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date: 19 October 2019

Neuroendocrine Regulation of Seasonal Reproduction

Summary and Keywords

Neuroendocrine mechanisms control the seasonal reproduction in birds and mammals. Seasonal reproduction is ubiquitous across vertebrate and invertebrate species, and its timing is extremely crucial in order to maximize offspring survival. The hypothalamus is the key brain region that integrates environmental cues. An endogenous circannual timer with oscillations that approximate one year is also localized in the hypothalamus. Successful timing of reproduction involves the combination of endogenous internal timers that are entrained by local environmental cues. Photoperiod, or the annual change in day length, is the primary cue most temperate animals use to predict future environmental conditions. Birds are able to detect light through photoreceptors located in the medio-basal hypothalamus. These photoreceptors are localized in neuroendocrine regions and regulate the key reproductive neuropeptide gonadotropin-releasing hormone (GnRH). In mammals, retinal photoreceptors transduce light information the suprachiasmatic nucleus in the hypothalamus, which then modulates the nocturnal duration of melatonin. Melatonin in mammals is crucial, as it regulates the neuroendocrine release of GnRH and downstream transitions across seasonal reproductive states. The tanycyte cells lining the third ventricle (3rdV) of the hypothalamus are the critical node for the integration of internal (i.e., circannual timing) and external (e.g., photoperiod) information necessary for the regulation of seasonal reproduction.

Keywords: hypothalamus, neuropeptides, photoreceptor, epigenetics, tanycytes, rhythmic epigenetics

Introduction

Seasonal reproduction is pervasive across the animal kingdom, and William Rowan in 1926 first showed experimentally the crucial effect day length has on reproduction. Working with the small finch Junco hyemalis, he brought the birds into breeding condition using artificial light in the depths of winter. Although seasonal rhythms in reproduction are more common in higher latitudes due to the salient changes in environmental conditions (Hut et al., 2013), it is not uncommon to observe annual variation in reproduction in species that are endemic to equatorial regions (Hau, 2001). Across avian and mammalian species, the hypothalamus is the key brain region that integrates environmental cues with the endogenous internal timing mechanism, leading to the optimal timing of reproduction necessary for the propagation of the species (Stevenson, Prendergast, & Nelson, 2017; Pérez et al., 2019). One common feature of seasonal reproduction is the robust and predictable molecular oscillations in key neuroendocrine brain regions. These rhythmic-molecular switches are essential to ensure that the birth of the offspring occurs during periods optimal for survival. How the hypothalamic-pituitary-gonadal (HPG) axis controls the annual variation in reproduction has been described in detail elsewhere (see Follett, 2015; Karsch et al., 1984; Saldanha, Leak, & Silver, 1994; Malpaux, Thiery, & Chemineau, 1999; Wood & Loudon, 2014). This article will focus on the neuropeptides and neural circuits in avian and mammalian species regulating seasonal breeding, exploring the role of tanycytes as the central loci for the control of annual reproductive rhythms, as well as the role of epigenetic modifications in timing seasonal gene transcription in neuroendocrine cells.

Environmental and Internal Regulation of Seasonal Reproduction

Environmental Control of Seasonal Reproduction

Environmental cues are divided into proximate and ultimate factors (Baker, 1938). Proximate factors include mechanisms essential for the initiation and progression of reproductive physiology during the breeding season. Ultimate factors are stimuli that affect individual fitness and survival by determining the optimal time for reproduction and birth of the offspring (Baker, 1938). Seasonally breeding species have developed neuroendocrine processes that respond to both ultimate and proximate factors (Nelson, Badura, & Goldman, 1990; Stevenson et al., 2017). Successful timing of seasonal reproduction requires the integration of multiple environmental cues with complex internal, endogenous timing mechanisms (Figure 1a). In general, the annual change in day length, known as photoperiod, is the predictive cue that many animals use to anticipate annual changes in the environment (Figure 1b) (e.g., Dawson, 2015; Paul, Zucker, & Schwartz, 2008; Stevenson & Ball, 2011; MacDougall-Shackleton et al., 2009).

