Semin Reprod Med 2019; 37(02): 056-063
DOI: 10.1055/s-0039-3400239
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Kisspeptin as a Behavioral Hormone

Edouard G.A. Mills
1   Section of Endocrinology and Investigative Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom
,
Kevin T. O'Byrne
2   Department of Anatomy, Department of Women and Children's Health, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
,
Alexander N. Comninos
1   Section of Endocrinology and Investigative Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom
3   Department of Endocrinology, Imperial College Healthcare NHS Trust, Hammersmith Hospital, London, United Kingdom
› Author Affiliations
Further Information

Publication History

Publication Date:
17 December 2019 (online)

Abstract

Successful reproduction is dependent not only on hormonal endocrine responses but also on suitable partner selection, copulatory acts, as well as associated emotional, behavioral, and cognitive processes many of which are supported by the limbic system. The reproductive hormone kisspeptin (encoded by the KISS1/kiss1 gene) is now recognized as the key orchestrator of the reproductive axis. In addition to the hypothalamus, prominent kisspeptin neuronal populations have been identified throughout limbic and paralimbic brain regions across an assortment of species. In this review, we detail the emerging roles of kisspeptin signaling in the broader aspects of behavioral, emotional, and cognitive control. Recent studies from zebrafish through humans have provided new molecular and neural insights into the complex role of kisspeptin in interpreting olfactory and auditory cues to govern sexual partner preference, in regulating copulatory behaviors and in influencing mood and emotions. Furthermore, emerging roles for kisspeptin in facilitating memory and learning are also discussed. To this end, these findings shed new light onto the importance of kisspeptin signaling, while informing the pharmacological development of kisspeptin as a potential therapeutic strategy for individuals suffering from associated reproductive, emotional, and cognitive disorders.

