Neuroanatomy of the Kisspeptin Signaling System in Mammals: Comparative and Developmental Aspects

  • Michael N. Lehman
  • Stanley M. Hileman
  • Robert L. Goodman
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 784)


Our understanding of kisspeptin and its actions depends, in part, on a detailed knowledge of the neuroanatomy of the kisspeptin signaling system in the brain. In this chapter, we will review our current knowledge of the distribution of kisspeptin cells, fibers, and receptors in the mammalian brain, including the development, phenotype, and projections of different kisspeptin subpopulations. A fairly consistent picture emerges from this analysis. There are two major groups of kisspeptin cell bodies: a large number in the arcuate nucleus (ARC) and a smaller collection in the rostral periventricular area of the third ventricle (RP3V) of rodents and preoptic area (POA) of non-rodents. Both sets of neurons project to GnRH cell bodies, which contain Kiss1r, and the ARC kisspeptin population also projects to GnRH axons in the median eminence. ARC kisspeptin neurons contain neurokinin B and dynorphin, while a variable percentage of those cells in the RP3V of rodents contain galanin and/or dopamine. Neurokinin B and dynorphin have been postulated to contribute to the control of GnRH pulses and sex steroid negative feedback, while the role of galanin and dopamine in rostral kisspeptin neurons is not entirely clear. Kisspeptin neurons, fibers, and Kiss1r are found in other areas, including widespread areas outside the hypothalamus, but their physiological role(s) in these regions remains to be determined.


Median Eminence GnRH Neuron Preoptic Region Kiss1 mRNA Kiss1 Expression 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We thank Dr. Lique M. Coolen for her valuable assistance in the preparation of Fig. 3.3. This work is supported by a grant from NIH (NIH RO1 HD033916)


  1. 1.
    Dungan HM, Clifton DK, Steiner RA (2006) Minireview: kisspeptin neurons as central processors in the regulation of gonadotropin-releasing hormone secretion. Endocrinology 147(3):1154–1158PubMedGoogle Scholar
  2. 2.
    Lehman MN, Merkley CM, Coolen LM, Goodman RL (2010) Anatomy of the kisspeptin neural network in mammals. Brain Res 1364:90–102PubMedGoogle Scholar
  3. 3.
    Mikkelsen JD, Simonneaux V (2009) The neuroanatomy of the kisspeptin system in the mammalian brain. Peptides 30(1):26–33PubMedGoogle Scholar
  4. 4.
    Oakley AE, Clifton DK, Steiner RA (2009) Kisspeptin signaling in the brain. Endocr Rev 30(6):713–743PubMedGoogle Scholar
  5. 5.
    Akazome Y, Kanda S, Okubo K, Oka Y (2010) Functional and evolutionary insights into vertebrate kisspeptin systems from studies of fish brain. J Fish Biol 76(1):161–182PubMedGoogle Scholar
  6. 6.
    Tena-Sempere M, Felip A, Gomez A, Zanuy S, Carrillo M (2012) Comparative insights of the kisspeptin/kisspeptin receptor system: lessons from non-mammalian vertebrates. Gen Comp Endocrinol 175(2):234–243PubMedGoogle Scholar
  7. 7.
    Brailoiu GC, Dun SL, Ohsawa M, Yin DL, Yang J, Chang JK et al (2005) KiSS-1 expression and metastin-like immunoreactivity in the rat brain. J Comp Neurol 481(3):314–329PubMedGoogle Scholar
  8. 8.
    Clarkson J, de Tassigny XD, Colledge WH, Caraty A, Herbison AE (2009) Distribution of kisspeptin neurones in the adult female mouse brain. J Neuroendocrinol 21(8):673–682PubMedGoogle Scholar
  9. 9.
    Franceschini I, Lomet D, Cateau M, Delsol G, Tillet Y, Caraty A (2006) Kisspeptin immunoreactive cells of the ovine preoptic area and arcuate nucleus co-express estrogen receptor alpha. Neurosci Lett 401(3):225–230PubMedGoogle Scholar
  10. 10.
    Goodman RL, Lehman MN, Smith JT, Coolen LM, De Oliveira CVR, Jafarzadehshirazi MR et al (2007) Kisspeptin neurons in the arcuate nucleus of the ewe express both dynorphin A and neurokinin B. Endocrinology 148(12):5752–5760PubMedGoogle Scholar
  11. 11.
    Clarkson J, Herbison AE (2006) Postnatal development of kisspeptin neurons in mouse hypothalamus; sexual dimorphism and projections to gonadotropin-releasing hormone neurons. Endocrinology 147(12):5817–5825PubMedGoogle Scholar
  12. 12.
    Gottsch ML, Cunningham MJ, Smith JT, Popa SM, Acohido BV, Crowley WF et al (2004) A role for kisspeptins in the regulation of gonadotropin secretion in the mouse. Endocrinology 145(9):4073–4077PubMedGoogle Scholar
  13. 13.
    Han SK, Gottsch ML, Lee KJ, Popa SM, Smith JT, Jakawich SK et al (2005) Activation of gonadotropin-releasing hormone neurons by kisspeptin as a neuroendocrine switch for the onset of puberty. J Neurosci 25(49):11349–11356PubMedGoogle Scholar
  14. 14.
    Kim J, Semaan SJ, Clifton DK, Steiner RA, Dhamija S, Kauffman AS (2011) Regulation of Kiss1 expression by sex steroids in the amygdala of the rat and mouse. Endocrinology 152(5):2020–2030PubMedGoogle Scholar
  15. 15.
    Smith JT, Cunningham MJ, Rissman EF, Clifton DK, Steiner RA (2005) Regulation of Kiss1 gene expression in the brain of the female mouse. Endocrinology 146(9):3686–3692PubMedGoogle Scholar
  16. 16.
