfield-Rucker and Cassone125 showed 2-[125I]iodomelatonin (IMEL) binding in the HVc, RA and Area X in male, but not in female, House Sparrows. However, IMEL in magnocellularis anterior (MAN) had melatonin binding sites in both the sexes. There was also a significant difference in the IMEL binding under different photoperiods between HVc and RA125. These IMEL binding studies clearly suggest the involvement of melatonin in the daily and seasonal regulation of TRIVEDI & KUMAR: MELATONINE & SEASONAL TIMING song in songbirds. This was confirmed through separate experiments by administering melatonin in birds kept under different photoperiods. Exogenous melatonin mitigates the long day induced increase in the volume of HVc and decrease in the volume of Area X, independent of the reproductive state, in European Starlings122. House Sparrows maintained inconstant light (LL) and received long duration of melatonin cycle (14 h melatonin and 10 h no melatonin) exhibited smaller HVc and RA, but those on the same light treatment with a shortmelatonin duration (8 h melatonin and 16 h no melatonin) or no melatonin exhibited larger HVc and RA126; all these effects were independent of the reproductive state of Sparrows. The circadian clock can influence song learning as well as the timing of song production127,128. There is growing evidence to suggest that circadian clock effect on bird song and learning behaviour are mediated through the rhythmic secretion of pineal melatonin.Wang et al.129, tested more directly this on Zebra Finches. They showed that pinealectomy led to the loss of circadian rhythmicity in the activity, song and call behaviour, and exogenous melatonin restored rhythmicity in all the three behaviours. Similarly, song in adult Zebra Finches and crowing in Japanese Quail was affected in adult birds when they were socially isolated for several weeks and transferred from a light-dark (LD) cycle to constant light (LL) condition, which caused loss of rhythmicity in the melatonin secretion130. A recent study on roosters further confirms circadian clock control of crowing131, but it is not known whether this is influenced by rhythmic melatonin secretion. Pineal and non-reproductive seasonal behaviour Many species of birds migrate to other continent to avoid hostile environment at home. Such night migratory birds when kept in captivity and hence disallowed migration exhibit migratory restlessness (phenotype by showing intense night time activity) or Zugunruhe, characterized by wing-whirring132. Such migratory phenotype expression is reported to be under the endogenous clock control133,134. Daily melatonin profile of migratory Garden Warbler showed corresponding changes inthe simulated nonmigratory and migratory conditionsin the melatonin levels; night melatonin peak had a lower amplitude in migratory than in the non-migratory state69. A similar higher amplitude of melatonin secretion in nonmigratory than in the migratory was also reported in 431 migratory Blackcaps (Sylvia atricapilla)135. Resident population of Blackcaps did not show seasonal changes in the amplitude of melatonin secretion135. There is an effect of the absence of pineal on development of Zugunruhe in the migratory Blackheaded Bunting; pinealectomized birds show significantly delayed Zugunruhe on exposure to long days (unpublished data). However, a relatively recent study on migratory Garden Warbler showed that food availability rather than melatonin played a role in the development of nocturnal migratory restlessness136. Melatonin and human health Melatonin has been implicated in various ways both indirectly and directlyin human health. It is beyond the scope of this review to address in detailthe role of melatonin in human health, but a few examples are given below to highlight the importance of melatonin in human physiology and diseases that appeared to be influenced by the biological clock. Jet lagJet lag describes a temporary disturbance in the physiology of an individual due to loss of synchrony between internal circadian clock and external day-night condition, when the person travels across multiple time zones in short duration of time, e.g. flying to a country with different time zone. Most common symptoms that a jet lagged person will show are poor night's sleep, feeling groggy during the day and general unease and gastrointestinal stress. In general, travelling to the west has a lesser effect than travelling eastwards. This is probably because we candaily delay our body clock by ~2 h, but we can advance only by ~1 to 1.5 h137. Melatonin has been found to overcome jet lag effects. It is reported that 2-5 mg of melatonin prior to bedtime helps to overcome jet lag effects and improves sleep quality138,139. SleepRole of melatonin in sleep regulation has been widely studied, and the relationship between two appears complex. The widely accepted mechanism for melatonin effects on sleep is through the circadian system. Melatonin opens the sleep gate140 and helps to lower the body temperature; peak melatonin levels coincide with low body temperature later in the night. An interesting case study