 
  • References

  • 1 Lee DK, Nguyen T, O'Neill GP. , et al. Discovery of a receptor related to the galanin receptors. FEBS Lett 1999; 446 (01) 103-107
  • 2 Ohtaki T, Shintani Y, Honda S. , et al. Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor. Nature 2001; 411 (6837): 613-617
  • 3 de Roux N, Genin E, Carel J-C, Matsuda F, Chaussain J-L, 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
  • 4 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
  • 5 Topaloglu AK, Tello JA, Kotan LD. , et al. Inactivating KISS1 mutation and hypogonadotropic hypogonadism. N Engl J Med 2012; 366 (07) 629-635
  • 6 Teles MG, Bianco SDC, Brito VN. , et al. A GPR54-activating mutation in a patient with central precocious puberty. N Engl J Med 2008; 358 (07) 709-715
  • 7 Han SK, Gottsch ML, Lee KJ. , et al. Activation of gonadotropin-releasing hormone neurons by kisspeptin as a neuroendocrine switch for the onset of puberty. J Neurosci 2005; 25 (49) 11349-11356
  • 8 Messager S, Chatzidaki EE, Ma D. , et al. Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54. Proc Natl Acad Sci U S A 2005; 102 (05) 1761-1766
  • 9 Gottsch ML, Cunningham MJ, Smith JT. , et al. A role for kisspeptins in the regulation of gonadotropin secretion in the mouse. Endocrinology 2004; 145 (09) 4073-4077
  • 10 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
  • 11 Mikkelsen JD, Simonneaux V. The neuroanatomy of the kisspeptin system in the mammalian brain. Peptides 2009; 30 (01) 26-33
  • 12 Rometo AM, Krajewski SJ, Voytko ML, Rance NE. Hypertrophy and increased kisspeptin gene expression in the hypothalamic infundibular nucleus of postmenopausal women and ovariectomized monkeys. J Clin Endocrinol Metab 2007; 92 (07) 2744-2750
  • 13 Pineda R, Plaisier F, Millar RP, Ludwig M. Amygdala kisspeptin neurons: putative mediators of olfactory control of the gonadotropic axis. Neuroendocrinology 2017; 104 (03) 223-238
  • 14 Muir AI, Chamberlain L, Elshourbagy NA. , et al. AXOR12, a novel human G protein-coupled receptor, activated by the peptide KiSS-1. J Biol Chem 2001; 276 (31) 28969-28975
  • 15 Kotani M, Detheux M, Vandenbogaerde A. , et al. The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54. J Biol Chem 2001; 276 (37) 34631-34636
  • 16 MacLean PD. Some psychiatric implications of physiological studies on frontotemporal portion of limbic system (visceral brain). Electroencephalogr Clin Neurophysiol 1952; 4 (04) 407-418
  • 17 Catani M, Dell'acqua F, Thiebaut de Schotten M. A revised limbic system model for memory, emotion and behaviour. Neurosci Biobehav Rev 2013; 37 (08) 1724-1737
  • 18 Fudge JL, Powers JM, Haber SN, Caine ED. Considering the role of the amygdala in psychotic illness: a clinicopathological correlation. J Neuropsychiatry Clin Neurosci 1998; 10 (04) 383-394
  • 19 Adolphs R, Tranel D, Damasio H, Damasio A. Impaired recognition of emotion in facial expressions following bilateral damage to the human amygdala. Nature 1994; 372 (6507): 669-672
  • 20 Baird AD, Wilson SJ, Bladin PF, Saling MM, Reutens DC. The amygdala and sexual drive: insights from temporal lobe epilepsy surgery. Ann Neurol 2004; 55 (01) 87-96
  • 21 Wood RI. Integration of chemosensory and hormonal input in the male Syrian hamster brain. Ann N Y Acad Sci 1998; 855: 362-372
  • 22 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
  • 23 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
  • 24 Dulac C, Torello AT. Molecular detection of pheromone signals in mammals: from genes to behaviour. Nat Rev Neurosci 2003; 4 (07) 551-562
  • 25 De Bond JAP, Li Q, Millar RP, Clarke IJ, Smith JT. Kisspeptin signaling is required for the luteinizing hormone response in anestrous ewes following the introduction of males. PLoS One 2013; 8 (02) e57972
  • 26 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
