Chapter 1 – Neuroendocrine Control of Reproduction in Birds · itary hormones that control avian reproduction by inducing gametogenesis (spermatogenesis, oogenesis) and sex steroidogenesis

Hormones and Reproduction of Vertebrates, Volume 4dBirds

Copyright � 2011 Elsevier Inc. All rights reserved.

Chapter 1

1

Neuroendocrine Controlof Reproduction in Birds

Takayoshi Ubuka and George E. BentleyUniversity of California at Berkeley, Berkeley, CA, USA

SUMMARYReproductive physiology and behavior of birds are ultimatelycontrolled by the hypothalamusehypophysial system. Hypotha-lamic neurons integrate internal and external signals, controllingreproduction by releasing neurohormones to the adenohypophysis(anterior pituitary). Reproductive activation occurs via gonado-tropin-releasing hormone (GnRH) stimulation of adenohypo-physial gonadotropin secretion. Gonadotropins (GTHs)(luteinizing hormone (LH), follicle-stimulating hormone (FSH))act on the gonads to stimulate gametogenesis and sex steroidproduction. Gonadotropin-inhibiting hormone (GnIH) may inhibitgonadotropin secretion directly or indirectly by decreasing theactivity of GnRH neurons. Another adenohypophysial hormonethat plays an important role in avian reproduction is prolactin(PRL). The secretion of PRL is thought to be regulated bya hypothalamic neuropeptide, vasoactive intestinal peptide.Arginine vasotocin (AVT) is released from the neurohypophysis(posterior pituitary) and regulates oviposition by directly inducinguterine contraction. Several mechanisms are discussed in terms ofhow the brain perceives and translates external environmentalinformation into internal hormonal signals to time seasonalreproduction.

1. INTRODUCTION

Birds (class Aves) are bipedal, homeothermic oviparousvertebrate animals. Modern birdsdcomprising nearly10 000 living speciesdare divided basally into two clades,Palaeognathae and Neognathae (Harshman, 2006). Palae-ognathae includes the ratites (e.g. ostrich (Struthio cam-elus), emu (Dromaius novaehollandiae), and kiwis(Apteryx)) and tinamous. Neognathae is divided into Gal-loanserae and Neoaves. Galloanserae consist of the sisterorders Anseriformes (e.g., ducks, geese, and swans) andGalliformes (e.g., turkeys, grouse, chickens, quail, andpheasants). Neoaves consist of 24 orders, includingColumbiformes (pigeons, doves) and Passeriformes.

Passeriformes include all songbirds, and contain more thanhalf of all bird species (Sibley & Monroe, 1990).

Reproductive activities of birds consist of multiplestages in their life history. Typically, males establishterritories after the initiation of gonadal maturation andform pairs with females. Male and female birds maturetheir gonads and engage in courtship, construct nests,and copulate, and female birds ovulate and lay eggs.After incubating their eggs, they feed nestlings andfledglings. Finally, the reproductive system regresses andthe next life-history stage follows, e.g., molt (Wingfieldet al., 1999). Many passerine species that breed at highlatitudes incorporate two migratory periods betweennonbreeding and breeding stages (Wingfield & Farner,1980).

Reproductive physiology and behavior of birds aregoverned by the hypothalamic (neuroendocrine) controlof pituitary hormone secretion (hypothalamusepituitarysystem (HPS)). Accordingly, this chapter will start witha brief summary of the anatomy of the HPS and theneurohormones involved in avian reproduction. Gonad-otropins (GTHs) (luteinizing hormone (LH), follicle-stimulating hormone (FSH)) are important anterior pitu-itary hormones that control avian reproduction byinducing gametogenesis (spermatogenesis, oogenesis)and sex steroidogenesis (androgens, estrogens, proges-togens) in the gonad. Accordingly, investigation of howthe hypothalamic neurohormones control GTH secretionfrom the pituitary is imperative to understand theneuroendocrine control of reproduction. Two hypotha-lamic neuropeptides, gonadotropin-releasing hormone(GnRH) and gonadotropin-inhibitory hormone (GnIH),which have opposite effects on GTH secretion, will beintroduced. Ovulation and egg-laying (oviposition) arehighly orchestrated female reproductive actions thatinvolve various hormones. Another hypothalamic neuro-hormone, arginine vasotocin (AVT), is released directlyfrom the neurohypophysis and induces oviposition. After

2 Hormones and Reproduction of Vertebrates

oviposition, incubation of the eggs and feeding of theoffspring are the typical next stages in avian life history.These parental behaviors seem to be controlled byanother anterior pituitary hormone, prolactin (PRL).Hypothalamic vasoactive intestinal peptide (VIP) isthought to regulate PRL secretion from the anteriorpituitary. Many birds reproduce seasonally. How do birdsperceive and translate external environmental informa-tion into internal hormonal signals to time reproduction?If reproductive physiology and behavior of birds areultimately controlled by the HPS, how does this systemcontrol seasonal reproductive activities of birds? Doesthe hypothalamus detect the external environmentalsignals itself, or are they detected by other organs and theinformation transduced to the hypothalamic neuronalsystem to control pituitary hormone secretion? Theseinteresting topics will be discussed in Section 3. Finally,we will investigate the lines of research that will benecessary in the future to reveal a more complete pictureof the neuroendocrine control mechanism of avianreproduction.

2. THE HYPOTHALAMUSePITUITARYSYSTEM (HPS)

Reproductive activity of birds is controlled by the HPS.Hypothalamic neurons somehow integrate external (light,temperature, sound, etc.) and internal (water, nutrition,hormones, etc.) information, and regulate the reproductivephysiology and behavior of the bird by releasing neuro-hormones to the pituitary. Figure 1.1 shows the general-ized anatomical structure of the hypothalamus andpituitary in the avian brain (Stokes, Leonard, & Notte-bohm, 1974; Foster, Plowman, Goldsmith, & Follett,1987; Matsumoto & Ishii, 1992). Table 1.1 summarizesthe molecular structures and the known functions of theidentified key neurohormones that control reproduction inbirds. The neuroendocrine system controlling reproduc-tion of birds is summarized in Figure 1.2. Variousneurohormones that seem to play important roles inreproduction, such as GnRH, GnIH, VIP, and AVT, aresynthesized in the brain nuclei of the hypothalamus.Gonadotropin-releasing hormone, GnIH, and VIP are

FIGURE 1.1 Generalized anatomical structure of

the hypothalamus and pituitary in the midsagittal

section of the avian brain. The hypothalamus is in the

anterior part of the diencephalon, which is located

between the telencephalon and midbrain (MB) (inset).

Neuronal cell bodies with a common function often

cluster in specific brain nuclei in the hypothalamus.

The pituitary gland consists of the anterior pituitary

including the pars distalis (PD) and pars tuberalis

(PT), and the posterior pituitary (pars nervosa (PN)).

There is either no pars intermedia in the adult avian

pituitary, or it is highly reduced (Norris, 2007). AHA,

anterior hypothalamic area; AHP, posterior hypotha-

lamic area; CA, anterior commissure; CO, optic

chiasm; IN, infundibular nucleus; ME, median

eminence; MM, medial mammillary nucleus; NIII,

nervus oculomotorius; POD, dorsal preoptic nucleus;

POM, medial preoptic area; PVN, paraventricular

nucleus; PVO, paraventricular organ; SC, supra-

chiasmatic nucleus; TSM, septomesencephalic tract.

Reconstructed from Stokes, Leonard, and Nottebohm

(1974); Foster, Plowman, Goldsmith, and Follett

(1987); Matsumoto and Ishii (1992).

TABLE 1.1 Molecular structure and function of neurohormones controlling reproduction in birds

Structure Species Function

aGnRH-I pEHWSYGLQPG-NH2 (chicken, turkey,goose, dove, zebra finch, Europeanstarling)

Chicken (King & Millar, 1982;Miyamoto et al., 1982; Dunn et al.,1993); turkey (Kang et al., 2006);goose (Huang et al., 2008); dove(Mantei et al., 2008); zebra finch(Stevenson et al., 2009; Ubuka &Bentley, 2009); European starling(Sherwood et al., 1988; Stevensonet al., 2009; Ubuka et al., 2009)

Stimulation of LH and FSH release(Millar & King, 1983; Hattori et al.,1985)

aGnRH-II pEHWSHGWYPG-NH2 (chicken) Chicken (Miyamoto et al., 1984) Stimulation of LH and FSH release(Hattori et al., 1986); stimulation ofcopulation solicitation (Maney et al.,1997b)

GnIH SIRPSAYLPLRF-NH2 (chicken);SIKPSAYLPLRF-NH2 (quail);SIKPFSNLPLRF-NH2 (white-crownedsparrow, zebra finch); SIKPFANLPLRF-NH2 (European starling)

Quail (Tsutsui et al., 2000; Satakeet al., 2001); white-crowned sparrow(Osugi et al., 2004); zebra finch(Tobari et al., 2010); European starling(Ubuka et al., 2008a)

Inhibition of LH and FSH release (Tsutsuiet al., 2000; Ciccone et al., 2004; Osugiet al., 2004; Bentley et al., 2006; Ubukaet al., 2006); inhibition of copulationsolicitation (Bentley et al., 2006)

VIP HSDAVFTDNYSRFRKQMAVKKYLNSVLT-NH2 (chicken, turkey)

Chicken (Nilsson, 1975; Talbot et al.,1995); turkey (You et al., 1995)

Stimulation of PRL release (Macnameeet al., 1986; Opel & Proudman, 1988;Proudman & Opel, 1988)

AVT CYIQNCPRG-NH2 (chicken, goose,turkey, ostrich)

Chicken (Acher et al., 1970); goose(Acher et al., 1970); turkey (Acheret al., 1970); ostrich (Rouille et al.,1986)

Induction of oviposition (Shimada et al.,1986; Saito & Koike, 1992); stimulationof sexual behavior (Kihlstrom &Danninge, 1972; Maney et al., 1997a;Castagna et al., 1998; Goodson, 1998a;1998b; Goodson & Adkins-Reagan,1999)

FSH, follicle-stimulating hormone; LH, luteinizing hormone; PRL, prolactin.

