Central nervous system regulation of gonadal development in the avian male1

Central Nervous System Regulation of Gonadal Development in the Avian Male1 W. J. Kuenzel2,3 Department of Animal and Avian Sciences, University of Maryland, College Park, Maryland 20742 ABSTRACT Many avian species, particularly domesticated ones used for egg and meat production, are photoperiodic. Research conducted over the past several years has revealed the neural components, neurotransmitters, neuromodulators, and gonadotropins that play an important role in responding to changes in day length. An ultimate effect of the neuroendocrine response of birds to

light is gonadal development and production of fertilized eggs and young for the next generation. The main purpose of this paper is to address the major neural systems that have been shown to affect reproductive function in males. Potential areas of research that would help elucidate the mechanism of neural activation of gonadal function are suggested.

(Key words: hypothalamus, neuropeptide Y, dopamine, norepinephrine, glutamic acid decarboxylase)

INTRODUCTION What neural mechanism brings an animal or bird into puberty? For many years a single hypothesis, called the ‘Gonadostat’ or ‘Central Restraint Theory,’ originally proposed by Harris (1955), was widely accepted. The hypothesis centered upon the hypothalamo-pituitary-gonadal (HPG) axis. At that time, specific neurons were known to exist in the hypothalamus [currently referred to as gonadotropin-releasing hormone (GnRH) neurons] that projected to the median eminence (ME). The GnRH, peptidergic neurons produced a secretory product, GnRH, transported to the pituitary gland via the portal vasculature that activated specific pituicytes to produce and secrete luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Both gonadotropins were then transported by the cardiovascular system to target tissue, namely the gonads. According to the Gonadostat theory, the HPG axis was fully functional at birth in mammals; however, tonic inhibitory inputs to the HPG prevented activation of this axis until a defined age, characteristic for a given species. Data employing electrolytic lesions to small loci within the hypothalamus of rats supported the theory. Donovan and van der Werff ten Bosch (1956, 1959) were the first to report that anterior hypothalamic lesions affected an early onset of puberty in female rats. Gellert and Ganong (1960) reported precocious appear-

Received for publication December 30, 1999. Accepted for publication April 24, 2000. 1 Contribution to the Symposium held at the 1999 PSA Meeting. 2 To whom correspondence should be addressed. 3 Present address: Poultry Science Center, University of Arkansas, Fayetteville, AR 72701, e-mail: [email protected].

ance of normal estrus cycles following lesions in the posterior tuberal area involving the arcuate nuclei. An advancement in the appearance of vaginal opening (an indicator of puberty) and first estrus, an increase in uterine weight, precocious ovarian luteinization, and premature sexual cycles were observed following anterior or posterior hypothalamic lesions (Schiavi, 1964). In contrast, Meijs-Roelofs and Moll (1972) showed differential effects of anterior and middle hypothalamic lesions on reproductive function in female rats. Anterior hypothalamic lesions advanced vaginal opening coupled with a tendency toward prolonged and persistent estrus. Middle hypothalamic lesions [destroying either parts of the arcuate nucleus (ARC) or nearly all of the ARC and extending into the area of the paraventricular nucleus (PVN)] effected an advancement of vaginal opening but had no marked influence on cyclicity. In nonhuman primates, anterior hypothalamic lesions involving damage to the medial preoptic area, the periventricular preoptic nucleus, and the anterior hypothalamic nucleus had no effect on the onset of puberty. Posterior hypothalamic lesions (major damage to the premamillary area and posterior nucleus and partial damage to the rostral ventromedial hypothalamic nucleus) resulted in advanced onset of puberty in the female rhesus monkey (Terasawa et al., 1984). In gen-

Abbreviation Key: ARC = arcuate nucleus; EPR = encephalic photoreceptors; FSH = follicle-stimulating hormone; GABA = gamma amino butyric acid; GAD = glutamic acid decarboxylase; GnRH = gonadotropin-releasing hormone; HPG = hypothalamo-pituitary-gonadal; IN = infundibular nucleus; LH = luteinizing hormone; lLHRH-III = lamprey LH-releasing hormone-III; ME = median eminence; nCPa = bed nucleus of the pallial commissure; NE = norepinephrine; NMDA = N-methylD,L-aspartic acid; NPY = neuropeptide Y; PVN = paraventricular nucleus; SCN = suprachiasmatic nucleus.

