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Seasonal Hormonal Changes and Behavior
Seasonal Hormonal Changes and Behavior
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Seasonal Hormonal Changes and Behavior B D Goldman, University of Connecticut, Storrs, CT, USA C K Song and T J Bartness, Georgia State University, Atlanta, GA, USA ã 2009 Elsevier Ltd. All rights reserved.
Mechanisms of Seasonal Timing It is adaptive for organisms to prepare for future changes in seasons so that biologically important physiological and behavioral responses occur at the optimal time of year. A number of environmental cues are used by various species to achieve seasonal timing. Of these, photoperiod is the most widely used cue, likely because it is readily detectable and is the most noise-free environmental signal for establishing seasonal time. Thus, although photoperiod may be of much less direct importance than factors such as food availability and temperature, in many environments it is the best single predictor of seasonal change. Most photoperiodic organisms employ circadian timing mechanisms to measure photoperiod (photoperiod time measurement (PTM)). This phenomenon has been most widely studied in birds, mammals, insects, and plants. In many organisms, including all mammals and birds studied to date, a biological circadian oscillator is involved in PTM.
Retinal Ganglion Cells Are Ultimately Connected to Pinealocytes via the Sympathetic Nervous System In mammals, the photoperiod cue is received by the retinal ganglion cells and is transmitted through a multisynaptic pathway to the pineal gland and their primary cell type, pinealocytes. This has been most elegantly demonstrated using a retrograde transneuronal viral tract tracer, pseudorabies virus (PRV). PRV infects chains of functionally connected neurons labeled from the site of injection (end of the circuit) to its beginning. In brief, the circuit begins with retinal ganglion cells that ultimately project to the pinealocytes through the following neuronal chain: suprachiasmatic nucleus, hypothalamic paraventricular nucleus, intermediolateral horn of the spinal cord, and superior cervical ganglia (Figure 1).
The Pineal Gland Is Part of the Mammalian Photoperiodic Mechanism In addition to the involvement of a circadian clock in PTM mammals, the pineal gland and its primary
hormone, melatonin (MEL), are also key features of PTM. Once the neural signal that codes day length information reaches the pineal via the circuit described previously, it is transduced into a neuroendocrine signal in the form of the rhythmic secretion of MEL into the circulation. Pineal and plasma MEL concentrations are at their nadir during the light phase of the photocycle and at their peak during the dark phase. This pattern of MEL synthesis and secretion results from the regulation of the pineal gland by an endogenous circadian oscillator that is entrained to the light:dark cycle. Thus, the duration of the night is faithfully coded into the duration of MEL secretion and serves to trigger seasonal responses: Long MEL secretion durations signal ‘fall/winter,’ whereas short MEL secretion durations signal ‘spring/summer’ (Figure 2). Photoperiodic mammals can be divided into two categories: Some species, such as the long day-breeding Syrian and Siberian hamsters, and several other rodent species, do not exhibit indications of seasonal change when held under a constant long day length in the laboratory. Exposure to the decreasing day lengths indicative of late summer is a necessary stimulus to induce a shift to the winter physiology/behavior that includes a complete inhibition of reproductive activity. Although an increase in day length can now stimulate a return to reproductive activity and other responses that are typical of spring/summer, this is not a necessary cue. Hamsters will ‘spontaneously’ return to a spring/summer physiological state after being held in short days for approximately 4 or 5 months, with the exact time depending on the species. The exact time of return to the spring/summer phase under constant conditions is apparently determined by the operation of an endogenous interval timer, the anatomical identity and underlying mechanisms of which are unknown. Regardless, the return to spring condition even under conditions of continuous short photoperiod is termed ‘short-day photorefractoriness,’ and this part of the seasonal timing mechanism appears to be a general characteristic of species with this type of annual cycle. A second category of photoperiodic mammals includes those termed ‘circannual.’ These species exhibit repeated cycles of seasonal changes even when held under seasonally constant conditions (fixed day length and unchanging temperature). Under constant conditions, however, the circannual cycles generally have period lengths that are substantially shorter than 365 days. Under field conditions, day length cues are used to adjust the timing of the circannual mechanism so as to yield a true annual periodicity. The domestic
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Figure 1 Using the pseudorabies virus, a transneuronal retrograde tract tracer, the multisynaptic pathway connecting the retina to the pineal gland was defined for the first time within an animal. Retinal projections via the retinohypothalamic tract (not shown) synapse on neurons in the suprachiasmatic nucleus (SCN). In turn, these neurons project to the hypothalamic paraventricular hypothalamic nucleus (PVN), then the preganglionic sympathetic neurons in the intermediolateral cell column (IML), then the postganglionic sympathetic neurons in the superior cervical ganglion (SCG), finally projecting to pinealocytes. Reproduced from Larsen PJ, Enquist LW, and Card JP (1998) Characterization of the multisynaptic neuronal control of the rat pineal gland using viral transneuronal tracing. European Journal of Neuroscience 10: 128–145, with permission.
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Figure 2 Schematic of photoperiod transduction into durational melatonin signals by the pineal gland. Long days and short nights generate short nocturnal melatonin (MEL) durations of synthesis/secretion (left), whereas short days and long nights generate long nocturnal MEL durations of synthesis/secretion (right).
sheep has been the most thoroughly studied of photoperiodic, circannual mammals with respect to how photoperiod cues interact with the endogenous circannual timing mechanism. Sheep are short-day breeders and hence show reproductive activation and mating during late summer, with lambs being born the following spring. As with hamsters, sheep become refractory to continuous short-day exposure; ewes held under constant short days stop showing ovulatory cycles after several months, hence returning to the spring condition. Unlike hamsters, sheep also become refractory to long days. Ewes held under continuous long days – which are initially inhibitory to reproduction – eventually return to ovulatory cyclicity (hamsters held under continuous long day lengths remain reproductively active indefinitely). Thus,
the circannual cycle of the sheep and the seasonal cycle of the hamster both include a role for photoperiodic responsiveness and an endogenous timing mechanism. Whereas both hamsters and sheep can show a spontaneous shift from winter to summer phase (short-day photorefractoriness), sheep show spontaneous shifts from summer to winter phases as well (long-day photorefractoriness). The presence of two distinct phases of ‘spontaneous’ change in the sheep (compared to a single spontaneous change in hamsters) may help to account for the expression of circannual cycles when this species is held under seasonally constant conditions. The process of PTM appears to be essentially the same in sheep and hamsters, despite the fact that sheep are short-day breeders with true circannual
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rhythmicity, whereas hamsters are long-day breeders that are not circannual. In both species, and in most mammals that have been studied, the duration of the nocturnal elevation of MEL secretion is roughly proportional to the length of the dark phase (or inversely proportional to day length). Thus, the duration of nocturnal MEL secretion contains information about the day length, and this information apparently is decoded and then triggers seasonally appropriate changes in target tissues either by direct effects (e.g., pars tuberalis) or via neural activation (e.g., white adipose tissue).