3Chapter | 1 Neuroendocrine Control of Reproduction in Birds

thought to be transmitted through neuronal axons andreleased into the portal vessels in the median eminence(ME). Other mechanisms may exist to orchestrate theactions of various neurohormones, such as direct inter-actions of neurohormones in the hypothalamus. Neuro-hormones released at the ME are directly conveyed to theanterior pituitary (adenohypophysis) in the blood andstimulate or inhibit anterior pituitary hormone secretion.Six adenohypophysial hormones have been identified inbirds: LH, FSH, PRL, thyrotropin (TSH), corticotropin(ACTH), and growth hormone (GH) (Scanes, 1986).Hypothalamic neurohormones, such as AVT and meso-tocin (MST), which are produced in magnocellularneurons in the hypothalamus, are transmitted throughtheir axons and released at the neural lobe of the pitui-tary, which is called the posterior pituitary or pars nerv-osa (Oksche & Farner, 1974). Anterior pituitary hormonesand hypothalamic neurohormones, which are released atthe posterior pituitary, travel in the general circulationand regulate the physiology and behavior of the bird.

3. MECHANISMS AND PATHWAYSREGULATING GONADOTROPIN (GTH)SECRETION

3.1. Gonadotropin-releasing Hormone(GnRH)

Reproductive activities of vertebrates are primarily regu-lated by hypothalamic GnRHs. This decapeptide wasoriginally isolated from mammals (Matsuo, Baba, Nair,Arimura, & Schally, 1971; Burgus et al., 1972) andsubsequently from chickens (King & Millar, 1982; Miya-moto et al., 1982). The molecular structure of the originallyisolated mammalian GnRH (mGnRH-I) is pEHW-SYGLRPG-NH2. Chicken GnRH-I (cGnRH-I) (pEHW-SYGLQPG-NH2) differs by one amino acid from mGnRH-Iin that glutamine is substituted for arginine at positioneight. Specific genes encoding the same cGnRH-I peptidehave been identified by cDNA cloning in Galliformes(chicken, quail, turkey) (Dunn, Chen, Hook, Sharp, &

Brain

Stresshormone

Environmental information (light, food availability, predation pressure etc.)Social interactions (sight, sound, contact etc.)

Melatonin

GnIHaGnRH-I aGnRH-II

GonadsSex steroid

synthesis, release

Spermatogenesis

Oogenesis

Ovulation

Thyroidhormone

AVT

VIP

Sexual behavior

AggressionCourtshipCopulation

Oviposition

Parental behavior

IncubationFeeding

Biological

clock

TSHLH

FSHPRL

PD PD NPTP

T3

T4

DII

FIGURE 1.2 The neuroendocrine system controlling

reproduction of birds. Environmental information, such

as light, food availability, predation pressure, and social

interactions, are perceived by the brain. Hypothalamic

neurohormones integrate external and internal signals to

control pituitary function. The activity of gonadotropin-

inhibiting hormone (GnIH) is likely to be stimulated by

the action of melatonin and stress. Gonadotropin-inhib-

iting hormone may suppress reproductive activities of

birds by directly inhibiting gonadotropin (GTH) (lutei-

nizing hormone (LH) and follicle-stimulating hormone

(FSH)) secretion from the pars distalis (PD), or by

inhibiting the actions of avian gonadotropin-releasing

hormone (aGnRH-I and aGnRH-II) neurons. The stim-

ulatory action of aGnRH-I on GTH secretion may be

accelerated by the action of triiodothyronine (T3) on the

reduction of glial processes encasing aGnRH-I nerve

terminals at the median eminence. Triiodothyronine is

converted from thyroxine (T4) by the action of DII, which

is induced by thyrotropin (TSH). Thyrotropin is synthe-

sized in the pars tuberalis (PT) by photostimulation.

Gonadotropins act on the gonads to induce steroidogen-

esis and gametogenesis. Sex steroids act on various

organs including the brain to organize and activate sex

characteristics. Ovulation in females seems to occur by

the synergistic actions of progesterone (P4), aGnRH-I,

and LH. Cell bodies containing aGnRH-II are found in

the midbrain. It is more likely that aGnRH-II regulates

sexual behavior rather than stimulating GTH secretion.

The neurohypophysial hormone arginine vasotocin

(AVT) produced in magnocellular neurons is released

from the pars nervosa (PN) to induce oviposition. Par-

vocellular AVT neurons are likely to regulate various

male sexual behaviors. Vasoactive intestinal peptide

(VIP) is released at the median eminence (ME) to stim-

ulate prolactin (PRL) release from the PD. Prolactin induces parental behaviors, such as incubation and feeding of the young. The seasonal reproductive

cycle of birds is initiated by the interactions of biological clocks and neurohormones, the actions of which are modified by various external and internal

signals.


Sang, 1993; Kang et al., 2006), Anseriformes (goose, duck)(Huang, Shi, Z. Liu, Y. Liu, & Li, 2008), and Colum-biformes (dove) (Mantei, Ramakrishnan, Sharp, & Buntin,2008). Although the existence of the same cGnRH-Ipeptide was unknown in passerine birds for a long time, themRNA encoding cGnRH-I was recently identified in zebrafinches (Ubuka & Bentley, 2009; Stevenson, Lynch,Lamba, Ball, & Bernard, 2009) and in European starlings(Ubuka, Cadigan, Wang, Liu, & Bentley, 2009; Stevensonet al., 2009). The expression of cGnRH-I peptide in song-birds also has been suggested from its high-performanceliquid chromatography (HPLC) elution pattern and itscross-reactivity with various GnRH antisera (Sherwood,Wingfield, Ball, & Dufty, 1988). Accordingly, cGnRH-Icould be called avian GnRH-I (aGnRH-I) and we will usethis naming in this chapter. There is a second form ofGnRH, which is called chicken GnRH-II (cGnRH-II).Chicken GnRH-II was first found in chickens and subse-quently in mammals (Miyamoto et al., 1984; King, Mehl,Tyndale-Biscoe, Hinds, & Millar, 1989; Morgan & Millar,2004; Millar, 2005) and eventually in all vertebrate groups

(Norris, 2007; see also Volume 1, Chapter 2; Volume 2,Chapter 2; Volume 5, Chapter 2). The structure of cGnRH-II (pEHWSHGWYPG-NH2) differs by three amino acidsfrom mGnRH-I or aGnRH-I at positions five, seven, andeight. We will also refer to cGnRH-II as avian GnRH-II(aGnRH-II) to be consistent with the naming of aGnRH-I.Note that aGnRH-I and -II were formerly named cGnRH-Iand -II, respectively.

Specific antibodies against avian GnRH peptides(aGnRH-I and aGnRH-II) have been made, and the histo-logical localization of aGnRHs has been studied in thechicken and quail (Mikami, Yamada, Hasegawa, & Miya-moto, 1988; Van Gils et al., 1993). In mammals, the GnRH-I neurons originate at the olfactory placode and migrate topreoptic-septal nuclei during embryonic development(Wray, Grant, & Gainer, 1989; Schwanzel-Fukuda & Pfaff,1989). The migration of aGnRH-I neurons from theolfactory placode to the forebrain along the olfactory nervealso has been observed in chickens (Norgren & Lehman,1991; Akutsu, Takada, Ohki-Hamazaki, Murakami, & Arai,1992; Yamamoto, Uchiyama, Ohki-Hamazaki, Tanaka, &


Ito, 1996). In adult birds, aGnRH-I-immunoreactive (-ir)cell bodies are found in a fairly wide area covering thehypothalamic preoptic area (POA) to the thalamic region.On the other hand, magnocellular aGnRH-II-ir cell bodieswere found in the area dorsomedial to the nervus oculo-motorius in the midbrain. Fibers immunoreactive foraGnRH-I or aGnRH-II were widely distributed in thetelencephalon, diencephalon, and mesencephalon(midbrain). In sharp contrast to the existence of abundantaGnRH-I-ir fibers in the external layer of the ME, aGnRH-II-ir fibers were absent or less prominent in this area,suggesting that the major GnRH controlling pituitaryfunction is aGnRH-I (Mikami et al., 1988; Van Gils et al.,1993).

Specific radioimmunoassays (RIAs) for chicken LH(Follett, Scanes, & Cunningham, 1972), turkey LH (Burke,Licht, Papkoff, & Bona-Gallo, 1979), and chicken FSH(Scanes, Godden, & Sharp, 1977; Sakai & Ishii, 1980) havebeen developed and used to measure the effect of GnRH onGTH release. The action of aGnRH-I on LH release fromchicken anterior pituitary cells was first shown in vitro(Millar & King, 1983). Subsequently, the activities ofaGnRH-I on LH and FSH release was shown both in vivoand in vitro in quail (Hattori et al., 1985). The activity ofaGnRH-I on LH release was more marked than that on FSHrelease both in vivo and in vitro (Hattori et al., 1985). Theactivity of aGnRH-II (Miyamoto et al., 1984) on LH andFSH release was also shown in vivo and in vitro (Hattori,Ishii, & Wada, 1986). The activity of aGnRH-II on LH andFSH release was almost equal to that of aGnRH-I. Again,the activity of aGnRH-II on LH release was more markedthan on FSH release both in vivo and in vitro. No synergismwas observed between aGnRH-I and aGnRH-II on LH orFSH release in vitro (Hattori et al., 1986).

The physiological roles of aGnRH-I and aGnRH-II onLH release also have been investigated in chickens (Sharpet al., 1990). Egg laying of somatically mature hens isregulated by strain differences and environmental condi-tions. As ovulation is controlled by the preovulatory LHsurge (as described in Section 4.1), the activity of GnRHmay be higher in laying hens. The amount of aGnRH-I inthe ME was higher in laying than in out-of-lay hens, asmeasured by RIA. Avian GnRH-II was not detected in theME. The amount of aGnRH-I in the hypothalamusincreased in cockerels at the onset of puberty, but theamount of aGnRH-II did not change. Active immunizationof laying hens against aGnRH-I but not against aGnRH-IIresulted in the complete regression of the reproductivesystem. Accordingly, it was concluded that GTH secretionin chickens is more likely to be controlled by aGnRH-I(Sharp et al., 1990). On the other hand, aGnRH-II may beinvolved in the control of sexual behaviors in variousanimals (Millar, 2003). Indeed aGnRH-II, but notaGnRH-I, administered to the brain increased copulation

solicitation display, a female courtship behavior, in femalewhite-crowned sparrows (Maney, Richardson, & Wing-field, 1997).