    Smith JT, Dungan HM, Stoll EA, Gottsch ML, Braun RE, Eacker SM et al (2005) Differential regulation of KiSS-1 mRNA expression by sex steroids in the brain of the male mouse. Endocrinology 146(7):2976–2984PubMedGoogle Scholar
  17. 17.
    Hanchate NK, Parkash J, Bellefontaine N, Mazur D, Colledge WH, de Tassigny XD et al (2012) Kisspeptin-GPR54 signaling in mouse NO-synthesizing neurons participates in the hypothalamic control of ovulation. J Neurosci 32(3):932–945PubMedGoogle Scholar
  18. 18.
    Adachi S, Yamada S, Takatsu Y, Matsui H, Kinoshita M, Takase K et al (2007) Involvement of anteroventral periventricular metastin/kisspeptin neurons in estrogen positive feedback action on luteinizing hormone release in female rats. J Reprod Dev 53(2):367–378PubMedGoogle Scholar
  19. 19.
    Desroziers E, Mikkelsen J, Simonneaux V, Keller M, Tillet Y, Caraty A et al (2010) Mapping of kisspeptin fibres in the brain of the pro-oestrous rat. J Neuroendocrinol 22(10):1101–1112PubMedGoogle Scholar
  20. 20.
    Irwig MS, Fraleyb GS, Smith JT, Acohido BV, Popa SM, Cunningham MJ et al (2004) Kisspeptin activation of gonadotropin releasing hormone neurons and regulation of KiSS-1 mRNA in the male rat. Neuroendocrinology 80(4):264–272PubMedGoogle Scholar
  21. 21.
    Kauffman AS, Gottsch ML, Roa J, Byquist AC, Crown A, Clifton DK et al (2007) Sexual differentiation of Kiss1 gene expression in the brain of the rat. Endocrinology 148(4):1774–1783PubMedGoogle Scholar
  22. 22.
    Kinoshita M, Tsukamura H, Adachi S, Matsui H, Uenoyama Y, Iwata K et al (2005) Involvement of central metastin in the regulation of preovulatory luteinizing hormone surge and estrous cyclicity in female rats. Endocrinology 146(10):4431–4436PubMedGoogle Scholar
  23. 23.
    Smith JT, Popa SM, Clifton DK, Hoffman GE, Steiner RA (2006) Kiss1 neurons in the forebrain as central processors for generating the preovulatory luteinizing hormone surge. J Neurosci 26(25):6687–6694PubMedGoogle Scholar
  24. 24.
    Xu ZF, Kaga S, Mochiduki A, Tsubomizu J, Adachi S, Sakai T et al (2012) Immunocytochemical localization of kisspeptin neurons in the rat forebrain with special reference to sexual dimorphism and interaction with GnRH neurons. Endocr J 59(2):161–171PubMedGoogle Scholar
  25. 25.
    Takase K, Uenoyama Y, Inoue N, Matsui H, Yamada S, Shimizu M et al (2009) Possible role of oestrogen in pubertal increase of Kiss1/kisspeptin expression in discrete hypothalamic areas of female rats. J Neuroendocrinol 21(6):527–537PubMedGoogle Scholar
  26. 26.
    Ansel L, Bolborea M, Bentsen AH, Klosen P, Mikkelsen JD, Simonneaux V (2010) Differential regulation of Kiss1 expression by melatonin and gonadal hormones in male and female Syrian hamsters. J Biol Rhythms 25(2):81–91PubMedGoogle Scholar
  27. 27.
    Greives TJ, Mason AO, Scotti MAL, Levine J, Ketterson ED, Kriegsfeld LJ et al (2007) Environmental control of kisspeptin: implications for seasonal reproduction. Endocrinology 148(3):1158–1166PubMedGoogle Scholar
  28. 28.
    Mason AO, Greives TJ, Scotti MAL, Levine J, Frommeyer S, Ketterson ED et al (2007) Suppression of kisspeptin expression and gonadotropic axis sensitivity following exposure to inhibitory day lengths in female Siberian hamsters. Horm Behav 52(4):492–498PubMedGoogle Scholar
  29. 29.
    Revel FG, Saboureau M, Masson-Pevet M, Pevet P, Mikkelsen JD, Simonneaux V (2006) Kisspeptin mediates the photoperiodic control of reproduction in hamsters. Curr Biol 16(17):1730–1735PubMedGoogle Scholar
  30. 30.
    Bosch MA, Xue CH, Ronnekleiv OK (2012) Kisspeptin expression in guinea pig hypothalamus: effects of 17 beta-estradiol. J Comp Neurol 520(10):2143–2162PubMedGoogle Scholar
  31. 31.
    Cheng G, Coolen LM, Padmanabhan V, Goodman RL, Lehman MN (2010) The kisspeptin/neurokinin B/dynorphin (KNDy) cell population of the arcuate nucleus: sex differences and effects of prenatal testosterone in sheep. Endocrinology 151(1):301–311PubMedGoogle Scholar
  32. 32.
    Estrada KM, Clay CM, Pompolo S, Smith JT, Clarke IJ (2006) Elevated KiSS-1 expression in the arcuate nucleus prior to the cyclic preovulatory gonadotrophin-releasing hormone/lutenising hormone surge in the ewe suggests a stimulatory role for kisspeptin in oestrogen-­positive feedback. J Neuroendocrinol 18(10):806–809PubMedGoogle Scholar
  33. 33.
    Smith JT, Clay CM, Caraty A, Clarke IJ (2007) KiSS-1 messenger ribonucleic acid expression in the hypothalamus of the ewe is regulated by sex steroids and season. Endocrinology 148(3):1150–1157PubMedGoogle Scholar
  34. 34.