MEL Receptors Occur in the Brain and Periphery, but Stimulation of Specific Central Sites Appears Necessary for Seasonal Changes in Reproductive Status and Adiposity Brain MEL receptors were first suggested by the binding of a radioactive MEL analogue (2-[125I]-iodomelatonin; IMEL) to neural tissue. Only a few IMEL binding sites in the brain exist, although MEL binds extensively to many peripheral tissues. IMEL binds in the brains of a wide range of mammals (e.g., sheep; deer; goats; rabbits; laboratory rats; Syrian, Siberian, and European hamsters; white-footed mice; goldenmantled ground squirrels; guinea pigs; nine-banded armadillos; and humans) as well as nonmammalian vertebrates (Atlantic hagfish, lamprey, hedgehog skates, rainbow trout, and clawed toads). Across many mammalian species, one brain and one peripheral site consistently show IMEL binding – the suprachiasmatic nucleus of the hypothalamus (SCN) and the pars tuberalis (PT) of the pituitary gland, respectively. Many of these species show binding in both the SCN and the PT, although there are a few seasonally breeding species in which IMEL binding only is found in the PT (mink and skunks). Gene expression for one of the MEL receptor subtypes, the MEL 1a receptor (mt1 receptor) is present in the SCN of Siberian hamsters, laboratory rats, and humans, as well as the PT of the first two. Despite extensive studies of MEL binding sites, the specific functional roles of most of these sites have not been established.
Several Model Systems Are Used to Study Seasonal Changes Studies of seasonal changes in endocrine-mediated events have revealed a number of interesting model systems that can be exploited to yield information of general application to both seasonal and nonseasonal species. Several of these systems are described next.
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There Is a Similarity between the Mechanisms Involved in the Alternation between Breeding and Nonbreeding Seasons Compared with Mechanisms Leading to Puberty Onset There is considerable similarity between the endocrine mechanisms that lead to a shift from the seasonal anestrous condition to breeding status and mechanisms involved in puberty onset. Two types of mechanisms have been found to account for the decreased secretion of the pituitary gonadotropic hormones (GTH), leuteinizing hormone (LH), and folliclestimulating hormone (FSH), during seasons of anestrus. In some species, the hypothalamic–pituitary axis shows considerably increased sensitivity to the negative feedback effects of gonadal steroid hormones on secretion of pituitary GTH during seasonal anestrus. The consequence is that blood GTH concentrations are held at very low levels even in the presence of the decreased amounts of steroid hormones produced by the unstimulated gonads. In other species, GTH levels decrease during anestrus even in gonadectomized individuals, indicating that a steroid-independent or direct drive mechanism is responsible for the inhibition of GTH during anestrus. The same two types of mechanisms also have been described as operative in prepubertal mammals, with changes occurring at puberty that lead to an increase in GTH secretion much as similar changes lead to the shift from seasonal anestrus to reproductive activation with the onset of the breeding season. Interestingly, GTH secretion always seems to be largely steroid dependent during the breeding season; that is, during reproductive activation steroid negative feedback always exerts a powerful influence on GTH secretion. This negative feedback system is important for regulating the level of reproductive activity during the breeding season, as has been most clearly illustrated in studies demonstrating the important role of negative feedback to regulate the number of ovarian follicles that develop during an ovulatory cycle and, hence, the number of ova that will be released. During prepubertal development and during the season of anestrus, such precise titration of GTH activity is not required; rather, in these states it is presumably only necessary to achieve an essentially total inhibition of reproductive activity. This can be achieved either via greatly increased sensitivity of the negative feedback regulatory system or by a neural overriding of the system. Pubertal mechanisms may be triggered at a particular age or in relation to attainment of a sufficient amount of utilizable metabolic fuels, usually lipid
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stores. Seasonal activation of the reproductive system generally depends on environmental cues and/or the operation of endogenous timing mechanisms that are relatively independent of age or fat stores. Some cases of puberty incorporate both age-related and environmentally cued components. For example, Siberian hamsters will achieve active reproductive status (puberty) when 40–50 days old if raised in long days; however, if day lengths are short from birth, as in young born at the end of the summer breeding season, puberty will not occur until approximately 5 or 6 months of age, coinciding with the beginning of the next breeding season. The roles of steroid negative feedback and steroid-independent regulation of GTH during the juvenile and pubertal phases are similar to what is seen in seasonal reproductive cycles.
Neuroendocrine Regulation of the Preovulatory Surge of GTH Considerable research has centered on determining the neuroendocrine pathways that regulate the timing of release of the preovulatory LH surge that is accompanied by an increase in FSH secretion of lesser magnitude. The amount of LH released is in excess of the amount required to lead to the ovulation of all mature follicles in the ovaries. The timing of preovulatory LH release is important in that it determines the time of actual ovulation – approximately 10 h after the LH surge in laboratory rodents – and ovulation time should most adaptively be bracketed by the time period when the female is most likely to mate. In mammals that are coitus-induced (or reflex) ovulators, sensory stimulation associated with mating triggers the release of LH so that ovulation will occur several hours later, when viable sperm are still present in the reproductive tract of the female. In spontaneous (or cyclic) ovulating species, a sharp increase in circulating estrogen, originating from newly matured ovarian follicles, is the endocrine stimulus that leads to release of the preovulatory surge of LH. Less emphasis has been placed on the ability of progesterone to delay the LH surge by one or more days; perhaps this is because in some species progesterone can actually advance the LH surge by a short period of time if administered early on the proestrous day, whereas progesterone administered earlier in the cycle may result in a 1- or 2-day delay of LH release. In rats and other cycling rodents studied in the laboratory, the LH surge occurs approximately 1 day after the initial large increase in circulating estrogen. In some species, the timing of the surge is further refined by the action of a circadian clock in the suprachiasmatic nuclei of the hypothalamus. For example, in laboratory rats and Syrian hamsters, the LH surge
occurs during the early afternoon of the day after increased estrogen, with ovulation occurring at approximately midnight or slightly thereafter. This is presumably a time when these nocturnal and relatively nonsocial species are most likely to be successfully inseminated during an encounter with a male. The involvement of a circadian clock in the precise timing of LH release has been clearly demonstrated in studies showing that ovariectomized laboratory rats subjected to continuous administration of estrogen exhibit daily LH surges, occurring at the same time of day as the preovulatory surge that normally occurs only every fourth or fifth day. Studies in the photoperiodic Syrian hamster have revealed an interesting variation on the theme of triggering LH surges by increased levels of estrogen. Syrian hamsters are long-day breeders and ovulatory cycles cease after 4–7 weeks of exposure to short day lengths (<12.5 h light/day). During the anovulatory phase of the annual cycle, female hamsters exhibit daily surges of LH. These surges occur during the early afternoon at about the same time as the preovulatory surges that occur during the breeding season, and the daily surges are of comparable magnitude to the preovulatory surges. These daily surges are expressed, however, even though estrogen levels are continuously very low. Indeed, the daily LH surges continue unabated in anestrous (short-day) females even following ovariectomy or combined ovariectomy and adrenalectomy. Curiously, daily LH surges are also observed in this species during lactation, another situation in which ovulatory cycles are suspended. It is not known whether the daily LH surges that occur in anestrous and lactating hamsters serve a physiological function. Syrian hamsters have extraordinarily regular, 4-day ovulatory cycles and have been well studied with respect to patterns of secretion of reproductive hormones, so the species may provide an interesting model in which to further examine factors that lead to the triggering of the preovulatory LH surge.