Three GnRH receptor (GnRH-R) subtypes (types I, II,and III) have been identified, each with distinct distribu-tions and functions in vertebrates (Millar et al., 2004).These receptor subtypes belong to the G-protein-coupledreceptor (GPCR) superfamily. Two receptor subtypes havebeen identified in chickens: type I (GnRH-R-I) (Sun et al.,2001a; 2001b) and type III (GnRH-R-III) (Shimizu &Bedecarrats, 2006), according to the classification byMillar et al. (2004). GnRH-R-I is widely expressed, andaGnRH-II has a higher binding affinity to this receptor andis more potent in stimulating accumulation of inositol tri-sphosphate, a secondary messenger molecule that caninduce GTH release, than aGnRH-I (Sun et al., 2001a;2001b). Inositol trisphosphate accumulation in response toaGnRH-II binding to GnRH-R-III was also more markedthan in response to aGnRH-I. As fully processed GnRH-R-III mRNAwas exclusively expressed in the pituitary, and itsmRNA level was positively correlated with reproductivestates in both sexes, it is likely that GnRH-R-III plays a rolein the regulation of GTH secretion by pituitary gonado-tropes (Shimizu & Bedecarrats, 2006). Despite the impli-cation here that aGnRH-II is more effective in regulation ofgonadotrope function, the current opinion is that aGnRH-I,and not aGnRH-II, is the dominant regulator of GTHrelease.

3.2. Gonadotropin-inhibiting Hormone(GnIH)

A hypothalamic neuropeptide, GnIH, has been found to bean inhibiting factor for LH release from the quail anteriorpituitary (Tsutsui et al., 2000). Gonadotropin-inhibitinghormone-ir neuronal cell bodies are located in the para-ventricular nucleus (PVN) in quail (Ubuka, Ueno, Ukena,& Tsutsui, 2003; Ukena, Ubuka, & Tsutsui, 2003). Theseneurons project to the ME, thus providing a functionalanatomical infrastructure that regulates anterior pituitaryfunction. A cDNA encoding the GnIH precursor poly-peptide has been cloned from the brains of quail (Satakeet al., 2001), white-crowned sparrows (Osugi et al., 2004),European starlings (Ubuka et al., 2008a), and zebrafinches (Tobari et al., 2010). The expression of GnIHprecursor mRNA also has been observed in the PVN ofthese birds.

Gonadotropin-inhibiting hormone homologs are presentin the brains of other vertebrates, such as mammals,amphibians, and fishes (Tsutsui & Ukena, 2006; Fukusumi,Fujii, & Hinuma, 2006). These peptides, categorized asRFamide-related peptides (RFRPs), possess a characteristicLPXRF-amide (X ¼ L or Q) motif at their C-termini in allvertebrates tested. Three LPXRF-amide (X ¼ L or Q)


peptide sequences are encoded in the GnIH precursorpolypeptide, designated GnIH-related peptide-1 (GnIH-RP-1), GnIH, and GnIH-RP-2. Quail GnIH (SIKPSAYLPLRF-amide), quail GnIH-RP-2 (SSIQSLLNLPQRF-amide),starling GnIH (SIKPFANLPLRF-amide), and zebra finchGnIH (SIKPFSNLPLRF-amide) have been identified asmature endogenous peptides by mass spectrometric analyses(Satake et al., 2001; Ubuka et al., 2008a, Tobari et al., 2010).

The receptor for quail GnIH has been identified and itsbinding activities have been investigated (Yin, Ukena,Ubuka, & Tsutsui, 2005). Structural analysis of the quailGnIH receptor revealed that it belongs to the GPCRsuperfamily. A crude membrane fraction of COS-7 cellstransfected with the quail GnIH receptor cDNA specificallybound GnIH, GnIH-RP-1, and GnIH-RP-2 in a concentra-tion-dependent manner. The identified quail GnIH receptormRNAwas expressed in the pituitary as well as in variousparts of the brain. The mammalian homolog of GnIHreceptor is GPR147 (OT7T022, NPFF-1), and the mecha-nism of RFRP action on mammalian cellular events hasbeen investigated (Fukusumi et al., 2006). RFamide-relatedpeptides suppressed the production of cyclic-3’,5’-adeno-sine monophosphate (cAMP) in Chinese hamster ovariancells transfected with GPR147, suggesting that the receptorcouples to the a-subunit of the inhibitory G-protein (Gai).GPR147 mRNA is also expressed in various parts of themammalian brain as well as in the pituitary, suggesting thatthere are multiple actions of GnIH within the centralnervous system (Hinuma et al., 2000).

The actual release of GnIH into the hypothal-amusehypophysial portal system has not been reported inany vertebrate. However, the dense population of GnIH-irfibers in the ME in quail (Tsutsui et al., 2000; Ubuka et al.,2003; Ukena et al., 2003), house sparrows and song sparrows(Bentley, Perfito, Ukena, Tsutsui, & Wingfield, 2003), andEuropean starlings (Ubuka et al., 2008a) suggests a role forGnIH in the regulation of pituitary function, at least in thesebirds. The same is true for white-crowned sparrows. The factthat GnIH inhibits release of GTHs from cultured quail andchicken anterior pituitary provides strong support for thisfunction (Tsutsui et al., 2000; Ciccone et al., 2004).Gonadotropin-inhibitory hormone administration to culturedchicken anterior pituitary inhibits not only the release ofGTHs but also the synthesis of GTH subunit mRNAs(Ciccone et al., 2004). Nevertheless, direct regulation ofpituitary function by GnIH may be regulated in a differentway in some bird species either developmentally ortemporally because there is no apparent GnIH-ir material inthe ME in adult male Rufous-winged sparrows (Small et al.,2008), although GnIH receptor is expressed in the pituitarygland in this species (McGuire, Ubuka, Perfito, & Bentley,2009). In other words, GnIH may directly inhibit pituitaryfunction only during certain periods before sexual matura-tion or in response to stress, as described in Section 7.

To clarify the functional significance of GnIH in thecontrol of avian reproduction, Ubuka, Ukena, Sharp, Bent-ley, and Tsutsui (2006) investigated the action of GnIH onthe hypothalamicepituitaryegonadal (HPG) axis in malequail. It is generally accepted that in avian species LHstimulates the formation of testosterone (T) by Leydig cells.Follicle-stimulating hormone and T stimulate growth,differentiation, and spermatogenetic activity of the testis(Follett, 1984; Johnson, 1986). Luteinizing hormone isa protein complex, which is made of GTH common a andLHb subunits, whereas FSH is a complex of GTH commona and FSHb subunits. Peripheral administration of GnIH tomature quail via osmotic pumps for twoweeks decreased theexpression of GTH common a and LHb subunit mRNAs inthe pituitary. Concentrations of plasma LH and T were alsodecreased dose-dependently. Further, administration ofGnIH to mature birds induced testicular apoptosis anddecreased spermatogenetic activity in the testis. In immaturebirds, daily administration of GnIH for two weeks sup-pressed testicular growth and the rise in the concentration ofplasma T. An inhibition of molt by juveniles also occurredafter GnIH administration. These results show that GnIHmay inhibit gonadal development and maintenance and alsosexual development of birds by decreasing the synthesis andrelease of GTHs (Ubuka et al., 2006).

Although a dense population of GnIH neuronal cellbodies was found only in the PVN, GnIH-ir fibers werewidely distributed in the diencephalic and mesencephalicregions in the Japanese quail (Ukena et al., 2003). Thus, itwas hypothesized that GnIH may participate not only in theregulation of pituitary function, but also in behavioral andautonomic mechanisms. Immunohistochemical studiesusing light and confocal microscopy indicate that GnIH-iraxon terminals are in probable contact with aGnRH-Ineurons in birds (Bentley et al., 2003). Thus, there ispotential for the direct regulation of aGnRH-I neurons byGnIH neurons. Recently, Ubuka et al. (2008a) investigatedthe interaction of GnIH and aGnRH-I neurons in theEuropean starling brain. Double-label immunocytochem-istry showed GnIH axon terminals on aGnRH-I andaGnRH-II neurons (Bentley et al., 2003; Ubuka et al.,2008a). Further, in-situ hybridization of European starlingGnIH receptor mRNA combined with immunocytochem-istry of aGnRHs showed the expression of GnIH receptormRNA in both aGnRH-I and aGnRH-II neurons (Ubukaet al., 2008a). Central administration of GnIH inhibits therelease of GTHs in white-crowned sparrows (Bentley et al.,2006a) in a manner similar to peripheral administration ofGnIH (Osugi et al., 2004; Ubuka et al., 2006). Accordingly,GnIH may inhibit the secretion of GTHs by decreasingaGnRH-I neuronal activity in addition to regulating therelease of pituitary GTHs directly.

Central administration of GnIH also inhibits reproduc-tive behavior of females in white-crowned sparrows


(Bentley et al., 2006a). It is known that aGnRH-II enhancescopulation solicitation in estrogen-primed female white-crowned sparrows exposed to male song (Maney et al.,1997b). As a result of the putative contact of GnIH neuronswith aGnRH-II neurons in white-crowned sparrows(Bentley et al., 2003), Bentley et al. (2006a) investigatedthe effect of GnIH on copulation solicitation in females ofthis species. Centrally administered GnIH inhibited copu-lation solicitation in estrogen-primed female white-crowned sparrows exposed to the song of males withoutaffecting locomotor activity. The result suggests that GnIHinhibits reproductive physiology and behavior not only byinhibiting the secretion of GTHs from the pituitary but alsoby directly inhibiting aGnRH-I and -II neuronal activitywithin the brain (Ubuka, McGuire, Calisi, Perfito, &Bentley, 2008).

Many hormones that are classified as neuropeptides aresynthesized in vertebrate gonads in addition to the brain.Recently, GnIH and its receptor were found to be expressedin the gonads and accessory reproductive organs in Pass-eriformes and Galliformes (Bentley et al., 2008). Immu-nocytochemistry detected GnIH peptide in ovarian thecaland granulosa cells, testicular interstitial cells and germcells, and pseudostratified columnar epithelial cells in theepididymis. Binding sites for GnIH were initially identifiedusing in-vivo and in-vitro receptor fluorography, and werelocalized in ovarian granulosa cells as well as in theinterstitial layer and seminiferous tubules of the testis. In-situ hybridization of GnIH-R mRNA in testes produceda strong reaction product that was localized to the germcells and interstitium. In the epididymis, the product wasalso localized in the pseudostratified columnar epithelialcells. Similar data have been gathered from chickens, andestradiol (E2) and/or progesterone (P4) treatment of sexu-ally immature chickens significantly decreased ovarianGnIH-R mRNA abundance (Maddineni, Ocon-Grove,Krzysik-Walker, Hendricks, Ramachandran, 2008).Further, GnIH decreased LH-induced T release fromcultured dispersed testis (McGuire et al., 2009). Thedistributions and action of GnIH and its receptor suggesta role for GnIH in autocrine/paracrine regulation ofgonadal steroid production and possibly germ cell differ-entiation and maturation in birds.

