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Functional Neuroanatomy of Relaxin-3/RXFP3 Systems in the Brain: Implications for Integrated Neuroendocrine and Behavioural Control

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Neuroanatomy of Neuroendocrine Systems

Part of the book series: Masterclass in Neuroendocrinology ((MANEURO,volume 12))

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Abstract

Neuropeptides play key neuromodulatory roles in the mammalian central nervous system. Relaxin-3, a neuropeptide discovered by homology searching of the human genome 20 years ago, and its cognate G-protein-coupled receptor, relaxin-family peptide receptor 3 (RXFP3), discovered in studies of brain-enriched ‘orphan’ receptors, have since been shown to modulate neuronal activity in multiple brain circuits. The early anatomical association of this neuropeptide/receptor signalling system with the enigmatic nucleus incertus (NI) located in the pontine tegmentum of a range of mammalian brains prompted a large number of anatomical, regulatory and pharmacological studies. In this chapter, we summarize current knowledge of the neuroanatomy of the relaxin-3/RXFP3 system in the mammalian brain and detail the comprehensive studies of its functional relationship with the magnocellular and parvocellular oxytocin (OXT) and arginine-vasopressin (AVP) neurons in the paraventricular nucleus of the hypothalamus (PVN) in the rat. More generally, we review pharmacological studies using novel, chimeric and truncated peptides selective for RXFP3 compared to other relaxin-family receptors, which have identified several aspects of physiology and behaviour in rats and mice that are likely to be regulated by the endogenous relaxin-3/RXFP3 system; these include arousal, circadian rhythms, feeding and metabolism, social and stress-related behaviour, autonomic responses and cognition. Lastly, as a future perspective, we highlight some key issues, including the nature and regulation of neuronal relaxin-3 release and the precise location and function of RXFP3 in specific neural circuits, which require further research to improve our understanding of this complex and therapeutically relevant neuromodulatory system.

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Abbreviations

Amy:

amygdala

AN:

anorexia nervosa

AVP:

arginine vasopressin

BED:

binge-eating disorder

BN:

bulimia nervosa

CRH:

corticotropin-releasing hormone

dHipp:

dorsal hippocampus

DMH:

dorsomedial hypothalamic nucleus

DpMe:

deep mesencephalon

dSN:

dorsal to substantia nigra

HPA:

hypothalamic-pituitary-adrenal (axis)

HPG:

hypothalamic-pituitary-gonadal (axis)

ICV:

intracerebroventricular

INSL3–6:

insulin-like peptide 3–6

IO:

inferior olive

IPN:

interpeduncular nucleus

LH:

lateral hypothalamus

LPA:

lateral preoptic area

MCH:

melanin-concentrating hormone

MNCs:

magnocellular neurosecretory cells

MnR:

median raphe nucleus

MS:

medial septum

MVe:

medial vestibular nucleus

NI:

nucleus incertus

NTS:

nucleus of solitary tract

OX (A/B):

orexin-A/B

OXT:

oxytocin

PH:

posterior hypothalamic area

PnR:

pontine raphé nucleus

PrH:

prepositus hypoglossal nucleus

PVN:

paraventricular nucleus of hypothalamus

RLN3:

relaxin-3

RXFP1–4:

relaxin-family peptide receptor 1–4

SON:

supraoptic nucleus

SuM:

supramammillary nucleus

vHipp:

ventral hippocampus

vlPAG:

ventrolateral periaqueductal grey

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Acknowledgements

The authors would like to acknowledge the major contribution of their colleagues working in the fields of relaxin-3/RXFP3 system chemistry, pharmacology, anatomy and neurobiology over the last two decades. The research studies reviewed in this chapter conducted in the authors’ laboratories were supported by The National Science Centre, Poland (project grant UMO-2018/30/E/NZ4/00687 to AB, and PhD Scholarship ETIUDA V UMO-2017/24/T/NZ4/00225 to AK) and the National Health and Medical Research Council of Australia (project grant 1067522 to ALG). All figures were created with BioRender.com.

Key Literature (5–12 Articles) (Further Recommended Reading)

  • Blasiak et al. (2013) The first description of the existence of specific relaxin-3 neuron projections from ventrolateral PAG (but not nucleus incertus) to the intergeniculate nucleus in the rat.

  • Blasiak et al. (2015) The first study to identify different electrophysiological phenotypes of nucleus incertus neurons and their responses to the arousal-related orexin neuropeptides.

  • Hosken et al. (2015) Description of the reduced running wheel activity of mice lacking the RXFP3 gene/protein relative to wildtype littermates, in line with a similar phenotype of mice with a relaxin-3 gene/protein deletion.

  • Kania et al. (2020) The first study to demonstrate an RXFP3-related blockade of binge eating in female rats via actions within the PVN on oxytocin and arginine-vasopressin neurons.

  • Ma S et al. (2007) Comprehensive description of the neuroanatomical distribution of relaxin-3 neurons (mRNA/peptide) and labelled fibres, and RXFP3 mRNA and binding sites in rat brain.

  • Ma et al. (2009) Description of the anatomy of relaxin-3 neurons and their projections in a non-human primate (Macaca fascicularis) brain.

