Brain Structure and Function

, Volume 224, Issue 1, pp 453–469 | Cite as

Central relaxin-3 receptor (RXFP3) activation impairs social recognition and modulates ERK-phosphorylation in specific GABAergic amygdala neurons

  • Hector Albert-Gasco
  • Sandra Sanchez-Sarasua
  • Sherie Ma
  • Cristina García-Díaz
  • Andrew L. Gundlach
  • Ana M. Sanchez-PerezEmail author
  • Francisco E. Olucha-BordonauEmail author
Original Article


In mammals, the extended amygdala is a neural hub for social and emotional information processing. In the rat, the extended amygdala receives inhibitory GABAergic projections from the nucleus incertus (NI) in the pontine tegmentum. NI neurons produce the neuropeptide relaxin-3, which acts via the Gi/o-protein-coupled receptor, RXFP3. A putative role for RXFP3 signalling in regulating social interaction was investigated by assessing the effect of intracerebroventricular infusion of the RXFP3 agonist, RXFP3-A2, on performance in the 3-chamber social interaction paradigm. Central RXFP3-A2, but not vehicle, infusion, disrupted the capacity to discriminate between a familiar and novel conspecific subject, but did not alter differentiation between a conspecific and an inanimate object. Subsequent studies revealed that agonist-infused rats displayed increased phosphoERK(pERK)-immunoreactivity in specific amygdaloid nuclei at 20 min post-infusion, with levels similar to control again after 90 min. In parallel, we used immunoblotting to profile ERK phosphorylation dynamics in whole amygdala after RXFP3-A2 treatment; and multiplex histochemical labelling techniques to reveal that after RXFP3-A2 infusion and social interaction, pERK-immunopositive neurons in amygdala expressed vesicular GABA-transporter mRNA and displayed differential profiles of RXFP3 and oxytocin receptor mRNA. Overall, these findings demonstrate that central relaxin-3/RXFP3 signalling can modulate social recognition in rats via effects within the amygdala and likely interactions with GABA and oxytocin signalling.


Arousal Emotion Nucleus incertus Oxytocin receptor 



The authors thank Dr. Mohammad Akhter Hossain (The Florey Institute of Neuroscience and Mental Health, Parkville, Australia) for providing the RXFP3-A2 peptide used in these studies. This research was supported by the following grants: Universitat Jaume I research grant UJI-B2016-40 and Program of Mobilities of the Spanish Ministerio de Educación y Cultura, PRX17/00646 (FEO-B); Universitat Jaume I FPI-UJI Predoctoral Research Scholarship PREDOC/2014/35 (HAG); E-2016-43 Research Travel Grant (HAG); Plan Propi Universitat Jaume I P1.1A2014-06 (AMS-P); NHMRC (Australia) Project Grant 1067522 (ALG); and Dorothy Levien Foundation research grant (ALG).

Author contributions

HA-G, performed most experiments, wrote the first draft of the manuscript, compiled and edited the figures, and edited successive drafts of the manuscript. SS-S, helped perform the behavioural experiments, and conducted analysis of behavioural data. SM, helped design and perform the multiplex in situ hybridization experiments, and edited successive drafts of the manuscript. CG-D, helped perform the behavioural experiments and the combined multiplex in situ hybridization and immunofluorescence studies, and analysed these data. ALG, participated in the design of the experiments, and edited the figures and successive drafts of the manuscript. AMS-P, participated in the conception of the study and directed the research, and edited successive drafts of the manuscript. FEO-B, conceived the study and directed the research, designed the experiments, and edited successive drafts of the manuscript.

Compliance with ethical standards

Conflict of interest

All authors declare no conflict of interest.

