Abstract
RF-amide peptides, a family of peptides characterized by a common carboxy-terminal Arg-Phe-NH2 motif, play various physiological roles in the brain including the modulation of neuroendocrine signaling. Neuropeptide FF (NPFF) receptors exhibit a high affinity for all RF-amide peptides, which suggests that the neurons expressing these NPFF receptors may have multiple functions in the brain. However, the distribution of the neurons expressing NPFF receptors in the rat brain remains poorly understood. This study aimed to determine the detailed histological distribution of mRNA that encodes the neuropeptide FF receptors (Npffr1 and Npffr2) in the rat brain using in situ hybridization. Neurons with strong Npffr1 expression were observed in the lateral septal nucleus and several hypothalamic areas related to neuroendocrine functions, including the paraventricular nucleus (PVN) and arcuate nucleus, whereas Npffr2-expressing neurons were observed mainly in brain regions involved in somatosensory pathways, such as several subnuclei of the thalamus. Npffr1 expression was observed in 70% of corticotropin-releasing hormone neurons, but in only a small population of oxytocin and vasopressin neurons in the PVN. Npffr1 expression was also observed in the dopaminergic neurons in the periventricular nucleus and the dorsal arcuate nucleus, and in the kisspeptin neurons in the anteroventral periventricular nucleus. These results suggest that NPFFR1-mediated signaling may be involved in neuroendocrine functions, such as in reproduction and stress response. In conjunction with a detailed histological map of NPFFRs, this study provides useful data for future neuroendocrine research.
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References
Aquino NSS, Kokay IC, Perez CT et al (2019) Kisspeptin stimulation of prolactin secretion requires Kiss1 receptor but not in tuberoinfundibular dopaminergic neurons. Endocrinology 160:522–533. https://doi.org/10.1210/en.2018-00932
Arima H, Murase T, Kondo K et al (1996) Centrally administered neuropeptide FF inhibits arginine vasopressin release in conscious rats. Endocrinology 137:1523–1529. https://doi.org/10.1210/endo.137.5.8612481
Atasoy D, Betley JN, Su HH, Sternson SM (2012) Deconstruction of a neural circuit for hunger. Nature 488:172–177. https://doi.org/10.1038/nature11270
Ayachi S, Simonin F (2014) Involvement of mammalian RF-amide peptides and their receptors in the modulation of nociception in rodents. Front Endocrinol (Lausanne). https://doi.org/10.3389/fendo.2014.00158
Chartrel N, Picot M, El Medhi M et al (2016) The neuropeptide 26RFa (QRFP) and its role in the regulation of energy homeostasis: a mini-review. Front Neurosci. https://doi.org/10.3389/fnins.2016.00549
Clarke H, Dhillo WS, Jayasena CN (2015) Comprehensive review on kisspeptin and its role in reproductive disorders. Endocrinol Metab (Seoul) 30:124–141. https://doi.org/10.3803/EnM.2015.30.2.124
Dungan HM, Gottsch ML, Zeng H et al (2007) The role of kisspeptin-GPR54 signaling in the tonic regulation and surge release of gonadotropin-releasing hormone/luteinizing hormone. J Neurosci 27:12088–12095. https://doi.org/10.1523/JNEUROSCI.2748-07.2007
Elhabazi K, Humbert JP, Bertin I et al (2013) Endogenous mammalian RF-amide peptides, including PrRP, kisspeptin and 26RFa, modulate nociception and morphine analgesia via NPFF receptors. Neuropharmacology 75:164–171. https://doi.org/10.1016/j.neuropharm.2013.07.012
Findeisen M, Rathmann D, Beck-Sickinger AG (2011a) Structure-activity studies of RFamide peptides reveal subtype-selective activation of neuropeptide FF1 and FF2 receptors. ChemMedChem 6:1081–1093. https://doi.org/10.1002/cmdc.201100089
Findeisen M, Rathmann D, Beck-Sickinger AG (2011b) RFamide peptides: structure, function, mechanisms and pharmaceutical potential. Pharmaceuticals (Basel) 4:1248–1280. https://doi.org/10.3390/ph4091248
Fukusumi S, Habata Y, Yoshida H et al (2001) Characteristics and distribution of endogenous RFamide-related peptide-1. Biochim Biophys Acta 1540:221–232. https://doi.org/10.1016/S0167-4889(01)00135-5
Goncharuk VD, Buijs RM, Mactavish D, Jhamandas JH (2006) Neuropeptide FF distribution in the human and rat forebrain: a comparative immunohistochemical study. J Comp Neurol 496:572–593. https://doi.org/10.1002/cne.20927
Gouardères C, Faura CC, Zajac J-M (2004a) Rodent strain differences in the NPFF1 and NPFF2 receptor distribution and density in the central nervous system. Brain Res 1014:61–70. https://doi.org/10.1016/j.brainres.2004.04.005