The timing of the termination of breeding is as critical as its stimulation. Photorefractoriness, or loss of a physiological ability to respond to the photoperiodic signal, tightly constrains reproduction to a breeding season. For example, in sheep, short-day refractoriness causes the gonads to regress spontaneously after many months on short days (e.g., Lincoln, Andersson, & Hazlerigg, 2003). Absolute refractoriness in birds is remarkable and rapid. For instance, in white-crowned sparrows (Zonotrichia leucophrys) and European starlings (Sturnus vulgaris), long days stimulate gonadal growth but after two to three months there is a spontaneous shutdown of the HPG axis resulting in gonadal regression (e.g., Nicholls, Goldsmith, & Dawson, 1988; Meddle et al., 2006; Stevenson, Lynch, Ball, & Bernard, 2009). For hamsters and other hibernating species, three to four months of short days result in refractoriness to the inhibitory effects and the gonads recrudesce (e.g., Ebling, 2015; Hut et al., 2013). The complex neuroendocrine machinery underlying photorefractoriness and its disappearance by the next breeding season still requires deciphering. One suggestion is that two separate photoperiodic mechanisms (photo-induction and photo-inhibition) are players in the asymmetrical breeding cycle (Dawson, 2015; Ebling, 2015) and thyroid hormones are key for timing these seasonal transitions; for instance, in sheep, thyroid hormones are crucial for the transition from the reproductive state to anestrus (e.g., Goldsmith & Nicholls, 1984, Nicholls et al., 1988, Parkinson, Douthwaite, & Follett, 1995; Moenter, Woodfill, & Karsch, 1991; Webster et al., 1991; Dahl et al., 1994). It is important to highlight that many animals use long summer days to time breeding (e.g., hamsters, quail) and other animals use short winter day lengths to initiate reproduction (e.g., sheep, emu). A comparison of the neuroendocrine mechanisms is beyond the scope of the current chapter and curious readers are encouraged to read Weems, Goodman, and Lehman (2015). Following the photoinduction of a breeding state, other supplementary cues, such as temperature, food availability, and social information serve to fine tune the timing of reproduction to maximize offspring survival (Wingfield & Kenagy, 1991). However, this article will solely focus on the role of photoperiod to regulate the neuroendocrine control of seasonal reproduction.

Neuroendocrine Regulation of Seasonal ReproductionClick to view larger

Figure 1. Schematic representation of seasonal reproductive rhythms. (A) Many northern hemisphere vertebrates time reproduction to occur during the long-day summer periods due to the significant increase in biomass. Annual cycles of long-day breeding animals are depicted by the black line and relative food abundance is represented by the green line. The two cycles are intrinsically linked, as species have evolved to lay eggs/give birth during times of high food abundance to maximize both parent and offspring survival. During winter when food availability is at its lowest, many temperate zone animals escape the harsh environments by annual endogenous programs in migration or hibernation. The principal forms of seasonal rhythms that have been characterized are Type I and Type II. (B) Type I (mixed) seasonal rhythms are dictated by both endogenous (interval timer) programming and environmental cues, for example, photoperiod. Long day breeders increase reproductive function in response to vernal increase in photoperiods and either terminate reproduction after prolonged exposure to long days (i.e., birds) or exhibit gonadal involution after exposure to decreasing day lengths (i.e., mammals). (C) Type II (circannual) seasonal rhythms are entirely generated by endogenous programs and typically have a period less than 12 months.

Adapted from Stevenson et al. (2017).

