title: Knockdown of hypothalamic RFRP3 prevents chronic stress-induced infertility and embryo resorption.
abstract: Whereas it is well established that chronic stress induces female reproductive dysfunction, whether stress negatively impacts fertility and fecundity when applied prior to mating and pregnancy has not been explored. In this study, we show that stress that concludes 4 days prior to mating results in persistent and marked reproductive dysfunction, with fewer successful copulation events, fewer pregnancies in those that successfully mated, and increased embryo resorption. Chronic stress exposure led to elevated expression of the hypothalamic inhibitory peptide, RFamide-related peptide-3 (RFRP3), in regularly cycling females. Remarkably, genetic silencing of RFRP3 during stress using an inducible-targeted shRNA completely alleviates stress-induced infertility in female rats, resulting in mating and pregnancy success rates indistinguishable from non-stress controls. We show that chronic stress has long-term effects on pregnancy success, even post-stressor, that are mediated by RFRP3. This points to RFRP3 as a potential clinically relevant single target for stress-induced infertility.
authors.affiliation: Department of Integrative Biology, University of California, Berkeley, Berkeley, United States.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Geraghty
authors.affiliation: Department of Integrative Biology, University of California, Berkeley, Berkeley, United States.
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Muroy
authors.affiliation: Department of Psychology, University of California, Berkeley, Berkeley, United States.
authors.forename: Sheng
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Department of Integrative Biology, University of California, Berkeley, Berkeley, United States.
authors.forename: George E
authors.initials: GE
authors.lastname: Bentley
authors.affiliation: Department of Psychology, University of California, Berkeley, Berkeley, United States.
authors.forename: Lance J
authors.initials: LJ
authors.lastname: Kriegsfeld
authors.affiliation: Department of Integrative Biology, University of California, Berkeley, Berkeley, United States.
authors.forename: Daniela
authors.initials: D
authors.lastname: Kaufer
mesh_terms: D000818:Animals; D004318:Doxycycline / Q000494:pharmacology; D020964:Embryo Loss / Q000209:etiology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D030762:Estrous Cycle / Q000235:genetics; D005260:Female; D055785:Gene Knockdown Techniques; D007028:Hypothalamic Hormones / Q000235:genetics* / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism*; D007247:Infertility, Female / Q000209:etiology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D012098:Reproduction; D013315:Stress, Psychological / Q000150:complications* / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics
chemical_list: D007028:Hypothalamic Hormones; C000588859:RFamide-related peptide-3, rat; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D004318:Doxycycline
keywords: RFRP3; infertility; neuroscience; rat; stress