4. MECHANISMS AND PATHWAYSREGULATING OVULATION ANDOVIPOSITION

4.1. Regulation of Ovulation

A hierarchy of developing follicles exists in the ovary ofbirds, and the largest follicle is ovulated at regular intervals.Many birds normally lay one egg each day during thebreeding season. They usually lay two to ten eggs (two to

ten days) in a sequence (clutch), but the actual numbervaries greatly among species. Between the clutches thereare one or more pause days. Generally clutch size is smallerand the interval between eggs is longer in speciesproducing large eggs. Many birds lay a fixed number ofeggs in a clutch (determinate layers), but others cancontinue laying for long periods (indeterminate layers)(Follett, 1984). Clutch size also tends to increase withlatitude (Ricklefs, 1970).

In domestic chickens, ovulation occurs six to eighthours after the preovulatory LH surge and the egg spendsabout 24 hours in the oviduct before it is laid. The nextovulation occurs 15 to 75 minutes after the oviposition,except after the last oviposition in a clutch. As a result ofthis temporal relationship, the time of oviposition isa practical index of the time of ovulation. Under lightedarkcycles of 14L : 10D, chickens usually lay their eggs in thefirst half of the photophase whereas quail lay late in the dayand early in the night. In both cases, the preovulatory surgeof LH occurs six hours plus one day before the egg is laid.Under continuous light, the oviposition rhythms are free-running, and egg laying occurs throughout the 24 hours(Warren & Scott, 1936; Morris, 1961; Wilson & Cun-ningham, 1981). Normally, the lightedark cycle entrainsthe rhythm, with dusk being the primary cue in chickens(Bhatti & Morris, 1978a; 1978b) and dawn in Japanesequail (Tanabe, 1977). Other factors such as feeding,temperature changes, and bright/dim light are capable ofentrainment when hens are illuminated constantly (Morris& Bhatti, 1978).

Ovulation depends on a surge of LH four to eight hoursearlier, as determined by studies employing injection of LHor GnRH in intact birds or hypophysectomy (Fraps, 1970;Van Tienhoven & Schally, 1972). A surge in plasma LHoccurs four to eight hours before ovulation in chickens(Wilson & Sharp, 1973; Etches & Cunningham, 1977),turkeys (Mashaly, Birrenkott, El-Begearmi, & Wentworth,1976), and quail (Tanabe, 1977), and presumably otherspecies. A constant relationship of about 30 hours existsbetween the peak of LH and the resulting oviposition, andthe LH peak is absent on the last day of a sequence. PlasmaFSH shows only minor changes during the ovulatory cycle(Scanes et al., 1977), although there is a small increase 14to 15 hours before ovulation. Prolactin levels appear to beinversely related to LH (Scanes, Chadwick, & Bolton,1976).

As P4, but not estrogens, can induce premature ovula-tion in the hen, Fraps (1955; 1970) proposed that P4 triggersthe preovulatory LH surge by a positive feedback mecha-nism. A single major peak of P4 coincides with that of LH(Furr, Bonney, England, & Cunningham, 1973; Senior &Cunningham, 1974; Etches & Cunningham, 1977). Thispeak is delayed by two to three hours each day in a layingsequence and is absent when no ovulation takes place.


A preovulatory peak of E2 occurs with that of LH butovulation can take place in its absence (Lague, Van Tien-hoven, & Cunningham, 1975). The effects of varioussteroids on the LH surge and ovulation have been tested.Progesterone almost always triggers an LH surge thatbegins 15 to 45 minutes after intramuscular injection, peakswithin two hours, and lasts for about six hours. Gonado-tropin-releasing hormone seems to relay the effect of P4 onthe LH surge, because anti-GnRH antibody administrationblocks the effect of P4 (Fraser & Sharp, 1978). Intra-hypothalamic injections of P4 also trigger ovulation (Ralph& Fraps, 1960). In summary, the P4 surge appears to beimportant for initiating ovulation.

The ovulated egg is captured by the ostium of theoviduct. Fertilization and deposition of the first layer ofalbumen occur here. The ovum passes down the oviductthrough highly differentiated regions that have specificfunctions. Further albumen is laid down in the magnum,and membranes surround the developing egg in theisthmus. On reaching the shell gland (also known as theuterus), a shell and pigment are deposited (Solomon, 1983).Finally, oviposition occurs through the vagina and cloaca.Note that since there is only one ovary and one oviduct,further ovulations cannot occur unless oviposition hasoccurred (Sharp, 1980).

4.2. Regulation of Oviposition

Oviposition means expulsion of the egg from the oviduct tothe external environment and is a common phenomenon invertebrates other than eutherian mammals. Avian oviposi-tion is thought to be regulated by a neurohypophysialhormone, AVT, together with ovarian hormones and pros-taglandins (PGs) through the induction of uterine contrac-tions (Munsick, Sawyar, & Van Dyke, 1960; Rzasa & Ewy,1970; Hertelendy, 1972; Wechsung & Houvenaghel, 1976;Olson, Biellier, & Hertelendy, 1978; Toth, Olson, & Her-telendy, 1979; Takahashi, Kawashima, Kamiyoshi, &Tanaka, 1992). Regulation of oviposition by the sympa-thetic nervous system using galanin as a neurotransmitterseems to exist in quail (Li, Tsutsui, Muneoka, Minakata, &Nomoto, 1996; Tsutsui, Azumaya, Muneoka, Minakata, &Nomoto, 1997; Tsutsui, Li, Ukena, Kikuchi, & Ishii, 1998;Sakamoto et al., 2000). The expression of galanin in thesympathetic ganglia is regulated by ovarian sex steroids(Ubuka, Sakamoto, Li, Ukena, & Tsutsui, 2001).

The neurohypophysial hormones AVT and MST repre-sent the nonmammalian homologs to arginine vasopressinand oxytocin, respectively (Acher, Chauvet, & Chauvet,1970). However, in birds, the oxytocic effect of AVT isgreater than that of MST (Saito & Koike, 1992; Barth et al.,1997). Plasma AVT increases sharply at the time ofoviposition to induce uterine contraction (Nouwen et al.,1984; Tanaka, Goto, Yoshioka, Terao, & Koga, 1984;

Shimada, Neldon, & Koike, 1986) and decreases within 30minutes of an egg being laid (Koike, Shimada, & Cornett,1988). Elevation of plasma AVT at the time of ovipositionis accompanied by a depletion of AVT concentration in theneurohypophysis (Sasaki, Shimada, & Saito, 1998).

Magnocellular neurons producing AVT are found in thepreoptic nucleus, the supraoptic nucleus, and the PVN ofthe hypothalamus. A sexually dimorphic population ofparvocellular AVT neurons is observed from the medi-ocaudal part of the preoptic region to the dorsolateral partof the bed nucleus of stria terminalis in male birds, sug-gesting a role in the control of male sexual behaviors(Jurkevich & Grossmann, 2003). Effects of AVTon variousmale reproductive behaviors, such as aggressive andcourtship behaviors, including song production, have beendocumented (Kihlstrom & Danninge, 1972; Maney, Goode,& Wingfield, 1997; Castagna, Absil, Foidart, & Balthazart,1998; Goodson, 1998a; 1998b; Goodson & Adkins-Regan,1999). There is also a role for AVT, along with cortico-tropin-releasing hormone (CRH), in ACTH release fromthe anterior pituitary (Castro, Estivariz, & Iturriza, 1986;Romero, Soma, & Wingfield, 1998; Madison, Jurkevich, &Kuenzel, 2008).

5. MECHANISMS AND PATHWAYSREGULATING PROLACTIN (PRL)SECRETION

A period of egg incubation occurs in the vast majority ofbirds (Drent, 1975). Brood patches develop in virtually allbirds and seem to be used to transfer body heat to the eggs.The changes in the brood pouch skin are substantial,involving hyperplasia of the epidermis, an edema leading towrinkling of the skin, and extra vascularization. The wholeprocess is thought to be controlled by a synergism betweenPRL and the sex steroids (Jones, 1971; Drent, 1975).Estrogens and P4 are the active agents in the female, butwhere males incubate these are replaced by androgens.

Injections of PRL induce chickens to incubate eggs(Riddle, Bates, & Lahr, 1935; Sharp, Macnamee, Sterling,Lea, & Pedersen, 1988), and maintain readiness of ringdoves to incubate their clutches (Lehrman & Brody, 1964;Janik & Buntin, 1985). In species that hatch precocialyoung, PRL levels rise slightly during egg-laying, but thenincrease markedly throughout incubation and fall imme-diately when the chicks have hatched. In female birds thatfail to incubate, as well as in males, PRL never rises abovebaseline concentrations (mallards (Goldsmith & Williams,1980)). In species that produce altricial young, PRL is alsovery high during incubation but it often stays high whilstthe young are fed in the nest (canary (Goldsmith, 1982)). Inring doves and other Columbiformes, PRL causes growthof the crop gland and production of crop milk for feeding of


young for the first few days after hatch. In these birds,plasma levels of PRL do not rise during egg-laying and theearly part of incubation but are high at the end of incubationand when the squabs are being fed (Goldsmith, Edwards,Koprucu, & Silver, 1981). It has been suggested that infemale turkeys the action of PRL on incubation behavior isfacilitated by the combined action of E2 and P4 (El Hala-wani, Silsby, Behnke, & Fehrer, 1986).