Endogenous Seasonal Timing Mechanisms

In addition to environmental cues, seasonal species possess internal timing mechanisms that act as an endogenous annual clock (Figure 1c) (Helm & Stevenson, 2015). The first suggestion that animals, and birds in particular, possess an endogenous circannual clock was demonstrated by Gwinner (1996). Using constant environmental conditions, Gwinner demonstrated that several tropical bird species, such as the East African stonechat and the garden warbler, maintain circannual rhythms in migratory behavior that showed period lengths ranging from 9 to 13 months (Gwinner, 1996). The presence of circannual timing mechanisms has since been identified in a range of species from single-celled organisms (Alexandrium tamarense; Anderson & Keafer, 1987) to mammals (Spermophilus lateralis; Dark, Pickard, Zucker, 1985). The exact molecular and cellular processes that underpin circannual rhythms are unknown. Two prevailing hypotheses have been proposed: the annual birth of new neurons (i.e., neurogenesis: Hazlerigg & Lincoln, 2011) and epigenetic modifications (Stevenson & Lincoln, 2017). A third conjecture is the involvement of circannual clock genes providing seasonal timing information in a manner similar to that of circadian clock genes. Several prospective hypothalamic regions have been proposed to act as the neural node for the central control of seasonal reproduction and include: the suprachiasmatic nucleus (SCN) (Ruby, Dark, Heller, & Zucker, 1998), the pars tuberalis (PT) (Lincoln et al., 2003), and the tanycyte cells that line the ependymal layer of the third ventricle (3rdV) (Meddle & Follett, 1997; Lewis & Ebling, 2017). The SCN is critical for the circadian regulation of daily rhythms of physiological, immunological, behavioral, and cognitive processes (Hastings, Maywood, & Brancaccio, 2018). However, given that golden-mantled ground squirrels maintain circannual rhythms in body weight despite lesioned SCN, it is likely that an alternative brain region provides the neural representation of seasonal time. Moreover, the argument for the PT is not supported from a comparative perspective as fish do not possess a PT, suggesting the anatomical structure is not evolutionarily conserved. Given that female rainbow trout show robust and consistent circannual rhythmicity in gonadal function an alternative cell substrate must provide long-term annual timing (Duston & Bromage, 1991). Overall, the present data support the proposition that the tanycytes in the ependymal layer of the 3rdV are an evolutionarily conserved cell population that are likely the anatomical substrate for the endogenous neuroendocrine timing of seasonal reproduction beyond mammals and birds.

Neuroendocrine Circuits Involved in Seasonal Reproduction in Birds and Mammals

Light Detection in the Avian Brain

For the majority of non-mammalian vertebrates, extra-retinal photoreceptors (ERPs) are critical for the detection of reproductive cues (Menaker, 1989). First identified in European minnows with respect to color change (Frisch, 1911), ERPs have since been identified throughout the brains of non-mammalian vertebrates (reviewed in Pérez et al., 2019). In non-mammalian species, seasonal rhythmicity in reproduction is maintained despite the removal of eyes and the pineal gland (fish: Frisch, 1911; birds: Benoit, 1935; Menaker & Keatts, 1968; lizards: Underwood & Menaker, 1976). The first conclusive evidence for a link between seasonal reproduction and extra-retinal photoreceptors was established by Benoit (1935), which demonstrated that direct long day illumination of the brain could induce breeding in ducks under winter photoperiods. In 1976, Menaker and colleagues continued Benoit’s research and further established a role for ERPs in the avian brain, as part of the seasonal framework that integrates light stimuli and translates them into a reproductive response (Menaker & Underwood, 1976). The medio-basal hypothalamus (MBH) was established to be necessary for the photoperiodic breeding response (Oliver, Jallageas, & Bayle, 1979; Meddle & Follett, 1997), leading to the identification of hypothalamic ERPs in virtually all non-mammalian vertebrates (Young, 1935; Shand & Foster, 1999; Pérez et al., 2019).

However, despite a century of research, the identity of avian breeding ERPs has not yet been established. Opsins can be divided into several subfamilies, depending on G-protein-coupled receptor patterns (reviewed in Pérez et al., 2019). The three main candidates are melanopsin (OPN4) (Provencio et al., 1998; Kang et al., 2010; Sandbakken, Ebbesson, Stefansson, & Helvik, 2012), neuropsin (OPN5) (Nakane et al., 2010; Yamashita et al., 2010; Tarttelin et al., 2003; Surbhi & Kumar, 2015) and vertebrate-ancient opsin (VA opsin) (Soni & Foster, 1997; Garcia-Fernandez et al., 2015). Based on the information gathered from prior studies, the candidate ERP must exhibit the following properties (as reviewed in García-Fernández et al., 2015): (1) the opsin(s) must be expressed in the hypothalamus (Halford et al., 2009); (2) the opsin(s) must be activated by wavelength of ~ 492 nm (Foster & Follett, 1985); (3) the opsin(s) must be linked to circadian clock genes; and (4) the opsin(s) need to be associated with the activation of downstream reproductive pathways. To date, VA opsin has been shown to address all criteria, therefore supporting its role as the main photoreceptor for seasonal breeding in the avian brain (Halford et al., 2009; reviewed in Pérez et al., 2019). Immunoreactive VA opsin cells are localized to the preoptic area, and paraventricular nucleus and fibers were identified in the anterior hypothalamus and basal hypothalamus. Of particular interest was the observation that fibers terminated adjacent to the PT (Halford et al., 2009). Opn5 cells are localized along the ependymal layer in the third and lateral ventricles; the main cell population appears to be in the periventricular organ (PVO) (Nakane et al., 2010). Immunoreactive fibers were shown to project from the PVO directly adjacent to the PT (Nakane et al., 2010).