on the role of melatonin in sleep comes from a 14 year old boy with germ cell tumor that involved pineal region was found to have suppressed melatonin level sand severe insomnia. His sleep continuity was restored when he took melatonin at a dose of 2 mg in the evening for 2 weeks141. In another case study of a 24 year old woman with 432 INDIAN J EXP BIOL, MAY 2014 reduced and arrhythmic melatonin production, night sleep consolidation was achieved after eight weeks of treatment with 2 mg melatonin shortly before bedtime142. However, a survey on the effects of melatonin in sleep disturbances that included all age groups did not find significant and clinically relevant role of melatonin on sleep quality, efficiency and latency143. Nonetheless, latter meta-analysis (a metaanalysis is a method that reconstruct the results based on different published studies, and try to identify the patterns or other relationship that may come to light in the context of multiple studies) studies drew different conclusions. Results from 17 different studies with 284 subjects of older age group subjected to metaanalysis revealed that melatonin had increased sleep efficiency and reduced sleep onset time144. Similarly, another meta-analysis study concluded that melatonin treatment advanced endogenous melatonin and sleepwake rhythms in subjects reported with delayed sleep phase disorder145. A recent meta-analysis demonstrated that melatonin decreased sleep onset latency, increased total sleep time and improved overall sleep quality in humans146. Overall, melatonin has been found effective in treating insomnia among elderly people147-150. Immune systemThe role of melatonin in influencing the activity of the immune system has been studied during last 15 years. In rodents, pinealectomy led to decrease151,152, andthe administration of melatonin led to increase153 in weight of immune organs like thymus and spleen. Extirpation of pineal in newborn rats causes structural disorganization of thymus154. Pinelacetomy delayed the development of thymus, spleen and bursa and affected humoral immune response in Chicks155, and non-specific immunity in Chicken156 and Ring Doves157. In Japanese Quail, melatonin given in drinking water caused an increase in humoral immune responses without prior immunosuppression158. Pinealectomy of 4-5 weeks old C57BL/6 mice resulted in significantly reduced interleukin-2 (IL-2) production and NK cell activity159. Melatonin plays a role in the recovery of the immune circadian organization in arthritic rats160. Melatonin can act directly on immune system since immunocompetent have been shown having nuclear receptor for melatonin161, although non-receptor mediated actions of melatonin are also known. CancerIn the last two decades, the medical implication of melatonin has been studied in relation to treatment of tumors. Anti-cancerous properties of melatonin have been reported. It is suggested that melatonin may control tumor growth partially by acting as a natural anti-angiogenic molecule162. Most studies suggest melatonin action on tumor either by promoting the apoptosis of cancerous cells or by inhibiting the growth of cancerous cells. At a dose of 50 mg/kg body weight, melatonin reduced the viability and volume of Ehrlich ascites-carcinoma cells and increased the survival in female mice163. A low dose of IL-2 combined with melatonin prolonged survival time in untreatable advance hematologic malignancies on 12 human cancer patients164. Melatonin could also play a role of potential therapeutic drugs in specific lymphoproliferative diseases165. Melatonin reduces the viability of human myeloid HL-60 cells via induction of apoptosis through the regulation of Bax/Bcl-2 expression166. Melatonin promoted cell cycle arrest and apoptosis in cell lines representing different human lymphoid malignancies including Epstein-Barr virus (EBV)negative BL, diffuse large B-cell lymphoma, follicular B non-Hodgkin's lymphoma and acute T-cell leukemia cells167. In combination with retinoic acid and somatostatin, melatonin enhanced anticancer activity and resulted in reduced number of cancerous cells through apoptosis activity in the MCF-7 breast cancer cells168. Conclusion and perspective Melatonin seems to have much of global effects on physiology of vertebrates, and has medical implications even for human health. Whereas melatonin research in years to come has potential of providing immense benefit to mankind, there is also great deal of importance of such research on nonhuman species, and in particular seasonal species like most, if not all, birds which appear to possess ahighly complex and diverse, yet plastic, biological clock system. The properties of avian clock system, and also clock system in groups like reptiles, amphibians and fish, hitherto not widely investigated, may vary from species to species. Species-specific clock could have tremendous ecological implications, and may be a part of the survival strategy of birds. This may enable, for example, species sharing the same environment to have different temporal strategies in order to perform optimally. Melatonin appears