In birds, PRL secretion is actively stimulated by releaseof VIP from the ME. Mammalian VIP specifically stimu-lated PRL release in vivo and in vitro in bantam hens(Macnamee, Sharp, Lea, Sterling, & Harvey, 1986) andturkeys (Opel & Proudman, 1988; Proudman & Opel, 1988),while immunohistochemical studies showed the presence ofVIP-ir nerve terminals in the ME in quail (Yamada, Mikami,& Yanaihara, 1982), bantam hens (Macnamee et al., 1986),and pigeons (Peczely & Kiss, 1988). The structure ofhypothalamic chicken and turkey VIP is regarded as thesame as that isolated from the chicken gut, which is a 28-amino-acid peptide differing from mammalian VIP in fouramino acids (Nilsson, 1975). Both chicken and turkey VIPcDNAs have been sequenced (Talbot, Dunn, Wilson, Sang,& Sharp, 1995; You, Silsby, Farris, Foster, & El Halawani,1995). Immunization against VIP inhibits PRL secretion inbantam hens (Sharp, Sterling, Talbot, & Huskisson, 1989)and turkeys (El Halawani, Pitts, Sun, Silsby, & Sivanandan,1996). Daily injections of anti-VIP caused incubatingbantam hens to desert their nests. On the other hand,disruption of incubation behavior with anti-VIP was pre-vented by concomitant administration of ovine PRL (Sharpet al., 1989). The amount of VIP was significantly higher inthe ME and cell bodies in the medial basal hypothalamus inincubating as compared to actively laying hens (Sharp et al.,1989). Vasoactive intestinal peptide mRNA and peptidelevels were low in nonphotostimulated turkeys, higher inlaying hens, and highest in incubating hens. Changes in VIPparalleled the changes in plasma PRL levels (Chaiseha,Tong, Youngren, & El Halawani, 1998). Dopaminergiccontrol of PRL secretion also has been suggested in turkeys(Youngren, Pitts, Phillips, & El Halawani, 1996; Youngren,Chaiseha, & El Halawani, 1998).

The peak in PRL concentrations coincides witha decrease in LH concentrations and coincident gonadalregression in many bird species (Sharp & Sreekumar,2001), which suggests a role for PRL in the termination ofbreeding. However, this is unlikely because administrationof exogenous PRL does not on its own cause the onset ofphotorefractoriness (Goldsmith, 1985). Further, activeimmunization of starlings against VIP completely blocksPRL secretion but does not prevent gonadal regression(Dawson & Sharp, 1998). The timing of high levels of PRLis also closely linked to molt, premigratory fattening, andmigration (Meier & MacGregor, 1972; Meier, 1972;Dawson & Goldsmith, 1983).

6. MECHANISMS AND PATHWAYSREGULATING SEASONAL REPRODUCTION

6.1. Seasonal Reproduction in Birds

Birds have presumably evolved the timing of their breedingso that they can maximize the production of offspring, andlaying is normally timed so that young are in the nest whenthere is enough food for them to be raised (Lack, 1968).Baker (1938) suggested that seasonal breeding is controlledby two sets of environment factors: ‘ultimate’ and ‘proxi-mate’ factors. The most important ultimate factor for birdsis the availability of an adequate food supply for thehatchlings as well as for the mother during the final stagesof ovarian development. Other ultimate factors operating inspecial situations are competition, nesting conditions,predation pressure, and climate factors. However, theseultimate factors are often not those that trigger and regulatethe secretion of reproductive hormones, because it isnecessary to anticipate the hatching date and to beginpreparations for breeding some weeks or months ahead ofthe time when young must be produced.

In birds living in mid and high latitudes, there isexcellent experimental evidence that the annual change inday length controls the timing of breeding, and it may beassumed that photoperiod is a proximate factor for birdsliving in such regions (Follett, 1984). Other environmentalfactors are also used to accelerate or retard photoperiodi-cally induced gonadal growth (Farner & Follett, 1979).These include the presence of males for stimulating ovariandevelopment (Marshall, 1936; Hinde, 1965; Cheng, 1979),ambient temperature (Perrins, 1973), and rainfall (Leopold,Erwin, Oh, & Browning, 1976). It is thought that photo-period is not the proximate factor for many tropical anddesert species (Marshall, 1970). Reproduction of tropicalbirds, such as African stonechats (Gwinner & Scheuerlein,1999) and zebra finches (Bentley, Spar, MacDougall-Shackleton, Hahn, & Ball, 2000) can respond to changingphotoperiod although the experimental length of thephotoperiods used in these studies exceeded that of thetropics. However, studies on spotted antbirds suggest thattropical birds can respond to natural slight photoperiodicchanges (Hau, Wikelski, & Wingfield, 1998; Beebe,Bentley, & Hau, 2005). The proximate factors used to timebreeding in tropical birds remain largely unknown althoughcorrelative analyses suggest rainfall, territory, nest siteavailability, nest materials, and food supply as beinginvolved (Immelmann, 1971; Zann, Morton, Jones, &Burley, 1995). Stonechats may respond to low light inten-sity as a predictive cue for rainfall (Gwinner & Scheuerlein,1999). The reproductive axis of tropical birds may remainin a state of ‘readiness to breed,’ and full functionality maybe triggered by the relevant proximate cues (Perfito,Bentley, & Hau, 2006; Perfito, Kwong, Bentley, & Hau,


2008). Although crossbills live in high latitudes, breedingcan occur opportunistically at any time between Januaryand August in response to their food supply. They feed onthe seeds of coniferous trees, which are produced indifferent amounts in different years, and at unpredictabletimes of the year. However, they have a short, fixednonbreeding period in fall when they appear to be photo-refractory (Hahn, 1998).

The vast majority of temperate-zone passerines undergodynamic seasonal changes in their reproductive activities.Gonadal development occurs in spring in response toincreasing day length (photostimulation). However, thegonads are maintained in a functional condition only fora short period, and they spontaneously regress afterextended exposure to long day lengths (absolute photo-refractoriness). After becoming photorefractory, exposureto short day length is required to regain photosensitivityand thus allow for photostimulation (Wingfield & Farner,1980). Photorefractoriness seems to have evolved tominimize the costs of reproducing in the rapidly deterio-rating environmental conditions of fall and winter (Follett,1984). The only well-studied birds that do not becomephotorefractory are some species of pigeon and dove(Murton & Westwood, 1977).

A condition similar to absolute photorefractoriness isrelative photorefractoriness. The main difference is that,once relative photorefractoriness has been induced and thegonads have regressed, a subsequent substantial increase inday length will once more initiate reproductivematurationdwithout the need for a short-day-length‘sensitization,’ or photosensitive, stage (Robinson &Follett, 1982). For example, if Japanese quail experienceday lengths of over 11.5 hours, rapid gonadal developmentoccurs. After about three months, and when (in the wild)day length decreases below 14.5 hours, complete gonadalregression occursdin a similar manner to absolute photo-refractoriness (Nicholls, Goldsmith, & Dawson, 1988).However, if the day length is subsequently artificiallyincreased further, a full return to reproductive maturityoccurs. Indeed, if quail are maintained on any constant longday length, no form of photorefractoriness will be elicitedunless they experience a decrease in day length, e.g., from23 to 16 hours (Nicholls et al., 1988). This suggests a shiftin the critical day length in birds that are relativelyphotorefractoryda shift that appears to depend on thephotoperiodic history of such birds (Robinson & Follett,1982). There does not seem to be any change in critical daylength in birds that exhibit absolute photorefractoriness,regardless of their photoperiodic history (Dawson, 1987).

Song sparrows and house sparrows show character-istics of both absolute and relative photorefractoriness(Dawson, King, Bentley, & Ball, 2001). Song sparrows(Wingfield, 1983) and house sparrows (Dawson, 1998a)eventually become photorefractory during exposure to long

photoperiods, but the timing can vary widely among indi-viduals. If the photophase is decreased slightly, gonadalregression occurs sooner and is more synchronized amongindividuals. Moreover, song sparrows can show renewedgonadal maturation before exposure to short photoperiods(Wingfield, 1993).

Seasonal changes in reproductive activities are corre-lated with GTH secretion. The primary effect of long daylengths on stimulating GTH secretion has been shown inquail (Follett, 1976), white-crowned sparrows (Wingfield& Farner, 1980), tree sparrows (Wilson & Follett, 1974),canaries (Nicholls, 1974), ducks (Balthazart, Hendrick, &Deviche, 1977), starlings (Dawson & Goldsmith, 1983),and many other birds. If male quail are transferred fromshort day lengths (8L : 16D) to long day lengths (20L : 4D),the levels of FSH and LH rise substantially during the firstweek of photostimulation. Testicular growth and steroido-genesis begin and maturity is reached in about five weeks(Follett & Robinson, 1980). Gonadal steroids affect GTHsecretion by negative feedback (King et al., 1989a; Dunn &Sharp, 1999). Gonadal steroids also induce sexual behavior,development of secondary sexual characteristics, andspermatogenesis (Follett & Robinson, 1980). Female quailalso grow their ovaries as a result of increased GTHsecretion induced by long day lengths (20L : 4D). Gonad-otropin levels becomes basal after transferring quail fromlong days to short days (8L : 16D) (Gibson, Follett, &Gledhill, 1975). On the other hand, in most of thetemperate-zone passerine birds, which undergo sponta-neous photorefractoriness after exposure to long days, GTHsecretion is diminished and gonadal collapse occurs aftera species-specific number of long days (Follett, 1984).

Seasonality continues in the absence of the gonads.Castrated or intact quail show an identical time-course inLH and FSH secretion under natural photoperiods over twoconsecutive years, the difference being that in summer theGTH levels in castrated birds are higher, as a result of lackof negative feedback from gonadal steroids (Follett, 1984).A similar annual cycle of LH secretion has been observedin the plasma of intact and castrated white-crowned spar-rows (Mattocks, Farner, & Follett, 1976). It is also thoughtthat gonads are not required for photorefractoriness todevelop, because castrated white-crowned sparrows(Wingfield, Follett, Matt, & Farner, 1980), canaries (Storey,Nicholls, & Follett, 1980), and starlings (Dawson &Goldsmith, 1984) show a spontaneous fall in GTH levelunder long days. Castration of photorefractory canariesdoes not cause enhanced LH secretion, but when photo-sensitivity is regained under short days there is an imme-diate rise in plasma LH (Nicholls & Storey, 1976).