In birds, one of the earliest confirmed molecular change in response to long-day exposure is an increase in thyrotrophin-stimulating hormone-β‎ (tshβ‎) in the PT (Nakao et al., 2008). Therefore, the photoreceptor that links photoperiodism with the seasonal reproductive response must also link with tshβ‎ expression. In 2012, Stevenson and Ball (2012) used siRNA that targeted OPN5 in the Border canary (Serinus canaria) and observed a significant increase in hypothalamic tshβ‎ expression. A similar negative correlation between OPN5 and tshβ‎ expression has been reported in the migratory redheaded bunting (Emberiza bruniceps) (Majumdar, Yadav, Rani, & Kumar, 2014). Conversely, in Japanese quail (Coturnix japonica), the inhibition of opn5 was observed to inhibit tshβ‎ expression (Nakane et al., 2014). Future studies will need to repeatedly measure tshβ‎ expression over the duration of the photoperiodic response in combination with manipulation of photoreceptor expression in order to definitively establish which photoreceptor(s) is responsible for the detection of light information. Overall, the neuroendocrine circuit that underlies the seasonal regulation of reproduction in birds requires light detection by hypothalamic ERPs that are connected to the PT thyrotrophs. The mechanism(s) by which ERPs are linked to the PT are currently unknown. The long-day increase in thyrotropin-stimulating hormone-β‎ secretion signals the tanycytes to induce T3-dependent morphological changes that permit the release of GnRH from the median eminence (Figure 2). Supplementary environmental cues are then integrated across a diverse range of hypothalamic and extra-hypothalamic nuclei that converge on reproductive neuropeptides, GnRH and GnIH (Meddle et al., 2006; Stevenson et al., 2012a; Kriegsfeld, Ubuka, Bentley, & Tsutsui, 2015).

Neuroendocrine Regulation of Seasonal ReproductionClick to view larger

Figure 2. Neuroendocrine pathways for the photoperiodic regulation of seasonal reproduction in mammals and birds. In avian species, light is detected by extra-retinal photoreceptors (ERPs) located in the hypothalamus. The identity of the photopigments responsible for deep brain photoreception is currently unknown; however, two major candidate genes are neuropsin (Opn5) and vertebrate-ancient opsin (VA opsin). ERPs are connected to the pars tuberalis (PT), which stimulates thyrotropin-stimulated hormone-β‎ (TSH) expression in response to long days. Photoperiodic regulation of TSH triggers tanycytes along the ependymal layer of the third ventricle (3rdV) to increase the expression of deiodinase Type-2 (dio2) and decrease Type-3 (dio3). The localized synthesis of thyroid hormone, triiodothyronine (T3) then induces a morphological change in the tanycytes that permist the pituitary gland to release gonadotrophs: luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Annual changes in day length also regulate neuropeptide expression, gonadotropin-releasing hormone (gnrh) and gonadotropin-inhibitory hormone (gnih). In mammals, annual changes in photoperiod are initially detected by the retina photoreceptors (e.g., melanopsin) and light information is then transmitted to the circadian pacemaker nucleus the suprachiasmatic nucleus of the hypothalamus (SCN). The SCN provides an internal code for daily secretion of melatonin by the pineal gland. The annual variation in nocturnal melatonin secretion regulates the levels of TSH produced by the PT. Similar to birds, long day breeders have high TSH levels that trigger the tanycytes to stimulate DIO2 expression leading to the release of LH and FSH from the pituitary gland. Other supplementary environmental cues also converge on tanycytes and neuropeptides in the hypothalamus to fine tune the timing of seasonal reproduction. The sinewave symbol represents the putative location for the endogenous circannual pacemaker. Solid arrows indicate well described direct connections, the dash arrow between the tanycytes and hypothalamic neuropeptides represents current undescribed connection.