to be a key component in this scheme in birds. In absence of melatonin, all bird clocks may become incapable of showing self-sustained circadian oscillations. We are TRIVEDI & KUMAR: MELATONINE & SEASONAL TIMING still far away, however, from understanding how melatonin exactly meets the demands of a multioscillatory avian circadian system to adjust to the temporal environment. Furthermore, the effect of melatonin on many aspects of bird behaviour (e.g. singing, nesting, parental care etc.) is yet to be investigated thoroughly. This may be essential to understand more comprehensively the effect of melatonin on birds life processes. Finally, most data on the effects of melatonin come from laboratory studies, and whether laboratory observations will hold good for the wild population remains to be investigated. References 1 Lerner A B, Case J D & Takahasi Y, Isolation of melatonin and 5-methoxyindole-3-acetic acid from bovine pineal glands, J Biol Chem,235 (1960) 1992. 2 Kumar V, Melatonin: A master hormone and a candidate of universal panacea, Indian J Exp Biol, 34 (1996) 391. 3 Zatz M, Mullen D A & Moskal J R, Photoendocrine transduction in cultured chick pineal cells: effects of light, dark and potassium on the melatonin rhythm, Brain Res, 438 (1988) 199. 4 Karaganis S P, Kumar V, Beremand P D, Bailey M J, Thomas T L & Cassone V M, Circadian genomics of the chick pineal gland in vitro, BMC Genomics, 3 (2008) 206. 5 Janik D, Dittami J & Gwinner E, The effect of pinealectomy on circadian plasma melatonin levels in House Sparrows and European Starlings, J Biol Rhythms, 7 (1992) 277. 6 Kumar V & Gwinner E, Pinealectomy shortens resynchronisation times of House Sparrow (Passer domesticus) circadian rhythms, Naturwissenschaften, 92 (2005) 419. 7 Underwood H & Siopes T, Circadian organization in Japanese Quail, J Exp Zool, 232 (1984) 557. 8 Ebihara S, Oshima I, Yamada H, Goto M & Sato K, Circadian organization in the pigeon, in Comparative aspects of circadian clock, edited by T Hiroshige &K Homma (Hokkaido University Press, Hokkaido, Japan) 1987, 84. 9 Underwood H, The circadian rhythm of thermoregulation in Japanese Quail. I. Role of the eyes and the pineal, J Comp Physiol A, 175 (1994) 639. 10 Shiu S Y& Pang S F, An updated phylogenetic analysis of vertebrate melatonin receptor sequences: Reflection on the melatonin receptor nomenclature by the Nomenclature Subcommittee of the International Union of Pharmacology, Biol Signals Recept, 7 (1998) 244. 11 Reppert S M, Weaver D R, Cassone V M, Godson C & Kolakowski L F Jr, Melatonin receptors are for the birds: Molecular analysis of two receptor subtypes differentially expressed in chick brain, Neuron, 15 (1995) 1003. 12 Dubocovich M L, Melatonin receptors: Are there multiple subtypes?, Trends Pharmacol Sci, 16 (1995) 50. 13 Jones C, Helfer G & Brandstätter R, Melatonin receptor expression in the zebra finch brain and peripheral tissues, Chronobiol Int, 29 (2012) 189. 14 Stephan F K & Zucker I, Circadian rhythms in drinking behavior and locomotor activity of rats are eliminated by hypothalamic lesions, Proc Natl Acad USA, 69 (1972) 1583. 433 15 Rusak B & Zucker I, Neural regulation of circadian rhythms, Physiol Rev, 59 (1979) 449. 16 Yoshimura T, Yasuo S, Watanabe M, Iigo M, Yamamura T, Hirunagi K & Ebihara S, Light induced hormone conversion of T4 to T3 regulates photoperiodic response of gonads in birds, Nature, 426 (2003) 178. 17 Nakao N, Ono H & Yoshimura T, Thyroid hormones and seasonal reproductive neuroendocrine interactions, Reprod, 136 (2008) 1. 18 Dardente H, Wyse C A, Birnie M J, Dupré S M, Loudon A S, Lincoln G A & Hazlerigg D G, A molecular switch for photoperiod responsiveness in mammals, Curr Biol,20 (2010) 2193. 19 Reppert S M, Weaver D R, Ebisawa T, Mahle C D & Kolakowski L F Jr, Cloning of a melatonin-related receptor from human pituitary, FEBS Lett, 386 (1996) 219. 20 Dufourny L, Levasseur A, Migaud M, Callebaut I, Pontarotti P, Malpaux B & Monget P, GPR50 is the mammalian ortholog of Mel1c: evidence of rapid evolution in mammals, BMC Evol Biol, 105 (2008). 21 Levoye A, Dam J, Ayoub M A, Guillaume J L, Couturier C, Delagrange P& Jockers R, The orphan GPR50 receptor specifically inhibits MT1 melatonin receptor function through heterodimerization, EMBO J, 25 (2006) 3012. 22 Drew J E, Barrett P, Mercer J G, Moar K M, Canet E, Delagrange P& Morgan P J, Localization of the melatonin-related receptor in the rodent brain and peripheral tissues, J Neuroendocrinol, 13 (2001) 453. 23 Sidibe A, Mullier A, Chen P, Baroncini M, Boutin J A, Delagrange P, Prevot V & Jockers R, Expression of the orphan GPR50 protein in rodent and human dorsomedial hypothalamus, tanycytes and median eminence, J Pineal Res, 48 (2010) 263. 24 Barrett P, Ivanova E, Graham E S, Ross A W, Wilson D, Plé H, Mercer J G, Ebling F J, Schuhler S, Dupré S M, Loudon A& Morgan P J, Photoperiodic regulation of cellular retinoic acid-binding protein 1, GPR50 and nestin in tanycytes of the third ventricle ependymal layer of the Siberian hamster, J Endocrinol, 191 (2006) 6876. 