Supplementary material

429_2018_1763_MOESM1_ESM.tif (8.3 mb)
Supplementary Fig. 1. (a) Heat maps for the three-chamber social interaction paradigm for the sociability and preference tests. Percentages on the corners of the trackings refer to the average percentage time spent in each room. Percentages on the heat maps next to “subject”, “object” u “conspecifics” refer to the average percentage time spent sniffing. (b) Percentage time sniffing the conspecific rat (green bars) and inanimate object (black bars), or (c) the familiar (white bars) and novel rat (red bars) for the different experimental groups. * p<0.05, **** p<0.0001, ns: not significant (TIF 8458 KB)
429_2018_1763_MOESM2_ESM.tif (7.9 mb)
Supplementary Fig. 2. Characterisation of the neurochemical phenotype of Rxfp3 mRNA-positive neurons in STMV an STOV. (a) Schematic illustrating Rxfp3 distribution and co-expression with Oxtr mRNA in STMV (a and b) Representative fluorescent images. Representative images of fluorescent ISH and quantification of co-expression percentages indicated (lower right corner). (c) Schematic illustrating Rxfp3 mRNA distribution and co-expression with Oxtr and Slc32a1 mRNAs in the MePV. (c and d). Scale barS: 100 µm (a′), 10µm (b) (TIF 8130 KB)
429_2018_1763_MOESM3_ESM.tif (8.7 mb)
Supplementary Fig. 3. pERK immunostaining in the CeA after social encounters. (a) Schematic illustrating the CeA sub-nuclei analysed. (b) Density of pERK-stained neurons was significantly increased in A2-Pref rats (red bars) compared to vehicle treated rats (dashed black line). Representative images of pERK immunostaining in the CeA of (c) vehicle, (d) A2-Pref and (e) A2-Soc group rats. *p < 0.05; **p < 0.01. Scale bar: 100 µm (c) (TIF 8955 KB)
429_2018_1763_MOESM4_ESM.tif (4.2 mb)
Supplementary material 4 (TIF 4332 KB)