The Role of Melatonin in Mammals

Although extra-retinal photoreceptors such as encephalopsin have been identified in the mammalian diencephalon and pineal gland (Blackshaw et al., 1999), it is likely that extra-retinal photoreceptors in the mammalian brain are not involved in photoperiodism as the evidence to support the capability of light to pass the skull and regulate these opsins is lacking. Instead, photoreceptors in the retina are linked to downstream neuroendocrine pathways via the daily nocturnal pineal secretion of melatonin (Stevenson et al., 2017). Melanopsin expression in the photosensitive retinal ganglion cells is critical for the daily entrainment of circadian rhythms and is likely required for annual photoperiodism (Hankins, Peirson, & Foster, 2008). In mammals, light integration by the SCN is critical for circadian regulation and the photoperiodic control of melatonin secretion by the pineal gland. Nocturnal melatonin provides an internal physiological code for the annual change in night length (Goldman & Nelson, 1993). Long days result in a small nocturnal duration of melatonin, whereas short winterlike days result in a greater nocturnal duration of melatonin (Reiter, 1991; Bartness et al., 1993; Wehr, 1991). The duration of melatonin is sufficient for mammals to initiate different aspects of the reproductive response, such as gonadal recrudescence during long days in summer-breeding species such as hamsters (Foster et al., 1989; Yamazaki, Goto, & Menaker, 1999) and a long duration melatonin signal is stimulatory for short-day breeding species such as sheep (Ovis aries; e.g., Lincoln et al., 2003; Weems et al., 2015; Karsch et al., 1984; Bittman & Karsch, 1984). A simple injection of melatonin in long days in the early afternoon is sufficient to extend the duration of exposure and subsequently induce reproductive involution in hamsters (Bartness et al., 1993). Thus, melatonin provides the internal representation of annual day length and acts in multiple brain regions, including the PT, to drive seasonal variation in reproduction. It is well established that melatonin binds to the melatonin receptor 1b to inhibit hamster reproductive physiology (Prendergast, 2010). Although the precise mechanisms are not well established, annual changes in melatonin have powerful effects on the expression of multiple neuropeptides, neurotransmitters and receptor function in discrete neuroendocrine cell populations. In mammals, melatonin receptors have been shown to be expressed in the PT (Williams & Morgan, 1988), where thyrotrophs are predominantly located. Melatonin binding in the thyrotrophs reduces thyroid-stimulating hormone (TSH) levels (Hanon et al., 2008). TSH triggers an upregulation of the enzyme deiodinase 2 (DIO2), which is responsible for converting thyroxine (T4) into triiodothyronine (T3) during the reproductive period (Klosen et al., 2013). Work by Hanon et al. (2008) indicated that TSHb-signaling system to be evolutionary conserved in seasonally breeding vertebrates (Hanon et al., 2008). In addition, TSH injections were sufficient to drive the long-day reproductive response in male Siberian and Syrian hamsters, through an increase in kisspeptin and RFRP expression (Klosen et al., 2013), implicating these neuropeptides in the seasonal control of reproduction. The mechanism for DIO3 action, responsible for inactivating T3 during the non-reproductive period, is currently unknown. However, its expression is likely to be affected by melatonin. In birds, nocturnal melatonin does not appear to be involved in the hypothalamic timing of seasonal reproduction (Juss, Meddle, Servant, & King, 1993) and instead, functions to synchronize peripheral tissues, particularly the gonads (McGuire et al., 2011).