    Smith JT, Coolen LM, Kriegsfeld LJ, Sari IP, Jaafarzadehshirazi MR, Maltby M et al (2008) Variation in kisspeptin and RFamide-related peptide (RFRP) expression and terminal connections to gonadotropin-releasing hormone neurons in the brain: a novel medium for seasonal breeding in the sheep. Endocrinology 149(11):5770–5782PubMedGoogle Scholar
  35. 35.
    Smith JT, Li Q, Pereira A, Clarke IJ (2009) Kisspeptin neurons in the ovine arcuate nucleus and preoptic area are involved in the preovulatory luteinizing hormone surge. Endocrinology 150(12):5530–5538PubMedGoogle Scholar
  36. 36.
    Matsuyama S, Ohkura S, Mogi K, Wakabayashi Y, Mori Y, Tsukamura H et al (2011) Morphological evidence for direct interaction between kisspeptin and gonadotropin-­releasing hormone neurons at the median eminence of the male goat: an immunoelectron microscopic study. Neuroendocrinology 94(4):323–332PubMedGoogle Scholar
  37. 37.
    Ohkura S, Wakabayashi Y, Uenoyama Y, Steiner RA, Tsukamura H, Maeda K et al (2010) Gonadotropin-releasing hormone pulse generator activity from the arcuate nucleus kisspeptin neurons in the goat hypothalamus. Endocr J 57:S516Google Scholar
  38. 38.
    Wakabayashi Y, Nakada T, Murata K, Ohkura S, Mogi K, Navarro VM et al (2010) Neurokinin B and dynorphin A in kisspeptin neurons of the arcuate nucleus participate in generation of periodic oscillation of neural activity driving pulsatile gonadotropin-releasing hormone secretion in the goat. J Neurosci 30(8):3124–3132PubMedGoogle Scholar
  39. 39.
    Ramaswamy S, Guerriero KA, Gibbs RB, Plant TM (2008) Structural interactions between kisspeptin and GnRH neurons in the mediobasal hypothalamus of the male rhesus monkey (Macaca mulatta) as revealed by double immunofluorescence and confocal microscopy. Endocrinology 149(9):4387–4395PubMedGoogle Scholar
  40. 40.
    Ramaswamy S, Seminara SB, Ali B, Ciofi P, Amin NA, Plant TM (2010) Neurokinin B stimulates GnRH release in the male monkey (Macaca mulatta) and is colocalized with ­kisspeptin in the arcuate nucleus. Endocrinology 151(9):4494–4503PubMedGoogle Scholar
  41. 41.
    Rometo AM, Krajewski SJ, Voytko ML, Rance NE (2007) Hypertrophy and increased kisspeptin gene expression in the hypothalamic infundibular nucleus of postmenopausal women and ovariectomized monkeys. J Clin Endocrinol Metab 92(7):2744–2750PubMedGoogle Scholar
  42. 42.
    Shahab M, Mastronardi C, Seminara SB, Crowley WF, Ojeda SR, Plant TM (2005) Increased hypothalamic GPR54 signaling: a potential mechanism for initiation of puberty in primates. Proc Natl Acad Sci U S A 102(6):2129–2134PubMedGoogle Scholar
  43. 43.
    Smith JT, Periera A, Shahab M, Pau KYF, Clarke IJ (2010) Hypothalamic expression of the kisspeptin gene (Kiss1) and the RFamide-related peptide (RFRP) gene during the menstrual cycle of a non-human primate. Endocr J 57:S534Google Scholar
  44. 44.
    Hrabovszky E, Ciofi P, Vida B, Horvath MC, Keller E, Caraty A et al (2010) The kisspeptin system of the human hypothalamus: sexual dimorphism and relationship with gonadotropin-­releasing hormone and neurokinin B neurons. Eur J Neurosci 31(11):1984–1998PubMedGoogle Scholar
  45. 45.
    Goodman RL, Lehman MN (2012) Kisspeptin neurons from mice to men: similarities and differences. Endocrinology 153(11):5105–5118PubMedGoogle Scholar
  46. 46.
    Decourt C, Tillet Y, Caraty A, Franceschini I, Briant C (2008) Kisspeptin immunoreactive neurons in the equine hypothalamus interactions with GnRH neuronal system. J Chem Neuroanat 36(3–4):131–137PubMedGoogle Scholar
  47. 47.
    Magee C, Foradori CD, Bruemmer JE, Arreguin-Arevalo JA, Mccue PM, Handa RJ et al (2009) Biological and anatomical evidence for kisspeptin regulation of the hypothalamic-­pituitary-gonadal axis of estrous horse mares. Endocrinology 150(6):2813–2821PubMedGoogle Scholar
  48. 48.
    Ginther OJ, Gastal EL, Gastal MO, Beg MA (2005) Regulation of circulating gonadotropins by the negative effects of ovarian hormones in mares. Biol Reprod 73(2):315–323PubMedGoogle Scholar
  49. 49.
    Clarkson J, Boon WC, Simpson ER, Herbison AE (2009) Postnatal development of an estradiol-­kisspeptin positive feedback mechanism implicated in puberty onset. Endocrinology 150(7):3214–3220PubMedGoogle Scholar
  50. 50.
    Gill JC, Wang OL, Kakar S, Martinelli E, Carroll RS, Kaiser UB (2010) Reproductive hormone-­dependent and -independent contributions to developmental changes in kisspeptin in GnRH-deficient hypogonadal mice. PLoS One 5(7):e11911PubMedGoogle Scholar
  51. 51.