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2000 Poultry Science 79:1679–1688

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the presence of one or more excitatory neural regions plus the primary HPG axis were essential for normal sexual maturation of avian species.

PRIMARY NEURAL SYSTEM Gonadotropin releasing hormone (GnRH) neurons comprise the primary neural system essential for reproductive development. To date, at least eight forms of GnRH have been characterized among vertebrates (Muske et al., 1994). Classes of vertebrates have two or more forms of GnRH. The first vertebrate species shown to have two distinct forms of GnRH in brain tissue was the domestic chicken, Gallus domesticus; both GnRH-I (King and Millar, 1982a,b) and GnRH-II (Miyamoto et al., 1984) were purified and sequenced in the early 1980s. A second form of GnRH has only recently been discovered in mammals. Kasten et al. (1996) reported a second prepro-GnRH mRNA found in a tree shrew, a placental mammal. Gene expression for the second form occurred in the mesencephalon, and, therefore, this novel mammalian decapeptide was equivalent to chicken GnRH-II. A second form of GnRH has been shown to occur in monkeys (Lesheid et al., 1997) and in humans (White et al., 1998). A second form of GnRH has not been reported in rodents. By using a technique called promoter-driven transgenics in which GnRH-I neurons were targeted, four distinct populations of GnRH-I neurons were identified. Only one population survived after birth, whereas three other groupings of GnRH-I neurons displayed different embryological origins with transient life spans in the developing mouse (Skynner et al., 1999). The data of Skynner et al. (1999) suggest that transcriptional repressors are important in restricting GnRH-I expression to the septopreoptic GnRH neurons in the adult. Perhaps in the rodent GnRH-II neurons have a small window of expression during development that has not yet been discovered. Three forms of GnRH have been found in the brain of the sea lamprey, Petromyzon marinus (Sower et al., 1993), teleost (Gothilf et al., 1996; Parhar et al., 1998), and amphibian (DiMatteo et al., 1996) as well as three putative GnRH receptor subtypes in vertebrates (Troskie et al., 1998). Of interest is that lamprey GnRH-III selectively releases FSH from male rat pituitaries in a dose-related manner. It has, therefore, been proposed as the long sought-after mammalian FSH-releasing factor (Yu et al., 1997). Some types of GnRH neurons are unusual. Rather than originating from cells lining the ventricles of the brain and migrating along radial glia away from the ventricles to their final position in brain tissue, a major population of GnRH neurons originate outside of the brain in the olfactory placode or terminal nerve in amphibians (Muske and Moore, 1988), mammals (Schwanzel-Fukuda and Pfaff, 1989; Wray et al., 1989), and birds (Norgren and Lehman, 1991). The GnRH neurons then migrate into the brain caudal to the olfactory bulb, move posteriorly along the ventromedial region of the forebrain, and establish residence in the anterior and dorsal-most region of