  1. Albert-Gascó H, García-Avilés Á, Moustafa S, Sánchez-Sarasua S, Gundlach AL, Olucha-Bordonau FE, Sánchez-Pérez AM (2017) Central relaxin-3 receptor (RXFP3) activation increases ERK phosphorylation in septal cholinergic neurons and impairs spatial working memory. Brain Struct Funct 222:449–463. Google Scholar
  2. Albert-Gascó H, Ma S, Ros-Bernal F, Sánchez-Pérez AM, Gundlach AL, Olucha-Bordonau FE (2018) GABAergic neurons in the rat medial septal complex express relaxin-3 receptor (RXFP3) mRNA. Front Neuroanat 11:133. Google Scholar
  3. Alheid GF (2006) Extended amygdala and basal forebrain. Ann N Y Acad Sci 985:185–205. Google Scholar
  4. Alheid GFF, Beltramino CAA, de Olmos JSS, Forbes MSS, Swanson DJJ, Heimer L (1998) The neuronal organization of the supracapsular part of the stria terminalis in the rat: the dorsal component of the extended amygdala. Neuroscience 84:967–996. Google Scholar
  5. Arakawa H (2017) Involvement of serotonin and oxytocin in neural mechanism regulating amicable social signal in male mice: Implication for impaired recognition of amicable cues in BALB/c strain. Behav Neurosci 131:176–191. Google Scholar
  6. Bannerman DM, Rawlins JN, McHugh SB, Deacon RM, Yee BK, Bast T, Zhang WN, Pothuizen HH, Feldon J (2004) Regional dissociations within the hippocampus memory and anxiety. Neurosci Biobehav Rev 28:273–283. Google Scholar
  7. Bathgate RA, Samuel CS, Burazin TC, Layfield S, Claasz AA, Reytomas IG, Dawson NF, Zhao C, Bond C, Summers RJ, Parry LJ, Wade JD, Tregear GW (2002) Human relaxin gene 3 (H3) and the equivalent mouse relaxin (M3) gene. Novel members of the relaxin peptide family. J Biol Chem 277:1148–1157. Google Scholar
  8. Baxter MG, Murray EA (2002) The amygdala and reward. Nat Rev Neurosci 3:563–573. Google Scholar
  9. Benarroch EE (2015) The amygdala: functional organization and involvement in neurologic disorders. Neurology 84:313–324. Google Scholar
  10. Blasiak A, Blasiak T, Lewandowski MH, Hossain MA, Wade JD, Gundlach AL (2013) Relaxin-3 innervation of the intergeniculate leaflet of the rat thalamus—neuronal tract-tracing and in vitro electrophysiological studies. Eur J Neurosci 37:1284–1294. Google Scholar
  11. Bonnet L, Comte A, Tatu L, Millot J-L, Moulin T, Medeiros de Bustos E (2015) The role of the amygdala in the perception of positive emotions: an “intensity detector”. Front Behav Neurosci 9:178. Google Scholar
  12. Burazin TC, Bathgate RA, Macris M, Layfield S, Gundlach AL, Tregear GW (2002) Restricted, but abundant, expression of the novel rat gene-3 (R3) relaxin in the dorsal tegmental region of brain. J Neurochem 82:1553–1557. Google Scholar
  13. Cádiz-Moretti B, Abellán-Álvaro M, Pardo-Bellver C, Martínez-García F, Lanuza E (2016) Afferent and efferent connections of the cortex-amygdala transition zone in mice. Front Neuroanat 10:125. Google Scholar
  14. Calvez J, de Ávila C, Matte L-O, Guèvremont G, Gundlach AL, Timofeeva E (2016) Role of relaxin-3/RXFP3 system in stress-induced binge-like eating in female rats. Neuropharmacology 102:207–215. Google Scholar
  15. Choleris E, Little SR, Mong JA, Puram SV, Langer R, Pfaff DW (2007) Microparticle-based delivery of oxytocin receptor antisense DNA in the medial amygdala blocks social recognition in female mice. Proc Natl Acad Sci USA 104:4670–4675. Google Scholar
  16. Dantzer R, Bluthe R-M, Koob GF, Le Moal M (1987) Modulation of social memory in male rats by neurohypophyseal peptides. Psychopharmacology 91:363–368. Google Scholar
  17. Davis MC, Green MF, Lee J, Horan WP, Senturk D, Clarke AD, Marder SR (2014) Oxytocin-augmented social cognitive skills training in schizophrenia. Neuropsychopharmacology 39:2070–2077. Google Scholar