Seasonal Changes in Pelage Are Also Governed by Changes in Hormones Triggered by Alterations in the Photoperiod Many temperate zone mammals undergo seasonal changes in pelage, molting their summer fur and developing a more insulative coat in the fall, with reversal of this process as spring approaches. In some species, the winter fur not only is more insulative but also may be different in color from the summer coat. One such species is the Siberian hamster,
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which molts from a grayish-brown summer coat to a white winter pelage that no doubt provides camouflage during winters of heavy snowfall. Several studies in Siberian hamsters have demonstrated that circulating levels of the pituitary hormone prolactin determine what type of fur will be grown following a molt (Figure 3). Baseline prolactin levels are high during the summer and several fold lower during the winter. These seasonal changes in prolactin levels are determined by day length and by the action of the pineal hormone, MEL, as described later. When prolactin levels are artificially manipulated either by administering drugs that stimulate (e.g., pimozide, the dopamine antagonist) or inhibit secretion of the hormone (e.g., bromocryptine, the dopamine agonist) or by direct administration of prolactin or hypophysectomy to remove its source, the type of fur that is produced is always governed by the levels of prolactin. Thus, summer fur grows when prolactin levels are elevated, and winter fur grows when prolactin is decreased or absent. Many photoperiodic mammals show seasonal changes in prolactin that parallel those observed in Siberian hamsters – with high levels of the hormone under long days and low levels under short photoperiods. Seasonal changes in blood prolactin concentrations also have been implicated in seasonal pelage changes in mink, arctic blue fox, and red deer. Thus, prolactin may prove to be the hormone that usually regulates seasonal changes in fur quality. It might seem strange that prolactin, which is known for its role in supporting mammary gland
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function (lactogenesis) in mammals, also should be the hormone that regulates the type of hair produced by hair follicles. Hair follicles, however, are one of a few types of integumentary glands in mammals, including sebaceous glands and sweat glands. Mammary glands are thought to have evolved as specializations of sweat glands so that there is an evolutionary connection between these two types of integumentary glands. Prolactin has also been reported to synergize with testosterone in the regulation of sebaceous gland activity in laboratory rats, suggesting a pattern of prolactin involvement in regulation of different types of integumentary glands and their derivatives, the mammary glands. It may be that for some species prolactin has actions on hair follicles that are not limited to seasonal pelage changes. Laboratory rats develop a more bristly type of hair at the time of puberty compared to the softer fur of juveniles. Furthermore, hypophysectomy of adult rats results in a return to this prepubertal fine/soft fur. An increase in prolactin associated with achievement of puberty has been implicated in this change in pelage quality as well. Finally, although prolactin has some documented effects on body fat, its role in the photoperiodic control of body fat appears minimal at best because manipulations of the hormone to produce long-day circulating physiological concentrations of prolactin in short days, and vice versa, do not in and of themselves create short-day- or long-day-like changes in adiposity, respectively.
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Figure 3 Neuropeptide and leptin receptor gene expression in the hypothalamic arcuate nucleus of adult male Siberian hamsters fed ad libitum (ADLIB) in long days (LD) or short days (SD) or held in long days with restricted food to mimic short day body mass changes (LD-R). Means SEM as percentages of values in LD-ADLIB hamsters. NPY, neuropeptide Y; AGRP, agouti-related protein; POMC, proopiomelanocortin; CART, cocaine and amphetamine-regulated transcript; OB-Rb, leptin receptor long form. Reproduced from Mercer JG and Tups A (2003) Neuropeptides and anticipatory changes in behaviour and physiology: Seasonal body weight regulation in the Siberian hamster. European Journal of Pharmacology 480(1–3): 43–50, with permission.
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Seasonal Changes in Adiposity and Food Intake Are Also Often Regulated by the Photoperiod and Melatonin Many animals exhibit seasonal changes in body mass, usually almost exclusively as changes in body fat (cf., collard lemmings). The patterns of seasonal changes in body fat fall into four major categories: (1) species in which body fat/mass increases in the short ‘winterlike’ days of the fall (e.g., Syrian hamsters and prairie voles) and then decrease, (2) species in which body fat/mass increases from spring to the beginning of fall and then decreases (e.g., Siberian hamsters, meadow and bank voles, deer, and domestic sheep, goats, and cattle), and (3) species that evidence photoperiodcontrolled reproductive responses but show no body mass/fat changes (e.g., Turkish hamsters). Because the photoperiod induces a functional gonadectomy of these animals and because gonadal steroids have profound effects on body mass/fat, it may seem that the seasonal changes in body fat are simply secondary to the changes in gonadal steroids. This notion, however, is not supported because the majority of the photoperiod-induced changes in body fat occur independent of the gonads (i.e., they still occur in previously gonadectomized animals subjected to the photoperiod change). There does not appear to be a hormonal intermediary of MEL for the photoperiod-mediated seasonal changes in adiposity because white adipose tissue lipolysis (fat mobilization) or lipogenesis (fat synthesis) are not triggered in isolated adipocytes (fat cells) by physiological doses of MEL in several species. Instead, at least in Siberian hamsters, it appears that MEL acts through a neural intermediary to decrease body fat in short days. Specifically, injections of PRV, the transneuronal viral tract tracer, into white
fat combined with identification of MEL1a receptor mRNA by in situ hybridization, reveal PRV þ MEL1a co-localization in neurons in brain sites that are part of the sympathetic outflow to white fat (e.g., suprachiasmatic anterior, arcuate, and paraventricular nuclei of the hypothalamus, reuniens/xiphoid, and paraventricular thalamic nuclei). These neuroanatomical data are supported functionally by the increased sympathetic drive to white fat in short-versus longday-housed Siberian hamsters. Moreover, surgical or chemical denervation of the sympathetic nerves innervating white fat blocks short-day-induced decreases in body fat by Siberian hamsters. In addition to seasonal body fat changes, often there are also corresponding changes in feeding; however, the changes in food intake do not completely account for the changes in body/lipid mass. In these cases, alterations in energy expenditure complete the accounting of the mechanisms underlying seasonal changes in body/lipid mass. The seasonal changes in food intake have most extensively been studied in Siberian hamsters, in which body/lipid mass most rapidly decrease during the first 5 or 6 weeks of short day exposure, but food intake only significantly decreases later, after approximately 7–12 weeks of short day exposure (Figure 4). The mechanisms underlying these ultimate decreases in food intake by Siberian hamsters are not precisely known, but in laboratory rodents, changes in food intake are often triggered by alterations in orexigenic (increased feeding) and anorexigenic (decreased feeding) peptides. In Siberian hamsters, however, the well-established roles of these peptides in laboratory rats and mice often do not, at least superficially, hold. For example, in laboratory rodents, decreases in body/lipid mass are associated with increases in gene expression of the orexigenic
Figure 4 Siberian hamster (Phodopus sungorus) littermates treated identically except the animal on the left has been housed in long ‘summer-like’ days, whereas the animal on the right has been housed in short ‘winter-like’ days. Note the change to a white winter pelage in the short day-housed hamster.