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eral, data from rats suggest that nuclei found near the midline, involving a relatively extensive longitudinal system (anterior, middle, and posterior hypothalamic areas), contain neural elements that affect gonadal development. In monkeys, the system is likewise medial; however, its longitudinal system is more restricted involving the posterior hypothalamic area and the premamillary nucleus. Hypothalamic areas that influence the timing of puberty have also been identified in developing male chicks (Mass and Kuenzel, 1983; Kuenzel and Sharp, 1985). When knife cuts were made on both sides of the brain, beginning in the lateral preoptic area and ending in the caudal lateral hypothalamic region of the posterior hypothalamus, male chicks displayed early sexual maturation. In contrast to mammalian data, parasagittal, microsurgical knife cuts were made through lateral hypothalamic tissue, such that little damage was done to any medial hypothalamic structures. Nonetheless, in both vertebrate classes, a relatively extensive longitudinal system appeared to be involved in gonadal development. In chicks, effective knife cuts had to extend from the preoptic area located rostrally to the posterior hypothalamus. When solely anterior hypothalamic knife cuts or posterior hypothalamic knife cuts were administered bilaterally, early sexual maturation was not observed (Mass and Kuenzel, 1983). A possible, although not inclusive, explanation for both the lesion and knife-cut data is that inhibitory systems were disrupted resulting in early gonadal development supporting the early Central Restraint Theory of Harris (1955). An alternative to the Gonadostat Theory was proposed in the late 1970s and mid-1980s. An ‘Excitatory Input’ or ‘Central Stimulatory Theory’ was proposed (Ruf and Sharpe, 1979; Ojeda et al., 1986), which implied that a prepubertal mammal develops excitatory inputs to the HPG axis near the point of sexual maturation. Data utilizing excitatory amino acids in mammals showed that a neural system existed that directly influenced gonadotropin output and could advance the time of puberty (Tal et al., 1983; Urbanski and Ojeda, 1987). Of relevance to the mammalian hypothesis is that early lesion and knifecut experiments in birds also supported this theory. A defined region, the infundibular nuclear complex comprising the infundibular nucleus (IN), inferior hypothalamic nucleus, ventromedial hypothalamic nucleus, dorsomedial hypothalamic nucleus, medial mamillary nucleus, periventricular hypothalamic nucleus, paraventricular organ, and intramedial nucleus contained neural elements that, if lesioned or isolated by knife cuts, completely blocked the expected photostimulated increase in gonadal size [refer to Kuenzel (1993) for a review of avian experimental studies that altered photoperiodic induction of gonadal development]. Past experiments also showed that if preoptic and septal regions of the brain were lesioned, gonadal development would not occur. Of interest was that lesions directed to the anterior ME did not prevent growth of the testes under long days (reviewed in Kuenzel, 1993). In summary, data suggested

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MAJOR NEUROMODULATORS/ NEUROTRANSMITTERS IMPACTING SEXUAL MATURATION Neuropeptide Y An important neuromodulator affecting gonadal function in mammals and birds is neuropeptide Y (NPY). In

FIGURE 1. Two brain regions where a close association exists between neurons producing neuropeptide Y (NPY) and gonadotropinreleasing hormone (GnRH). In Panel A neurons shown as solid black circles in the bed nucleus of pallial commissure (nCPa) that produce mRNA for NPY, whereas in Panel C are perikarya in the inferior hypothalamic nucleus (IH), infundibular nucleus (IN), and median eminence (ME) that synthesize mRNA for NPY (Kuenzel, Koehler, Boswell, Dunn and Grossmann, unpublished data). The same brain sections taken from atlas plates A8.0 and A5.4 (Kuenzel and Masson, 1988) are shown in Panels B and D, respectively. Note that a major population of GnRH neurons occur in the nCPa (Panel B), whereas their terminal projections are indicated as small dots in the ME (Panel D). AM = anterior hypothalamic nucleus, CO = optic chiasma, ME(EZ) = external zone of the ME, PVO = paraventricular organ, SL = lateral septal nucleus, SM = medial septal nucleus, SSO = subseptal organ, V III = third ventricle, and VL = lateral ventricle.

developing chicks, it has been shown that NPY neurons migrate into the avian brain from the olfactory placode, similar to GnRH neurons (Hilal et al., 1996). When gene expression is examined for NPY in the avian brain there are several regions where one finds high levels, particularly in and about the bed nucleus of the pallial commissure (nCPa) and the IN, including parts of the ME (Figure 1). Upon examination of the major distribution of GnRH neurons and their terminal fields, the major group of GnRH-I neurons occurs in and about the nCPa, whereas the terminal field of the neurons occurs in the ME (Figure 1; Kuenzel and Bla¨ hser, 1991). The close association of NPY and GnRH perikarya and fibers in these two areas of the chick brain suggests a functional interaction between the two peptides for regulating gonadal function. In mammals, more direct evidence has been shown between NPY fibers and GnRH perikarya. Specifically, in the septopreoptic area of the rat brain where a key population of GnRH neurons occurs, NPY neurons have been shown to synapse directly with GnRH perikarya (Tsuruo et al., 1990). The ARC, equivalent to the IN in birds,