  18. de Ávila C, Chometton S, Lenglos C, Calvez J, Gundlach AL, Timofeeva E (2018) Differential effects of relaxin-3 and a selective relaxin-3 receptor agonist on food and water intake and hypothalamic neuronal activity in rats. Behav Brain Res 336:135–144. Google Scholar
  19. Everts HG, Koolhaas JM (1997) Lateral septal vasopressin in rats: role in social and object recognition? Brain Res 760:1–7Google Scholar
  20. Everts HGJ, De Ruiter AJH, Koolhaas JM (1997) Differential lateral septal vasopressin in wild-type rats: correlation with aggression. Horm Behav 31:136–144. Google Scholar
  21. Faridar A, Jones-Davis D, Rider E, Li J, Gobius I, Morcom L, Richards LJ, Sen S, Sherr EH (2014) Mapk/Erk activation in an animal model of social deficits shows a possible link to autism. Mol Autism 5:57. Google Scholar
  22. Ferguson JN, Aldag JM, Insel TR, Young LJ (2001) Oxytocin in the medial amygdala is essential for social recognition in the mouse. J Neurosci 21:8278–8285Google Scholar
  23. Fox AS, Oler JA, Tromp DPMM, Fudge JL, Kalin NH (2015) Extending the amygdala in theories of threat processing. Trends Neurosci 38:319–329. Google Scholar
  24. Gheusi G, Bluthé R-M, Goodall G, Dantzer R (1994) Social and individual recognition in rodents: methodological aspects and neurobiological bases. Behav Processes 33:59–87. Google Scholar
  25. Giese KP, Mizuno K (2013) The roles of protein kinases in learning and memory. Learn Mem 20:540–552. Google Scholar
  26. Gobrogge KL, Liu Y, Young LJ, Wang Z (2009) Anterior hypothalamic vasopressin regulates pair-bonding and drug-induced aggression in a monogamous rodent. Proc Natl Acad Sci USA 106:19144–19149. Google Scholar
  27. Green MF, Horan WP, Lee J (2015) Social cognition in schizophrenia. Nat Rev Neurosci 16:620–631. Google Scholar
  28. Gupta R, Koscik TR, Bechara A, Tranel D (2011) The amygdala and decision-making. Neuropsychologia 49:760–766. Google Scholar
  29. Gur R, Tendler A, Wagner S (2014) Long-term social recognition memory is mediated by oxytocin-dependent synaptic plasticity in the medial amygdala. Biol Psychiatry 76:377–386. Google Scholar
  30. Gutiérrez-Castellanos N, Pardo-Bellver C, Martínez-García F, Lanuza E (2014) The vomeronasal cortex—afferent and efferent projections of the posteromedial cortical nucleus of the amygdala in mice. Eur J Neurosci 39:141–158. Google Scholar
  31. Haidar M, Guèvremont G, Zhang C, Bathgate RAD, Timofeeva E, Smith CM, Gundlach AL (2017) Relaxin-3 inputs target hippocampal interneurons and deletion of hilar relaxin-3 receptors in “floxed-RXFP3” mice impairs spatial memory. Hippocampus 27:529–546. Google Scholar
  32. Halls ML, van der Westhuizen ET, Bathgate R, Summers D RJ (2007) Relaxin family peptide receptors–former orphans reunite with their parent ligands to activate multiple signalling pathways. Br J Pharmacol 150:677–691. Google Scholar
  33. Happé F, Conway JR (2016) Recent progress in understanding skills and impairments in social cognition. Curr Opin Pediatr 28:736–742. Google Scholar
  34. Hatalski CG, Guirguis C, Baram TZ (1998) Corticotropin releasing factor mRNA expression in the hypothalamic paraventricular nucleus and the central nucleus of the amygdala is modulated by repeated acute stress in the immature rat. J Neuroendocrinol 10:663–669Google Scholar
  35. Hitti FL, Siegelbaum SA (2014) The hippocampal CA2 region is essential for social memory. Nature 508:88–92. Google Scholar
  36. Hurlemann R, Patin A, Onur OA, Cohen MX, Baumgartner T, Metzler S, Dziobek I, Gallinat J, Wagner M, Maier W, Kendrick KM (2010) Oxytocin enhances amygdala-dependent, socially reinforced learning and emotional empathy in humans. J Neurosci 30:4999–5007. Google Scholar