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peptides neuropeptide Y (NPY) in the arcuate nucleus and melanin concentrating hormone (MCH) and orexin A in the lateral hypothalamus. In addition, there are decreases in two anorexigenic peptides – leptin, mostly synthesized by adipocytes and secreted into the circulation, and arcuate nucleus cocaine- and amphetamine-regulated transcript (CART). In contrast, when short days trigger decreases in body/lipid mass in Siberian hamsters, these relations do not hold in that arcuate nucleus NPY gene expression and lateral hypothalamic MCH and orexin A do not change and arcuate nucleus CART decreases (Figure 5), but circulating leptin concentrations are decreased. In terms of the latter, when leptin is decreased in laboratory rodents, food intake is increased (as is arcuate nucleus NPY gene expression), but in Siberian hamsters food intake is decreased. Some of the disparity between the photoperiodic control of these peptides
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appears to be reconciled by embracing two views. The first is that unlike the fasting-induced body mass/ fat-reduced laboratory rats and mice, the decreases in body mass/fat of short day-exposed Siberian hamsters are seasonally appropriate; thus, because these peptides serve to counteract deviations in body mass/ fat, they might not be expected to be engaged because the short day decreases are not true ‘deviations’ from normal. Indeed, if Siberian hamsters are fasted to promote decreased body/fat mass in either long or short days, they show the same changes in these peptides as do laboratory rats and mice. Second, the unusual inability of decreased circulating leptin concentrations to stimulate food intake in short days and vice versa appears to be due to changes in leptin sensitivity. That is, long day-housed hamsters are leptin insensitive when circulating leptin concentrations are high, whereas short day-housed hamsters are leptin
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Figure 5 Representation of mechanism by which mother hamster is thought to transmit photoperiod information to her fetuses. Photoperiod information received by the mother’s eye is conveyed by a neural pathway (the retinohypothalamic tract) to the circadian pacemaker in the suprachiasmatic nuclei (SCN). Neural signals from SCN traverse a multisynaptic pathway to the maternal pineal gland to regulate the circadian rhythm of melatonin secretion. Maternal melatonin not only acts on target tissues in the mother but also crosses the placenta to act on similar targets in fetus. (The fetal SCN may be one of these targets.) The fetus does not yet have neural connections between the eye and SCN or between SCN and pineal. Hence, the fetal SCN/pineal unit does not generate a melatonin rhythm of its own. At approximately 2 weeks after birth, all appropriate neural pathways have become established and juvenile hamster (bottom) is able to generate its own melatonin rhythm, shaped by the prevailing photoperiod. The day lengths to which the juvenile is exposed will be either longer or shorter than those that were in effect during gestation, and both absolute day length and direction of change influence the trajectory of early reproductive development. Photoperiod information provided from the mother to the fetus may allow the juvenile to more rapidly assess the direction of change in photoperiod and, hence, to ‘determine’ the time of year. Reproduced from Goldman BD (2003) Pattern of melatonin secretion mediates transfer of photoperiod information from mother to fetus in mammals. Science STKE 2003(192): pe29 (DOI: 10.1126/stke.2003.192.pe29), with permission.
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sensitive when circulating leptin concentrations are naturally low.
Photoperiod Information Is Transmitted from Mother to Fetus It has been demonstrated that the photoperiod experienced by a female rodent during late pregnancy can influence the photoperiodic responses of her offspring. MEL passes from the maternal to the fetal circulation so that the rhythm of circulating MEL is similar in mother and fetus. In Siberian hamsters, there is strong evidence that the mother’s MEL rhythm acts on fetal MEL target tissues and that this allows the fetus to establish a photoperiodic history that can influence its responses to the photoperiod experienced during forthcoming juvenile life. This early photoperiod history is a particularly important influence on juvenile testis development in male Siberian hamster pups that are born into ‘intermediate day lengths’ (14 h of light (14L)). Males born to dams that experienced shorter day lengths (e.g., light:dark cycle 8:16) show relatively rapid testis growth when exposed to 14L postnatally, whereas males born to dams that experienced a longer gestation photoperiod (e.g., light:dark cycle 16:8) show slow testis development in a postnatal 14L day length. This mechanism may allow for rapid and appropriate adjustments with respect to reproductive development. Testis growth is rapid when the photoperiod is increasing, as it would be at the beginning of the breeding season, but is inhibited when the photoperiod is decreasing. See also: Circadian Function and Therapeutic Potential of Melatonin in Humans; Gonadotropin-Releasing Hormone: GnRH-1 System; Melatonin Regulation of Circadian Rhythmicity in Vertebrates; Neuroendocrine Aging: Pituitary–Gonadal Axis in Males; Neuroendocrine Aging: Hypothalamic–Pituitary–Gonadal Axis in Women; Photoperiodic Regulation of Reproductive Cycles; Pineal Gland and Melatonin; Seasonal Changes in Night-Length and Impact on Human Sleep; Seasonal Timing: Neural Mechanisms.
Further Reading Bartness TJ, Demas GE, and Song CK (2002) Seasonal changes in adiposity: The roles of the photoperiod, melatonin and other hormones and the sympathetic nervous system. Experimental Biology and Medicine 227: 363–376. Bartness TJ and Goldman BD (1989) Mammalian pineal melatonin: A clock for all seasons. Experientia 45: 939–945. Bartness TJ, Powers JB, Hastings MH, Bittman EL, and Goldman BD (1993) The timed infusion paradigm for melatonin delivery: What has it taught us about the melatonin signal, its reception, and the photoperiodic control of seasonal responses? Journal of Pineal Research 15: 161–190. Bittman EL (1993) The sites and consequences of melatonin binding in mammals. American Zoologist 33: 200–211. Elliott JA and Goldman BD (1981) Seasonal reproduction: Photoperiodism and biological clocks. In: Adler NT (ed.) Neuroendocrinology of Reproduction, pp. 377–423. New York: Plenum. Goldman BD (2003) Pattern of melatonin secretion mediates transfer of photoperiod information from mother to fetus in mammals. Science STKE 2003(192): pe29 (DOI: 10.1126/ stke.2003.192.pe29). Hastings MH and Herzog ED (2004) Clock genes, oscillators, and cellular networks in the suprachiasmatic nuclei. Journal of Biological Rhythms 19: 400–413. Karsch FJ, Malpaux B, Wayne NL, and Robinson JE (1988) Characteristics of the melatonin signal that provide the photoperiodic code for timing seasonal reproduction in the ewe. Reproduction, Nutrition and Development 28: 459–472. Larsen PJ, Enquist LW, and Card JP (1998) Characterization of the multisynaptic neuronal control of the rat pineal gland using viral transneuronal tracing. European Journal of Neuroscience 10: 128–145. Malpaux B, Viguie C, Skinner DC, Thiery JC, and Chemineau P (1997) Control of the circannual rhythm of reproduction by melatonin in the ewe. Brain Research Bulletin 44: 431–438. Mercer JG and Tups A (2003) Neuropeptides and anticipatory changes in behaviour and physiology: Seasonal body weight regulation in the Siberian hamster. European Journal of Pharmacology 480(1–3): 43–50. Morgan PJ, Ross AW, Mercer JG, and Barrett P (2003) Photoperiodic programming of body weight through the neuroendocrine hypothalamus. Journal of Endocrinology 177: 27–34. Nelson RJ, Demas GE, Klein SL, and Kriegsfeld LJ (1995) The influence of season, photoperiod, and pineal melatonin on immune function. Journal of Pineal Research 19: 149–165. Reiter RJ (1993) The melatonin rhythm: Both a clock and a calendar. Experientia 49: 654–664. Reppert SM (1997) Melatonin receptors: Molecular biology of a new family of G protein-coupled receptors. Journal of Biological Rhythms 12: 528–531.