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the hypothalamus known as the septopreoptic area. Of the three forms of GnRH that exist in the brain of some vertebrate species, GnRH-I neurons appear to have the unusual origin outside of the central nervous system. In the developing rodent and bird, GnRH neurons migrating into the brain from the olfactory placode take up residence mostly in the septo-anterior hypothalamic region (Schwanzel-Fukuda and Pfaff, 1989; Wray et al., 1989; Norgren and Lehman, 1991; Sullivan and Silverman, 1993). If the olfactory placode of chick embryos is unilaterally ablated, or if olfactory placodes from quail embryos are transplanted into chick embryos having unilaterally ablated olfactory placodes to form avian embryonic chimeras, the evidence suggests that many GnRH neurons migrating into the telencephalon are found in the septopreoptic area (Gao et al., 1996; Yamamoto et al. 1996). For humans who suffer from Kallmann’s syndrome, it has been hypothesized that affected individuals have a defect in GnRH neurons that fail to migrate into the brain from the olfactory placode (Schwanzel-Fukuda and Pfaff, 1989). Affected individuals are more commonly males who display both hypogonadism and anosmia. The majority of GnRH neurons that enter the brain near the olfactory bulb form a major population of neurons, which finally resides in the septopreoptic region. This group of neurons has been shown to be GnRH-I neurons in mammals; the majority of which project to the ME where GnRH is released into the pituitary portal system (Silverman et al., 1994). In contrast, GnRH-II neurons are found in the midbrain or mesencephalon in birds in and about the oculomotor complex (Mikami et al., 1988; Kuenzel and Bla¨ hser, 1991; Millam et al., 1993; van Gils et al., 1993; Ball and Hahn, 1997). Terminals from GnRH-II neurons have been found in the external zone of the ME; however, the degree of immunoreactivity in this terminal field is less than that reported for GnRH-I. The function of GnRH-II is not clearly known for birds. Recent evidence suggests that GnRH-II stimulates sexual behavior in avian females (Maney et al., 1997). Evidence has been reported of ostriches having a possible third form of GnRH found in hypothalamic and extrahypothalmic brain tissues (Powell et al., 1987). The sequence of this avian GnRHIII was not determined (Powell et al., 1987). Of interest is that an antibody to lamprey LH-releasing hormone-III (lLHRH-III) has been shown to immunstain neurons in the PVN of the rat brain. This particular form of LHRH was also effective in releasing FSH in the rat (Yu et al., 1997). A similar antibody to lLHRH-III has also revealed a population of GnRH-III-like perikarya in the chicken PVN (Berghman et al., 1999). The function of this form of GnRH in birds is unknown.

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In birds, there is direct evidence of noradrenergic neurons in the locus ceruleus (A6 group; Moons et al., 1995) that project to the septopreoptic area and mediobasal hypothalamus (Figure 2; Kitt and Brauth, 1986); however, it is not known whether adrenergic projections from A6 continue into the ME. Nonetheless, the A6 group at this time is the best candidate as a source of NE that could influence gonadal development, particularly in light of the evidence that NE neurons in the mouse locus ceruleus appear to be involved in LH release (Saitoh et al., 1991). Dopamine. Evidence has accumulated, for Leghorn and broiler chicks, that DA is associated with sexual maturation. Leghorn cockerels approaching sexual maturation or subjected to castration display elevated LH levels and significantly increased concentrations of DA in the mediobasal hypothalamus (Knight et al., 1981, 1983; Knight, 1983). Broiler chicks showing advanced sexual maturation following parasagittal hypothalamic knife cuts (Davison and Kuenzel, 1991) or increased testes size induced by chronic intracranial administration of NPY (Fraley and