25 Ivanova E A, Bechtold D A, Dupré S M, Brennand J, Barrett P, Luckman S M & Loudon A S, Altered metabolism in the melatonin-related receptor (GPR50) knockout mouse, Am J Physiol Endocrinol Metab, 294 (2008)176. 26 Bailey M J, Beremand P D, Hammer R, Bell-Pedersen D, Thomas T L & Cassone V M, Transcriptional profiling of the chicken pineal gland, a photoreceptive circadian oscillator and pacemaker, Mol Endocrinol, 17 (2003) 2084. 27 Kumar V & Follett B K, The circadian nature of melatonin secretion in Japanese quail (Coturnix coturnix japonica), J Pineal Res, 14 (1993) 192. 28 Brandstätter R, Kumar V, Abraham U & Gwinner E, Photoperiodic information acquired and stored in vivo is retained in vitro by a circadian oscillator, the avian pineal gland, Proc NatlAcad Sci USA, 97 (2000) 12324. 29 Brandstätter R, Kumar V, Van’t Hof T J & Gwinner E, Seasonal variations of in vivo and in vitro melatonin production in a passeriform bird, the house sparrow (Passer domesticus), J Pineal Res, 31 (2001) 120. 30 Robertson L M & Takahashi J S, Circadian clock in the cell culture: I. Oscillation of melatonin release from dissociated chick pineal cells inflow-through microcarrier culture, J Neurosci, 8 (1988a) 12. 434 INDIAN J EXP BIOL, MAY 2014 31 Robertson L M & Takahashi J S, Circadian clock in the cell culture: II. In vitro photic entrainment of melatonin oscillation from dissociated chick pineal cells, J Neurosci, 8 (1988b) 22. 32 Kumar V & Jain N, Circadian regulation of melatonin secretion in Blackheaded Buntings (Emberiza melanocephala), Indian J Exp Biol, 33 (1995) 333. 33 Bernard M, Iuvone P M, Cassone V M, Rosenboom P H, Coon S L & Klein D C, Avian melatonin synthesis: Photic and circadian regulation of serotonin N-acetyltransferase mRNA in the chicken pineal gland and retina, J Neurochem, 68 (1997) 213. 34 Cassone V M, The self-same beat of time’s wide wings, Proc Nat Acad Sci USA,97 (2000) 11677. 35 Takahashi J S, Hamm H & Menaker M, Circadian rhythms of melatonin release from superfused chicken pineal glands in vitro, Proc Nat Acad Sci USA, 77 (1980) 2319. 36 Murakami N, Nakamura H, Nishi R, Marumoto N & Nasu T, Comparison of circadian oscillation of melatonin release in pineal cells of House Sparrow, Pigeon and Japanese Quail using cell perfusion system, Brain Res, 651 (1994) 209. 37 Cassone V M & Menaker M, Is the avian circadian system a neuroendocrine loop? J Exp Zool, 232 (1984) 539. 38 Gwinner E, Hau M & Heigl S, Melatonin: Generation and modulation of avian circadian rhythms, Brain Res Bull, 44 (1997) 439. 39 Kumar V, Singh B P & Rani S, The Bird Clock: A complex multi-oscillatory and highly diversified system, Biol Rhythm Res, 35 (2004) 121. 40 Gaston S & Menaker M, Pineal function: The biological clock in the sparrow? Science, 160 (1968) 1125. 41 Binkley S, Kluth E & Menaker M, Pineal function in sparrows: Circadian rhythm and body temperature, Science, 174 (1971) 311. 42 Zimmerman N H & Menaker M, Neural connections of sparrow pineal: Role in circadian control of activity, Science, 190 (1975) 477. 43 Zimmerman N H & Menaker M, The pineal gland: A pacemaker within the circadian system of the House Sparrow, Proc Natl Acad Sci USA,76 (1979) 999. 44 Chabot C C & Menaker M, Effects of physiological cycles of infused melatonin on circadian rhythmicity in pigeons, J Comp Physiol A,170 (1992a) 615. 45 Chabot C C & Menaker M, Circadian feeding and locomotor rhythms in pigeons and house sparrows, J Biol Rhythms, 7 (1992b) 287. 46 Heigl S & Gwinner E, Periodic melatonin in the drinking water synchronizes circadian rhythms in sparrows, Naturwissenschaften, 81 (1994) 83. 47 Rani S, Singh S, Malik S, Singh J & Kumar V, Synchronization of Indian weaver bird circadian rhythms to food and light zeitgebers: Role of pineal, Chronobiol Int, 26 (2009) 653. 48 Gwinner E, Effects of pinealectomy on circadian locomotor activity rhythms in European Starlings, Sturnus vulgaris, J Comp Physiol, 126 (1978)123. 49 McBride S, Pineal biochemical rhythms of the Chicken (Gallus domesticus), Ph.D. thesis, University of Pittsburgh, Pittsburgh, PA, 1973 50 Simpson S M & Follett B K, Pineal and hypothalamic pacemakers: their role in regulating circadian rhythmicity in Japanese quail, J Comp Physiol, 141 (1981) 381. 51 Underwood H, Barrett R K & Siopes T, Melatonin does link the eyes to the rest of the circadian system in quail: A neural pathway is involved, J Biol Rhythms, 5 (1990) 349. 52 Oshima I, Yamada H, Goto M, Sato K & Ebihara S, Pineal and retinal melatonin is involved in the control of circadian locomotor activity and body temperature rhythms in the Pigeon, J Comp Physiol A, 166 (1989) 217. 53 Wever R, Pendulum versus relaxation oscillation, in Circadianclocks, edited by J Aschoff, (North-Holland Publ. Company, Amsterdam) 1965, 74. 54 Gwinner E, Circadian and circannual programmes in avian migration, J Exp Biol, 199 (1996) 39. 55 Heigl S & Gwinner E, Synchronization of circadian rhythms of house sparrows by oral melatonin: Effects of changing period, J Biol Rhythms,10 (1995) 225. 56 Heigl S & Gwinner E, Periodic food availability synchronizes locomotor and feeding activity in pinealectomised house sparrows, Zool, 102 (1999) 1. 