  • Ma et al. (2009) Pharmacological studies demonstrating the modulation of hippocampal theta oscillations and spatial memory by RXFP3 signalling in medial septum.

  • Ma et al. (2013) Heterogeneous responses of nucleus incertus neurons to corticotropin-releasing hormone and coherent activity with hippocampal theta rhythm in the rat.

  • McGowan et al. (2005) The first description of the effect of central administration of relaxin-3 to increase feeding in rats.

  • Smith et al. (2010) Comprehensive description of the neuroanatomy of relaxin-3 neurons (mRNA/peptide) and immunolabelled fibres, and RXFP3 mRNA/binding sites in mouse brain.

  • Tanaka et al. (2005) The first description of the neuroanatomical distribution of relaxin-3 neurons and immunolabelled nerve fibres in rat brain and their response to environmental stressors.

Details of Key References

  • [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.]

  • [Blasiak A, Siwiec M, Grabowiecka A, Blasiak T, Czerw A, Blasiak E, Kania A, Rajfur Z, Lewandowski MH, Gundlach AL (2015) Excitatory orexinergic innervation of rat nucleus incertus – Implications for ascending arousal, motivation and feeding control. Neuropharmacology 99:432–447.]

  • [Hosken IT, Sutton SW, Smith CM, Gundlach AL (2015) Relaxin-3 receptor (Rxfp3) gene knockout mice display reduced running wheel activity: Implications for role of relaxin-3/RXFP3 signalling in sustained arousal. Behav Brain Res 278:167–175.]

  • [Kania A, Szlaga A, Sambak P, Gugula A, Blasiak E, Micioni Di Bonaventura MV, Hossain MA, Cifani C, Hess G, Gundlach AL, Blasiak A (2020) Relaxin-3/RXFP3 signaling in the PVN inhibits magnocellular neurons via M-like current activation and contributes to binge eating behavior. J Neurosci 40:5362–5375.]

  • [Ma S, Bonaventure P, Ferraro T, Shen PJ, Burazin TCD, Bathgate RAD, Liu C, Tregear GW, Sutton SW, 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.]

  • [Ma S, Olucha-Bordonau FE, Hossain MA, Lin F, Kuei C, Liu C, Wade JD, Sutton SW, Nunez A, Gundlach AL (2009) Modulation of hippocampal theta oscillations and spatial memory by relaxin-3 neurons of the nucleus incertus. Learn Mem 16:730–742.]

  • [Ma S, Sang Q, Lanciego JL, Gundlach AL (2009) Localization of relaxin-3 in brain of Macaca fascicularis: identification of a nucleus incertus in primate. J Comp Neurol 517:856–872.]

  • [Ma S, Blasiak A, Olucha-Bordonau FE, Verberne AJ, Gundlach AL (2013) Heterogeneous responses of nucleus incertus neurons to corticotrophin-releasing factor and coherent activity with hippocampal theta rhythm in the rat. J Physiol (Lond) 591:3981–4001.]

  • [McGowan BM, Stanley SA, Smith KL, White NE, Connolly MM, Thompson EL, Gardiner JV, Murphy KG, Ghatei MA, Bloom SR (2005) Central relaxin-3 administration causes hyperphagia in male Wistar rats. Endocrinology 146:3295–3300.]

  • [Smith CM, Shen PJ, Banerjee A, Bonaventure P, Ma S, Bathgate RAD, Sutton SW, Gundlach AL (2010) Distribution of relaxin-3 and RXFP3 within arousal, stress, affective and cognitive circuits of mouse brain. J Comp Neurol 518:4016–4045.]

  • [Tanaka M, Iijima N, Miyamoto Y, Fukusumi S, Itoh Y, Ozawa H, Ibata Y (2005) Neurons expressing relaxin 3/INSL7 in the nucleus incertus respond to stress. Eur Neurosci 21:1659–1670.]

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Authors and Affiliations

  1. Department of Neurophysiology and Chronobiology, Jagiellonian University, Krakow, Poland

    Alan Kania & Anna Blasiak

  2. Department of Neuropeptide Research in Psychiatry, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany

    Alan Kania

  3. The Florey Institute of Neuroscience and Mental Health, and Department of Anatomy and Physiology, The University of Melbourne, Melbourne, VIC, Australia

    Andrew L. Gundlach

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  1. Alan Kania
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  2. Anna Blasiak
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Correspondence to Anna Blasiak or Andrew L. Gundlach .

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  1. Department of Neuropeptide Research in Psychiatry, Central Institute of Mental Health, University of Heidelberg, Mannheim, Baden-Württemberg, Germany

    Valery Grinevich

  2. Department of Physiology & Neurobiology, Eötvös Loránd University, Budapest, Hungary

    Árpád Dobolyi

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Kania, A., Blasiak, A., Gundlach, A.L. (2021). Functional Neuroanatomy of Relaxin-3/RXFP3 Systems in the Brain: Implications for Integrated Neuroendocrine and Behavioural Control. In: Grinevich, V., Dobolyi, Á. (eds) Neuroanatomy of Neuroendocrine Systems. Masterclass in Neuroendocrinology, vol 12. Springer, Cham. https://doi.org/10.1007/978-3-030-86630-3_16

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