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Seasonal Hormonal Changes and Behavior B D Goldman, University of Connecticut, Storrs, CT, USA C K Song and T J Bartness, Georgia State University, Atlanta, GA, USA ã 2009 Elsevier Ltd. All rights reserved.
Mechanisms of Seasonal Timing It is adaptive for organisms to prepare for future changes in seasons so that biologically important physiological and behavioral responses occur at the optimal time of year. A number of environmental cues are used by various species to achieve seasonal timing. Of these, photoperiod is the most widely used cue, likely because it is readily detectable and is the most noise-free environmental signal for establishing seasonal time. Thus, although photoperiod may be of much less direct importance than factors such as food availability and temperature, in many environments it is the best single predictor of seasonal change. Most photoperiodic organisms employ circadian timing mechanisms to measure photoperiod (photoperiod time measurement (PTM)). This phenomenon has been most widely studied in birds, mammals, insects, and plants. In many organisms, including all mammals and birds studied to date, a biological circadian oscillator is involved in PTM.
Retinal Ganglion Cells Are Ultimately Connected to Pinealocytes via the Sympathetic Nervous System In mammals, the photoperiod cue is received by the retinal ganglion cells and is transmitted through a multisynaptic pathway to the pineal gland and their primary cell type, pinealocytes. This has been most elegantly demonstrated using a retrograde transneuronal viral tract tracer, pseudorabies virus (PRV). PRV infects chains of functionally connected neurons labeled from the site of injection (end of the circuit) to its beginning. In brief, the circuit begins with retinal ganglion cells that ultimately project to the pinealocytes through the following neuronal chain: suprachiasmatic nucleus, hypothalamic paraventricular nucleus, intermediolateral horn of the spinal cord, and superior cervical ganglia (Figure 1).
The Pineal Gland Is Part of the Mammalian Photoperiodic Mechanism In addition to the involvement of a circadian clock in PTM mammals, the pineal gland and its primary
hormone, melatonin (MEL), are also key features of PTM. Once the neural signal that codes day length information reaches the pineal via the circuit described previously, it is transduced into a neuroendocrine signal in the form of the rhythmic secretion of MEL into the circulation. Pineal and plasma MEL concentrations are at their nadir during the light phase of the photocycle and at their peak during the dark phase. This pattern of MEL synthesis and secretion results from the regulation of the pineal gland by an endogenous circadian oscillator that is entrained to the light:dark cycle. Thus, the duration of the night is faithfully coded into the duration of MEL secretion and serves to trigger seasonal responses: Long MEL secretion durations signal ‘fall/winter,’ whereas short MEL secretion durations signal ‘spring/summer’ (Figure 2). Photoperiodic mammals can be divided into two categories: Some species, such as the long day-breeding Syrian and Siberian hamsters, and several other rodent species, do not exhibit indications of seasonal change when held under a constant long day length in the laboratory. Exposure to the decreasing day lengths indicative of late summer is a necessary stimulus to induce a shift to the winter physiology/behavior that includes a complete inhibition of reproductive activity. Although an increase in day length can now stimulate a return to reproductive activity and other responses that are typical of spring/summer, this is not a necessary cue. Hamsters will ‘spontaneously’ return to a spring/summer physiological state after being held in short days for approximately 4 or 5 months, with the exact time depending on the species. The exact time of return to the spring/summer phase under constant conditions is apparently determined by the operation of an endogenous interval timer, the anatomical identity and underlying mechanisms of which are unknown. Regardless, the return to spring condition even under conditions of continuous short photoperiod is termed ‘short-day photorefractoriness,’ and this part of the seasonal timing mechanism appears to be a general characteristic of species with this type of annual cycle. A second category of photoperiodic mammals includes those termed ‘circannual.’ These species exhibit repeated cycles of seasonal changes even when held under seasonally constant conditions (fixed day length and unchanging temperature). Under constant conditions, however, the circannual cycles generally have period lengths that are substantially shorter than 365 days. Under field conditions, day length cues are used to adjust the timing of the circannual mechanism so as to yield a true annual periodicity. The domestic
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Figure 1 Using the pseudorabies virus, a transneuronal retrograde tract tracer, the multisynaptic pathway connecting the retina to the pineal gland was defined for the first time within an animal. Retinal projections via the retinohypothalamic tract (not shown) synapse on neurons in the suprachiasmatic nucleus (SCN). In turn, these neurons project to the hypothalamic paraventricular hypothalamic nucleus (PVN), then the preganglionic sympathetic neurons in the intermediolateral cell column (IML), then the postganglionic sympathetic neurons in the superior cervical ganglion (SCG), finally projecting to pinealocytes. Reproduced from Larsen PJ, Enquist LW, and Card JP (1998) Characterization of the multisynaptic neuronal control of the rat pineal gland using viral transneuronal tracing. European Journal of Neuroscience 10: 128–145, with permission.
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Figure 2 Schematic of photoperiod transduction into durational melatonin signals by the pineal gland. Long days and short nights generate short nocturnal melatonin (MEL) durations of synthesis/secretion (left), whereas short days and long nights generate long nocturnal MEL durations of synthesis/secretion (right).
sheep has been the most thoroughly studied of photoperiodic, circannual mammals with respect to how photoperiod cues interact with the endogenous circannual timing mechanism. Sheep are short-day breeders and hence show reproductive activation and mating during late summer, with lambs being born the following spring. As with hamsters, sheep become refractory to continuous short-day exposure; ewes held under constant short days stop showing ovulatory cycles after several months, hence returning to the spring condition. Unlike hamsters, sheep also become refractory to long days. Ewes held under continuous long days – which are initially inhibitory to reproduction – eventually return to ovulatory cyclicity (hamsters held under continuous long day lengths remain reproductively active indefinitely). Thus,
the circannual cycle of the sheep and the seasonal cycle of the hamster both include a role for photoperiodic responsiveness and an endogenous timing mechanism. Whereas both hamsters and sheep can show a spontaneous shift from winter to summer phase (short-day photorefractoriness), sheep show spontaneous shifts from summer to winter phases as well (long-day photorefractoriness). The presence of two distinct phases of ‘spontaneous’ change in the sheep (compared to a single spontaneous change in hamsters) may help to account for the expression of circannual cycles when this species is held under seasonally constant conditions. The process of PTM appears to be essentially the same in sheep and hamsters, despite the fact that sheep are short-day breeders with true circannual
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rhythmicity, whereas hamsters are long-day breeders that are not circannual. In both species, and in most mammals that have been studied, the duration of the nocturnal elevation of MEL secretion is roughly proportional to the length of the dark phase (or inversely proportional to day length). Thus, the duration of nocturnal MEL secretion contains information about the day length, and this information apparently is decoded and then triggers seasonally appropriate changes in target tissues either by direct effects (e.g., pars tuberalis) or via neural activation (e.g., white adipose tissue).
