Semin Reprod Med 2019; 37(02): 084-092
DOI: 10.1055/s-0039-3400992
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

The Role of Kisspeptin in Sexual Behavior

Vincent Hellier
1   GIGA Neurosciences, Liège University, Liège, Belgium
2   Group of Neurocircuit Wiring and Function (S. Steculorum group), Max Planck Institute for Metabolism Research, Koln, Germany
,
Olivier Brock
1   GIGA Neurosciences, Liège University, Liège, Belgium
3   Department of Basic and Clinical Neuroscience, Headache Group, James Black Centre, King's College London, London, United Kingdom
,
Julie Bakker
1   GIGA Neurosciences, Liège University, Liège, Belgium
› Author Affiliations
Further Information

Publication History

Publication Date:
17 December 2019 (online)

Abstract

Sexual behavior is essential for the perpetuation of a species. In female rodents, mate preference and lordosis behavior depend heavily on the integration of olfactory cues into the neuroendocrine brain, yet its underlying neural circuits are not well understood. We previously revealed that kisspeptin neurons in the anteroventral periventricular nucleus/periventricular nucleus continuum (AVPv/PeN) are activated by male olfactory cues in female mice. Here, we further reveal that male-directed mate preferences and lordosis are impaired in kisspeptin knockout mice but are rescued by a single injection with kisspeptin. Acute ablation of AVPV/PeN kisspeptin neurons in adult females impaired mate preference and lordosis behavior. Conversely, optogenetic activation of these neurons triggered lordosis behavior. Kisspeptin neurons act through classical GPR54/GnRH signaling in stimulating mate preferences, but unexpectedly, GPR54/GnRH neuronal ablation did not affect lordosis behavior. Therefore, to identify the downstream components of the neural circuit involved in lordosis behavior, we employed genetic transsynaptic tracing in combination with viral tract tracing from AVPV/PeN kisspeptin neurons. We observed that kisspeptin neurons are communicating with neurons expressing the neuronal form of nitric oxide synthase. These results suggest that hypothalamic nitric oxide signaling is an important mechanism downstream of kisspeptin neurons in the neural circuit governing lordosis behavior in female mice.