Catecholamines Norepinephrine (NE) and dopamine (DA) are neurotransmitters that are associated with gonadal development in mammals and birds. Norepinephrine. In mammals, NE has been shown to stimulate GnRH release in ovarian-intact or ovariectomized, estrogen-primed rodents (Barraclough and Wise, 1982; Ramirez et al., 1984). Intracerebroventricular administration of NE stimulates GnRH release in adult rhesus monkeys (Terasawa et al., 1988) and in the developing female rhesus monkey (Gore and Terasawa, 1991). In in vitro systems, NE has been shown to increase GnRH release from hypothalamic slices, ME, or medial basal hypothalamic pieces of Japanese quail (Millam et al., 1984; Li et al., 1994; Millam et al., 1998) and laying hens (Contijoch et al., 1990). With respect to the source of NE in the brain that may influence reproductive function, there are four possible sources: A1, A2, A5, and A6 (Figure 2). The specific cell groups in which NE neurons have been identified in the rat brain include the nucleus lateralis reticularis (A1); the nucleus tractus solitarius and dorsal motor nucleus of the vagus (A2); neurons in and about the superior olive, lateral lemniscus and nucleus of the seventh nerve (A5); and locus ceruleus (A6). In the mammal, NE neurons in those four adrenergic groups of neurons have been shown to contain estradiol receptors, suggesting their importance in reproduction (Sar and Stumpf, 1981). Another neuroanatomical indicator suggesting an involvement with gonadal development is evidence of the neural group projecting directly to GnRH neurons or their terminal field, i.e., the septopreoptic area or ME, respectively.

FIGURE 2. Major groups of noradrenergic neurons that may play a role in reproductive function. Group A6 (the locus ceruleus) is a likely candidate, as it has projections to the medial preoptic nucleus (POM) and mediobasal hypothalamus and, therefore, can influence gonadotropinreleasing hormone neurons. Panel A shows a sagittal section near midline, whereas Panel B is a cross-section taken at the level of A2.0, or 2 mm anterior to the zero reference point of a chick brain atlas where the locus ceruleus (LoC) can be observed (Kuenzel and Masson, 1988). BnSTmc = bed nucleus of the stria terminalis, pars magnocellularis; CA = anterior commissure; Cb = cerebellum; DMnX = dorsal motor nucleus of the vagus; FLM = fasciculus longitudinalis medialis; LHy = lateral hypothalamic area; ME = median eminence; nTS = nucleus tractus solitarius; n VII = nucleus of the facial nerve; OP LOBE = optic lobe; PVN = paraventricular nucleus; RST = nucleus reticularis subtrigeminalis; SCE = stratum celluare externum; SCv = nucleus subceruleus ventralis, SL = lateral septal nucleus; SLu = nucleus semilunaris; SM = medial septal nucleus; and TSM = septomesencephalic tract.

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contains one of the largest groups of NPY perikarya found in the mammalian brain (Everitt et al., 1984; Cronwall et al., 1985; Sabatino et al., 1987). One of the projection areas of the ARC is the septopreoptic region, as destruction of the ARC has been shown to reduce significantly NPY content within the septopreoptic area (Kagotani et al., 1989). Second and third major projection systems are to the PVN and ME, respectively. The latter is relevant to reproductive function because the ME contains terminals of both NPY (Everitt et al., 1984; Cronwall et al., 1985; Sabatino et al., 1987) and GnRH neurons (Silverman et al., 1994). In ovariectomized rats treated with estrogen and progesterone, NPY administered into the brain, intracerebroventricularly, affected an increase in LH release (Kalra and Crowley, 1984). In chicks, chronic intracerebroventricular administration of NPY affected advanced development of the testes (Fraley and Kuenzel, 1993). Another method we have used to stimulate gonadal development in male chicks is to add sulfamethazine (SMZ) to a standard broiler ration. Chronic intake of sulfamethazine, beginning at 1 wk of age, results in semen production as early as 9 wk of age. When brains were sampled and examined for NPY-like neurons in the IN, significantly more NPY neurons were found in this mediobasal region of the hypothalamus (Macko Walsh and Kuenzel, 1997).