MEL Receptors Occur in the Brain and Periphery, but Stimulation of Specific Central Sites Appears Necessary for Seasonal Changes in Reproductive Status and Adiposity Brain MEL receptors were first suggested by the binding of a radioactive MEL analogue (2-[125I]-iodomelatonin; IMEL) to neural tissue. Only a few IMEL binding sites in the brain exist, although MEL binds extensively to many peripheral tissues. IMEL binds in the brains of a wide range of mammals (e.g., sheep; deer; goats; rabbits; laboratory rats; Syrian, Siberian, and European hamsters; white-footed mice; goldenmantled ground squirrels; guinea pigs; nine-banded armadillos; and humans) as well as nonmammalian vertebrates (Atlantic hagfish, lamprey, hedgehog skates, rainbow trout, and clawed toads). Across many mammalian species, one brain and one peripheral site consistently show IMEL binding – the suprachiasmatic nucleus of the hypothalamus (SCN) and the pars tuberalis (PT) of the pituitary gland, respectively. Many of these species show binding in both the SCN and the PT, although there are a few seasonally breeding species in which IMEL binding only is found in the PT (mink and skunks). Gene expression for one of the MEL receptor subtypes, the MEL 1a receptor (mt1 receptor) is present in the SCN of Siberian hamsters, laboratory rats, and humans, as well as the PT of the first two. Despite extensive studies of MEL binding sites, the specific functional roles of most of these sites have not been established.
Several Model Systems Are Used to Study Seasonal Changes Studies of seasonal changes in endocrine-mediated events have revealed a number of interesting model systems that can be exploited to yield information of general application to both seasonal and nonseasonal species. Several of these systems are described next.
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There Is a Similarity between the Mechanisms Involved in the Alternation between Breeding and Nonbreeding Seasons Compared with Mechanisms Leading to Puberty Onset There is considerable similarity between the endocrine mechanisms that lead to a shift from the seasonal anestrous condition to breeding status and mechanisms involved in puberty onset. Two types of mechanisms have been found to account for the decreased secretion of the pituitary gonadotropic hormones (GTH), leuteinizing hormone (LH), and folliclestimulating hormone (FSH), during seasons of anestrus. In some species, the hypothalamic–pituitary axis shows considerably increased sensitivity to the negative feedback effects of gonadal steroid hormones on secretion of pituitary GTH during seasonal anestrus. The consequence is that blood GTH concentrations are held at very low levels even in the presence of the decreased amounts of steroid hormones produced by the unstimulated gonads. In other species, GTH levels decrease during anestrus even in gonadectomized individuals, indicating that a steroid-independent or direct drive mechanism is responsible for the inhibition of GTH during anestrus. The same two types of mechanisms also have been described as operative in prepubertal mammals, with changes occurring at puberty that lead to an increase in GTH secretion much as similar changes lead to the shift from seasonal anestrus to reproductive activation with the onset of the breeding season. Interestingly, GTH secretion always seems to be largely steroid dependent during the breeding season; that is, during reproductive activation steroid negative feedback always exerts a powerful influence on GTH secretion. This negative feedback system is important for regulating the level of reproductive activity during the breeding season, as has been most clearly illustrated in studies demonstrating the important role of negative feedback to regulate the number of ovarian follicles that develop during an ovulatory cycle and, hence, the number of ova that will be released. During prepubertal development and during the season of anestrus, such precise titration of GTH activity is not required; rather, in these states it is presumably only necessary to achieve an essentially total inhibition of reproductive activity. This can be achieved either via greatly increased sensitivity of the negative feedback regulatory system or by a neural overriding of the system. Pubertal mechanisms may be triggered at a particular age or in relation to attainment of a sufficient amount of utilizable metabolic fuels, usually lipid
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stores. Seasonal activation of the reproductive system generally depends on environmental cues and/or the operation of endogenous timing mechanisms that are relatively independent of age or fat stores. Some cases of puberty incorporate both age-related and environmentally cued components. For example, Siberian hamsters will achieve active reproductive status (puberty) when 40–50 days old if raised in long days; however, if day lengths are short from birth, as in young born at the end of the summer breeding season, puberty will not occur until approximately 5 or 6 months of age, coinciding with the beginning of the next breeding season. The roles of steroid negative feedback and steroid-independent regulation of GTH during the juvenile and pubertal phases are similar to what is seen in seasonal reproductive cycles.
Neuroendocrine Regulation of the Preovulatory Surge of GTH Considerable research has centered on determining the neuroendocrine pathways that regulate the timing of release of the preovulatory LH surge that is accompanied by an increase in FSH secretion of lesser magnitude. The amount of LH released is in excess of the amount required to lead to the ovulation of all mature follicles in the ovaries. The timing of preovulatory LH release is important in that it determines the time of actual ovulation – approximately 10 h after the LH surge in laboratory rodents – and ovulation time should most adaptively be bracketed by the time period when the female is most likely to mate. In mammals that are coitus-induced (or reflex) ovulators, sensory stimulation associated with mating triggers the release of LH so that ovulation will occur several hours later, when viable sperm are still present in the reproductive tract of the female. In spontaneous (or cyclic) ovulating species, a sharp increase in circulating estrogen, originating from newly matured ovarian follicles, is the endocrine stimulus that leads to release of the preovulatory surge of LH. Less emphasis has been placed on the ability of progesterone to delay the LH surge by one or more days; perhaps this is because in some species progesterone can actually advance the LH surge by a short period of time if administered early on the proestrous day, whereas progesterone administered earlier in the cycle may result in a 1- or 2-day delay of LH release. In rats and other cycling rodents studied in the laboratory, the LH surge occurs approximately 1 day after the initial large increase in circulating estrogen. In some species, the timing of the surge is further refined by the action of a circadian clock in the suprachiasmatic nuclei of the hypothalamus. For example, in laboratory rats and Syrian hamsters, the LH surge
occurs during the early afternoon of the day after increased estrogen, with ovulation occurring at approximately midnight or slightly thereafter. This is presumably a time when these nocturnal and relatively nonsocial species are most likely to be successfully inseminated during an encounter with a male. The involvement of a circadian clock in the precise timing of LH release has been clearly demonstrated in studies showing that ovariectomized laboratory rats subjected to continuous administration of estrogen exhibit daily LH surges, occurring at the same time of day as the preovulatory surge that normally occurs only every fourth or fifth day. Studies in the photoperiodic Syrian hamster have revealed an interesting variation on the theme of triggering LH surges by increased levels of estrogen. Syrian hamsters are long-day breeders and ovulatory cycles cease after 4–7 weeks of exposure to short day lengths (<12.5 h light/day). During the anovulatory phase of the annual cycle, female hamsters exhibit daily surges of LH. These surges occur during the early afternoon at about the same time as the preovulatory surges that occur during the breeding season, and the daily surges are of comparable magnitude to the preovulatory surges. These daily surges are expressed, however, even though estrogen levels are continuously very low. Indeed, the daily LH surges continue unabated in anestrous (short-day) females even following ovariectomy or combined ovariectomy and adrenalectomy. Curiously, daily LH surges are also observed in this species during lactation, another situation in which ovulatory cycles are suspended. It is not known whether the daily LH surges that occur in anestrous and lactating hamsters serve a physiological function. Syrian hamsters have extraordinarily regular, 4-day ovulatory cycles and have been well studied with respect to patterns of secretion of reproductive hormones, so the species may provide an interesting model in which to further examine factors that lead to the triggering of the preovulatory LH surge.