  • 27 Watanabe Y, Ikegami K, Ishigaki R. , et al. Enhancement of the luteinising hormone surge by male olfactory signals is associated with anteroventral periventricular Kiss1 cell activation in female rats. J Neuroendocrinol 2017 29(08):
  • 28 Aggarwal S, Tang C, Sing K, Kim HW, Millar RP, Tello JA. Medial amygdala Kiss1 neurons mediate female pheromone stimulation of LH in male mice. Neuroendocrinology 2019; 108 (03) 172-189
  • 29 Adekunbi DA, Li XF, Lass G. , et al. Kisspeptin neurones in the posterodorsal medial amygdala modulate sexual partner preference and anxiety in male mice. J Neuroendocrinol 2018; 30 (03) e12572
  • 30 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
  • 31 Hellier V, Brock O, Candlish M. , et al. Female sexual behavior in mice is controlled by kisspeptin neurons. Nat Commun 2018; 9 (01) 400
  • 32 Charlton BD, Martin-Wintle MS, Owen MA, Zhang H, Swaisgood RR. Vocal behaviour predicts mating success in giant pandas. R Soc Open Sci 2018; 5 (10) 181323
  • 33 Dombret C, Capela D, Poissenot K. , et al. Neural mechanisms underlying the disruption of male courtship behavior by adult exposure to Di(2-ethylhexyl) phthalate in mice. Environ Health Perspect 2017; 125 (09) 097001
  • 34 Herbison AE, de Tassigny Xd, Doran J, Colledge WH. Distribution and postnatal development of Gpr54 gene expression in mouse brain and gonadotropin-releasing hormone neurons. Endocrinology 2010; 151 (01) 312-321
  • 35 Asaba A, Osakada T, Touhara K, Kato M, Mogi K, Kikusui T. Male mice ultrasonic vocalizations enhance female sexual approach and hypothalamic kisspeptin neuron activity. Horm Behav 2017; 94: 53-60
  • 36 Hull EM, Rodríguez-Manzo G. Male sexual behavior. In: Pfaff DW, Joels M. , eds. Hormones, Brain and Behavior. 3rd ed., Vol 1. Cambridge: Academic Press; 2016: 1-57
  • 37 Seward GH. , ed. Sexual behavior in rodents. In: Sex and the Social Order. New York: McGraw-Hill Book Company; 1946: 44-56
  • 38 Liu X, Herbison A. Kisspeptin regulation of arcuate neuron excitability in kisspeptin receptor knockout mice. Endocrinology 2015; 156 (05) 1815-1827
  • 39 Gresham R, Li S, Adekunbi DA, Hu M, Li XF, O'Byrne KT. Kisspeptin in the medial amygdala and sexual behavior in male rats. Neurosci Lett 2016; 627: 13-17
  • 40 Hanchate NK, Parkash J, Bellefontaine N. , et al. Kisspeptin-GPR54 signaling in mouse NO-synthesizing neurons participates in the hypothalamic control of ovulation. J Neurosci 2012; 32 (03) 932-945
  • 41 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
  • 42 Fox MD, Raichle ME. Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging. Nat Rev Neurosci 2007; 8 (09) 700-711
  • 43 Raichle ME, MacLeod AM, Snyder AZ, Powers WJ, Gusnard DA, Shulman GL. A default mode of brain function. Proc Natl Acad Sci U S A 2001; 98 (02) 676-682
  • 44 Comninos AN, Demetriou L, Wall MB. , et al. Modulations of human resting brain connectivity by kisspeptin enhance sexual and emotional functions. JCI Insight 2018; 3 (20) 121958
  • 45 Banks SJ, Eddy KT, Angstadt M, Nathan PJ, Phan KL. Amygdala-frontal connectivity during emotion regulation. Soc Cogn Affect Neurosci 2007; 2 (04) 303-312
  • 46 Chase HW, Moses-Kolko EL, Zevallos C, Wisner KL, Phillips ML. Disrupted posterior cingulate-amygdala connectivity in postpartum depressed women as measured with resting BOLD fMRI. Soc Cogn Affect Neurosci 2014; 9 (08) 1069-1075
  • 47 Sander K, Frome Y, Scheich H. FMRI activations of amygdala, cingulate cortex, and auditory cortex by infant laughing and crying. Hum Brain Mapp 2007; 28 (10) 1007-1022
  • 48 Phelps EA. Human emotion and memory: interactions of the amygdala and hippocampal complex. Curr Opin Neurobiol 2004; 14 (02) 198-202