  37. Kania A, Gugula A, Grabowiecka A, de Ávila C, Blasiak T, Rajfur Z, Lewandowski MH, Hess G, Timofeeva E, Gundlach AL, Blasiak A (2017) Inhibition of oxytocin and vasopressin neuron activity in rat hypothalamic paraventricular nucleus by relaxin-3-RXFP3 signalling. J Physiol 595:3425–3447. Google Scholar
  38. Kocan M, Sarwar M, Hossain M, Wade JD, Summers RJ (2014) Signalling profiles of H3 relaxin, H2 relaxin and R3(B∆23–27)R/I5 acting at the relaxin family peptide receptor 3 (RXFP3). Br J Pharmacol 171:2827–2841. Google Scholar
  39. Korzan WJ, Summers TR, Ronan PJ, Renner KJ, Summers CH (2001) The role of monoaminergic nuclei during aggression and sympathetic social signaling. Brain Behav Evol 57:317–327Google Scholar
  40. Kruk MR (1991) Ethology and pharmacology of hypothalamic aggression in the rat. Neurosci Biobehav Rev 15:527–538. Google Scholar
  41. Kuhlmann S, Piel M, Wolf OT (2005) Impaired memory retrieval after psychosocial stress in healthy young men. J Neurosci 25:2977–2982. Google Scholar
  42. Landgraf R, Gerstberger R, Montkowski A, Probst JC, Wotjak CT, Holsboer F, Engelmann M (1995) V1 vasopressin receptor antisense oligodeoxynucleotide into septum reduces vasopressin binding, social discrimination abilities, and anxiety-related behavior in rats. J Neurosci 15:4250–4258Google Scholar
  43. Lee LC, Rajkumar R, Dawe GS (2014) Selective lesioning of nucleus incertus with corticotropin releasing factor-saporin conjugate. Brain Res 1543:179–190. Google Scholar
  44. Lenglos C, Mitra A, Guèvremont G, Timofeeva E (2014) Regulation of expression of relaxin-3 and its receptor RXFP3 in the brain of diet-induced obese rats. Neuropeptides 48:119–132. Google Scholar
  45. Liu C, Eriste E, Sutton S, Chen J, Roland B, Kuei C, Farmer N, Jörnvall H, Sillard R, Lovenberg TW (2003) Identification of relaxin-3/INSL7 as an endogenous ligand for the orphan G-protein-coupled receptor GPCR135. J Biol Chem 278:50754–50764. Google Scholar
  46. Lukas M, Toth I, Veenema AH, Neumann ID (2013) Oxytocin mediates rodent social memory within the lateral septum and the medial amygdala depending on the relevance of the social stimulus: male juvenile versus female adult conspecifics. Psychoneuroendocrinology 38:916–926. Google Scholar
  47. Ma S, Bonaventure P, Ferraro T, Shen PJ, Burazin TCD, Bathgate R, Liu D, Tregear C, Sutton GW, Gundlach AL (2007) Relaxin-3 in GABA projection neurons of nucleus incertus suggests widespread influence on forebrain circuits via G-protein-coupled receptor-135 in the rat. Neuroscience 144:165–190. Google Scholar
  48. Ma S, Smith CM, Blasiak A, Gundlach AL (2017) Distribution, physiology and pharmacology of relaxin-3/RXFP3 systems in brain. Br J Pharmacol 174:1034–1048. Google Scholar
  49. Mairesse J, Gatta E, Reynaert M-L, Marrocco J, Morley-Fletcher S, Soichot M, Deruyter L, Camp G, Van Bouwalerh H, Fagioli F, Pittaluga A, Allorge D, Nicoletti F, Maccari S (2015) Activation of presynaptic oxytocin receptors enhances glutamate release in the ventral hippocampus of prenatally restraint stressed rats. Psychoneuroendocrinology 62:36–46. Google Scholar
  50. Maski K, Holbrook H, Manoach D, Hanson E, Kapur K, Stickgold R (2015) Sleep dependent memory consolidation in children with autism spectrum disorder. Sleep 38:1955–1963. Google Scholar
  51. Nelson RJ, Trainor BC (2007) Neural mechanisms of aggression. Nat Rev Neurosci 8:536–546. Google Scholar
  52. Okuyama T, Kitamura T, Roy DS, Itohara S, Tonegawa S (2016) Ventral CA1 neurons store social memory. Science 353:1536–1541. Google Scholar
  53. Olucha-Bordonau FE, Teruel V, Barcia-González J, Ruiz-Torner A, Valverde-Navarro AA, Martínez-Soriano F (2003) Cytoarchitecture and efferent projections of the nucleus incertus of the rat. J Comp Neurol 464:62–97. Google Scholar