Neuroendocrine Substrates That Regulate Reproduction in Birds and Mammals

The Role of Neuropeptides: GnRH, Kisspeptin, and GnIH/RFRP3

The master neuroendocrine peptide in the regulation of reproduction is gonadotropin-releasing hormone (GnRH) (Herbison, 2016). GnRH is released from the median eminence in response to photostimulation and targets the gonadotrophs in the anterior pituitary, which, in turn, release the gonadotropins—luteinising hormone (LH) and follicle-stimulating hormone (FSH)—linking the brain to peripheral endocrine systems. LH and FSH both play key roles in the development of characteristics essential for reproductive success. GnRH-secreting cells are expressed in the anterior hypothalamus, preoptic area (POA) in all sexually reproducing species (Stevenson, MacDougall-Shackleton, Hahn, & Ball, 2012a). In birds, the number of cells that express GnRH exhibit robust variation; in some species such as the European starling (Sturnus vulgaris), there is a 10-fold change in the number of detectable cells (Stevenson et al., 2009; Dawson & Goldsmith, 1997) between seasons. However, in other species, such as Galliformes (e.g., chickens) the level of annual mRNA changes in GnRH is significantly less (Dunn & Sharp, 1999). The primary driver of annual plasticity in GnRH expression in birds is the change in photoperiod, as increased day length in the summer triggers a rapid increase in expression leading to a reproductive state (Dawson et al., 2001). However, long days also initiate a cascade of events that terminate the reproductive period (Stevenson et al., 2012b; Dawson & Goldsmith, 1997). How light directly regulates GnRH expression is not entirely clear and may be driven by the localization of photoreceptors in GnRH cells such as VA opsin (Halford et al., 2009) in avian species, or by the coordinated activity of other neuropeptides such as Gonadotropin-inhibitory hormone (GnIH) also referred to as RFamide-related peptide-3 (RFRP3) in mammals.

GnIH neurons are predominantly localized to the paraventricular nucleus (PVN) and have widely distributed projections into diencephalic and mesencephalic regions in birds (Kriegsfeld et al., 2015; Ubuka, Bentley, & Tsutsui, 2013a). GnIH receptors are expressed in the median eminence in quail and gonadotropes in the pituitary gland in quail and chickens (Tsutsui et al., 2000; Ubuka et al., 2013b). Unlike GnRH, the photoperiodic regulation of GnIH expression is minimal. For example, house sparrows (Passer domesticus) show only a small increase in immunoreactive GnIH cells during the non-breeding season (Bentley et al., 2003). The mammalian ortholog, RFRP3, is expressed in the dorsomedial nucleus of the hypothalamus (DMH), projects to the median eminence, and inhibits gonadotropin release in hamsters (Kriegsfeld et al., 2006). However, the direct link between RFRP3 signaling and gonadotropin function has not been clearly delineated. Exposure to short days was found to significantly reduce RFRP3 expression in hamsters (Prendergast, Pyter, Patel, & Stevenson, 2013; Mason et al., 2010), and appears to be downregulated by melatonin (Revel et al., 2008). In sheep, RFRP3 does not directly regulate LH secretion and may instead have indirect effects on reproduction via food intake or stress (Decourt et al., 2016).

In mammals, kisspeptin is generally located in two distinct hypothalamic brain regions, the arcuate nucleus (Arc), and the anteroventral periventricular nucleus (AvPv) in rodents (Yeo & Colledge, 2018). In Siberian hamsters, exposure to reproductively inhibitory short days resulted in a significant increase in Arc kisspeptin cell numbers and a reduction in AvPv cell numbers (Greives et al., 2007). Castration significantly reduced AvPv kisspeptin cells indicating a role for gonadal-dependent regulation of expression (Greives et al., 2008). Conversely, in Syrian hamsters, SD was observed to significantly reduce Arc kisspeptin cell numbers. Syrian hamsters that were pinealectomized and moved to short days showed elevated kisspeptin expression (Revel et al., 2006), suggesting a primary regulatory role for melatonin. This is consistent with the knowledge that short days stimulate weight gain in this species, while causing weight loss in Siberian hamsters (Bartness & Wade, 1984), although they are long-day breeders as well. To date, kisspeptin has not been identified in an avian genome, nor the cognate receptor, G-protein coupled receptor 54 (GPR54) (Kim et al., 2012; Tena-Sempere et al., 2012). The complete absence of these two genes provides strong evidence that kisspeptin-GPR54 signaling is not an evolutionarily conserved mechanism for the control of reproduction. The evidence provided suggests that the neuroendocrine network responsible for seasonal species is complex and differs not only between birds and mammals but also within mammalian species.