    Mayer C, Acosta-Martinez M, Dubois SL, Wolfe A, Radovick S, Boehm U et al (2010) Timing and completion of puberty in female mice depend on estrogen receptor alpha-­signaling in kisspeptin neurons. Proc Natl Acad Sci U S A 107(52):22693–22698PubMedGoogle Scholar
  52. 52.
    Newman SW (1999) The medial extend amygdala in male reproductive behavior. A node in the mammalian social behavior network. Ann N Y Acad Sci 877:242–257PubMedGoogle Scholar
  53. 53.
    Veening JG, Coolen LM (1998) Neural activation following sexual behavior in the male and female rat brain. Behav Neurosci 92:181–193Google Scholar
  54. 54.
    Beltramino C, Taleusbik S (1978) Facilitory and inhibitory effects of electrochemical stimulation of the amygdala on the release of luteinizing hormone. Brain Res 144:95–107PubMedGoogle Scholar
  55. 55.
    Cravo RM, Margatho LO, Osborne-Lawrence S, Donato J, Atkin S, Bookout AL et al (2011) Characterization of Kiss1 neurons using transgenic mouse models. Neuroscience 173:37–56PubMedGoogle Scholar
  56. 56.
    Padilla SL, Carmody JS, Zeltser LM (2010) Pomc-expressing progenitors give rise to antagonistic neuronal populations in hypothalamic feeding circuits. Nat Med 16(4):403–405PubMedGoogle Scholar
  57. 57.
    de Tassigny XD, Fagg LA, Carlton MBL, Colledge WH (2008) Kisspeptin can stimulate gonadotropin-releasing hormone (GnRH) release by a direct action at GnRH nerve terminals. Endocrinology 149(8):3926–3932Google Scholar
  58. 58.
    Goodman RL, Coolen LM, Anderson GM, Hardy SL, Valent M, Connors JM et al (2004) Evidence that dynorphin plays a major role in mediating progesterone negative feedback on gonadotropin-releasing hormone neurons in sheep. Endocrinology 145(6):2959–2967PubMedGoogle Scholar
  59. 59.
    Topaloglu AK, Reimann F, Guclu M, Yalin AS, Kotan LD, Porter KM et al (2009) TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction. Nat Genet 41(3):354–358PubMedGoogle Scholar
  60. 60.
    Lehman MN, Coolen LM, Goodman RL (2010) Minireview: kisspeptin/neurokinin B/dynorphin (KNDy) cells of the arcuate nucleus: a central node in the control of gonadotropin-­releasing hormone secretion. Endocrinology 151(8):3479–3489PubMedGoogle Scholar
  61. 61.
    Navarro VM, Gottsch ML, Wu M, Garca-Galiano D, Hobbs SJ, Bosch MA et al (2011) Regulation of NKB pathways and their roles in the control of Kiss1 neurons in the arcuate nucleus of the male mouse. Endocrinology 152(11):4265–4275PubMedGoogle Scholar
  62. 62.
    Rance NE, Krajewski SJ, Smith MA, Cholanian M, Dacks PA (2010) Neurokinin B and the hypothalamic regulation of reproduction. Brain Res 1364:116–128PubMedGoogle Scholar
  63. 63.
    Navarro VM, Gottsch ML, Chavkin C, Okamura H, Clifton DK, Steiner RA (2009) Regulation of gonadotropin-releasing hormone secretion by kisspeptin/dynorphin/neurokinin B neurons in the arcuate nucleus of the mouse. J Neurosci 29(38):11859–11866PubMedGoogle Scholar
  64. 64.
    Clarkson J, Herbison AE (2011) Dual phenotype kisspeptin-dopamine neurones of the rostral periventricular area of the third ventricle project to gonadotrophin-releasing hormone neurones. J Neuroendocrinol 23(4):293–301PubMedGoogle Scholar
  65. 65.
    Semaan SJ, Murray EK, Poling MC, Dhamija S, Forger NG, Kauffman AS (2010) BAX-­dependent and BAX-independent regulation of Kiss1 neuron development in mice. Endocrinology 151(12):5807–5817PubMedGoogle Scholar
  66. 66.
    Merkley CM, Coolen LM, Goodman RL, Lehman MN. Colocalization of met-enkephalin, but not galanin or tyrosine hydroxylase, within kisspeptin neurons in the sheep. In: Annual Meeting of the Endocrine Society 2012Google Scholar
  67. 67.
    Porteous R, Petersen SL, Yeo SH, Bhattarai JP, Ciofi P, de Tassigny XD et al (2011) Kisspeptin neurons co-express met-enkephalin and galanin in the rostral periventricular region of the female mouse hypothalamus. J Comp Neurol 519(17):3456–3469PubMedGoogle Scholar
  68. 68.
    Merkley CM, Jackson L, Goodman RL, Lehman MN. Evidence for transcriptional activation of arcuate kisspeptin neurons, and glutamatergic input to kisspeptin during the preovulatory GnRH surge in sheep. In: Annual Meeting of the Endocrine Society 2009, P3–220Google Scholar
  69. 69.
    Wintermantel TM, Campbell RE, Porteous R, Bock D, Grone HJ, Todman MG et al (2006) Definition of estrogen receptor pathway critical for estrogen positive feedback to gonadotropin-­releasing hormone neurons and fertility. Neuron 52(2):271–280PubMedGoogle Scholar
  70. 70.
    Clarkson J, d’Anglemont X, Moreno AS, Colledge WH, Herbison AE (2008) Kisspeptin-­GPR54 signaling is essential for preovulatory gonadotropin-releasing hormone neuron activation and the luteinizing hormone surge. J Neurosci 28(35):8691–8697PubMedGoogle Scholar
  71. 71.
    Simerly RB, Chang C, Muramatsu M, Swanson LW (1990) Distribution of androgen and estrogen-receptor messenger RNA-containing cells in the rat-brain—an in situ hybridization study. J Comp Neurol 294(1):76–95PubMedGoogle Scholar
  72. 72.
