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Effects of chronic silencing of relaxin-3 production in nucleus incertus neurons on food intake, body weight, anxiety-like behaviour and limbic brain activity in female rats

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Abstract

Eating disorders are frequently triggered by stress and are more prevalent in women than men. First signs often appear during early adolescence, but the biological basis for the sex-specific differences is unknown. Central administration of native relaxin-3 (RLN3) peptide or chimeric/truncated analogues produces differential effects on food intake and HPA axis activity in adult male and female rats, but the precise role of endogenous RLN3 signalling in metabolic and neuroendocrine control is unclear. Therefore, we examined the effects of microRNA-induced depletion (knock-down) of RLN3 mRNA/(peptide) production in neurons of the brainstem nucleus incertus (NI) in female rats on a range of physiological, behavioural and neurochemical indices, including food intake, body weight, anxiety, plasma corticosterone, mRNA levels of key neuropeptides in the paraventricular nucleus of hypothalamus (PVN) and limbic neural activity patterns (reflected by c-fos mRNA). Validated depletion of RLN3 in NI neurons of female rats (n = 8) produced a small, sustained (~ 2%) decrease in body weight, an imbalance in food intake and an increase in anxiety-like behaviour in the large open field, but not in the elevated plus-maze or light/dark box. Furthermore, NI RLN3 depletion disrupted corticosterone regulation, increased oxytocin and arginine-vasopressin, but not corticotropin-releasing factor, mRNA, in PVN, and decreased basal levels of c-fos mRNA in parvocellular and magnocellular PVN, bed nucleus of stria terminalis and the lateral hypothalamic area, brain regions involved in stress and feeding. These findings support a role for NI RLN3 neurons in fine-tuning stress and neuroendocrine responses and food intake regulation in female rats.

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Acknowledgments

The authors thank Prof Ross Bathgate and Dr Gabrielle Callander (The Florey Institute of Neuroscience and Mental Health) for providing the AAV(1/2)-EmGFP miR499 and AAV(1/2)- EmGFP miRC used in these studies.

Funding

This research was supported by NHMRC (Australia) project grant 1067522 (ALG), a NARSAD Independent Investigator Award (ALG), and a grant from the Dorothy Levien Foundation (ALG). CDÁ was supported by scholarships from the Centre thématique de recherche en neurosciences and Fonds de recherche du Québec - Santé, and by a Commonwealth Government (Australia) Endeavour Research Fellowship. We also acknowledge financial support from the Victorian State Government Infrastructure Program to The Florey Institute of Neuroscience and Mental Health.

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  1. Sherie Ma

    Present address: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia

  2. ET, CC and ALG jointly supervised this research

Authors and Affiliations

  1. Department of Psychiatry and Neuroscience, CRIUCPQ, Faculty of Medicine, Université Laval, Québec, Canada

    Camila de Ávila, Sandrine Chometton, Elena Timofeeva & Carlo Cifani

  2. The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia

    Camila de Ávila, Sherie Ma & Andrew L. Gundlach

  3. NNF CBMR, Nutrient and Metabolite Sensing, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark

    Camila de Ávila & Lola Torz Pedersen

  4. Pharmacology Unit, School of Pharmacy, University of Camerino, Camerino, Italy

    Carlo Cifani

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  1. Camila de Ávila
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Correspondence to Camila de Ávila or Andrew L. Gundlach.

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Experiments described were conducted with the approval of The Florey Institute of Neuroscience and Mental Health Animal Ethics Committee and according to ethical guidelines issued by the National Health and Medical Research Council of Australia.

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This article is dedicated to Elena Timofeeva (deceased 28/09/2017), a fine scientist, colleague, supervisor and mentor

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de Ávila, C., Chometton, S., Ma, S. et al. Effects of chronic silencing of relaxin-3 production in nucleus incertus neurons on food intake, body weight, anxiety-like behaviour and limbic brain activity in female rats. Psychopharmacology 237, 1091–1106 (2020). https://doi.org/10.1007/s00213-019-05439-1

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