The Kisspeptin/Neurokinin B/Dynorphin (KNDy) Cell Population of the Arcuate Nucleus: Sex Differences and Effects of Prenatal Testosterone in Sheep

Cheng, Guanliang; Coolen, Lique M.; Padmanabhan, Vasantha; Goodman, Robert L.; Lehman, Michael N.

doi:10.1210/en.2009-0541

Cited by 268 publications

(232 citation statements)

References 43 publications

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“…Reduced P4 sensitivity was most dramatic within the ARN, with a nearly 60% decrease in PR-positive cells. This finding is in line with previous work showing decreased PR mRNA within the hypothalamus of PNA rats (32) and the ARN of PNA ewes (33). Although the mechanism of reduced PR expression remains to be determined, we can rule out reduced estrogen or P4 levels, as these remain unchanged in PNA mice.…”

Section: Discussionsupporting

confidence: 92%

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Enhancement of a robust arcuate GABAergic input to gonadotropin-releasing hormone neurons in a model of polycystic ovarian syndrome

Moore

Prescott

Marshall

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

180

254

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Polycystic ovarian syndrome (PCOS), the leading cause of female infertility, is associated with an increase in luteinizing hormone (LH) pulse frequency, implicating abnormal steroid hormone feedback to gonadotropin-releasing hormone (GnRH) neurons. This study investigated whether modifications in the synaptically connected neuronal network of GnRH neurons could account for this pathology. The PCOS phenotype was induced in mice following prenatal androgen (PNA) exposure. Serial blood sampling confirmed that PNA elicits increased LH pulse frequency and impaired progesterone negative feedback in adult females, mimicking the neuroendocrine abnormalities of the clinical syndrome. Imaging of GnRH neurons revealed greater dendritic spine density that correlated with increased putative GABAergic but not glutamatergic inputs in PNA mice. Mapping of steroid hormone receptor expression revealed that PNA mice had 59% fewer progesterone receptor-expressing cells in the arcuate nucleus of the hypothalamus (ARN). To address whether increased GABA innervation to GnRH neurons originates in the ARN, a viral-mediated Cre-lox approach was taken to trace the projections of ARN GABA neurons in vivo. Remarkably, projections from ARN GABAergic neurons heavily contacted and even bundled with GnRH neuron dendrites, and the density of fibers apposing GnRH neurons was even greater in PNA mice (56%). Additionally, this ARN GABA population showed significantly less colocalization with progesterone receptor in PNA animals compared with controls. Together, these data describe a robust GABAergic circuit originating in the ARN that is enhanced in a model of PCOS and may underpin the neuroendocrine pathophysiology of the syndrome.GnRH | PCOS | GABA | progesterone receptor | luteinizing hormone G onadotropin-releasing hormone (GnRH) neurons, located in the hypothalamus, control fertility by driving the secretion of the gonadotrophins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) from the pituitary gland. The pulse amplitude and frequency of LH and FSH shape the sequence of events that occur at the ovary, including follicular development, gonadal steroid synthesis, and ovulation.

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Section: Discussionsupporting

confidence: 92%

“…Likewise, in the ewe, the ARN plays a major role in mediating P4 negative feedback to GnRH neurons (42), predominantly through dynorphin and kappa opioid receptor actions (43). Interestingly, the number of dynorphin, neurokinin B, and PR-positive cells are significantly reduced in the ARN of PNA ewes (33).…”

Section: Discussionmentioning

confidence: 99%

Enhancement of a robust arcuate GABAergic input to gonadotropin-releasing hormone neurons in a model of polycystic ovarian syndrome

Moore

Prescott

Marshall

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

180

254

View full text Add to dashboard Cite

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“…In another study of rats, DHT treatment had no effect on Kiss1 mRNA in the hypothalamus; however, it significantly elevated Kiss1 mRNA levels in pituitary tissue, ovary, and adipose tissue (Brown et al 2009). A study on female sheep found that prenatal androgen treatment resulted in a reduction by half of the number of NKB cells, whereas the number of kisspeptin cells remained at levels similar to those in the KNDy subpopulation of control females (Cheng et al 2010). The conflicting observations in these studies may result from differences between the action of DHT and testosterone, different neuron populations, species differences, and different age/sex groupings.…”

Section: Discussionmentioning

confidence: 96%

Prenatal androgen excess enhances stimulation of the GNRH pulse in pubertal female rats