57 Abraham U, Gwinner E & Van’t Hof T J, Exogenous melatonin reduces the resynchronization time after phase shifts of a nonphotic zeitgeber in the house sparrow (Passer domesticus), J Biol Rhythms, 15 (2000) 48. 58 Hau M & Gwinner E, Continuous melatonin administration accelerates resynchronization following phase shifts of a light-dark cycle, Physiol Behav,58 (1995) 89. 59 Takahashi J S & Menaker M, Role of suprachiasmatic nuclei in the circadian system of the House Sparrow, Passer domesticus, J Neurosci, 2 (1982) 815. 60 Oishi K, Murai I, Sakamoto K, Otsuka H, Miyake Y, Nagase T & Ishida N, The pineal gland is not essential for circadian expression of rat period homologue (rper2) mRNA in the suprachiasmatic nucleus and peripheral tissues, Brain Res, 885 (2000) 298. 61 Amir S, Harbour V L& Robinson B, Pinealectomy does not affect diurnal PER2 expression in the rat limbic forebrain, Neurosci Lett, 399 (2006) 147. 62 Dardente H, Menet J S, Poirel V J, Streicher D, Gauer F, Vivien-Roels B, Klosen P, Pévet P& Masson-Pévet M, Melatonin induces Cry1 expression in the pars tuberalis of the rat, Brain Res Mol Brain Res,114 (2003) 101. 63 Cassone V M, Brooks D S & Kelm T A, Comparative distribution of 2[125I] iodomelatonin binding in the brains of diurnal birds: outgroup analysis with turtles, Brain Behav Evol, 45 (1995) 241. 64 Underwood H & Edmonds K, The circadian rhythm of thermoregulation in Japanese quail: III. Effects of melatonin administration, J Biol Rhythms, 10 (1995) 284. 65 Lumineau S, Guyomarc'h C, Vivien-Roels B & Houdelier C, Cyclic melatonin synchronizes the circadian rhythm of feeding activity in Japanese quail, Coturnix c. japonica, C R Biol, 325 (2002) 205. 66 Yasuo S, Yoshimura T, Bartell P A, Iigo M, Makino E, Okabayashi N & Ebihara S, Effect of melatonin administration on qPer2, qPer3, and qClock gene expression in the suprachiasmatic nucleus of Japanese quail, Eur J Neurosci, 16 (2002) 1541. 67 Abraham U, Albrecht U & Brandstätter R, Hypothalamic circadian organization in birds. II. Clock gene expression, Chronobiol Int, 20 (2003) 657. 68 Karaganis S P, Bartell P A, Shende V R, Moore A F& Cassone V M, Modulation of metabolic and clock gene TRIVEDI & KUMAR: MELATONINE & SEASONAL TIMING 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 mRNA rhythms by pineal and retinal circadian oscillators, Gen Comp Endocrinol, 161 (2009) 179. Gwinner E, Schwabl-Benzinger I, Schwabl H & Dittami J, Twenty-four hour melatonin profiles in a noucturnally migrating bird during and between migratory seasons, Gen Comp Endocrinol, 90 (1993) 119. Cockrem J F, Plasma melatonin in the Adelie penguin (Pygoscelis adeliae) under continuous daylight in Antarctica, J Pineal Res, 10 (1991) 2. Miche F, Vivien-Roels B, Pevet P, Spehner C, Robin J P & Le Maho T, Daily pattern of melatonin secretion in an Antarctic bird, the Emperor Penguin, Aptenodytes forsteri: Seasonal variations, effect of constant illumination and of administration of isoproterenol or propranolol, Gen Comp Endocrinol, 84 (1991) 249. Reierth E, Van’t Hof TJ & Stokkan K A, Seasonal and daily variations in plasma melatonin in the high Arctic svalbard ptarmigan (Lagopus mutus hyperboreus, Gen Comp Endocrinol, 90 (1999) 119. Piesiewicz A, Kedzierska U, Podobas E, Adamska I, Zuzewicz K & Majewski P M, Season-dependent postembryonic maturation of the diurnal rhythm of melatonin biosynthesis in the chicken pineal gland, Chronobiol Intl, 29 (2012) 1227. Gwinner E & Dittami J, Pinealectomy affects the circannual testicular rhythm in European Starlings (Sturnus vulgaris), J Comp Physiol A,136 (1980) 345. Chandola-Saklani A, Bhatt D & Lakhera P, Effect of pinealectomy on free-running reproductive cycle of tropical spotted munia, J Comp Physiol A, 164 (1988) 117. Wilson F E, Neither retinal nor pineal photoreceptors mediate photoperiodic control of seasonal reproduction in American tree sparrows, J Exp Zool, 259 (1991) 117. Kumar V, Effect of melatonin in blocking the response to a skeleton photoperiod in the blackheaded bunting, Physiol Behav, 59 (1996b) 617. Kumar V, Singh S, Misra M, Malik S & Rani S, Role of melatonin in photoperiodic time measurement in the migratory redheaded bunting (Emberiza bruniceps) and the non-migratory Indian Weaver Bird (Ploceus philippinus), J Exp Zool,292 (2002) 277. Saldanha C J, Siverman A J & Silver R, Direct innervation of GnRH neurons by encephalic photoreceptors in birds, J Biol Rhythms,16 (2001) 39. Cardinalli D P, Cuello A E, Tramezzani J H & Rosner J M, Effects of pinealectomy on the testicular function of the adult male duck, Endocrinol, 89 (1971) 1082. Balasubramanian K S & Saxena R N, Effect of pinealectomy and photoperiodism in the reproduction of the Indian weaver birds, Ploceus philippinus, J Exp Zool, 185 (1973) 333. Haldar C & Ghosh M, Annual pineal and testicular cycle in the Indian jungle bush quail, Perdicula asiatica, with reference to the effect of pinealectomy, Gen Comp Endocrinol, 77 (1990)150. Maitra S K & Dey M, Testicular responsiveness to exogenous melatonin during different phases of the annual testicular cycle in rose-ringed parakeet, Psittacula krameri, Eur