title: Increased anxiety-like phenotype in female guinea pigs following reduced neurosteroid exposure in utero.
abstract: Neurosteroids are essential for aiding proper fetal neurodevelopment. Pregnancy compromises such as preterm birth, prenatal stress and intrauterine growth restriction are associated with an increased risk of developing behavioural and mood disorders, particularly during adolescence. These pathologies involve the premature loss or alteration of trophic steroid hormones reaching the fetus leading to impaired neurodevelopment. While the specific programming mechanisms are yet to be fully elucidated, in adult life, dysfunctions of allopregnanolone action are prevalent in individuals with depression, post-traumatic stress disorder and anxiety disorders. The objective of this study was to assess if changes in concentrations of the neurosteroid, allopregnanolone, may be a fetal programming factor in priming the brain towards a negative behavioural phenotype during the childhood to adolescent period using a guinea pig model. Pregnant guinea pigs received either vehicle (45% (2-hydroxypropyl)-β-cyclodextrin) or the 5α-reductase inhibitor, finasteride (25mg/kg maternal weight) from gestational age 60 until spontaneous delivery (∼71days gestation). Male and female offspring from vehicle and finasteride treated dams were tested at postnatal day 20 (juvenile-equivalence) in an open field arena, and hippocampus and amygdala subsequently assessed for neurological changes in markers of development and GABA production pathways 24h later. Females with reduced allopregnanolone exposure in utero displayed increased neophobic-like responses to a change in their environment compared to female controls. There were no differences in the neurodevelopmental markers assessed; MAP2, NeuN, MBP, GFAP or GAD67 between intrauterine finasteride or vehicle exposure, in either the hippocampus or amygdala whereas GAT1 staining was decreased. This study indicates that an intrauterine reduction in the supply of allopregnanolone programs vulnerability of female offspring to anxiety-like disorders in juvenility without impacting long term allopregnanolone concentrations.
authors.affiliation: University of Newcastle, School of Biomedical Sciences and Pharmacy, Newcastle 2308, New South Wales, Australia; Hunter Medical Research Institute, Mothers and Babies Research Centre, Newcastle 2305, New South Wales, Australia. Electronic address: Angela.Cumberland@uon.edu.au.
authors.forename: Angela L
authors.initials: AL
authors.lastname: Cumberland
authors.affiliation: University of Newcastle, School of Biomedical Sciences and Pharmacy, Newcastle 2308, New South Wales, Australia; Hunter Medical Research Institute, Mothers and Babies Research Centre, Newcastle 2305, New South Wales, Australia.
authors.forename: Hannah K
authors.initials: HK
authors.lastname: Palliser
authors.affiliation: University of Newcastle, School of Biomedical Sciences and Pharmacy, Newcastle 2308, New South Wales, Australia; Hunter Medical Research Institute, Mothers and Babies Research Centre, Newcastle 2305, New South Wales, Australia.
authors.forename: Gabrielle K
authors.initials: GK
authors.lastname: Crombie
authors.affiliation: Department of Obstetrics and Gynaecology, The Hudson Institute of Medical Research, Clayton 3168, Victoria, Australia.
authors.forename: David W
authors.initials: DW
authors.lastname: Walker
authors.affiliation: University of Newcastle, School of Biomedical Sciences and Pharmacy, Newcastle 2308, New South Wales, Australia; Hunter Medical Research Institute, Mothers and Babies Research Centre, Newcastle 2305, New South Wales, Australia.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Hirst
mesh_terms: D058891:5-alpha Reductase Inhibitors / Q000633:toxicity; D000818:Animals; D000831:Animals, Newborn; D001007:Anxiety / Q000097:blood / Q000188:drug therapy* / Q000209:etiology*; D001921:Brain / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D018120:Finasteride / Q000633:toxicity; D006168:Guinea Pigs; D006854:Hydrocortisone / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000008:administration & dosage*; D011247:Pregnancy; D011280:Pregnanolone / Q000097:blood*; D011297:Prenatal Exposure Delayed Effects / Q000209:etiology / Q000503:physiopathology; D011863:Radioimmunoassay; D012737:Sex Factors; D018709:Statistics, Nonparametric
chemical_list: D058891:5-alpha Reductase Inhibitors; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; D018120:Finasteride; D011280:Pregnanolone; D006854:Hydrocortisone
keywords: Allopregnanolone; Anxiety; Fetal programming; Juvenility