 
  • References

  • 1 Boling JL, Blandau RJ. The estrogen-progesterone induction of mating responses in the spayed female rat. Endocrinology 1939; 25: 359-364
  • 2 Bakker J, Brand T, van Ophemert J, Slob AK. Hormonal regulation of adult partner preference behavior in neonatally ATD-treated male rats. Behav Neurosci 1993; 107 (03) 480-487
  • 3 Bakker J, De Mees C, Douhard Q. , et al. Alpha-fetoprotein protects the developing female mouse brain from masculinization and defeminization by estrogens. Nat Neurosci 2006; 9 (02) 220-226
  • 4 Brock O, Baum MJ, Bakker J. The development of female sexual behavior requires prepubertal estradiol. J Neurosci 2011; 31 (15) 5574-5578
  • 5 Bakker J, Honda S, Harada N, Balthazart J. The aromatase knock-out mouse provides new evidence that estradiol is required during development in the female for the expression of sociosexual behaviors in adulthood. J Neurosci 2002; 22 (20) 9104-9112
  • 6 Pfaff DW. Estrogens and Brain Function: Neural Analysis for a Hormone - Controlled Mammalian Reproductive Behavior. New York: Springer-Verlag; 1980
  • 7 McCarthy MM, Malik KF, Feder HH. Increased GABAergic transmission in medial hypothalamus facilitates lordosis but has the opposite effect in preoptic area. Brain Res 1990; 507 (01) 40-44
  • 8 Olster DH. Ibotenic acid-induced lesions of the medial preoptic area/anterior hypothalamus enhance the display of progesterone-facilitated lordosis in male rats. Brain Res 1993; 626 (1-2): 99-105
  • 9 Mills RH, Sohn RK, Micevych PE. Estrogen-induced mu-opioid receptor internalization in the medial preoptic nucleus is mediated via neuropeptide Y-Y1 receptor activation in the arcuate nucleus of female rats. J Neurosci 2004; 24 (04) 947-955
  • 10 Sakuma Y, Pfaff DW. Modulation of the lordosis reflex of female rats by LHRH, its antiserum and analogs in the mesencephalic central gray. Neuroendocrinology 1983; 36 (03) 218-224
  • 11 Marson L, Murphy AZ. Identification of neural circuits involved in female genital responses in the rat: a dual virus and anterograde tracing study. Am J Physiol Regul Integr Comp Physiol 2006; 291 (02) R419-R428
  • 12 Keller M, Pierman S, Douhard Q, Baum MJ, Bakker J. The vomeronasal organ is required for the expression of lordosis behaviour, but not sex discrimination in female mice. Eur J Neurosci 2006; 23 (02) 521-530
  • 13 Keller M, Douhard Q, Baum MJ, Bakker J. Destruction of the main olfactory epithelium reduces female sexual behavior and olfactory investigation in female mice. Chem Senses 2006; 31 (04) 315-323
  • 14 Moss RL, McCann SM. Induction of mating behavior in rats by luteinizing hormone-releasing factor. Science 1973; 181 (4095): 177-179
  • 15 Pfaff DW. Luteinizing hormone-releasing factor potentiates lordosis behavior in hypophysectomized ovariectomized female rats. Science 1973; 182 (4117): 1148-1149
  • 16 Moss RL, Foreman MM. Potentiation of lordosis behavior by intrahypothalamic infusion of synthetic luteinizing hormone-releasing hormone. Neuroendocrinology 1976; 20 (02) 176-181
  • 17 Sirinathsinghji DJ. GnRH in the spinal subarachnoid space potentiates lordosis behavior in the female rat. Physiol Behav 1983; 31 (05) 717-723
  • 18 Boehm U, Zou Z, Buck LB. Feedback loops link odor and pheromone signaling with reproduction. Cell 2005; 123 (04) 683-695
  • 19 Wen S, Götze IN, Mai O, Schauer C, Leinders-Zufall T, Boehm U. Genetic identification of GnRH receptor neurons: a new model for studying neural circuits underlying reproductive physiology in the mouse brain. Endocrinology 2011; 152 (04) 1515-1526
  • 20 de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, Milgrom E. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci U S A 2003; 100 (19) 10972-10976
  • 21 Seminara SB, Messager S, Chatzidaki EE. , et al. The GPR54 gene as a regulator of puberty. N Engl J Med 2003; 349 (17) 1614-1627
  • 22 Castellano JM, Roa J, Luque RM. , et al. KiSS-1/kisspeptins and the metabolic control of reproduction: physiologic roles and putative physiopathological implications. Peptides 2009; 30 (01) 139-145
  • 23 Smith JT, Dungan HM, Stoll EA. , et al. Differential regulation of KiSS-1 mRNA expression by sex steroids in the brain of the male mouse. Endocrinology 2005; 146 (07) 2976-2984
  • 24 Smith JT, Cunningham MJ, Rissman EF, Clifton DK, Steiner RA. Regulation of Kiss1 gene expression in the brain of the female mouse. Endocrinology 2005; 146 (09) 3686-3692
  • 25 Clarkson J, Herbison AE. Postnatal development of kisspeptin neurons in mouse hypothalamus; sexual dimorphism and projections to gonadotropin-releasing hormone neurons. Endocrinology 2006; 147 (12) 5817-5825
  • 26 Kauffman AS, Park JH, McPhie-Lalmansingh AA. , et al. The kisspeptin receptor GPR54 is required for sexual differentiation of the brain and behavior. J Neurosci 2007; 27 (33) 8826-8835
  • 27 Brock O, Bakker J. The two kisspeptin neuronal populations are differentially organized and activated by estradiol in mice. Endocrinology 2013; 154 (08) 2739-2749
  • 28 Clarkson J, d'Anglemont de Tassigny X, Colledge WH, Caraty A, Herbison AE. Distribution of kisspeptin neurones in the adult female mouse brain. J Neuroendocrinol 2009; 21 (08) 673-682