Birds seem to measure daylength using their circadianclock. In a classic experiment, white-crowned sparrowsheld on short day lengths (8L : 16D) were placed incontinuous darkness. When birds were exposed to a single


eight-hour photophase, an increase in LH occurred only ifthe photophase coincided with a time period 12e20 hoursafter the subjective dawn, as judged by the circadianrhythms of the birds (Follett, Mattocks, & Farner, 1974).These data imply that a circadian rhythm of sensitivity tolight, or photoinducibility, exists in the photoperiodic timemeasurement system of these birds. There are two possiblemodels of how circadian rhythms might be involved inphotoperiodic time measurement in birds (Goldman, 2001).The ‘external coincidence model’ assumes the organismpossesses a circadian rhythm of ‘photosensitivity’. Ifcoincidence between this rhythm and light occurs underlong days, it induces GTH secretion. The ‘internal coinci-dence model’ assumes the induction to occur when coin-cidence is established between two separate circadianoscillators (usually dawn and dusk oscillators). Asa consequence of using a circadian clock for photoperiodictime measurement, light is not required throughout the dayto induce gonadal growth, but pulses of light simulatingdawn and dusk can cause induction if one of the pulsescoincides with the phase of photosensitivity (Follett, 1973).As with white-crowned sparrows, when 15-minute pulsesof light were given at different times in the night to quail onthe basic photoperiod of 6L : 18D, induction occurred onlyif the pulses were within 12 to 16 hours of dawn (Follett &Sharp, 1969).

Light intensity can also modify the reproductiveresponses of birds under the same photoperiod (Bisson-nette, 1931; Bartholomew, 1949). In the experiment con-ducted by Bentley, Goldsmith, Dawson, Briggs, andPemberton (1998), photosensitive starlings transferredfrom short days to long days of different light intensitiesunderwent graded reproductive responses according to thelight intensities they experienced. Interestingly, theresponses observed, such as the growth in their testes sizeand the development of photorefractoriness, were similar tothose seen in starlings exposed to different photoperiods. Atface value, these data contradict the external coincidencemodel in that light falling in the photoinducible phaseshould cause a long-day response. However, this discrep-ancy might be explained by the possibility that low lightintensities only weakly entrain the circadian oscillations ofthe photoinducible phase, so that light is experienced inonly part of the photoinducible phase.

6.2. Seasonal Changes in Gonadotropin-releasing Hormone (GnRH)

Radioimmunoassay and immunocytochemistry (ICC)using GnRH antisera have numerous times demonstratedcyclic changes in GnRH in songbirds in response tochanging photoperiod. Radioimmunoassay revealed thathypothalamic GnRH content did not increase significantly

during the first six weeks of photostimulation in femalestarlings. However, by 12 weeks after the onset of photo-stimulation, as birds became photorefractory, GnRH haddecreased to levels significantly lower than those beforephotostimulation (Dawson, Follett, Goldsmith, & Nicholls,1985). Immunocytochemistry with quantitative imageanalyses for both GnRH and its precursor, proGnRH-GAP,was performed after a photoperiodically induced repro-ductive cycle in male starlings (Parry, Goldsmith, Millar, &Glennie, 1997). The size of cells staining for GnRH andproGnRH-GAP increased during gonadal maturation. Areduction in the number of cells staining for GnRH and thesize of cells staining for both GnRH and proGnRH-GAPoccurred during gonadal regression, though staining forGnRH and proGnRH-GAP in the ME remained high.Staining for GnRH and proGnRH-GAP was reducedsignificantly after gonadal regression. These observationssuggest that photorefractoriness is promoted by a reductionin pro-GnRH-GAP and GnRH synthesis (Parry et al.,1997). Changes in aGnRH-I in the POA and mediobasalhypothalamus (MBH) including the ME have beenmeasured in starlings during the recovery of photosensi-tivity under short days, and following photostimulation atvarious times during the recovery of photosensitivity(Dawson & Goldsmith, 1997). During exposure of long-day photorefractory starlings to short days for 10 days,there was a significant increase in aGnRH-I in the POA butnot in the MBH. Photostimulation after 20 short dayscaused an immediate increase in aGnRH-I in the POA,a delayed increase in the MBH, but no increase in plasmaLH. Photostimulation after 30 short days caused animmediate increase in aGnRH-I in the POA and the MBHand in plasma LH. These results show that the recovery ofphotosensitivity is gradual and the first measurable changeoccurs in the POA, consistent with photosensitivity beingdue to renewed aGnRH-I synthesis (Dawson & Goldsmith,1997). Recently, the complete sequence of aGnRH-Iprecursor mRNA was identified in songbirds: starlings(Ubuka et al., 2009; Stevenson et al., 2009) and zebrafinches (Ubuka & Bentley, 2009; Stevenson et al., 2009).The expression of aGnRH-I precursor mRNAwas found tobe regulated as a function of age and reproductive conditionin zebra finches (Ubuka & Bentley, 2009). In starlings,there was regulation of aGnRH-I precursor mRNAexpression as a function of season (Ubuka et al., 2009) andphotoperiod (Stevenson et al., 2009). Photostimulation ofshort-day-exposed chickens and turkeys can also increaseaGnRH-I precursor mRNA expression (Dunn & Sharp,1999; Kang et al., 2006).

What is the molecular mechanism regulating aGnRH-Isynthesis and release? Is GTH secretion solely controlledby aGnRH-I? If photoperiod is the proximate factorcontrolling seasonal reproduction, how is the photoperiodicinformation acquired and processed in the brain?


Photoreceptors to perceive light and a biological clock toprocess photoperiodic information seem necessary to timeseasonal reproduction. How autonomous are the seasonalreproductive activities? In other words, does externalinformation such as day length need to be sensed throughthe whole year to time seasonal reproduction? Does thedaily melatonin (MEL) rhythm control reproductive cyclesof birds? Thyroid hormones seem to be required to achieveseasonal reproduction, but what is the mechanisminvolved? Studies on the potential mechanisms controllingseasonal reproduction of birds will be discussed in thefollowing sections.

6.3. Photoreceptor

It is believed that light can affect the activity of birds viathree different pathways: the eyes, the pineal, and the deepbrain (Underwood, Steele, & Zivkovic, 2001). The avianeye is not only a functional photoreceptor, but also containsa circadian clock and produces a circadian rhythm of MELrelease (Binkley, Reilly, & Hryschchyshyn, 1980; Hamm&Menaker, 1980). The principal cell types within the pinealof most nonmammalian vertebrates have characteristics ofa photosensory cell, including the presence of an outersegment composed of stacked disks containing photopig-ments (Collin & Oksche, 1981). The avian pineal organ isdirectly photosensitive and it is also the locus of a circadianpacemaker (Takahashi &Menaker, 1984; Okano & Fukada,2001). The location of the extrapinealeextraretinal photo-receptors mediating circadian entrainment in birds has notbeen established. In a study using opsin antibodies, cere-brospinal fluid-contacting cells were labeled in the septaland the tuberal areas in the ring dove (Silver et al., 1988),and lateral septum in the pigeon (Wada, Okano, & Fukada,2000). Light and confocal microscopy revealed interactionsof GnRH-ir and opsin-ir materials in the POA and in theME, suggesting a direct communication between theseputative deep brain photoreceptors and GnRH neurons(Saldanha, Silverman, & Silver, 2001).

6.4. Biological Clock

The circadian system of birds is composed of severalinteracting sites, including the pineal organ, the supra-chiasmatic nucleus (SCN) of the hypothalamus, and eyes,in at least some species. Each of these sites may containa circadian clock (Underwood et al., 2001). Significantvariation can occur among birds in the relative roles that thepineal, the SCN, and the eyes play within the circadiansystem. For example, in the house sparrow, circadianpacemakers in the pineal play the predominant role,whereas in the pigeon circadian pacemakers in both thepineal and eyes play a significant role. In Japanese quail,ocular pacemakers play the predominant role. There has

been controversy concerning the precise location of theavian homologs of the mammalian SCN. The medialhypothalamic nucleus (MHN) (also termed the medialSCN) and the lateral hypothalamic retinorecipient nucleus(LHRN) (also termed the visual SCN) are the possiblehomologs of the mammalian SCN (Norgren & Silver, 1989;1990; Shimizu, Cox, Karten, & Britto, 1994; Cassone &Moore, 1987).

The self-sustaining circadian oscillation in anyorganism is thought to be generated by a tran-scriptionetranslation feedback loop of clock genes, thepresence of which appears to be a conserved property fromfruit flies to humans. Clock and Period homologs (qClock,qPer2, and qPer3) have been cloned in the Japanese quail.qPer2 and qPer3 showed robust circadian oscillations in theeye and in the pineal gland, although qClock mRNA wasexpressed throughout the day. In addition, qPer2 mRNAwas induced by light, whereas qClock or qPer3 were not(Yoshimura et al., 2000). These clock genes were expressedin the MHN, but not in the LHRN in quail (Yoshimuraet al., 2001). On the other hand, Per2 mRNA is expressedboth in the MHN and in the LHRN with rhythmic expres-sion patterns in the house sparrow (Abraham, Albrecht,Gwinner, & Brandstatter, 2002). Clock genes such as Per,Cry, Clock, Bmal, and E4bp4 are all expressed and differ-entially oscillate in quail and chicken pineal glands (Doi,Nakajima, Okano, & Fukada, 2001; Okano et al., 2001;Yamamoto, Okano, & Fukada, 2001; Fukada & Okano,2002; Yasuo, Watanabe, Okabayashi, Ebihara, & Yoshi-mura, 2003). The avian pineal gland seems to possessa functional circadian oscillator composed of a transcrip-tion-/translation-based autoregulatory feedback loop, as inthe mammalian SCN (Fukada & Okano, 2002). Thus,multiple oscillators are present in birds, and they aresomehow coordinated to convey circadian rhythmicity.

Annual seasonal activities of birds, such as reproduction,molt, and migration, can persist for many cycles, witha period deviating from 12 months under constant condi-tions. These cycles have been named ‘circannual rhythms’(Gwinner, 2003), although many of them deviate signifi-cantly from a 12-month period. These cycles have beenexperimentally demonstrated for at least 20 species of birdunder specific lighting conditions (Gwinner, 1986; Gwinner& Dittami, 1990; C. Guyomarc’h & J. Guyomarc’h, 1995).In European starlings, a cycle of reproduction composed ofphotosensitive and photorefractory phases continues inconstant photoperiods close to 12 hours (Gwinner, 1996;Dawson, 1997). Under photoperiods longer than 12 hours,starlings remain in the photorefractory state, whereas undershorter photoperiods they remain in the photosensitive state(Gwinner, 1996). Castrated starlings exposed to 12L : 12Ddid not exhibit cyclic rhythms of this type (Dawson &McNaughton, 1993). Accordingly, the reproductive cyclethat was observed for intact birds under this specific


constant photoperiod (12L : 12D) might be generated asa result of complex interactions within the HPG axis, ratherthan as a result of a circannual ‘calendar’ in the brain.