    Oakley AE, Coolen LM, Lehman MN, Wagenmaker ER, Karsch FJ. Are dynorphin neurons in the arcuate nucleus responsive to cortisol and influenced by the combined presence of cortisol and estradiol. In: Annual Meeting of the Endocrine Society 2009Google Scholar
  73. 73.
    Li Q, Rao A, Pereira A, Clarke IJ, Smith JT (2011) Kisspeptin cells in the ovine arcuate nucleus express prolactin receptor but not melatonin receptor. J Neuroendocrinol 23(10):871–882PubMedGoogle Scholar
  74. 74.
    Cernea M, Phillips R, Padmanabhan V, Coolen LM, Lehman MN. Colocalization of insulin receptors in KNDy but not GnRH neurons inthe ewe: effects of excess prenatal testosterone. In: Annual Meeting of the Endocrine Society 2012Google Scholar
  75. 75.
    Kotani M, Detheux M, Vandenbbogaerde A, Communi D, Vanderwinden JM, Le Poul E et al (2001) The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54. J Biol Chem 276(37):34631–34636PubMedGoogle Scholar
  76. 76.
    Muir AI, Chamberlain L, Elshourbagy NA, Michalovich D, Moore DJ, Calamari A et al (2001) AXOR12, a novel human G protein-coupled receptor, activated by the peptide KiSS-­1. J Biol Chem 276(31):28969–28975PubMedGoogle Scholar
  77. 77.
    Lee DK, Nguyen T, O’Neill GP, Cheng R, Liu Y, Howard AD et al (1999) Discovery of a receptor related to the galanin receptors. FEBS Lett 446(1):103–107PubMedGoogle Scholar
  78. 78.
    Herbison AE, de Tassigny XD, Doran J, Colledge WH (2010) Distribution and postnatal development of Gpr54 gene expression in mouse brain and gonadotropin-releasing hormone neurons. Endocrinology 151(1):312–321PubMedGoogle Scholar
  79. 79.
    Kim W, Jessen HM, Auger AP, Terasawa E (2009) Postmenopausal increase in KiSS-1, GPR54, and luteinizing hormone releasing hormone (LHRH-1) mRNA in the basal hypothalamus of female rhesus monkeys. Peptides 30(1):103–110PubMedGoogle Scholar
  80. 80.
    Shibata M, Friedman RL, Ramaswamy S, Plant TM (2007) Evidence that down regulation of hypothalamic KiSS-1 expression is involved in the negative feedback action of testosterone to regulate luteinising hormone secretion in the adult male rhesus monkey (Macaca mulatta). J Neuroendocrinol 19(6):432–438PubMedGoogle Scholar
  81. 81.
    Kinsey-Jones JS, Li XF, Knox AMI, Wilkinson ES, Zhu XL, Chaudhary AA et al (2009) Down-regulation of hypothalamic kisspeptin and its receptor, Kiss1r, mRNA expression is associated with stress-induced suppression of luteinising hormone secretion in the female rat. J Neuroendocrinol 21(1):20–29PubMedGoogle Scholar
  82. 82.
    Knox AMI, Li XF, Kinsey-Jones JS, Wilkinson ES, Wu XQ, Cheng YS et al (2009) Neonatal lipopolysaccharide exposure delays puberty and alters hypothalamic Kiss1 and Kiss1r mRNA expression in the female rat. J Neuroendocrinol 21(8):683–689PubMedGoogle Scholar
  83. 83.
    Quennell JH, Rizwan MZ, Relf HL, Anderson GM (2010) Developmental and steroidogenic effects on the gene expression of RFamide related peptides and their receptor in the rat brain and pituitary gland. J Neuroendocrinol 22(4):309–316PubMedGoogle Scholar
  84. 84.
    Yamada S, Uenoyama Y, Kinoshita M, Iwata K, Takase K, Matsui H et al (2007) Inhibition of metastin (kisspeptin-54)-GPR54 signaling in the arcuate nucleus-median eminence region during lactation in rats. Endocrinology 148(5):2226–2232PubMedGoogle Scholar
  85. 85.
    Fu LY, van den Pol AN (2010) Kisspeptin directly excites anorexigenic proopiomelanocortin neurons but inhibits orexigenic neuropeptide Y cells by an indirect synaptic mechanism. J Neurosci 30(30):10205–10219PubMedGoogle Scholar
  86. 86.
    Smith JT, Li Q, Yap KS, Shahab M, Roseweir AK, Millar RP et al (2011) Kisspeptin is essential for the full preovulatory LH surge and stimulates GnRH release from the isolated ovine median eminence. Endocrinology 152(3):1001–1012PubMedGoogle Scholar
  87. 87.
    Li Q, Roa J, Clarke IJ, Smith JT (2012) Seasonal variation in the gonadotropin-releasing hormone response to kisspeptin in sheep: possible kisspeptin regulation of the kisspeptin receptor. Neuroendocrinology 96(3):212–221PubMedGoogle Scholar
  88. 88.
    Messager S, Chatzidaki EE, Ma D, Hendrick AG, Zahn D, Dixon J et al (2005) Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54. Proc Natl Acad Sci U S A 102(5):1761–1766PubMedGoogle Scholar
  89. 89.
    Luque RM, Kineman RD, Tena-Sempere M (2007) Regulation of hypothalamic expression of KiSS-1 and GPR54 genes by metabolic factors: analyses using mouse models and a cell line. Endocrinology 148(10):4601–4611PubMedGoogle Scholar
  90. 90.
