title: Prenatal Testosterone Treatment Leads to Changes in the Morphology of KNDy Neurons, Their Inputs, and Projections to GnRH Cells in Female Sheep.
abstract: Prenatal testosterone (T)-treated ewes display a constellation of reproductive defects that closely mirror those seen in PCOS women, including altered hormonal feedback control of GnRH. Kisspeptin/neurokinin B/dynorphin (KNDy) neurons of the arcuate nucleus (ARC) play a key role in steroid feedback control of GnRH secretion, and prenatal T treatment in sheep causes an imbalance of KNDy peptide expression within the ARC. In the present study, we tested the hypothesis that prenatal T exposure, in addition to altering KNDy peptides, leads to changes in the morphology and synaptic inputs of this population, kisspeptin cells of the preoptic area (POA), and GnRH cells. Prenatal T treatment significantly increased the size of KNDy cell somas, whereas POA kisspeptin, GnRH, agouti-related peptide, and proopiomelanocortin neurons were each unchanged in size. Prenatal T treatment also significantly reduced the total number of synaptic inputs onto KNDy neurons and POA kisspeptin neurons; for KNDy neurons, the decrease was partly due to a decrease in KNDy-KNDy synapses, whereas KNDy inputs to POA kisspeptin cells were unaltered. Finally, prenatal T reduced the total number of inputs to GnRH cells in both the POA and medial basal hypothalamus, and this change was in part due to a decreased number of inputs from KNDy neurons. The hypertrophy of KNDy cells in prenatal T sheep resembles that seen in ARC kisspeptin cells of postmenopausal women, and together with changes in their synaptic inputs and projections to GnRH neurons, may contribute to defects in steroidal control of GnRH observed in this animal model.
authors.affiliation: Department of Neurobiology and Anatomical Sciences (M.C., L.M.C., M.N.L.), The University of Mississippi Medical Center, Jackson, Mississippi 39232; Department of Obstetrics and Gynecology, Pediatrics, and Reproductive Sciences Program (V.P.), University of Michigan, Ann Arbor, Michigan 48109; and Department of Physiology and Pharmacology (R.L.G.), West Virginia University, Morgantown, West Virginia 26506.
authors.forename: Maria
authors.initials: M
authors.lastname: Cernea
authors.affiliation: Department of Neurobiology and Anatomical Sciences (M.C., L.M.C., M.N.L.), The University of Mississippi Medical Center, Jackson, Mississippi 39232; Department of Obstetrics and Gynecology, Pediatrics, and Reproductive Sciences Program (V.P.), University of Michigan, Ann Arbor, Michigan 48109; and Department of Physiology and Pharmacology (R.L.G.), West Virginia University, Morgantown, West Virginia 26506.
authors.forename: Vasantha
authors.initials: V
authors.lastname: Padmanabhan
authors.affiliation: Department of Neurobiology and Anatomical Sciences (M.C., L.M.C., M.N.L.), The University of Mississippi Medical Center, Jackson, Mississippi 39232; Department of Obstetrics and Gynecology, Pediatrics, and Reproductive Sciences Program (V.P.), University of Michigan, Ann Arbor, Michigan 48109; and Department of Physiology and Pharmacology (R.L.G.), West Virginia University, Morgantown, West Virginia 26506.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Goodman
authors.affiliation: Department of Neurobiology and Anatomical Sciences (M.C., L.M.C., M.N.L.), The University of Mississippi Medical Center, Jackson, Mississippi 39232; Department of Obstetrics and Gynecology, Pediatrics, and Reproductive Sciences Program (V.P.), University of Michigan, Ann Arbor, Michigan 48109; and Department of Physiology and Pharmacology (R.L.G.), West Virginia University, Morgantown, West Virginia 26506.
authors.forename: Lique M
authors.initials: LM
authors.lastname: Coolen
authors.affiliation: Department of Neurobiology and Anatomical Sciences (M.C., L.M.C., M.N.L.), The University of Mississippi Medical Center, Jackson, Mississippi 39232; Department of Obstetrics and Gynecology, Pediatrics, and Reproductive Sciences Program (V.P.), University of Michigan, Ann Arbor, Michigan 48109; and Department of Physiology and Pharmacology (R.L.G.), West Virginia University, Morgantown, West Virginia 26506.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Lehman
mesh_terms: D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000166:cytology*; D004195:Disease Models, Animal; D004399:Dynorphins; D005260:Female; D007987:Gonadotropin-Releasing Hormone; D059648:Kisspeptins; D015287:Neurokinin B; D009474:Neurons / Q000166:cytology*; D011085:Polycystic Ovary Syndrome / Q000209:etiology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011301:Preoptic Area / Q000166:cytology; D012756:Sheep; D013739:Testosterone
chemical_list: D059648:Kisspeptins; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D004399:Dynorphins; D015287:Neurokinin B