  54. Olucha-Bordonau FE, Fortes-Marco L, Otero-García M, Lanuza E, Martínez-García F (2014) The amygdala structure and function. In: Paxinos G (ed) The rat nervous system. IV edn. pp 441–490Google Scholar
  55. Paxinos GG, Watson C (2014) The rat brain in stereotaxic coordinates. Academic Press, San DicegoGoogle Scholar
  56. Pellissier LP, Gandía J, Laboute T, Becker JAJ, Le Merrer J (2017) µ opioid receptor, social behaviour and autism spectrum disorder: reward matters. Br J Pharmacol 16:620–631. Google Scholar
  57. Peng S, Zhang Y, Zhang J, Wang H, Ren B (2010) ERK in learning and memory: a review of recent research. Int J Mol Sci 11:222–232. Google Scholar
  58. Pereira CW, Santos FN, Sanchez-Perez AM, Otero-Garcia M, Marchioro M, Ma S, Gundlach AL, Olucha-Bordonau FE (2013) Electrolytic lesion of the nucleus incertus retards extinction of auditory conditioned fear. Behav Brain Res 247:201–210. Google Scholar
  59. Pro-Sistiaga P, Mohedano-Moriano A, Ubeda-Bañon I, Del Mar Arroyo-Jimenez M, Marcos P, Artacho-Pérula E, Crespo C, Insausti R, Martinez-Marcos A (2007) Convergence of olfactory and vomeronasal projections in the rat basal telencephalon. J Comp Neurol 504:346–362. Google Scholar
  60. Rasia-Filho AA, Londero RG, Achaval M (2000) Functional activities of the amygdala: an overview. J Psychiatry Neurosci 25:14–23Google Scholar
  61. Richter K, Wolf G, Engelmann M (2005) Social recognition memory requires two stages of protein synthesis in mice. Learn Mem 12:407–413. Google Scholar
  62. Ryan PJ, Ma S, Olucha-Bordonau FE, Gundlach AL (2011) Nucleus incertus an emerging modulatory role in arousal, stress and memory. Neurosci Biobehav Rev 35:1326–1341. Google Scholar
  63. Ryan PJ, Buchler E, Shabanpoor F, Hossain MA, Wade JD, Lawrence AJ, Gundlach AL (2013a) Central relaxin-3 receptor (RXFP3) activation decreases anxiety- and depressive-like behaviours in the rat. Behav Brain Res 244:142–151. Google Scholar
  64. Ryan PJ, Kastman HE, Krstew EV, Rosengren KJ, Hossain MA, Churilov L, Wade JD, Gundlach AL, Lawrence AJ (2013b) Relaxin-3/RXFP3 system regulates alcohol-seeking. Proc Natl Acad Sci USA 110:20789–20794. Google Scholar
  65. Santos FN, Pereira CW, Sánchez-Pérez AM, Otero-García M, Ma SK, Gundlach AL, Olucha-Bordonau FE (2016) Comparative distribution of relaxin-3 inputs and calcium-binding protein-positive neurons in rat amygdala. Front Neuroanat. Google Scholar
  66. Scalia F, Winans SS (1975) The differential projections of the olfactory bulb and accessory olfactory bulb in mammals. J Comp Neurol 161:31–55. Google Scholar
  67. Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, Preibisch S, Rueden C, Saalfeld S, Schmid B, Tinevez J-Y, White DJ, Hartenstein V, Eliceiri K, Tomancak P, Cardona A (2012) Fiji: an open-source platform for biological-image analysis. Nat Methods 9:676–682. Google Scholar
  68. Seese RR, Maske AR, Lynch G, Gall CM (2014) Long-term memory deficits are associated with elevated synaptic ERK1/2 activation and reversed by mGluR5 antagonism in an animal model of autism. Neuropsychopharmacology 39:1664–1673. Google Scholar
  69. Servan A, Brunelin J, Poulet E (2017) The effects of oxytocin on social cognition in borderline personality disorder. Encephale 44:46–51. Google Scholar
  70. Seymour B, Dolan R (2008) Emotion, decision making, and the amygdala. Neuron 58:662–671. Google Scholar
  71. Shabanpoor F, Akhter Hossain M, Ryan PJ, Belgi A, Layfield S, Kocan M, Zhang S, Samuel CS, Gundlach AL, Bathgate RAD, Separovic F, Wade JD (2012) Minimization of human relaxin-3 leading to high-affinity analogues with increased selectivity for relaxin-family peptide 3 receptor (RXFP3) over RXFP1. J Med Chem 55:1671–1681. Google Scholar