  • 49 Williams KE, Marsh WK, Rasgon NL. Mood disorders and fertility in women: a critical review of the literature and implications for future research. Hum Reprod Update 2007; 13 (06) 607-616
  • 50 Tanaka M, Csabafi K, Telegdy G. Neurotransmissions of antidepressant-like effects of kisspeptin-13. Regul Pept 2013; 180: 1-4
  • 51 Silvers JA, Wager TD, Weber J, Ochsner KN. The neural bases of uninstructed negative emotion modulation. Soc Cogn Affect Neurosci 2015; 10 (01) 10-18
  • 52 Hedon F. Anxiety and erectile dysfunction: a global approach to ED enhances results and quality of life. Int J Impot Res 2003; 15 (Suppl. 02) S16-S19
  • 53 Ogawa S, Nathan FM, Parhar IS. Habenular kisspeptin modulates fear in the zebrafish. Proc Natl Acad Sci U S A 2014; 111 (10) 3841-3846
  • 54 Csabafi K, Jászberényi M, Bagosi Z, Lipták N, Telegdy G. Effects of kisspeptin-13 on the hypothalamic-pituitary-adrenal axis, thermoregulation, anxiety and locomotor activity in rats. Behav Brain Res 2013; 241 (01) 56-61
  • 55 Delmas S, Porteous R, Bergin DH, Herbison AE. Altered aspects of anxiety-related behavior in kisspeptin receptor-deleted male mice. Sci Rep 2018; 8 (01) 2794
  • 56 Rao YS, Mott NN, Pak TR. Effects of kisspeptin on parameters of the HPA axis. Endocrine 2011; 39 (03) 220-228
  • 57 Thompson EL, Patterson M, Murphy KG. , et al. Central and peripheral administration of kisspeptin-10 stimulates the hypothalamic-pituitary-gonadal axis. J Neuroendocrinol 2004; 16 (10) 850-858
  • 58 Nathan FM, Ogawa S, Parhar IS. Kisspeptin1 modulates odorant-evoked fear response via two serotonin receptor subtypes (5-HT1A and 5-HT2) in zebrafish. J Neurochem 2015; 133 (06) 870-878
  • 59 Kongsted AG. Stress and fear as possible mediators of reproduction problems in group housed sows: a review. Acta Agric Scand - Sect A Anim Sci 2004; 54 (02) 58-66
  • 60 Kitahashi T, Ogawa S, Parhar IS. Cloning and expression of kiss2 in the zebrafish and medaka. Endocrinology 2009; 150 (02) 821-831
  • 61 Ogawa S, Parhar IS. Biological significance of kisspeptin-Kiss 1 receptor signaling in the habenula of teleost species. Front Endocrinol (Lausanne) 2018; 9: 222
  • 62 Ogawa S, Ng KW, Ramadasan PN, Nathan FM, Parhar IS. Habenular Kiss1 neurons modulate the serotonergic system in the brain of zebrafish. Endocrinology 2012; 153 (05) 2398-2407
  • 63 Servili A, Le Page Y, Leprince J. , et al. Organization of two independent kisspeptin systems derived from evolutionary-ancient kiss genes in the brain of zebrafish. Endocrinology 2011; 152 (04) 1527-1540
  • 64 Lillesaar C, Tannhäuser B, Stigloher C, Kremmer E, Bally-Cuif L. The serotonergic phenotype is acquired by converging genetic mechanisms within the zebrafish central nervous system. Dev Dyn 2007; 236 (04) 1072-1084
  • 65 Lisman J, Buzsáki G, Eichenbaum H, Nadel L, Ranganath C, Redish AD. Viewpoints: how the hippocampus contributes to memory, navigation and cognition. Nat Neurosci 2017; 20 (11) 1434-1447
  • 66 Eagle AL, Wang H, Robison AJ. Sensitive assessment of hippocampal learning using temporally dissociated passive avoidance task. Bio Protoc 2016; 6 (11) e1821
  • 67 Telegdy G, Adamik Á. The action of kisspeptin-13 on passive avoidance learning in mice. Involvement of transmitters. Behav Brain Res 2013; 243: 300-305
  • 68 Lupton C, Sengupta M, Cheng R-K, Chia J, Thirumalai V, Jesuthasan S. Loss of the Habenula Intrinsic Neuromodulator Kisspeptin1 Affects Learning in Larval Zebrafish. eNeuro 2017; 4 (03) ENEURO.0326–16.2017
  • 69 Jiang JH, He Z, Peng YL. , et al. Kisspeptin-13 enhances memory and mitigates memory impairment induced by Aβ1-42 in mice novel object and object location recognition tasks. Neurobiol Learn Mem 2015; 123: 187-195
  • 70 Milton NG, Chilumuri A, Rocha-Ferreira E, Nercessian AN, Ashioti M. Kisspeptin prevention of amyloid-β peptide neurotoxicity in vitro. ACS Chem Neurosci 2012; 3 (09) 706-719