The Role of Thyroid Hormones in the Hypothalamus

Thyroid hormones, specifically the bioactive form, triiodothyronine (T3), are thought to play a central role in the seasonal photoperiodic reproductive response (Wu & Koenig, 2000). Thyroid hormones have been tied to the induction of the hypothalamic-pituitary-gonadal (HPG) axis hormonal cascade responsible for development of the physiological characteristics associated with breeding in multiple species (Follett & Nicholls, 1988; Nicholls et al., 1988; Wilson & Reinert, 1995; Reinert & Wilson, 1996; Wilson & Reinert, 1999; Dawson et al., 2001, Pérez, Meddle, Wingfield, & Ramenofsky, 2018). Thyroid hormone delivered directly to the hypothalamus rescues gonadal growth in thyroidectomized animals (Wilson & Reinert, 2000) and induce HPG activation in Japanese quail held under short day lengths (Watanabe et al., 2007). Localized thyroid signaling within the brain is mediated by the diodinase enzyme system. T3 is generated from the corresponding prohormone thyroxine (T4) by the enzyme deiodinase 2 (DIO2) in most tissues (Yoshimura et al., 2003). Deiodinase 1 (DIO1) can also catalyze this reaction; however, it is mainly found in peripheral tissues (Bianco et al., 2002). Conversely, DIO3 is the enzyme responsible for inactivating T3 (Bianco & Kim, 2006; Schweizer et al., 2014). Increasing day-length results in the release of TSHβ‎ from thyrotroph cells of the PT, which act in a paracrine manner to trigger a shift in deiodinase expression within tanycytes lining the 3rdV of the hypothalamus (Yoshimura et al., 2003; Yasuo et al., 2005). The resulting increase in DIO2 and decrease in DIO3 expression results in increased net conversion of T4 to T3 (Watanabe et al., 2007; Nakao et al., 2008; Nakane & Yoshimura, 2010; Mishra et al., 2017). This local increase in T3 has a downstream effect on tanycytes to permit the release of GnRH from the median eminence in long-day breeding species (Figure 2) (Whitlock, 2005; Yamamura, Hirunangi, Ebihara, & Yoshimura, 2004; Lehman et al., 1997), and the inhibition of reproduction in short-day breeders such as sheep (Webster et al., 1991).

Tanycytes Function as an Evolutionarily Conserved Neuroendocrine Regulator

Tanycytes along the 3rdV in the hypothalamus have been proposed to be the predominant neuroendocrine cell population for the regulation of long-term physiological processes, such as seasonal breeding (Figure 3) (e.g., Meddle & Follett, 1997; Lewis & Ebling, 2017). Since tanycytes are derived from an evolutionarily ancient neuroepithelium in vertebrates, these cells are well positioned to be the conserved brain region for endogenous seasonal rhythmicity (Szele & Szuchet, 2003). Furthermore, these cells have been shown to exhibit a photoperiodic change in epigenetic modifications (Stevenson & Prendergast, 2013) as well as contain a stem cell niche (Lee et al., 2012) that could serve as a source of cyclical histogenesis (Hazlerigg & Lincoln, 2011). In addition, tanycytes integrate a range of environmental cues, such as photoperiodic information from the PT (Wood & Loudon, 2018), peripheral endocrine changes in energetic state (Bolborea & Dale, 2013), and respond to gonadal steroids (i.e., estrogen) (de Seranno et al., 2010). Tanycytes also send long projections into adjacent nuclei, such as the Arc, POA, and DMH, and have direct contacts with multiple neuroendocrine systems, such as reproductive, orexogenic, and anorexigenic neuropeptides (Figure 3) (Lechan & Fekete, 2007). The evolutionarily conserved nature of the tanycyte cells, the endogenous regulation of timing mechanisms, and the interaction with well-characterized reproductive neuroendocrine systems all support the conjecture that tanycytes are critical for the regulation of seasonal reproduction.

Neuroendocrine Regulation of Seasonal ReproductionClick to view larger

Figure 3. Tanycytes are an evolutionarily conserved cell population for neuroendocrine function. All vertebrates have tanycyte cells that line the third ventricle (3rdV) and project into the adjacent parenchyma (e.g., Arcuate nucleus [Arc] and median eminence [ME]). (A) representative schematic of a coronal section through the hypothalamus to highlight the distribution of tanycytes along the 3rdV. The black box is represented at a higher resolution in (B). Tanycytes indicated in purple integrate photoperiodic information derived from the PT via thyrotropin-stimulating hormone (TSH) binding to the cognate receptor in long-day photoperiods. TSH triggers the synthesis of triiodothyronine (T3), which induces a morphological change in tanycytes that permits neuropeptide release from the median eminence (e.g., GnRH). Tanycytes also respond to peripheral signals of energy balance such as neuromedin U (NMU) and Glucose (Glu). NMU is photoperiodically regulated in rodents and provides an internal cue of energy state by binding receptors located on tanycytes. Acute, short-term signaling of energy balance is also provided by Glu binding to the GLUT2 receptor on tanycytes. TSH and NMU are downregulated in short-day conditions. These findings indicate that tanycytes integrate environmental and endogenous cues and are therefore a key cell population for the neuroendocrine timing of seasonal reproduction.