    Bellingham M, Fowler PA, Amezaga MR, Rhind SM, Cotinot C, Mandon-Pepin B et al (2009) Exposure to a complex cocktail of environmental endocrine-disrupting compounds disturbs the kisspeptin/GPR54 system in ovine hypothalamus and pituitary gland. Environ Health Perspect 117(10):1556–1562PubMedGoogle Scholar
  91. 91.
    Smith JT, Rao A, Pereira A, Caraty A, Millar RP, Clarke IJ (2008) Kisspeptin is present in ovine hypophysial portal blood but does not increase during the preovulatory luteinizing hormone surge: evidence that gonadotropes are not direct targets of kisspeptin in vivo. Endocrinology 149(4):1951–1959PubMedGoogle Scholar
  92. 92.
    Li S, Ren J, Yang G, Guo Y, Huang L (2008) Characterization of the porcine Kisspeptins receptor gene and evaluation as candidate for timing of puberty in sows. J Anim Breed Genet 125(4):219–227PubMedGoogle Scholar
  93. 93.
    Gutierrez-Pascual E, Martinez-Fuentes AJ, Pinilla L, Tena-Sempere M, Malagon MM, Castano JP (2007) Direct pituitary effects of kisspeptin: activation of gonadotrophs and somatotrophs and stimulation of luteinising hormone and growth hormone secretion. J Neuroendocrinol 19(7):521–530PubMedGoogle Scholar
  94. 94.
    Richard N, Galmiche G, Corvaisier S, Caraty A, Kottler ML (2008) KiSS-1 and GPR54 genes are co-expressed in rat gonadotrophs and differentially regulated in vivo by oestradiol and gonadotrophin-releasing hormone. J Neuroendocrinol 20(3):381–393PubMedGoogle Scholar
  95. 95.
    Matsui H, Takatsu Y, Kumano S, Matsumoto H, Ohtaki T (2004) Peripheral administration of metastin induces marked gonadotropin release and ovulation in the rat. Biochem Biophys Res Commun 320(2):383–388PubMedGoogle Scholar
  96. 96.
    Thompson EL, Patterson M, Murphy KG, Smith KL, Dhillo WS, Todd JF et al (2004) Central and peripheral administration of kisspeptin-10 stimulates the hypothalamic-pituitary-gonadal axis. J Neuroendocrinol 16(10):850–858PubMedGoogle Scholar
  97. 97.
    Navarro VM, Castellano JM, Fernandez-Fernandez R, Tovar S, Roa J, Mayen A et al (2005) Characterization of the potent luteinizing hormone-releasing activity of KiSS-1 peptide, the natural ligand of GPR54. Endocrinology 146(1):156–163PubMedGoogle Scholar
  98. 98.
    Suzuki S, Kadokawa H, Hashizume T (2008) Direct kisspeptin-10 stimulation on luteinizing hormone secretion from bovine and porcine anterior pituitary cells. Anim Reprod Sci 103(3–4):360–365PubMedGoogle Scholar
  99. 99.
    Ramaswamy S, Gibbs RB, Plant TM (2009) Studies of the localisation of kisspeptin within the pituitary of the rhesus monkey (Macaca mulatta) and the effect of kisspeptin on the release of non-gonadotropic pituitary hormones. J Neuroendocrinol 21(10):795–804PubMedGoogle Scholar
  100. 100.
    Poling MC, Kim J, Dhamija S, Kauffman AS (2012) Development, sex steroid regulation, and phenotypic characterization of RFamide-related peptide (Rfrp) gene expression and RFamide receptors in the mouse hypothalamus. Endocrinology 153(4):1827–1840PubMedGoogle Scholar
  101. 101.
    Quaynor S, Hu L, Leung PK, Feng H, Mores N, Krsmanovic LZ et al (2007) Expression of a functional G protein-coupled receptor 54-kisspeptin autoregulatory system in hypothalamic gonadotropin-releasing hormone neurons. Mol Endocrinol 21(12):3062–3070PubMedGoogle Scholar
  102. 102.
    Pielecka-Fortuna J, Chu Z, Moenter SM (2008) Kisspeptin acts directly and indirectly to increase gonadotropin-releasing hormone neuron activity and its effects are modulated by estradiol. Endocrinology 149:1979–1986PubMedGoogle Scholar
  103. 103.
    Arai AC, Xia YF, Suzuki E, Kessler M, Civelli O, Nothacker HP (2005) Cancer metastasis-­suppressing peptide metastin upregulates excitatory synaptic transmission in hippocampal dentate granule cells. J Neurophysiol 94(5):3648–3652PubMedGoogle Scholar
  104. 104.
    Arai AC, Orwig N (2008) Factors that regulate KiSS1 gene expression in the hippocampus. Brain Res 1243:10–18PubMedGoogle Scholar
  105. 105.
    Burke MC, Letts PA, Krajewski SJ, Rance NE (2006) Coexpression of dynorphin and neurokinin B immunoreactlivity in the rat hypothalamus: morphologic evidence of interrelated function within the arcuate nucleus. J Comp Neurol 498(5):712–726PubMedGoogle Scholar
  106. 106.
    Kallo I, Vida B, Deli L, Molnar CS, Hrabovszky E, Caraty A et al (2012) Co-localisation of kisspeptin with galanin or neurokinin B in afferents to mouse GnRH neurones. J Neuroendocrinol 24(3):464–476PubMedGoogle Scholar
  107. 107.
    True C, Kirigiti M, Ciofi P, Grove KL, Smith MS (2011) Characterisation of arcuate nucleus kisspeptin/neurokinin B neuronal projections and regulation during lactation in the rat. J Neuroendocrinol 23(1):52–64PubMedGoogle Scholar
  108. 108.