6.5. Melatonin (MEL)

The pineal glands of all vertebrates show daily rhythms inthe activity of the enzymes in the indolamine-synthesizingpathway that produces MEL. Levels of MEL are higher atnight in both diurnal and nocturnal animals. In the pinealgland, serotonin (5-HT) is converted by the action of N-acetyltransferase (NAT) to N-acetylserotonin, and then byhydroxyindole-O-methyltransferase (HIOMT) to MEL. In-vitro rhythms of melatonin synthesis and release from thepineal gland occur in pigeons, house sparrows, quail, andchickens. Circadian rhythms in MEL secretion from thecultured pineal gland can persist under constant conditionsand they can be entrained by 24-hour lightedark cycles(Murakami, Nakamura, Nishi, Marumoto, & Nasu, 1994;Barrett & Takahashi, 1997; Brandstatter, Kumar, Abraham,& Gwinner, 2000; Brandstatter, Kumar, Van’t Hof, &Gwinner, 2001). The eyes can contribute significantly (upto 30%) to blood MEL levels in pigeons and Japanese quail(Underwood, Binkley, Siopes, & Mosher, 1984; Oshima,Yamada, Goto, Soto, & Ebihara, 1989). The eyes of Japa-nese quail show a rhythm in MEL content that can beentrained by light directed exclusively to the eyes, which ishigh at scotophase and low at photophase (Underwood,Barrett, & Siopes, 1990). Circadian pacemakers in thepineal and in the eyes of some species are thought tocommunicate with the hypothalamic pacemakers via therhythmic synthesis and release of MEL (Chabot &Menaker, 1992; Underwood et al., 2001). Three MELreceptor (MEL-R) subtypes, Mel1a, Mel1b, and Mel1c, havebeen identified in birds. These are G-protein-coupledreceptors (Reppert, Weaver, Cassone, Godson, & Kola-kowski, 1995). Mel1a and Mel1c receptors are present in theLHRN in the chicken brain (Reppert et al., 1995). Contraryto the MEL rhythm, which exhibits higher MEL secretionduring the scotophase, [125I]-iodomelatonin binding in thebrain is higher during the photophase and lower during thescotophase in chickens (Yuan & Pang, 1992), quail (Yuan &Pang, 1990), and pigeons (Yuan & Pang, 1991). Sexdifferences and the effect of photoperiod on [125I]-iodo-melatonin binding also have been observed in the avianbrain (Aste, Cozzi, Stankov, & Panzica, 2001; Panzicaet al., 1994). Higher densities of MEL binding sites inmales than in females were detected in some telencephalicnuclei of songbirds, as well as in the visual pathways and inthe POA of quail (Aste et al., 2001). Japanese quail undershort days exhibited higher MEL-R density in the optictectum and nucleus triangularis, whereas long-day birdshad a higher density of MEL-R in the hyperstriatum andnucleus preopticus dorsalis (Panzica et al., 1994). Seasonal

changes in the volumes of song control nuclei are at leastpartly regulated by MEL binding to these brain nuclei(Bentley, Van’t Hof, & Ball, 1999; Bentley & Ball, 2000).

Photoperiodic mammals rely on the annual cycle ofchanges in nocturnal secretion of MEL to drive theirreproductive responses (Bronson, 1990). In contrast,a dogma exists that birds do not use seasonal changes inMEL secretion to time their reproductive effort, and a rolefor MEL in birds has remained enigmatic. The effects ofpinealectomy (Px), bilateral orbital enucleation (Ex), andPxþ Ex on seasonal regulation of reproduction were testedin tree sparrows, a highly photoperiodic species (Wilson,1991). Although there was an accelerating effect of Ex onthe changes in their testicular size, Px, Ex, and Px þ Exbirds exhibited photostimulation, photorefractoriness, andrecovery of photosensitivity in the same way as did theintact birds. The effects of artificial extension of the dura-tion of circulating MEL on reproductive status were testedusing Japanese quail by exogenous MEL injection (Juss,Meddle, Servant, & King, 1993). Male quail reared undernonstimulatory short days (8L : 16D) were switched to12L : 12D and given daily MEL injections at the time oflights-on or before and at the time of lights-off or for threeweeks. Contrary to the prediction, MEL injection resultedin significant stimulation of LH concentration and testicularsize. Despite the accepted dogma, there is increasingevidence that MEL is involved in the regulation of seasonalreproductive processes. Male Japanese quail reared undernonstimulatory short days (8L : 16D) were used to test theeffect of anti-MEL antibody (anti-MEL) administration onthe reproductive status (Ohta, Kadota, & Konishi, 1989).Intravenous injection of anti-MEL just before lights-off forthree days significantly increased T concentration andtesticular size after two weeks even if quail were kept underthe same nonstimulatory photoperiod (8L : 16D). There arealso reports showing inhibitory effects of MEL on seasonalrecrudescence in quail (Guyomarc’h, Lumineau, Vivien-Roels, Richard, & Deregnaucourt, 2001) and on LHsecretion in chickens (Rozenboim, Aharony, & Yahav,2002).

In light of these reports and considering GnIH’s inhib-itory effects on the secretion of GTH, Ubuka, Bentley,Ukena, Wingfield, and Tsutsui (2005) hypothesized thatMEL may be involved in the induction of GnIH expression,thus influencing gonadal activity. As the pineal gland andeyes are the major sources of MEL in the quail (Underwoodet al., 1984), Ubuka et al. (2005) analyzed the effects of Pxand Ex on the expression of GnIH precursor mRNA andGnIH peptide. Subsequently, MEL was administered to Pxþ Ex birds. Pinealectomyþ Ex decreased the expression ofGnIH precursor mRNA and the content of GnIH peptide inthe hypothalamus. Further, MEL administration to Pxþ Exbirds caused a dose-dependent increase in the expression ofGnIH precursor mRNA and the production of the mature


peptide. The expression of GnIH was photoperiodicallycontrolled and increased under short-day photoperiods,when the duration of MEL secretion increases. A MEL-Rsubtype, Mel1c mRNA, was expressed in GnIH-ir neuronsin the PVN. Autoradiography of MER-Rs further revealedspecific binding of [125I]-MEL in the PVN. Accordingly,MEL appears to act directly on GnIH neurons through itsreceptor to induce GnIH expression. Recently, it was shownthat MEL also stimulates the release of GnIH from the quailhypothalamus (Chowdhury et al., 2010). Gonadotropin-inhibiting hormone may transduce photoperiodic informa-tion by means of changes in the MEL signal, and thusinfluences the reproductive activities of birds (Ubuka et al.,2005).

Although Px þ Ex treatment for one week eliminatedMEL concentration in the plasma, there was a substantialamount of MEL-immunoreactive (ir) material remaining inthe quail diencephalon (Ubuka et al., 2005). Recently,a group of neurons that synthesize both dopamine (DA) andMEL were identified in the premammillary nucleus of theturkey hypothalamus (Kang, Thayananuphat, Bakken, & ElHalawani, 2007; El Halawani, Kang, Leclerc, Kosonsiriluk,& Chaiseha, 2009). These neurons express clock genes anda photoreceptor, melanopsin. Dopamine-MEL neurons areactivated when a light pulse is given during the photosen-sitive phase, associated with an upregulation of GnRH-ImRNA expression. The expression of tryptophan hydrox-ylase-1 (TPH1) (5-HT-synthesizing enzyme) mRNA levelis low during the photophase and high during the scoto-phase, and tyrosine hydroxylase (TH) (rate-limiting DA-synthesizing enzyme) mRNA shows the opposite cycle.These hypothalamic DAeMEL neurons may providea novel role for MEL in the regulation of seasonal repro-ductive cycles in birds.

6.6. Thyroid Hormones

It has been known for many decades that thyroid hormonescan affect reproductive function, but the effects ofthyroidectomy on seasonal breeding were often contradic-tory (Dawson et al., 2001). Gonadal regression caused byphotorefractoriness is normally prevented by thyroidec-tomy, but in some studies photorefractoriness appears tohave been accelerated (Dawson & Thapliyal, 2001).Treatment with one of the thyroid hormones, thyroxine(T4), can mimic the effects of long photoperiods (Follett &Nicholls, 1988; Goldsmith & Nicholls, 1992; Wilson &Reinert, 1995). Reinert and Wilson (1996) argue that, intree sparrows, the increase in plasma T4 concentrationsfollowing photostimulation (Dawson, 1984; Sharp &Klandorf, 1981) serves to program the subsequent gonadalcycle and molt. The contrary view is taken by Bentley et al.(1997). When they maintained T4 concentrations at sub-physiological levels by treating thyroidectomized starlings

held on long days with appropriate amounts of T4, thesebirds became photorefractory and molted. This suggeststhat T4 simply has to be present for the appropriateresponses to photoperiod to occur.

The site(s) of action of thyroid hormones may lie withinthe central nervous system since, in starlings and sparrows,the prevention of photorefractoriness by thyroidectomy isassociated with maintenance of high levels of aGnRH-I,typical of photosensitive birds (Dawson et al., 1985;Reinert & Wilson, 1996; Dawson, 1998b), and thyroidec-tomy of photorefractory birds results in an increase inaGnRH-I (Dawson, Goldsmith, Nicholls, & Follett, 1986).Central administration of thyroid hormones to thyroidec-tomized tree sparrows restores all of the photoperiodicresponses, with the effects of T4 being more potent thantriiodothyronine (T3) (Wilson & Reinert, 2000). Chronicthyroidectomy appears to render starlings ‘photoperiodi-cally blind,’ because the GnRH response to an increase ora decrease in photoperiod is greatly attenuated (Bentley,Dawson, & Goldsmith, 2000a). In house sparrows, theeffects of thyroidectomy are very different. Again,thyroidectomized birds appear to be photoperiodicallyblind; testicular size and GnRH-I are the same whetherbirds are on long or short photoperiods (Dawson, 1998b).However, although GnRH-I remains high, which is typicalof photosensitive birds, testicular size remains minimal,which is typical of photorefractory birds. Thyroid hormonemay have different effects on GnRH-I synthesis andrelease, which may account for the apparently contradic-tory results regarding the effects of thyroidectomy onreproductive processes.