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FIGURE 3. Major groups of dopaminergic neurons that may play a role in reproductive function. Groups A9 (substantia nigra; SN), A10 (area ventralis of Tsai; AVT), A12 (lateral mamillary nucleus; ML), and A14 (paraventricular nucleus; PVN) are the most likely candidates. Panel A shows a sagittal section near midline, whereas Panels B, C, and D show cross-sections indicating the locations of A9, A10, A12, and A14. CA = anterior commissure, Cb = cerebellum, CDL = area corticoidea dorsolateralis, CO = optic chiasma, CP = posterior commissure, DMnX = dorsal motor nucleus of the vagus, DSM = supramamillary decussation, GCt = central gray, HA = hyperstriatum accessorium, Hp = hippocampus, ICo = nucleus intercollicularis, LHy = lateral hypothalamic area, ME = median eminence, MM = medial mamillary nucleus, nBOR = nucleus of the basal optic root, nTS = nucleus tractus solitarius, OP LOBE = optic lobe, PA = paleostriatum augmentatum (caudate putamen), POM = medial preoptic nucleus, QF = quintofrontal tract, ROT = nucleus rotundus, Ru = nucleus ruber, TSM = septomesencephalic tract, and V III = third ventricle.

rons. Their distribution in the avian brain is similar to dopaminergic neurons; however, their number is less (Moons et al., 1994). This particular catecholamine may play a role in reproductive function and warrants careful study. Amino Acid Neurotransmitters. In the mammalian literature it has been hypothesized that excitatory amino acids play a critical role in reproductive neuroendocrine functions such as puberty and LH pulsatility (Brann and Mahesh, 1997). A key excitatory amino acid is glutamate, which is stored in synaptic vesicles and released into the synaptic cleft following depolarization in a Ca2+-dependent manner (Erecinska and Silver, 1990). Peripheral injection of N-methyl-D,L-aspartic acid (NMDA), which is

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Kuenzel, 1993) have significantly higher concentrations of DA in the ME and adjacent tissue. There are six possible sources of DA in the avian brain. The first three are the substantia nigra (A9), ventral tegmental area, specifically the area ventralis of Tsai (A10) and a midline group of neurons directly above the paraventricular organ in the nucleus of I that continues dorsally into the nucleus paramedianus internus thalami; at more caudal levels, neurons extend dorsally into the central gray. This winglike group of dopaminergic neurons comprise A11. The fourth group of dopaminergic neurons occurs in the tuberal region of the hypothalamus near the lateral mamillary nucleus and is comparable to the A12 group of mammals. The fifth group, A14, occupies a major portion of the PVN. A sixth group, A15, can be found in the lateral hypothalamic area and extends rostrocaudally for a considerable distance, beginning in the preoptic area and ending in the mamillary region. The neuronal groups mentioned previously immunostain with an antibody to tyrosine hydroxylase as well as DA (Kuenzel et al., 1992; Moons et al., 1994; Reiner et al., 1994). Of the six major groups of dopaminergic neurons discussed above, three project to the septopreoptic area, including the A9, A10, and A12, and, therefore, could influence GnRH neurons (Figure 3). Two groups, the A12 and A14, appear to influence terminal projections in the ME. Curiously, even though the A12 group resides in the tuberal region near the ME, its major projections are to the telencephalic region, including the hyperstriatum accessorium, hippocampus, parahippocampal area, area corticoidea dorsolateralis, and Wulst (Berk and Hawkin, 1985). Although not mentioned by Berk and Hawkin (1985), there are some projections from the A12 group into the ME (Figure 3G of Berk and Hawkin, 1985). The most important dopaminergic group projecting to the ME appears to be A14. It is a large, neuronal group termed the nucleus periventricularis magnocellularis by Berk and Finkelstein (1983) that is equivalent to the PVN of mammals (Berk and Finkelstein, 1983). Of the six groups of dopaminergic neurons, the A14 or PVN group and, perhaps, A12 are the most likely dopaminergic neural loci to influence gonadal maturation. Indirect evidence to support this has been obtained in developing chicks. Experimental chicks displaying advanced gonadal development from parasagittal knife cuts (Davison and Kuenzel, 1991) or chronic intracerebroventricular injections of NPY (Fraley and Kuenzel, 1993) also showed significantly higher levels of DA or L-dopa in the ME. L-Dopa. In the rat brain, levels of L-dopa are usually less than 1 ng/mg protein, and therefore L-dopa is usually not detected without the use of decarboxylase blockers (Demarest and Moore, 1980). In the chick brain, one can quantitate levels of L-dopa in at least three areas of importance to reproductive function by HPLC without the need of decarboxylase inhibitors (Fraley and Kuenzel, 1993). By use of antibodies directed to L-dopa and the technique of immunocytochemistry, L-dopa-like neurons have been detected (Moons et al., 1994; Macko Walsh et al., 1995). The avian brain, therefore, appears to have L-dopa neu-