  72. Shojo H, Kaneko Y (2000) Characterization and expression of oxytocin and the oxytocin receptor. Mol Genet Metab 71:552–558. Google Scholar
  73. Smith SM, Vale WW (2006) The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. Dialogues Clin Neurosci 8:383–395Google Scholar
  74. Takahashi T, Ikeda K, Ishikawa M, Tsukasaki T, Nakama D, Tanida S, Kameda T (2004) Social stress-induced cortisol elevation acutely impairs social memory in humans. Neurosci Lett 363:125–130. Google Scholar
  75. Tanaka M, Iijima N, Miyamoto Y, Fukusumi S, Itoh Y, Ozawa H, Ibata Y (2005) Neurons expressing relaxin 3/INSL 7 in the nucleus incertus respond to stress. Eur J Neurosci 21:1659–1670. Google Scholar
  76. Terenzi MG, Ingram CD (2005) Oxytocin-induced excitation of neurones in the rat central and medial amygdaloid nuclei. Neuroscience 134:345–354. Google Scholar
  77. Trainor BC, Crean KK, Fry WHD, Sweeney C (2010) Activation of extracellular signal-regulated kinases in social behavior circuits during resident-intruder aggression tests. Neuroscience 165:325–336. Google Scholar
  78. Trezza V, Campolongo P, Vanderschuren L (2011) Evaluating the rewarding nature of social interactions in laboratory animals. Dev Cogn Neurosci 1:444–458. Google Scholar
  79. Tyzio R, Cossart R, Khalilov I, Minlebaev M, Hübner CA, Represa A, Ben-Ari Y, Khazipov R (2006) Maternal oxytocin triggers a transient inhibitory switch in GABA signaling in the fetal brain during delivery. Science 314:1788–1792. Google Scholar
  80. Tyzio R, Nardou R, Ferrari DC, Tsintsadze T, Shahrokhi A, Eftekhari S, Khalilov I, Tsintsadze V, Brouchoud C, Chazal G, Lemonnier E, Lozovaya N, Burnashev N, Ben-Ari Y (2014) Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring. Science 343:675–679. Google Scholar
  81. Van der Westhuizen ET, Van Der Werry TD, Sexton PM, Summers RJ (2007) The relaxin family peptide receptor 3 activates extracellular signal-regulated kinase 1/2 through a protein kinase C-dependent mechanism. Mol Pharmacol 71:1618–1629. Google Scholar
  82. Van der Westhuizen ET, Christopoulos A, Sexton PM, Wade JD, Summers RJ (2010) H2 relaxin is a biased ligand relative to H3 relaxin at the relaxin family peptide receptor 3 (RXFP3). Mol Pharmacol 77:759–772. Google Scholar
  83. Veenema AH (2008) Central vasopressin and oxytocin release: regulation of complex social behaviours. Prog Brain Res 170:261–276. Google Scholar
  84. Vuilleumier P, Sander D (2008) Trust and valence processing in the amygdala. Soc Cogn Affect Neurosci 3:299–302. Google Scholar
  85. Williams DL, Goldstein G, Minshew NJ (2006) The profile of memory function in children with autism. Neuropsychology 20:21–29. Google Scholar
  86. Winslow JT, Insel TR (2004) Neuroendocrine basis of social recognition. Curr Opin Neurobiol 14:248–253. Google Scholar
  87. Winslow JT, Ferguson JN, Young LJ, Hearn EF, Matzuk MM, Insel TR, Winslow JT (2000) Social amnesia in mice lacking the oxytocin gene. Nat Genet 25:284–288. Google Scholar
  88. Zhang C, Chua BE, Yang A, Shabanpoor F, Hossain MA, Wade JD, Rosengren KJ, Smith CM, Gundlach AL (2015) Central relaxin-3 receptor (RXFP3) activation reduces elevated, but not basal, anxiety-like behaviour in C57BL/6J mice. Behav Brain Res 292:125–132. Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Departamento de Medicina, Facultad de Ciencias de la SaludUniversitat Jaume ICastellón de la PlanaSpain
  2. 2.The Florey Institute of Neuroscience and Mental HealthParkvilleAustralia
  3. 3.Florey Department of Neuroscience and Mental HealthThe University of MelbourneParkvilleAustralia
  4. 4.Department of Clinical NeurosciencesUniversity of CambridgeCambridgeUK
  5. 5.Drug Discovery Biology, Monash Institute of Pharmaceutical SciencesMonash UniversityParkvilleAustralia

Personalised recommendations