Seasonal Changes in Pelage Are Also Governed by Changes in Hormones Triggered by Alterations in the Photoperiod Many temperate zone mammals undergo seasonal changes in pelage, molting their summer fur and developing a more insulative coat in the fall, with reversal of this process as spring approaches. In some species, the winter fur not only is more insulative but also may be different in color from the summer coat. One such species is the Siberian hamster,
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which molts from a grayish-brown summer coat to a white winter pelage that no doubt provides camouflage during winters of heavy snowfall. Several studies in Siberian hamsters have demonstrated that circulating levels of the pituitary hormone prolactin determine what type of fur will be grown following a molt (Figure 3). Baseline prolactin levels are high during the summer and several fold lower during the winter. These seasonal changes in prolactin levels are determined by day length and by the action of the pineal hormone, MEL, as described later. When prolactin levels are artificially manipulated either by administering drugs that stimulate (e.g., pimozide, the dopamine antagonist) or inhibit secretion of the hormone (e.g., bromocryptine, the dopamine agonist) or by direct administration of prolactin or hypophysectomy to remove its source, the type of fur that is produced is always governed by the levels of prolactin. Thus, summer fur grows when prolactin levels are elevated, and winter fur grows when prolactin is decreased or absent. Many photoperiodic mammals show seasonal changes in prolactin that parallel those observed in Siberian hamsters – with high levels of the hormone under long days and low levels under short photoperiods. Seasonal changes in blood prolactin concentrations also have been implicated in seasonal pelage changes in mink, arctic blue fox, and red deer. Thus, prolactin may prove to be the hormone that usually regulates seasonal changes in fur quality. It might seem strange that prolactin, which is known for its role in supporting mammary gland
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function (lactogenesis) in mammals, also should be the hormone that regulates the type of hair produced by hair follicles. Hair follicles, however, are one of a few types of integumentary glands in mammals, including sebaceous glands and sweat glands. Mammary glands are thought to have evolved as specializations of sweat glands so that there is an evolutionary connection between these two types of integumentary glands. Prolactin has also been reported to synergize with testosterone in the regulation of sebaceous gland activity in laboratory rats, suggesting a pattern of prolactin involvement in regulation of different types of integumentary glands and their derivatives, the mammary glands. It may be that for some species prolactin has actions on hair follicles that are not limited to seasonal pelage changes. Laboratory rats develop a more bristly type of hair at the time of puberty compared to the softer fur of juveniles. Furthermore, hypophysectomy of adult rats results in a return to this prepubertal fine/soft fur. An increase in prolactin associated with achievement of puberty has been implicated in this change in pelage quality as well. Finally, although prolactin has some documented effects on body fat, its role in the photoperiodic control of body fat appears minimal at best because manipulations of the hormone to produce long-day circulating physiological concentrations of prolactin in short days, and vice versa, do not in and of themselves create short-day- or long-day-like changes in adiposity, respectively.
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Figure 3 Neuropeptide and leptin receptor gene expression in the hypothalamic arcuate nucleus of adult male Siberian hamsters fed ad libitum (ADLIB) in long days (LD) or short days (SD) or held in long days with restricted food to mimic short day body mass changes (LD-R). Means SEM as percentages of values in LD-ADLIB hamsters. NPY, neuropeptide Y; AGRP, agouti-related protein; POMC, proopiomelanocortin; CART, cocaine and amphetamine-regulated transcript; OB-Rb, leptin receptor long form. Reproduced from Mercer JG and Tups A (2003) Neuropeptides and anticipatory changes in behaviour and physiology: Seasonal body weight regulation in the Siberian hamster. European Journal of Pharmacology 480(1–3): 43–50, with permission.
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Seasonal Changes in Adiposity and Food Intake Are Also Often Regulated by the Photoperiod and Melatonin Many animals exhibit seasonal changes in body mass, usually almost exclusively as changes in body fat (cf., collard lemmings). The patterns of seasonal changes in body fat fall into four major categories: (1) species in which body fat/mass increases in the short ‘winterlike’ days of the fall (e.g., Syrian hamsters and prairie voles) and then decrease, (2) species in which body fat/mass increases from spring to the beginning of fall and then decreases (e.g., Siberian hamsters, meadow and bank voles, deer, and domestic sheep, goats, and cattle), and (3) species that evidence photoperiodcontrolled reproductive responses but show no body mass/fat changes (e.g., Turkish hamsters). Because the photoperiod induces a functional gonadectomy of these animals and because gonadal steroids have profound effects on body mass/fat, it may seem that the seasonal changes in body fat are simply secondary to the changes in gonadal steroids. This notion, however, is not supported because the majority of the photoperiod-induced changes in body fat occur independent of the gonads (i.e., they still occur in previously gonadectomized animals subjected to the photoperiod change). There does not appear to be a hormonal intermediary of MEL for the photoperiod-mediated seasonal changes in adiposity because white adipose tissue lipolysis (fat mobilization) or lipogenesis (fat synthesis) are not triggered in isolated adipocytes (fat cells) by physiological doses of MEL in several species. Instead, at least in Siberian hamsters, it appears that MEL acts through a neural intermediary to decrease body fat in short days. Specifically, injections of PRV, the transneuronal viral tract tracer, into white
fat combined with identification of MEL1a receptor mRNA by in situ hybridization, reveal PRV þ MEL1a co-localization in neurons in brain sites that are part of the sympathetic outflow to white fat (e.g., suprachiasmatic anterior, arcuate, and paraventricular nuclei of the hypothalamus, reuniens/xiphoid, and paraventricular thalamic nuclei). These neuroanatomical data are supported functionally by the increased sympathetic drive to white fat in short-versus longday-housed Siberian hamsters. Moreover, surgical or chemical denervation of the sympathetic nerves innervating white fat blocks short-day-induced decreases in body fat by Siberian hamsters. In addition to seasonal body fat changes, often there are also corresponding changes in feeding; however, the changes in food intake do not completely account for the changes in body/lipid mass. In these cases, alterations in energy expenditure complete the accounting of the mechanisms underlying seasonal changes in body/lipid mass. The seasonal changes in food intake have most extensively been studied in Siberian hamsters, in which body/lipid mass most rapidly decrease during the first 5 or 6 weeks of short day exposure, but food intake only significantly decreases later, after approximately 7–12 weeks of short day exposure (Figure 4). The mechanisms underlying these ultimate decreases in food intake by Siberian hamsters are not precisely known, but in laboratory rodents, changes in food intake are often triggered by alterations in orexigenic (increased feeding) and anorexigenic (decreased feeding) peptides. In Siberian hamsters, however, the well-established roles of these peptides in laboratory rats and mice often do not, at least superficially, hold. For example, in laboratory rodents, decreases in body/lipid mass are associated with increases in gene expression of the orexigenic
Figure 4 Siberian hamster (Phodopus sungorus) littermates treated identically except the animal on the left has been housed in long ‘summer-like’ days, whereas the animal on the right has been housed in short ‘winter-like’ days. Note the change to a white winter pelage in the short day-housed hamster.