Yan¹,

Yuan²,

Zhao³

et al. 2014

Journal of Endocrinology

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In adolescent girls with polycystic ovary syndrome (PCOS), neuroendocrine derangements manifest after the onset of puberty, characterized by rapid LH pulse frequency. The early mechanism underlying the pubertal regulation of the GNRH/LH pulsatile release in adolescents with PCOS remains uncertain. To determine the effects of prenatal androgen exposure on the activation of GNRH neurons and generation of LH pulse at puberty, we administrated 5a-dihydrotestosterone to pregnant rats and observed serum LH levels and expression of hypothalamic genes in female offspring from postnatal 4 to 8 weeks. The 6-week-old prenatally androgenized (PNA) female rats exhibited an increase in LH pulse frequency. The hypothalamic expression of neurokinin B (Nkb (Tac2)) and Lepr mRNA levels in PNA rats increased remarkably before puberty and remained high during puberty, whereas elevated Kiss1 mRNA levels were detected only after the onset of puberty. Exogenous kisspeptin, NK3R agonist, and leptin triggered tonic stimulation of GNRH neurons and increased LH secretion in 6-week-old PNA rats. Leptin upregulated Kiss1 mRNA levels in the hypothalamus of pubertal PNA rats; however, pretreatment with a kisspeptin antagonist failed to suppress the elevated serum LH stimulated by leptin, indicating that the stimulatory effects of leptin may be conveyed indirectly to GNRH neurons via other neural components within the GNRH neuronal network, rather than through the kisspeptin-GPR54 pathway. These findings validate the hypotheses that NKB and leptin play an essential role in the activation of GNRH neurons and initiation of increased LH pulse frequency in PNA female rats at puberty and that kisspeptin may coordinate their stimulatory effects on LH release.

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“…4 A-F), and Kiss1ra was shown previously to bind Kiss2, considered to be the more important form, with higher affinity than Kiss1 (32). In mammals there is strong evidence of sexual dimorphism of NKB neurons: larger numbers of NKB neurons have been identified in ARC of ewes than of rams (33). The transcription of NKB could be directly altered by estrogen receptors, as sequences corresponding to the estrogen responsive element and imperfect palindromic estrogen responsive element have been reported upstream of the TAC3 gene transcriptional start site (8).…”

Section: Pharmacological Analysis and Signal Transduction Pathways Ofmentioning

confidence: 91%

Neurokinin Bs and neurokinin B receptors in zebrafish-potential role in controlling fish reproduction

Biran

Palevitch

Ben‐Dor

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

120

172

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The endocrine regulation of vertebrate reproduction is achieved by the coordinated actions of several peptide neurohormones, tachykinin among them. To study the evolutionary conservation and physiological functions of neurokinin B (NKB), we identified tachykinin (tac) and tac receptor (NKBR) genes from many fish species, and cloned two cDNA forms from zebrafish. Phylogenetic analysis showed that piscine Tac3s and mammalian neurokinin genes arise from one lineage. High identity was found among different fish species in the region encoding the NKB; all shared the common Cterminal sequence. Although the piscine Tac3 gene encodes for two putative tachykinin peptides, the mammalian ortholog encodes for only one. The second fish putative peptide, referred to as neurokinin F (NKF), is unique and found to be conserved among the fish species when tested in silico. tac3a was expressed asymmetrically in the habenula of embryos, whereas in adults zebrafish tac3a-expressing neurons were localized in specific brain nuclei that are known to be involved in reproduction. Zebrafish tac3a mRNA levels gradually increased during the first few weeks of life and peaked at pubescence. Estrogen treatment of prepubertal fish elicited increases in tac3a, kiss1, kiss2, and kiss1ra expression. The synthetic zebrafish peptides (NKBa, NKBb, and NKF) activated Tac3 receptors via both PKC/Ca 2+ and PKA/cAMP signal-transduction pathways in vitro. Moreover, a single intraperitoneal injection of NKBa and NKF significantly increased leuteinizing hormone levels in mature female zebrafish. These results suggest that the NKB/NKBR system may participate in neuroendocrine control of fish reproduction.gonadotropin-releasing hormone | kisspeptin | teleost | gonadotropin R eproduction is a highly integrated and complex function that requires synchronized production of gametes by both sexes at an optimum time for offspring survival. Fish show an enormous variety of reproductive strategies (1), and were recently chosen as models for the study of growth, metabolism, and human diseases. The hypothalamic regulation of gonadotropin secretion in fish is different from that of mammals, from both endocrinal and anatomical aspects. In teleosts, the pituitary is innervated directly by neurons projecting to the vicinity of the pituitary gonadotrophs (2). Among the neuropeptides released by these nerve endings are gonadotrophin-releasing hormones (GnRHs) and dopamine, which act as stimulatory and inhibitory factors on the release of luteinizing hormone (LH) and follicle-stimulating hormone (3). However, new actors have recently entered the field of reproductive physiology: kisspeptins, neurokinin, and dynorphin have all been implicated in controlling GnRH (4).Topaloglu et al. (5) found that humans bearing loss-of-function mutations of the genes encoding either neurokinin B (NKB) or its cognate receptor, neurokinin receptor 3 (NKBR, Tac3r) displayed hypogonadotropic hypogonadism; this seminal report implicated NKB signaling as an essential factor in the onset of puberty...

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The Kisspeptin/Neurokinin B/Dynorphin (KNDy) Cell Population of the Arcuate Nucleus: Sex Differences and Effects of Prenatal Testosterone in Sheep

Cited by 268 publications

References 43 publications

Enhancement of a robust arcuate GABAergic input to gonadotropin-releasing hormone neurons in a model of polycystic ovarian syndrome

Enhancement of a robust arcuate GABAergic input to gonadotropin-releasing hormone neurons in a model of polycystic ovarian syndrome

Prenatal androgen excess enhances stimulation of the GNRH pulse in pubertal female rats

Neurokinin Bs and neurokinin B receptors in zebrafish-potential role in controlling fish reproduction

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