Rhythmic Epigenetics Involved in the Seasonal Regulation of Reproduction

One mechanism by which environmental conditions can modulate patterns of gene expression (Bird & Wolffe, 1999) is through epigenetic processes such as DNA methylation and histone acetylation. DNA methylation is by far the most studied form of epigenetic modification, as it has been characterized in a range of species, from unicellular organisms (Harony & Ankri, 2008) to plants (Zhang et al., 2006), to complex mammals (Klose & Bird, 2006). The main enzymes that carry out this process are the DNA methyltransferases (DNMTs), which add a methyl group to mostly cytosine nucleotides in promoter regions (Boyes & Bird, 1991; Bird & Wolffe, 1999; Santoro & Grummt, 2005), although methylation at other nucleotides may occur. Since methylated DNA is more tightly packaged compared to non-methylated DNA, therefore less exposed to transcription components, DNA methylation is most commonly associated with gene inactivation (Bird & Wolffe, 1999). In contrast, the removal of methyl groups increases DNA accessibility and implies increases in gene expression. Different types of DNMTs have been associated with maintaining DNA methylation patterns through cell division (Dnmt1) (Bestor, Laudano, Mattaliano, & Ingram, 1988), as well as establishing new ones (Dnmt3a and Dnmt3b) (Okano et al., 1998; Okano et al., 1999; Robertson et al., 1999).

Indeed, DNA methylation has been associated with both daily and annual changes in light in seasonally breeding species. In the wasp (Nasonia vitripennis), annual changes in DNA methylation have been linked to the stimulation of seasonal diapause (Pegoraro et al., 2015). A seasonal increase in DNA methylation has also been observed in the testes and uteri of Siberian hamsters (Phodopus sungorus. Lynch et al., 2016) and in squirrel (Ictidomys tridecemlineatus) livers (Alvarado et al., 2015) during non-reproductive winter periods. In addition, exposure to short days in Siberian hamsters resulted in a significant decrease in DNA methylation in the proximal promoter regions for DIO3; suggesting a direct link between epigenetic regulation and enzymes involved in the local thyroid hormone catabolism (Stevenson & Prendergast, 2013). Recently, high-throughput analyses have revealed widespread tissue- and nuclei-specific genomic variation in DNA methyltransferase and histone deacetylase enzymes expression (Yoshimura et al., 2003; Mukai et al., 2009; Stevenson et al., 2012c; Cubuk, Kemmling, Fabrizius, & Herwig, 2017; Lomet et al., 2018). The precise downstream genomic targets and functional outcome of rhythmic oscillations in epigenetic modifications remain uncharacterized. Taken together, these studies indicate that epigenetic enzymes show predictable rhythmic patterns that regulate genomic regions critical for the neuroendocrine timing of seasonal reproduction. Thus, it is possible that these rhythmic epigenetic modifications are an adaptive response, especially for species living in extreme environmental settings (Stevenson, 2018), to ensure that reproductive physiological changes occur at the most appropriate time of the year, when factors such as temperature and food availability are able to favor optimal fitness and survival of an individual. It is likely that epigenetic modifications beyond DNA methylation show cell-tissue- and nuclei-specific patterns that are ultimately critical for species variation in the neuroendocrine regulation of seasonal reproduction.

Future Directions

This chapter has provided an overview of the neuroendocrine mechanisms that regulate seasonal reproduction in birds and mammals. There are a number of key questions that remain to be addressed. How do VA opsin and Opn5 cells communicate photoperiodic cues the thyrotrophs in the pars tuberalis to regulate TSH expression in birds? What is the functional role of increased T3 in tanycytes beyond neuromorphological plasticity? And, why do hamsters have high RFRP3 expression when in the long-day breeding conditions? Finally, across all seasonally breeding species, a greater understanding of the mechanisms that time gene transcription in discrete nuclei and cell populations is warranted.

Acknowledgments

The chapter was funded by a Leverhulme Trust Research Project Grant to TJS, ICD, and SLM.

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