    Yeo SH, Herbison AE (2011) Projections of arcuate nucleus and rostral periventricular kisspeptin neurons in the adult female mouse brain. Endocrinology 152(6):2387–2399PubMedGoogle Scholar
  109. 109.
    Krajewski SJ, Burke MC, Anderson MJ, McMullen NT, Rance NE (2010) Forebrain projections of arcuate neurokinin B neurons demonstrated by anterograde tract-tracing and monosodium glutamate lesions in the rat. Neuroscience 166(2):680–697PubMedGoogle Scholar
  110. 110.
    Dungan Lemko HM, Elias CF (2012) Kiss of the mutant mouse: how genetically altered mice advanced our understanding of kisspeptin’s role in reproductive physiology. Endocrinology 153(11):5119–5129PubMedGoogle Scholar
  111. 111.
    Foradori CD, Amstalden M, Goodman RL, Lehman MN (2006) Colocalisation of dynorphin A and neurokinin B immunoreactivity in the arcuate nucleus and median eminence of the sheep. J Neuroendocrinol 18(7):534–541PubMedGoogle Scholar
  112. 112.
    Foradori CD, Coolen LM, Fitzgerald ME, Skinner DC, Goodman RL, Lehman MN (2002) Colocalization of progesterone receptors in parvicellular dynorphin neurons of the ovine preoptic area and hypothalamus. Endocrinology 143(11):4366–4374PubMedGoogle Scholar
  113. 113.
    Louis GW, Greenwald-Yarnell M, Phillips R, Coolen LM, Lehman MN, Myers MG (2011) Molecular mapping of the neural pathways linking leptin to the neuroendocrine reproductive axis. Endocrinology 152(6):2302–2310PubMedGoogle Scholar
  114. 114.
    Tena-Sempere M (2006) KiSS-1 and reproduction: focus on its role in the metabolic regulation of fertility. Neuroendocrinology 83(5–6):275–281PubMedGoogle Scholar
  115. 115.
    Backholer K, Smith JT, Rao A, Pereira A, Iqbal J, Ogawa S et al (2010) Kisspeptin cells in the ewe brain respond to leptin and communicate with neuropeptide Y and proopiomelanocortin cells. Endocrinology 151(5):2233–2243PubMedGoogle Scholar
  116. 116.
    Mohawk JA, Green CB, Takahasi JS (2012) Central and peripheral circadian clocks in mammals. Annu Rev Neurosci 35:445–462PubMedGoogle Scholar
  117. 117.
    Robertson JL, Clifton DK, de la Iglesia HO, Steiner RA, Kauffman AS (2009) Circadian regulation of Kiss1 neurons: implications for timing the preovulatory gonadotropin-releasing hormone/luteinizing hormone surge. Endocrinology 150(8):3664–3671PubMedGoogle Scholar
  118. 118.
    Ducret E, Gaidamaka G, Herbison AE (2010) Electrical and morphological characteristics of anteroventral periventricular nucleus kisspeptin and other neurons in the female mouse. Endocrinology 151(5):2223–2232PubMedGoogle Scholar
  119. 119.
    Bentley GE, Ubuka T, McGuire NL, Calisi R, Perfito N, Kriegsfeld LJ et al (2009) Gonadotrophin-inhibitory hormone: a multifunctional neuropeptide. J Neuroendocrinol 21(4):276–281PubMedGoogle Scholar
  120. 120.
    Smith JT (2008) Kisspeptin signalling in the brain: steroid regulation in the rodent and ewe. Brain Res Rev 57(2):288–298PubMedGoogle Scholar
  121. 121.
    Lehman MN, Karsch FJ, Robinson JE, Silverman AJ (1988) Ultrastructure and synaptic organization of luteinizing-hormone-releasing hormone (Lhrh) neurons in the anestrous ewe. J Comp Neurol 273(4):447–458PubMedGoogle Scholar
  122. 122.
    Witkin JW, O’Sullivan H, Miller R, Ferin M (1997) GnRH perikarya in medial basal hypothalamus of pubertal female rhesus macaque are ensheathed with glia. J Neuroendocrinol 9(12):881–885PubMedGoogle Scholar
  123. 123.
    Uenoyama Y, Inoue N, Pheng V, Homma T, Takase K, Yamada S et al (2011) Ultrastructural evidence of kisspeptin-gonadotrophin-releasing hormone (GnRH) interaction in the median eminence of female rats: implication of axo-axonal regulation of GnRH release. J Neuroendocrinol 23(10):863–870PubMedGoogle Scholar
  124. 124.
    Nunemaker CS, DeFazio RA, Geusz ME, Herzog ED, Pitts GR, Moenter SM (2001) Long-­term recordings of networks of immortalized GnRH neurons reveal episodic patterns of electrical activity. J Neurophysiol 86(1):86–93PubMedGoogle Scholar
  125. 125.
    Navarro VM, Fernandez-Fernandez R, Castellano JM, Roa J, Mayen A, Barreiro ML et al (2004) Advanced vaginal opening and precocious activation of the reproductive axis by KiSS-1 peptide, the endogenous ligand of GPR54. J Physiol 561(Pt 2):379–386PubMedGoogle Scholar
  126. 126.
    Desroziers E, Mikkelsen JD, Duittoz A, Franceschini I (2012) Kisspeptin-immunoreactivity changes in a sex- and hypothalamic-region specific manner across rat postnatal development. J Neuroendocrinol 24(8):1154–1165PubMedGoogle Scholar
  127. 127.
    Takumi K, Iijima N, Ozawa H (2011) Developmental changes in the expression of kisspeptin mRNA in rat hypothalamus. J Mol Neurosci 43(2):138–145PubMedGoogle Scholar
  128. 128.