Arch Biol, 103 (1992) 157. Gupta B B P, Haldar-Misra C, Ghosh M & Thapliyal J P, Effect of melatonin on gonads, body weight and luteinizing hormone (LH) dependent coloration of the Indian finch, lal 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 435 munia (Estrilda amandava), Gen Comp Endocrinol, 65 (1987) 451. Kumar V, Role of melatonin in time-keeping of birds, J Endocr Reprod, 1 (2006) 1. Trivedi A K, Rani S & Kumar V, Melatonin blocks inhibitory effects of prolactin on photoperiodic induction of body fattening, testicular growth and feather regeneration in the migratory male redheaded bunting (Emberiza bruniceps), Reprod Biol Endocr, 2 (2004). Tewary P D, Tripathi B K & Kumar V, Effects of exogenous prolactin on ovarian growth and fattening in the redheaded bunting, Emberiza bruniceps, Gen Comp Endocrinol, 52 (1983) 315. Yoshimura T, Neuroendocrine mechanism of seasonal reproduction in birds and mammals, Anim Sci J, 81 (2010) 403. Foster R G, Follett B K & Lythgoe J N, Rhodopsin-like sensitivity of extra-retinal photoreceptors mediating the photoperiodic response in quail, Nature, 313 (1985) 50. Kumar V, Wingfield J C, Dawson A, Ramenofsky M, Rani S & Bartell P, Biological clocks and regulation of seasonal reproduction and migration in birds, Physiol Biochem Zool, 83 (2010) 827. Ono H, Nakao N & Yoshimura T, Identification of the photoperiodic signaling pathway regulating seasonal reproduction using the functional genomics approach, Gen Comp Endocrinol, 163 (2009) 2. King J A & Millar R P, Structure of chicken hypothalamic luteinizing hormone-releasing hormone. I. Structural determination on partially purified material, J Biol Chem, 257 (1982) 10722. Tsutsui K, Saigoh E, Ukena K, Teranishi H, Fujisawa Y, Kikuchi M, Ishii S & Sharp P J, A novel avian hypothalamic peptide inhibiting gonadotropin release, Biochem Biophys Res Commun, 275 (2000) 661. Ukena K, Ubuka T & Tsutsui K, Distribution of a novel avian gonadotropin-inhibitory hormone in the quail brain, Cell Tissue Res, 312 (2003) 73. Osugi T, Ukena K, Bentley G E, O'Brien S, Moore I T, Wingfield J C & Tsutsui K, Gonadotropin-inhibitory hormone in Gambel's white-crowned sparrow (Zonotrichia leucophrys gambelii): cDNA identification, transcript localization and functional effects in laboratory and field experiments, J Endocrinol, 182 (2004) 33. Perfito N, Zann R, Ubuka T, Bentley G & Hau M, Potential roles for GNIH and GNRH-II in reproductive axis regulation of an opportunistically breeding songbird, Gen Comp Endocrionl, 173 (2011) 20. Ubuka T, Ueno M, Ukena K& Tsutsui K, Developmental changes in gonadotropin-inhibitory hormone in the Japanese quail (Coturnix japonica) hypothalamo-hypophysial system, J Endocrinol, 178 (2003) 311. Ubuka T, Bentley G E, Ukena K, Wingfield J C & Tsutsui K, Melatonin induces the expression of gonadotropin-inhibitory hormone in the avian brain, Proc Natl Acad Sci USA, 102 (2005) 3052. Chowdhury V S, Yamamoto K, Ubuka T, Bentley G E, Hattori A& Tsutsui K, Melatonin stimulates the release of gonadotropin-inhibitory hormone by the avian hypothalamus, Endocrinol, 151 (2010) 271. McGuire N L, Kangas K & Bentley G E, Effects of melatonin on peripheral reproductive function: Regulation of testicular 436 INDIAN J EXP BIOL, MAY 2014 GnIH and testosterone, Endocrinology, 152 (2011) 3461. 101 Bittman E L, Dempsey R J & Karsch F J, Pineal melatonin secretion drives the reproductive response to daylength in the ewe, Endocrinol, 113(1983) 2276. 102 Hoffman R A & Reiter R J, Pineal gland: influence on gonads on male hamsters, Science, 148 (1965) 1609. 103 Carter D S & Goldman B D, Antigonadal effects of timed melatonin infusion in pinealectomized male Djungarian hamsters (Phodopus sungorus sungorus): duration is the critical parameter, Endocrinol, 113 (1983) 1261. 104 Chemineau P, Pelletier J, Guérin Y, Colas G, Ravault J P, Touré G, Almeida G, Thimonier J& Ortavant R, Photoperiodic and melatonin treatments for the control of seasonal reproduction in sheep and goats, Reprod Nutr Dev, 28 (1988) 409. 105 Zarazaga L A, Celi I, Guzmán J L& Malpaux B, Melatonin concentrations in the two jugular veins, and relationship with the seasonal reproductive activity in goats, Theriogenology, 74 (2010) 221. 106 Viguie C, Caraty A, Locatelli A & Malpaux B, Regulation of luteinizing hormone-releasing hormone (LHRH) secretion by melatonin in the ewe. II. Changes in N-methyl-D, L-aspartic acid-induced LHRH release during the stimulation of luteinizing hormone secretion by melatonin, Biol Reprod, 52 (1995) 1156. 107 McMillan W H & Sealey R C, Do melatonin implants influence the breeding season in Coopworth ewes’? Proc NZ Sot Anim Prod, 49 (1989) 43. 108 Haresign W, Peters A R & Staples L D, The effect of melatonin implants on breeding activity and litter size in commercial sheep flocks in the U.K.,Anim Prod, 50 (1990) 111. 109 Zúñiga O, Forcada F & Abecia J A, The effect of melatonin implants on the response to the male effect and on the subsequent cyclicity of Rasa Aragonesa ewes implanted in April, Anim Reprod Sci,72 (2002) 165. 