Recent molecular analyses suggest that local thyroidhormone activation in the hypothalamus may play a criticalrole in the regulation of seasonal reproduction in birds(Nakao, Ono, & Yoshimura, 2008b). If the light exposureoccurs around 11 to 16 hours after dawn (photoinduciblephase), the first detectable change in GTH secretion beginsaround 22 hours after dawn in Japanese quail (Follett &Sharp, 1969), and a wave of GTH secretion occurs over thenext few days (Follett, Davies, & Gledhill, 1977; Nicholls,Follett, & Robinson, 1983). Meddle and Follett (1997)examined the effect of the first long day on expression ofa transcription factor, Fos, in the basal tuberal hypothal-amus, a brain area that includes GnRH-I neuronal termi-nals. Transfer of short-day (6L : 18D) quail to long daysinduced Fos-ir in neuronal cells in the infundibular nucleus(IFN) and glial cells in the ME by 18 hours of the first longday. This activation of specific brain areas was followed bythe first rise in LH, 20 hours after dawn (Meddle & Follett,1997). Fos-ir in the IFN, and LH release were also stimu-lated by subcutaneous N-methyl-D-aspartate administra-tion in the white-crowned sparrow (Meddle, Maney, &Wingfield, 1999). Yoshimura et al. (2003) hypothesizedthat important molecular events would be triggered in the


MBH, when light was given to quail during the photo-inducible phase. Acute induction of type 2 iodothyroninedeiodinase (DII) mRNA expression was observed in theependymal cells of the MBH and in the IFN by long-daytreatments. Type 2 iodothyronine deiodinase is an enzymethat catalyzes the conversion of T4 to T3, whereas type 3iodothyronine deiodinase (DIII) catalyzes the conversion ofT4 and T3 to their inactive forms. Interestingly, theexpression of DIII was downregulated under long-dayconditions, when DII was upregulated (Yasuo et al., 2005).Central administration of DII inhibitor, iopanoic acid,reduced testicular growth of quail that were transferredfrom short- to long-day conditions (Yoshimura et al., 2003).Triiodothyronine implantation to the MBH caused testic-ular growth and reduced encasement of nerve terminals byglial processes in the ME of quail (Yamamura, Yasuo,Hirunagi, Ebihara, & Yoshimura, 2006). The glialprocesses do not physically occupy and block space inbetween axon terminals and capillaries of the portal systemin the ME of photostimulated white-crowned sparrows, butthey do in photorefractory birds (Bern, Nishioka, Mewaldt,& Farner, 1966; Mikami, Oksche, Farner, & Vitums, 1970).As GnRH nerve terminals are also in closer proximity to thebasal lamina of the ME in long-day quail (Yamamura,Hirunagi, Ebihara, & Yoshimura, 2004), Yamamura et al.(2006) suggest a role for T3 in the regulation of photope-riodic GnRH secretion via neuroeglial plasticity in the ME.

In a more recent study, functional genomic analysis wasperformed using a chicken high-density oligonucleotidemicroarray during photoinduction in quail (Nakao et al.,2008a). The microarray detected two waves of geneexpression in the MBH. Interestingly, thyrotropin b subunit(TSHb) mRNA expression peaked around 14 hours afterdawn, and upregulation of DII and downregulation of DIIIoccurred around 18e19 hours after dawn of the first longday. Spatiotemporal expression analyses of the genesrevealed that the first wave events occurred in the parstuberalis (PT) of the pituitary gland, whereas the secondwave events occurred in the ependymal cells in theventrolateral walls of the third ventricle in the MBH.Glycoprotein-a mRNA, which codes for the commonsubunit for TSH, LH, and FSH, was cyclically expressed inthe PT. TSH receptor also was observed in the ependymalcells in the ventrolateral walls of the third ventricle in theMBH, where the second wave genes were expressed, andthe binding of [125I]-TSH was further observed. Intra-cerebroventricular administration of TSH induced theexpression of DII, whereas anti-TSHb antibody reducedDII expression (Nakao et al., 2008a). Although the mech-anism of TSHb mRNA induction by the first long day wasnot identified in this study, the removal of the inhibitoryeffect of melatonin on TSHb mRNA expression isa possible mechanism, because MEL-R (Mel1c) mRNA isexpressed in the PT in chickens (Kameda, Miura, &

Maruyama, 2002). Glycoprotein-a is also expressed in thePT in chickens, and Px induces glycoprotein-a subunitmRNA expression in the PT (Kameda et al., 2002). Thus,local induction of thyroid hormones caused by changes inMEL signaling might well be involved in at least the initialphotoperiodic response.

7. FUTURE RESEARCH DIRECTIONS

The neuroendocrine system controlling reproductiveactivities of birds is summarized in Figure 1.2. The func-tional significance of each action may vary among speciesand between sexes, developmental processes, and repro-ductive stages. It is important to continue searching forunidentified hypothalamic and pituitary hormones and/ornetworks to reveal the whole picture of neuroendocrinemechanisms that control avian reproduction. Chicken(Galliformes) and zebra finch (Passeriformes) genomeshave been published recently. A functional genomic anal-ysis such as microarray is a powerful tool to identifyimportant genes and molecules related to reproductiveprocesses. Gene silencing of target substances by RNAi,and physiological administration of the gene products, arepowerful approaches that will provide greater under-standing of the reproductive processes.

Reproduction in birds consists of various stages that aretimed to maximize the survival of the species. Birds haveamazing abilities to adjust their physiology and behaviorappropriately to the external environment. As annualchanges in photoperiod are the most reliable predictor ofseasonal change outside the tropics, most birds have anability to respond to changing photoperiods. In this chapter,we have described many studies on the effects of photo-period on reproductive activities of birds. However, socialinteractions also have dramatic effects on reproductivephysiology in birds (Hinde, 1965; Lehrman, 1965; Wing-field, Whaling, & Marler, 1994). For example, malecourtship behaviors can greatly enhance the developmentof reproductive physiology and behaviors of female birds(Crews & Silver, 1985; Searcy, 1992; Bentley, Wingfield,Morton, & Ball, 2000; Stevenson et al., 2008). To maxi-mize reproductive success, some bird species categorizedas opportunistic breeders integrate various environmentalcues, such as temperature, rainfall, and food availability,independently from, or in addition to, photoperiodicchanges to initiate breeding (Immelmann, 1971; Zannet al., 1995; Perfito et al., 2008). These indispensablefactors for reproduction, such as the establishment ofterritory, interactions with the opposite sex, and foodavailability, are obviously very important to the timing ofbreeding. Our knowledge of how this type of environmentalinformation and social interactions are processed andintegrated in the HPG axis is minimal. For example, there isexperimental evidence that sounds including vocalization


of birds can stimulate the HPG axis during the scotophaseof the lightedark cycle (Millam, El Halawani, & Burke,1985; Li & Burke, 1987). This brings about the question ofwhether there is a circadian rhythm of audioinducibility,just as there is for photoinducibility. Stress can also modifythe reproductive activity of birds. Inhibitory effects ofstress on reproductive function may be mediated via thehypothalamic GnIH system (Calisi, Rizzo, & Bentley,2008). Activation of the immune system can also impairreproductive function in birds (Owen-Ashley & Wingfield,2007).

Coordination of several neural mechanisms is necessaryto translate various environmental information and socialinteractions and produce appropriately timed changes in thereproductive physiology and behavior of birds (Figure 1.2).For each mechanism that we wish to study, it is important touse an appropriate model animal and analysis. However,reductionism can lead us to emphasize only one aspect ofa specific mechanism that may be applicable to a specificavian species or only in certain artificial situations.Accordingly, whole-animal experiments have a great dealto offer in terms of our understanding of these complexbiological systems, as do experiments in real-world envi-ronments. Only when we integrate studies from themolecular and cellular levels into the physiological,behavioral, and ecological levels can we begin to reveal thewhole picture of neuroendocrine control of avianreproduction.

ABBREVIATIONS

5-HT
Serotonin
ACTH
Corticotropin
aGnRH-I
Avian gonadotropin-releasing hormone-I
aGnRH-II
Avian gonadotropin-releasing hormone-II
anti-MEL
Anti-melatonin antibody
AVT
Arginine vasotocin
cAMP
Cyclic-3’,5’-adenosine monophosphate
cGnRH-I
Chicken gonadotropin-releasing hormone-I
cGnRH-II
Chicken gonadotropin-releasing hormone-II
CRH
Corticotropin-releasing hormone
DA
Dopamine
DII
Type 2 iodothyronine deiodinase
DIII
Type 3 iodothyronine deiodinase
E2
Estradiol
Ex
Bilateral orbital enucleation
FSH
Follicle-stimulating hormone
Gai
a-subunit of the inhibitory G-protein
GH
Growth hormone
GnIH
Gonadotropin-inhibiting hormone
GnIH-RP
Gonadotropin-inhibiting hormone-related peptide
GnRH
Gonadotropin-releasing hormone
GnRH-R
Gonadotropin-releasing hormone receptor
GPCR
G-protein-coupled receptor
GTH
Gonadotropin
HIOMT
Hydroxyindole-O-methyltransferase
HPG
Hypothalamicepituitaryegonadal
HPLC
High performance liquid chromatography
HPS
Hypothalamusepituitary system
ICC
Immunocytochemistry
IFN
Infundibular nucleus
ir
Immunoreactive
LH
Luteinizing hormone
LHRN
Lateral hypothalamic retinorecipient nucleus
MBH
Mediobasal hypothalamus
ME
Median eminence
MEL
Melatonin
MEL-R
Melatonin receptor
mGnRH-I
Mammalian gonadotropin-releasing hormone
MHN
Medial hypothalamic nucleus
MST
Mesotocin
NAT
N-acetyltransferase
P4
Progesterone
PG
Prostaglandin
PN
Pars nervosa
POA
Preoptic area
PRL
Prolactin
proGnRH-GAP
Precursor protein of gonadotropin-releasing
hormone

PT
Pars tuberalis
PVN
Paraventricular nucleus
Px
Pinealectomy
RFRP
RFamide-related peptide
RIA
Radioimmunoassay
SCN
Suprachiasmatic nucleus
T
Testosterone
T3
Triiodothyronine
T4
Thyroxine
TH
Tyrosine hydroxylase
TPH1
Tryptophan hydroxylase-1
TSH
Thyrotropin
TSHb
Thyrotropin b subunit
VIP
Vasoactive intestinal peptide
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Chapter 1 – Neuroendocrine Control of Reproduction in Birds · itary hormones that control avian reproduction by inducing gametogenesis (spermatogenesis, oogenesis) and sex steroidogenesis