    Bentsen AH, Ansel L, Simonneaux V, Tena-Sempere M, Juul A, Mikkelsen JD (2010) Maturation of kisspeptinergic neurons coincides with puberty onset in male rats. Peptides 31(2):275–283PubMedGoogle Scholar
  129. 129.
    Cao J, Patisaul HB (2011) Sexually dimorphic expression of hypothalamic estrogen receptors alpha and beta and Kiss1 in neonatal male and female rats. J Comp Neurol 519(15):2954–2977PubMedGoogle Scholar
  130. 130.
    Nestor CC, Briscoe AM, Davis SM, Valent M, Goodman RL, Hileman SM (2012) Evidence of a role for kisspeptin and neurokinin B in puberty of female sheep. Endocrinology 153(6):2756–2765PubMedGoogle Scholar
  131. 131.
    Redmond JS, Baez-Sandoval GM, Spell KM, Spencer TE, Lents CA, Williams GL et al (2011) Developmental changes in hypothalamic Kiss1 expression during activation of the pulsatile release of luteinising hormone in maturing ewe lambs. J Neuroendocrinol 23(9):815–822PubMedGoogle Scholar
  132. 132.
    Keen KL, Wegner FH, Bloom SR, Ghatei MA, Terasawa E (2008) An increase in kisspeptin-­54 release occurs with the pubertal increase in luteinizing hormone-releasing hormone-1 release in the stalk-median eminence of female rhesus monkeys in vivo. Endocrinology 149(8):4151–4157PubMedGoogle Scholar
  133. 133.
    Kurian JR, Keen KL, Guerriero KA, Terasawa E (2012) Tonic control of kisspeptin release in prepubertal monkeys: implications to the mechanism of puberty onset. Endocrinology 153(7):3331–3336PubMedGoogle Scholar
  134. 134.
    Clarkson J, Han SK, Liu X, Lee K, Herbison AE (2010) Neurobiological mechanisms underlying kisspeptin activation of gonadotropin-releasing hormone (GnRH) neurons at puberty. Mol Cell Endocrinol 324(1–2):45–50PubMedGoogle Scholar
  135. 135.
    Kauffman AS, Navarro VM, Kim J, Clifton DK, Steiner RA (2009) Sex differences in the regulation of Kiss1/NKB neurons in juvenile mice: implications for the timing of puberty. Am J Physiol Endocrinol Metab 297(5):E1212–E1221PubMedGoogle Scholar
  136. 136.
    Plant TM, Ramaswamy S, Dipietro MJ (2006) Repetitive activation of hypothalamic G protein-­coupled receptor 54 with intravenous pulses of kisspeptin in the juvenile monkey (Macaca mulatta) elicits a sustained train of gonadotropin-releasing hormone discharges. Endocrinology 147(2):1007–1013PubMedGoogle Scholar
  137. 137.
    Dumalska I, Wu M, Morozova E, Liu R, van den PA, Alreja M (2008) Excitatory effects of the puberty-initiating peptide kisspeptin and group I metabotropic glutamate receptor agonists differentiate two distinct subpopulations of gonadotropin-releasing hormone neurons. J Neurosci 28(32):8003–8013PubMedGoogle Scholar
  138. 138.
    Clarkson J, Shamas S, Mallinson S, Herbison AE (2012) Gonadal steroid induction of kisspeptin peptide expression in the rostral periventricular area of the third ventricle during postnatal development in the male mouse. J Neuroendocrinol 24(6):907–915PubMedGoogle Scholar
  139. 139.
    Olster DH, Foster DL (1986) Control of gonadotropin secretion in the male during puberty: a decrease in response to steroid inhibitory feedback in the absence of an increase in steroid-­independent drive in the sheep. Endocrinology 118(6):2225–2234PubMedGoogle Scholar
  140. 140.
    Herbison AE (2008) Estrogen positive feedback to gonadotropin-releasing hormone (GnRH) neurons in the rodent: the case for the rostral periventricular area of the third ventricle (RP3V). Brain Res Rev 57(2):277–287PubMedGoogle Scholar
  141. 141.
    Bakker J, Pierman S, Gonzalez-Martinez D (2010) Effects of aromatase mutation (ArKO) on the sexual differentiation of kisspeptin neuronal numbers and their activation by same versus opposite sex urinary pheromones. Horm Behav 57(4–5):390–395PubMedGoogle Scholar
  142. 142.
    Gonzalez-Martinez D, De Mees C, Douhard Q, Szpirer C, Bakker J (2008) Absence of gonadotropin-releasing hormone 1 and Kiss1 activation in alpha-fetoprotein knockout mice: prenatal estrogens defeminize the potential to show preovulatory luteinizing hormone surges. Endocrinology 149(5):2333–2340PubMedGoogle Scholar
  143. 143.
    Homma T, Sakakibara M, Yamada S, Kinoshita M, Iwata K, Tomikawa J et al (2009) Significance of neonatal testicular sex steroids to defeminize anteroventral periventricular kisspeptin neurons and the GnRH/LH surge system in male rats. Biol Reprod 81(6):1216–1225PubMedGoogle Scholar
  144. 144.
    D’Anglemont de Tassigny X, Fagg LA, Dixon JPC, Day K, Leitch HG, Hendrick AG et al (2007) Hypogonadotropic hypogonadism in mice lacking a functional Kiss1 gene. Proc Natl Acad Sci U S A 104(25):10714–10719PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2013

Authors and Affiliations

  • Michael N. Lehman
    • 1
  • Stanley M. Hileman
    • 2
  • Robert L. Goodman
    • 2
  1. 1.Department of Neurobiology and Anatomical SciencesUniversity of Mississippi Medical CenterJacksonUSA
  2. 2.Department of Physiology and PharmacologyWest Virginia University School of MedicineMorgantownUSA

Personalised recommendations