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peptides neuropeptide Y (NPY) in the arcuate nucleus and melanin concentrating hormone (MCH) and orexin A in the lateral hypothalamus. In addition, there are decreases in two anorexigenic peptides – leptin, mostly synthesized by adipocytes and secreted into the circulation, and arcuate nucleus cocaine- and amphetamine-regulated transcript (CART). In contrast, when short days trigger decreases in body/lipid mass in Siberian hamsters, these relations do not hold in that arcuate nucleus NPY gene expression and lateral hypothalamic MCH and orexin A do not change and arcuate nucleus CART decreases (Figure 5), but circulating leptin concentrations are decreased. In terms of the latter, when leptin is decreased in laboratory rodents, food intake is increased (as is arcuate nucleus NPY gene expression), but in Siberian hamsters food intake is decreased. Some of the disparity between the photoperiodic control of these peptides
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appears to be reconciled by embracing two views. The first is that unlike the fasting-induced body mass/ fat-reduced laboratory rats and mice, the decreases in body mass/fat of short day-exposed Siberian hamsters are seasonally appropriate; thus, because these peptides serve to counteract deviations in body mass/ fat, they might not be expected to be engaged because the short day decreases are not true ‘deviations’ from normal. Indeed, if Siberian hamsters are fasted to promote decreased body/fat mass in either long or short days, they show the same changes in these peptides as do laboratory rats and mice. Second, the unusual inability of decreased circulating leptin concentrations to stimulate food intake in short days and vice versa appears to be due to changes in leptin sensitivity. That is, long day-housed hamsters are leptin insensitive when circulating leptin concentrations are high, whereas short day-housed hamsters are leptin
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Figure 5 Representation of mechanism by which mother hamster is thought to transmit photoperiod information to her fetuses. Photoperiod information received by the mother’s eye is conveyed by a neural pathway (the retinohypothalamic tract) to the circadian pacemaker in the suprachiasmatic nuclei (SCN). Neural signals from SCN traverse a multisynaptic pathway to the maternal pineal gland to regulate the circadian rhythm of melatonin secretion. Maternal melatonin not only acts on target tissues in the mother but also crosses the placenta to act on similar targets in fetus. (The fetal SCN may be one of these targets.) The fetus does not yet have neural connections between the eye and SCN or between SCN and pineal. Hence, the fetal SCN/pineal unit does not generate a melatonin rhythm of its own. At approximately 2 weeks after birth, all appropriate neural pathways have become established and juvenile hamster (bottom) is able to generate its own melatonin rhythm, shaped by the prevailing photoperiod. The day lengths to which the juvenile is exposed will be either longer or shorter than those that were in effect during gestation, and both absolute day length and direction of change influence the trajectory of early reproductive development. Photoperiod information provided from the mother to the fetus may allow the juvenile to more rapidly assess the direction of change in photoperiod and, hence, to ‘determine’ the time of year. Reproduced from Goldman BD (2003) Pattern of melatonin secretion mediates transfer of photoperiod information from mother to fetus in mammals. Science STKE 2003(192): pe29 (DOI: 10.1126/stke.2003.192.pe29), with permission.
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sensitive when circulating leptin concentrations are naturally low.
Photoperiod Information Is Transmitted from Mother to Fetus It has been demonstrated that the photoperiod experienced by a female rodent during late pregnancy can influence the photoperiodic responses of her offspring. MEL passes from the maternal to the fetal circulation so that the rhythm of circulating MEL is similar in mother and fetus. In Siberian hamsters, there is strong evidence that the mother’s MEL rhythm acts on fetal MEL target tissues and that this allows the fetus to establish a photoperiodic history that can influence its responses to the photoperiod experienced during forthcoming juvenile life. This early photoperiod history is a particularly important influence on juvenile testis development in male Siberian hamster pups that are born into ‘intermediate day lengths’ (14 h of light (14L)). Males born to dams that experienced shorter day lengths (e.g., light:dark cycle 8:16) show relatively rapid testis growth when exposed to 14L postnatally, whereas males born to dams that experienced a longer gestation photoperiod (e.g., light:dark cycle 16:8) show slow testis development in a postnatal 14L day length. This mechanism may allow for rapid and appropriate adjustments with respect to reproductive development. Testis growth is rapid when the photoperiod is increasing, as it would be at the beginning of the breeding season, but is inhibited when the photoperiod is decreasing. See also: Circadian Function and Therapeutic Potential of Melatonin in Humans; Gonadotropin-Releasing Hormone: GnRH-1 System; Melatonin Regulation of Circadian Rhythmicity in Vertebrates; Neuroendocrine Aging: Pituitary–Gonadal Axis in Males; Neuroendocrine Aging: Hypothalamic–Pituitary–Gonadal Axis in Women; Photoperiodic Regulation of Reproductive Cycles; Pineal Gland and Melatonin; Seasonal Changes in Night-Length and Impact on Human Sleep; Seasonal Timing: Neural Mechanisms.
Further Reading Bartness TJ, Demas GE, and Song CK (2002) Seasonal changes in adiposity: The roles of the photoperiod, melatonin and other hormones and the sympathetic nervous system. Experimental Biology and Medicine 227: 363–376. Bartness TJ and Goldman BD (1989) Mammalian pineal melatonin: A clock for all seasons. Experientia 45: 939–945. Bartness TJ, Powers JB, Hastings MH, Bittman EL, and Goldman BD (1993) The timed infusion paradigm for melatonin delivery: What has it taught us about the melatonin signal, its reception, and the photoperiodic control of seasonal responses? Journal of Pineal Research 15: 161–190. Bittman EL (1993) The sites and consequences of melatonin binding in mammals. American Zoologist 33: 200–211. Elliott JA and Goldman BD (1981) Seasonal reproduction: Photoperiodism and biological clocks. In: Adler NT (ed.) Neuroendocrinology of Reproduction, pp. 377–423. New York: Plenum. Goldman BD (2003) Pattern of melatonin secretion mediates transfer of photoperiod information from mother to fetus in mammals. Science STKE 2003(192): pe29 (DOI: 10.1126/ stke.2003.192.pe29). Hastings MH and Herzog ED (2004) Clock genes, oscillators, and cellular networks in the suprachiasmatic nuclei. Journal of Biological Rhythms 19: 400–413. Karsch FJ, Malpaux B, Wayne NL, and Robinson JE (1988) Characteristics of the melatonin signal that provide the photoperiodic code for timing seasonal reproduction in the ewe. Reproduction, Nutrition and Development 28: 459–472. Larsen PJ, Enquist LW, and Card JP (1998) Characterization of the multisynaptic neuronal control of the rat pineal gland using viral transneuronal tracing. European Journal of Neuroscience 10: 128–145. Malpaux B, Viguie C, Skinner DC, Thiery JC, and Chemineau P (1997) Control of the circannual rhythm of reproduction by melatonin in the ewe. Brain Research Bulletin 44: 431–438. Mercer JG and Tups A (2003) Neuropeptides and anticipatory changes in behaviour and physiology: Seasonal body weight regulation in the Siberian hamster. European Journal of Pharmacology 480(1–3): 43–50. Morgan PJ, Ross AW, Mercer JG, and Barrett P (2003) Photoperiodic programming of body weight through the neuroendocrine hypothalamus. Journal of Endocrinology 177: 27–34. Nelson RJ, Demas GE, Klein SL, and Kriegsfeld LJ (1995) The influence of season, photoperiod, and pineal melatonin on immune function. Journal of Pineal Research 19: 149–165. Reiter RJ (1993) The melatonin rhythm: Both a clock and a calendar. Experientia 49: 654–664. Reppert SM (1997) Melatonin receptors: Molecular biology of a new family of G protein-coupled receptors. Journal of Biological Rhythms 12: 528–531.