  • 29 Kim J, Semaan SJ, Clifton DK, Steiner RA, Dhamija S, Kauffman AS. Regulation of Kiss1 expression by sex steroids in the amygdala of the rat and mouse. Endocrinology 2011; 152 (05) 2020-2030
  • 30 Comninos AN, Anastasovska J, Sahuri-Arisoylu M. , et al. Kisspeptin signaling in the amygdala modulates reproductive hormone secretion. Brain Struct Funct 2016; 221 (04) 2035-2047
  • 31 Revel FG, Saboureau M, Masson-Pévet M, Pévet P, Mikkelsen JD, Simonneaux V. Kisspeptin mediates the photoperiodic control of reproduction in hamsters. Curr Biol 2006; 16 (17) 1730-1735
  • 32 Smith JT, Popa SM, Clifton DK, Hoffman GE, Steiner RA. Kiss1 neurons in the forebrain as central processors for generating the preovulatory luteinizing hormone surge. J Neurosci 2006; 26 (25) 6687-6694
  • 33 Tena-Sempere M. Hypothalamic KiSS-1: the missing link in gonadotropin feedback control?. Endocrinology 2005; 146 (09) 3683-3685
  • 34 Clarkson J, d'Anglemont de Tassigny X, Moreno AS, Colledge WH, Herbison AE. Kisspeptin-GPR54 signaling is essential for preovulatory gonadotropin-releasing hormone neuron activation and the luteinizing hormone surge. J Neurosci 2008; 28 (35) 8691-8697
  • 35 Simonneaux V, Ansel L, Revel FG, Klosen P, Pévet P, Mikkelsen JD. Kisspeptin and the seasonal control of reproduction in hamsters. Peptides 2009; 30 (01) 146-153
  • 36 Tolson KP, Garcia C, Yen S. , et al. Impaired kisspeptin signaling decreases metabolism and promotes glucose intolerance and obesity. J Clin Invest 2014; 124 (07) 3075-3079
  • 37 Clakson J, d’Anglemont de Tassigny X, Colledge WH, Caraty A, Herbison AE. Distribution of kisspeptin neurones in the adult female mouse brain. J Neuroendocrinol 2009; 21 (08) 673-682
  • 38 Bakker J, Pierman S, González-Martínez D. 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 2010; 57 (4-5): 390-395
  • 39 Taziaux M, Bakker J. Absence of female-typical pheromone-induced hypothalamic neural responses and kisspeptin neuronal activity in α-fetoprotein knockout female mice. Endocrinology 2015; 156 (07) 2595-2607
  • 40 Haga S, Hattori T, Sato T. , et al. The male mouse pheromone ESP1 enhances female sexual receptive behaviour through a specific vomeronasal receptor. Nature 2010; 466 (7302): 118-122
  • 41 Hellier V, Brock O, Candlish M. , et al. Female sexual behavior in mice is controlled by kisspeptin neurons. Nat Commun 2018; 9 (01) 400
  • 42 Comninos AN, Wall MB, Demetriou L. , et al. Kisspeptin modulates sexual and emotional brain processing in humans. J Clin Invest 2017; 127 (02) 709-719
  • 43 d'Anglemont de Tassigny X, Fagg LA, Carlton MBL, Colledge WH. Kisspeptin can stimulate gonadotropin-releasing hormone (GnRH) release by a direct action at GnRH nerve terminals. Endocrinology 2008; 149 (08) 3926-3932
  • 44 Mayer C, Boehm U. Female reproductive maturation in the absence of kisspeptin/GPR54 signaling. Nature Neuroscience 2011; 14: 704-710
  • 45 Messina A, Langlet F, Chachlaki K. , et al. A microRNA switch regulates the rise in hypothalamic GnRH production before puberty. Nat Neurosci 2016; 19 (06) 835-844
  • 46 Lyubimov Y, Engstrom M, Wurster S, Savola JM, Korpi ER, Panula P. Human kisspeptins activate neuropeptide FF2 receptor. Neuroscience 2010; 170 (01) 117-122
  • 47 Oishi S, Misu R, Tomita K. , et al. Activation of neuropeptide FF receptors by kisspeptin receptor ligands. ACS Med Chem Lett 2010; 2 (01) 53-57
  • 48 Elhabazi K, Humbert JP, Bertin I. , et al. Endogenous mammalian RF-amide peptides, including PrRP, kisspeptin and 26RFa, modulate nociception and morphine analgesia via NPFF receptors. Neuropharmacology 2013; 75: 164-171
  • 49 Liu X, Herbison A. Kisspeptin regulation of arcuate neuron excitability in kisspeptin receptor knockout mice. Endocrinology 2015; 156 (05) 1815-1827
  • 50 Gouardères C, Faura CC, Zajac JM. Rodent strain differences in the NPFF1 and NPFF2 receptor distribution and density in the central nervous system. Brain Res 2004; 1014 (1-2): 61-70
  • 51 Mani SK, Allen JM, Rettori V, McCann SM, O'Malley BW, Clark JH. Nitric oxide mediates sexual behavior in female rats. Proc Natl Acad Sci U S A 1994; 91 (14) 6468-6472
  • 52 González-Flores O, Etgen AM. The nitric oxide pathway participates in estrous behavior induced by progesterone and some of its ring A-reduced metabolites. Horm Behav 2004; 45 (01) 50-57
  • 53 Argiolas A, Melis MR. Neuropeptides and central control of sexual behaviour from the past to the present: a review. Prog Neurobiol 2013; 108: 80-107
  • 54 Becker RO, Lazzari VM, Menezes IC. , et al. Sexual behavior and dendritic spine density of posterodorsal medial amygdala neurons in oxytocin knockout female mice. Behav Brain Res 2013; 256: 95-100
  • 55 Chachlaki K, Nalone SA, Qualls-Creekmore E, Hrabovsky E, Munzberg H, Giacobini P, Ango F, Prevot V. Phenotyping of nNOS neurons in the postnatal and adult female mouse hypothalamus. J Comp Neurol 2017; 525 (15) 3177-3189
  • 56 Hanchate NK, Parkash J, Bellefontaine N, Mazur D, Colledge WH, d’Anglemont de Tassigny X, Prevot V. Kisspeptin-GPR54 signaling in mouse NO-synthesizing neurons participates in the hypothalamic control of ovulation. J Neurosci 2012; 32: 932-945