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1999). The results were similar to those obtained from birds transferred from a short, nonstimulatory photoperiod to one that was stimulatory for the release of LH (Meddle and Follett, 1995).

BASIC NEURAL COMPONENTS FOR A SYSTEM REGULATING PUBERTY IN BIRDS When one examines the two theories introduced to explain the regulation of puberty in animals (Gonadostat Theory vs. the Excitatory Input or Central Stimulatory Theory), data to date, from birds, appear to favor the latter. Therefore, in attempting to develop a neuroendocrine model for gonadal development, there is a bias toward including neural components that activate the release of GnRH and gonadotropins. More importantly, the neural components selected are limited and highly simplified, and the system presented in the following paragraphs is clearly incomplete. There appear to be at least three basic components for a neural system regulating puberty in birds: 1) receptors that can receive and respond appropriately to external light and photoperiod, 2) a GnRH pulse generator and primary neural system comprising the HPG axis, and 3) neural loci having elements that activate the HPG axis.

Encephalic Photoreceptors Progress has been made in studies of birds suggesting that the eyes and pineal gland are not involved in effecting gonadal development, rather encephalic photoreceptors (EPR, receptors in brain tissue) are responsible for responding to light and initiating gonadal development in birds that are photoperiodic (reviewed in Kuenzel, 1993). A key experiment showed that there are two sites in the avian brain, septal and mediobasal hypothalamic regions, that contain cerebrospinal fluid contacting neurons that are immunoreactive with an antibody to opsin (Silver et al., 1988). Data suggest that the two brain loci contain neurons with receptors that can respond to light. In chicks, the septal region that contains the reported EPR is the lateral septal organ, a circumventricular organ in birds (Kuenzel and Bla¨ hser, 1994; Kuenzel et al., 1997), whereas the mediobasal region that contains EPR is the IN and ventral periventricular hypothalamic nucleus.

GnRH Pulse Generator and HPG Axis Data from mammals have shown that the SCN is a circadian pacemaker and that direct projections exist from ganglion cells in the retina to the SCN. Therefore, external light striking some mammalian eyes can entrain the output obtained from the SCN (Moore and Card, 1990). The avian homologue of SCN is unclear. It has been proposed to be a small medial group of neurons called the medial SCN found near the base of the third ventricle (Hartwig, 1974). A second possibility is a more laterally positioned nucleus between the optic chiasma and supraoptic decussation designated the nucleus decussationis supraopticae,