110 Zarazaga L A, Gatica M C, Celi I, Guzma´n J L & Malpaux B, Effect of melatonin implants on sexual activity in Mediterranean goat females without separation from males. Theriogenology, 72 (2009) 910. 111 Zarazaga L A, Gatica M C, Celi I, Guzma´n J L & Malpaux B, Artificial long days in addition to exogenous melatonin and daily contact with bucks stimulate the ovarian and oestrous activity in Mediterranean goat females, Animal, 5 (2011) 1414. 112 Zarazaga L A, Gatica M C, Celi I & Guzmán J L, Reproductive performance is improved during seasonal anoestrus when female and male Murciano-Granadina goats receive melatonin implants and in Payoya goats when females are thus treated, Reprod Domest Anim, 47 (2012) 436. 113 Mousa-Balabel T M & Mohamed R A, Effect of different photoperiods and melatonin treatment on rabbit reproductive performance, Vet Q, 31 (2011) 165. 114 Zann R A, (1996) The zebra finch: A synthesis of field and laboratory studies, edited by R A Zann, (New York: Oxford University Press) 1996. 115 Margoliash D, Functional organization of forebrain pathways for song production and perception, J Neurobiol, 33 (1997) 671. 116 Nottebohm F & Liu W C, The origins of vocal learning: New sounds, new circuits, new cells, Brain Language, 115 (2010) 3. 117 Wild J M, The avian nucleus retroambigualis: a nucleus for breathing, singing and calling, Brain Res, 606 (1993) 319. 118 Wild J M, Neural pathways for the control of birdsong production, J Neurobiol, 33 (1997) 653. 119 Nottebohm F, Nottebohm M E, Crane L A & Wingfield J C, Seasonal changes in gonadal hormone levels of adult male canaries and their relation to song, Behav Neural Biol, 47 (1987) 197. 120 Smith G T, Brenowitz E A, Wingfield J C& Baptista L F, Seasonal changes in song nuclei and song behavior in Gambel's white-crowned sparrows, J Neurobiol, 28 (1995) 114. 121 Whitfield-Rucker M & Cassone VM, Photoperiodic regulation of the male house sparrow song control system: gonadal dependent and independent mechanisms, Gen Comp Endocrinol, 118 (2000) 173. 122 Bentley G E, Van’t Hof T J & Ball G F, Seasonal neuroplasticity in the songbird telencephalon: a role for melatonin, Proc Natl Acad Sci USA, 96 (1999) 4674. 123 Rivkees S A, Cassone V M, Weaver D R & Reppert S M, Melatonin receptors in chick brain: characterization and localization, Endocrinol, 125 (1989) 363. 124 Gahr M & Kosar E, Identification, distribution, and developmental changes of a melatonin binding site in the song control system of the zebra finch, J Comp Neurol, 367 (1996) 308. 125 Whitfield-Rucker M G and Cassone V M, Melatonin binding in the house sparrow song control system: sexual dimorphism and the effect of photoperiod, Horm Behav, 30 (1995) 528. 126 Cassone V M, Bartell P A, Earnest B J & Kumar V, Duration of melatonin regulates seasonal changes in song control nuclei of the house sparrow, Passer domesticus: independence from gonads and circadian entrainment, J Biol Rhythms, 23 (2008) 49. 127 Nottebohm F, Stokes T M & Leonard CM, Central control of song in the canary, Serinus canaria, J Comp Neurol, 165 (1976) 457. 128 Ball G F & Balthazart J, Seasonal and hormonal modulation of neurotransmitter systems in the song control circuit, J Chem Neuroanat, 39 (2010) 82. 129 Wang G, Harpole C E, Trivedi A K & Cassone V M, Circadian regulation birdsong, call and locomotor activity by pineal melatonin in the zebra finch, J Biol Rhythms, 27 (2012) 145. 130 Derégnaucourt S, Poirier C, Kant A V, Linden A V& Gahr M, Comparisons of different methods to train a young zebra finch (Taeniopygia guttata) to learn a song, J Physiol Paris, 107 (2013) 210. 131 Shimmura T & Yoshimura T, Circadian clock determines the timing of rooster crowing, Curr Biol, 23 (2013) R231. 132 Berthold P, Bird migration (Oxford University Press, Oxford) 2nd edition, 2001. 133 Bartell P A & Gwinner E, A separate circadian oscillator controls nocturnal migratory restlessness in the song bird Sylvia borin, J Biol Rhythms, 20 (2005) 538. 134 Rani S, Malik S, Trivedi A K, Singh S & Kumar V, A circadian clock regulates migratory restlessness in the blackheaded bunting, Emberiza melanocephala, 91 (2006) 1093. 135 Fusani L & Gwinner E, Reduced amplitude of melatonin secretion during migration in the blackcap (Sylvia TRIVEDI & KUMAR: MELATONINE & SEASONAL TIMING 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 atricapilla), in Perspectives in comparative endocrinology: Unity and diversity, edited by HJTGoos et al. (Monduzzi. Bologna Italy) 2001, 295. Fusani L, Cardinale M, Schwabl I & Goymann W, Food availability but not melatonin affects nocturnal restlessness in a wild migrating passerine, Horm Behav, 59 (2011) 187. Waterhouse J, Reilly T, Atkinson G& Edwards B, Jet lag: trends and coping strategies, Lancet, 369 (2007) 1117. Suhner A, Schlagenhauf P, Höfer I, Johnson R, Tschopp A & Steffen R, Effectiveness and tolerability of melatonin and zolpidem for the alleviation of jet lag, Aviat Space Environ Med, 72 (2001) 638. Paul M A, Gray G, Sardana T M & Pigeau R A, Melatonin and zopiclone as facilitators of early circadian sleep in operational air transport crews, Aviat Space Environ Med, 75 (2004) 439. Kennaway D J & Wright H, Melatonin