Gouardères C, Puget A, Zajac J-M (2004b) Detailed distribution of neuropeptide FF receptors (NPFF1 and NPFF2) in the rat, mouse, octodon, rabbit, guinea pig, and marmoset monkey brains: a comparative autoradiographic study. Synapse 51:249–269. https://doi.org/10.1002/syn.10305
Higo S, Honda S, Iijima N, Ozawa H (2016) Mapping of kisspeptin receptor mRNA in the whole rat brain and its co-localisation with oxytocin in the paraventricular nucleus. J Neuroendocrinol. https://doi.org/10.1111/jne.12356
Higo S, Iijima N, Ozawa H (2017) Characterisation of Kiss1r (Gpr54)-expressing neurones in the arcuate nucleus of the female rat hypothalamus. J Neuroendocrinol. https://doi.org/10.1111/jne.12452
Iijima N, Kataoka Y, Kakihara K et al (1999) Cytochemical study of prolactin-releasing peptide (PrRP) in the rat brain. NeuroReport 10:1713–1716
Kanaya M, Higo S, Ozawa H (2019) Neurochemical characterization of neurons expressing estrogen receptor β in the hypothalamic nuclei of rats using in situ hybridization and immunofluorescence. Int J Mol Sci. https://doi.org/10.3390/ijms21010115
Kim JS, Brownjohn PW, Dyer BS et al (2015) Anxiogenic and stressor effects of the hypothalamic neuropeptide RFRP-3 are overcome by the NPFFR antagonist GJ14. Endocrinology 156:4152–4162. https://doi.org/10.1210/en.2015-1532
Kriegsfeld LJ, Mei DF, Bentley GE et al (2006) Identification and characterization of a gonadotropin-inhibitory system in the brains of mammals. Proc Natl Acad Sci U S A 103:2410–2415. https://doi.org/10.1073/pnas.0511003103
Liu X, Herbison AE (2016) Kisspeptin regulation of neuronal activity throughout the central nervous system. Endocrinol Metab (Seoul) 31:193–205. https://doi.org/10.3803/EnM.2016.31.2.193
Maruyama M, Matsumoto H, Fujiwara K et al (1999) Immunocytochemical localization of prolactin-releasing peptide in the rat brain. Endocrinology 140:2326–2333. https://doi.org/10.1210/endo.140.5.6685
Maruyama M, Matsumoto H, Fujiwara K et al (2001) Prolactin-releasing peptide as a novel stress mediator in the central nervous system. Endocrinology 142:2032–2038. https://doi.org/10.1210/endo.142.5.8118
Murase T, Arima H, Kondo K, Oiso Y (1996) Neuropeptide FF reduces food intake in rats. Peptides 17:353–354. https://doi.org/10.1016/0196-9781(95)02137-X
Overgaard A, Tena-Sempere M, Franceschini I et al (2013) Comparative analysis of kisspeptin-immunoreactivity reveals genuine differences in the hypothalamic Kiss1 systems between rats and mice. Peptides 45:85–90. https://doi.org/10.1016/j.peptides.2013.04.013
Paxinos G, Watson C (2007) The rat brain in stereotaxic coordinates, 6th edn. Elsevier, Amsterdam
Pineda R, Plaisier F, Millar RP, Ludwig M (2017) Amygdala kisspeptin neurons: putative mediators of olfactory control of the gonadotropic axis. Neuroendocrinology 104:223–238. https://doi.org/10.1159/000445895
Qi Y, Oldfield BJ, Clarke IJ (2009) Projections of RFamide-related peptide-3 neurones in the ovine hypothalamus, with special reference to regions regulating energy balance and reproduction. J Neuroendocrinol 21:690–697. https://doi.org/10.1111/j.1365-2826.2009.01886.x
Ubuka T, Morgan K, Pawson AJ et al (2009) Identification of human GnIH homologs, RFRP-1 and RFRP-3, and the cognate receptor, GPR147 in the human hypothalamic pituitary axis. PLoS ONE. https://doi.org/10.1371/journal.pone.0008400
Wakabayashi Y, Yamamura T, Sakamoto K et al (2012) Electrophysiological and morphological evidence for synchronized GnRH pulse generator activity among Kisspeptin/neurokinin B/dynorphin A (KNDy) neurons in goats. J Reprod Dev. https://doi.org/10.1262/jrd.2012-136
Wang HJ, Hoffman GE, Smith MS (1993) Suppressed tyrosine hydroxylase gene expression in the tuberoinfundibular dopaminergic system during lactation. Endocrinology 133:1657–1663. https://doi.org/10.1210/endo.133.4.8104777
Yang H-YT, Tao T, Iadarola MJ (2008) Modulatory role of neuropeptide FF system in nociception and opiate analgesia. Neuropeptides 42:1–18. https://doi.org/10.1016/j.npep.2007.06.004
Acknowledgements
This work was supported by the Grant-in-Aid (18K06860 to HO and 18K16818 to MK) from the Japan Society for the Promotion of Science, and Young Investigator Grant of Japan Neuroendocrine Society to SH.
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Higo, S., Kanaya, M. & Ozawa, H. Expression analysis of neuropeptide FF receptors on neuroendocrine-related neurons in the rat brain using highly sensitive in situ hybridization. Histochem Cell Biol 155, 465–475 (2021). https://doi.org/10.1007/s00418-020-01956-9
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DOI: https://doi.org/10.1007/s00418-020-01956-9