title: Maternal testosterone exposure increases anxiety-like behavior and impacts the limbic system in the offspring.
abstract: During pregnancy, women with polycystic ovary syndrome (PCOS) display high circulating androgen levels that may affect the fetus and increase the risk of mood disorders in offspring. This study investigated whether maternal androgen excess causes anxiety-like behavior in offspring mimicking anxiety disorders in PCOS. The PCOS phenotype was induced in rats following prenatal androgen (PNA) exposure. PNA offspring displayed anxiety-like behavior in the elevated plus maze, which was reversed by flutamide [androgen receptor (AR) blocker] and tamoxifen [selective estrogen receptor (ER) modulator]. Circulating sex steroids did not differ between groups at adult age. The expression of serotonergic and GABAergic genes associated with emotional regulation in the amygdala was consistent with anxiety-like behavior in female, and partly in male PNA offspring. Furthermore, AR expression in amygdala was reduced in female PNA offspring and also in females exposed to testosterone in adult age. To determine whether AR activation in amygdala affects anxiety-like behavior, female rats were given testosterone microinjections into amygdala, which resulted in anxiety-like behavior. Together, these data describe the anxiety-like behavior in PNA offspring and adult females with androgen excess, an impact that seems to occur during fetal life, and is mediated via AR in amygdala, together with changes in ERα, serotonergic, and GABAergic genes in amygdala and hippocampus. The anxiety-like behavior following testosterone microinjections into amygdala demonstrates a key role for AR activation in this brain area. These results suggest that maternal androgen excess may underpin the risk of developing anxiety disorders in daughters and sons of PCOS mothers.
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, 17177 Stockholm, Sweden; Department of Obstetrics and Gynecology, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, 150040 Harbin, China;
authors.forename: Min
authors.initials: M
authors.lastname: Hu
authors.affiliation: Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden;
authors.forename: Jennifer Elise
authors.initials: JE
authors.lastname: Richard
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, 17177 Stockholm, Sweden; Endocrinology and Metabolism Laboratory, Department of Medicine West Division, School of Medicine, University of Chile, 8320000 Santiago, Chile;
authors.forename: Manuel
authors.initials: M
authors.lastname: Maliqueo
authors.affiliation: Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden;
authors.forename: Milana
authors.initials: M
authors.lastname: Kokosar
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, 17177 Stockholm, Sweden;
authors.forename: Romina
authors.initials: R
authors.lastname: Fornes
authors.affiliation: Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden;
authors.forename: Anna
authors.initials: A
authors.lastname: Benrick
authors.affiliation: Department of Obstetrics & Gynecology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045;
authors.forename: Thomas
authors.initials: T
authors.lastname: Jansson
authors.affiliation: Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, 413 45 Gothenburg, Sweden.
authors.forename: Claes
authors.initials: C
authors.lastname: Ohlsson
authors.affiliation: Department of Obstetrics and Gynecology, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, 150040 Harbin, China; xiaokewu2002@vip.sina.com Elisabet.stener-victorin@ki.se.
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden;
authors.forename: Karolina Patrycja
authors.initials: KP
authors.lastname: Skibicka
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, 17177 Stockholm, Sweden; xiaokewu2002@vip.sina.com Elisabet.stener-victorin@ki.se.
authors.forename: Elisabet
authors.identifier: http://orcid.org/0000-0002-3424-1502
authors.initials: E
authors.lastname: Stener-Victorin
mesh_terms: D000679:Amygdala / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D001007:Anxiety / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001522:Behavior, Animal / Q000187:drug effects*; D005260:Female; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D011944:Receptors, Androgen / Q000378:metabolism; D013739:Testosterone / Q000009:adverse effects* / Q000494:pharmacology
chemical_list: D011944:Receptors, Androgen; D013739:Testosterone
keywords: amygdala; anxiety; behavior; maternal androgen excess; polycystic ovary syndrome