and circadian rhythms, Curr Top Med Chem, 2 (2002) 199. Etzioni A, Luboshitzky R, Tiosano D, Ben-Harush M, Goldsher D & Lavie P, Melatonin replacement corrects sleep disturbances in a child with pineal tumor, Neurology, 46 (1996) 261. Lehmann E D, Cockerell O C & Rudge P, Somnolence associated with melatonin deficiency after pinealectomy, Lancet, 347 (1996) 323. Buscemi N, Vandermeer B, Pandya R, Hooton N, Tjosvold L, Hartling L, Baker G, Vohra S & Klassen T, Melatonin for treatment of sleep disorders, Evid Rep Technol Assess (Summ), 108 (2004) 1. Brzezinski A, Vangel M G, Wurtman R J, Norrie G, Zhdanova I, Ben-Shushan A & Ford I, Effects of exogenous melatonin on sleep: a meta-analysis, Sleep Med Rev, 9 (2005) 41. van Geijlswijk I M, Korzilius H P & Smits M G, The use of exogenous melatonin in delayed sleep phase disorder: a meta-analysis, Sleep, 33 (2010) 1605. Ferracioli-Oda E, Qawasmi A& Bloch M H, Meta-analysis: melatonin for the treatment of primary sleep disorders, Plos One, 8 (2013) e63773. MacFarlane J G, Cleghorn J M, Brown G M & Streiner D L, The effects of exogenous melatonin on the total sleep time and daytime alertness of chronic insomniacs: a preliminary study, Biol Psychiatry, 30 (1991) 371. Dollins A B, Zhdanova I V, Wurtman R J, Lynch H J & Deng M H, Effect of inducing nocturnal serum melatonin concentrations in daytime on sleep, mood, body temperature, and performance, Proc Natl Acad Sci USA, 91 (1994) 1824. Garfinkel D, Laudon M, Nof D & Zisapel N, Improvement of sleep quality in elderly people by controlled-release melatonin, Lancet, 346 (1995) 541. Leger D, Laudon M & Zisapel N, Nocturnal 6-sulfatoxymelatonin excretion in insomnia and its relation to the response to melatonin replacement therapy, Am J Med, 116 (2004) 91. Vaughan M K& Reiter R J, Transient hypertrophy of the ventral prostate and coagulating glands and accelerated thymic involution following pinealectomy in the mouse, Tex Rep Biol Med, 29 (1971) 579. View publication stats 437 152 McKinney T D, Vaughan M K& Reiter R J, Pineal influence on intermale aggression in adult house mice, Physiol Behav, 15 (1975) 213. 153 Tian Y M, Zhang G Y & Dai Y R, Melatonin rejuvenates degenerated thymus and redresses peripheral immune functions in aged mice, Immuno Letters, 88 (2003) 101. 154 Csaba G & Baráth P, Morphological changes of thymus and the thyroid gland after postnatal extirpation of pineal body, Endocrinol Exp, 9 (1975) 59. 155 Jankovic B D, Kneievic Z, Koji L, & Nikoli V, Pineal gland and immune system. Immune functions in the chick embryo pinealectomized at 86 hours of incubation, Ann N Y Acad Sci, 719 (1994) 398. 156 Rosolowska-Huszcz D, Thaela M J, Jagura M, Stepien D & Skwarlo-Sonta K, Pineal influence on the diurnal rhythm of nonspecific immunity indices in chickens, J Pineal Res, 10 (1991) 190. 157 Rodriguez A B & Lea R W, Effect of pinealectomy upon the nonspecific immune response of the ring-dove (Streptopelia risoria), J Pineal Res, 16 (1994) 159. 158 Moore C B & Siopes T D, Melatonin can produce immuno enhancement in Japanese quail (Coturnix coturnix japonica) without prior immuno suppression, Gen Comp Endocrinol, 129 (2002) 122. 159 del Gobbo V, Libri V, Villani N, Caliò R& Nisticò G, Pinealectomy inhibits interleukin-2 production and natural killer activity in mice, Int J Immunopharmacol,11 (1989) 567. 160 Cardinali D P & Esquifino A L, Circadian disorganization in experimental arthritis, Neurosignals, 12 (2003) 267. 161 Gonzalez-Haba M G, Garcia-Mauriño S, Calvo J R, Goberna R& Guerrero J M, High-affinity binding of melatonin by human circulating T lymphocytes (CD4+), FASEB J, 9 (1995) 1331. 162 Lissoni P, Rovelli F, Malugani F, Bucovec R, Conti A& Maestroni G J, Anti-angiogenic activity of melatonin in advanced cancer patients, Neuro Endocrnol Lett, 22 (2001) 45. 163 El-Missiry M A& Abd El-Aziz A F, Influence of melatonin on proliferation and antioxidant system in Ehrlich ascites carcinoma cells, Cancer Lett,151 (2000) 119. 164 Lissoni P, Bolis S, Brivio F & Fumagalli L, A phase II study of neuroimmunotherapy with subcutaneous low-dose IL-2 plus the pineal hormone melatonin in untreatable advanced hematologic malignancies, Anticancer Res, 20 (2000) 2103. 165 Trubiani O, Recchioni R, Moroni F, Pizzicannella J, Caputi S & Di Primio R, Melatonin provokes cell death in human B-lymphoma cells by mitochondrial-dependent apoptotic pathway activation, J Pineal Res, 39 (2005) 425. 166 Rubio S, Estévez F, Cabrera J, Reiter R J, Loro J& Quintana J, Inhibition of proliferation and induction of apoptosis by melatonin in human myeloid HL-60 cells, J Pineal Res, 42 (2007) 131. 167 Sánchez-Hidalgo M, Guerrero J M, Villegas I, Packham G& de la Lastra C A, Melatonin, a natural programmed cell death inducer in cancer, Curr Med Chem, 19 (2012) 3805. 168 Margheri M, Pacini N, Tani A, Nosi D, Squecco R, Dama A, Masala E, Francini F, Zecchi-Orlandini S & Formigli L, Combined effects of melatonin and all-trans retinoic acid and somatostatin on breast cancer cell proliferation and death: molecular basis for the anticancer effect of these molecule, E J Pharmacol, 681 (2012) 34.