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an excitatory glutamate analog, results in a significant plasma LH increase in prepubertal primates (Plant et al., 1989) and prepubertal rats (Urbanski and Ojeda, 1987). The distribution of glutamate has been shown to occur in hypothalamic areas of importance to reproductive function including the PVN, ventromedial hypothalalamic nucleus, suprachiasmatic nucleus (SCN), ARC, and ME (van den Pol et al., 1990). In addition, excitatory amino acid receptors have also been identified and their distribution determined. Two principal groups of excitatory amino acid receptors have been determined: ionotropic and metabotropic. The former contain integral, cationspecific channels, whereas the latter are coupled to G proteins and modulate the production of second messengers such as inositol phosphates or adenylate cyclase. The ionotropic are rapid acting, whereas the metabotropic exert prolonged synaptic modulation (Brann and Mahesh, 1997). Immunocytochemical studies have shown that glutamate receptors (NMDA-R1) are located in hypothalamic nuclei of reproductive importance to include the organum vasculosum of the lamina terminalis, ventromedial hypothalalamic nucleus, supraoptic nucleus, ARC, ME, medial preoptic area, and PVN (Bhat et al., 1995). More recently, attention has focused upon the enzyme glutamic acid decarboxylase (GAD), which is a catalytic enzyme responsible for gamma amino butyric acid (GABA) synthesis from glutamate (Mitsushima et al., 1996). The enzyme GAD may play a critical role in the onset of puberty, because GABA is regarded as an inhibitory amino acid and is responsible for low levels of GnRH release in prepubertal monkeys (Mitsushima et al., 1994), whereas glutamate is stimulatory. An experiment was designed to utilize an antisense oligodeoxynucleotide for GAD. If deposited into the stalk ME of pubertal monkeys, it was hypothesized that the antisense oligodeoxynucleotide would interfere with GAD synthesis, leading to a decrease in GABA production and release followed by an increase in GnRH release. Prepubertal and pubertal female rhesus monkeys showed a significant increase in GnRH release after administration of the antisense probe. It is suggested that the increased GnRH release after antisense treatment resulted in an increase in glutamate tone mediated by NMDA receptors as well as a decrease in GABA release (Kasuya et al., 1999). To date, little research has been conducted on birds involving excitatory amino acids and puberty. It has been shown in cockerels that NMDA released LH (Jo´ zsa et al., 1997). An interesting study was completed in Whitecrowned Sparrows (Zonotrochia leucophrys gambelii). Peripheral administration of NMDA to photosensitive, photostimulated, or photorefractory white-crowned sparrows resulted in a significant release of LH, suggesting that migratory birds have sufficient stores of GnRH in their primary neuronal system for gonadal function, regardless of the time of year or physiological state, even when the birds are photorefractory to long days (Meddle et al., 1999). In addition, fos-like immunoreactivity was found in the medial basal hypothalamus and in and about the nCPa following NMDA injections (Meddle et al.,

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Neural Loci Containing Elements that Activate the HPG Axis There have been several studies since 1938 (Table 4 of Kuenzel, 1993) showing that the infundibular nuclear complex, found in the mediobasal hypothalamus, contains two groups of neural elements essential for photoperiodic induction of gonadal development or the maintenance of gonadal function in birds. The general location of the two groups is directly above the ME (shown in Figure 2A). Of interest is that the infundibular nuclear complex as well as an area in and about the nCPa contain neurons that show fos-like immunoreactivity following LH release induced by long-day exposure or after administration of NMDA (Meddle and Follett, 1995; Meddle et al., 1999). Therefore two possible sites exist in the mediobasal hypothalamus and a third site occurs near the nCPa that may serve to initiate sexual maturation in birds by activating a neuroendocrine system to increase the baseline output of the GnRH pulse generator resulting in increased gonadotropin release. In summary, although we may know the location and major components of a system regulating puberty in birds, how the components are connected as well as the major neuromodulators and neurotransmitters released

by each neuronal group remain to be determined for avian species.

ACKNOWLEDGMENTS The author thanks M. Hamilton for completing the figures found in the manuscript. The work was supported in part by competitive grant AASC-00-51 from the Maryland Agricultural Experiment Station.

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