title: Preadolescent Adversity Programs a Disrupted Maternal Stress Reactivity in Humans and Mice.
abstract: Adverse childhood experiences (ACEs) are one of the greatest predictors of affective disorders for women. Periods of dynamic hormonal flux, including pregnancy, exacerbate the risk for affective disturbance and promote hypothalamic-pituitary-adrenal (HPA) axis dysregulation, a key feature of affective disorders. Little is understood as to how stress experienced in late childhood, defined as preadolescence, alters the programming unique to this period of brain maturation and its interaction with the hormonal changes of pregnancy and postpartum.
  
  
  
  Preadolescent female mice were exposed to chronic stress and examined for changes in their HPA axis during pregnancy and postpartum, including assessment of maternal-specific stress responsiveness and transcriptomics of the paraventricular nucleus of the hypothalamus. Translationally, pregnant women with low or high ACEs were examined for their maternal stress responsiveness.
  
  
  
  As predicted, preadolescent stress in mice resulted in a significant blunting of the corticosterone response during pregnancy. Transcriptomic analysis of the paraventricular nucleus revealed widespread changes in expression of immediate early genes and their targets, supporting the likely involvement of an upstream epigenetic mechanism. Critically, in our human studies, the high ACE women showed a significant blunting of the HPA response.
  
  
  
  This unique mouse model recapitulates a clinical outcome of a hyporesponsive HPA stress axis, an important feature of affective disorders, during a dynamic hormonal period, and suggests involvement of transcriptional regulation in the hypothalamus. These studies identify a novel mouse model of female ACEs that can be used to examine how additional life adversity may provoke disease risk or resilience.
authors: Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Penn PROMOTES Research on Sex and Gender in Health, University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Kathleen E
authors: KE
authors: Morrison
authors: Penn PROMOTES Research on Sex and Gender in Health, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors: C Neill
authors: CN
authors: Epperson
authors: Penn PROMOTES Research on Sex and Gender in Health, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Mary D
authors: MD
authors: Sammel
authors: Penn PROMOTES Research on Sex and Gender in Health, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Grace
authors: G
authors: Ewing
authors: Penn PROMOTES Research on Sex and Gender in Health, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Jessica S
authors: JS
authors: Podcasy
authors: Penn PROMOTES Research on Sex and Gender in Health, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Liisa
authors: L
authors: Hantsoo
authors: Penn PROMOTES Research on Sex and Gender in Health, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Deborah R
authors: DR
authors: Kim
authors: Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Penn PROMOTES Research on Sex and Gender in Health, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: tbale@vet.upenn.edu.
authors: Tracy L
authors: TL
authors: Bale
mesh_terms: D000328:Adult; D000069586:Adult Survivors of Child Adverse Events; D000818:Animals; D003345:Corticosterone / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism / Q000503:physiopathology*; D008425:Maternal Behavior / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000378:metabolism / Q000503:physiopathology*; D049590:Postpartum Period; D011247:Pregnancy; D013315:Stress, Psychological / Q000378:metabolism / Q000503:physiopathology*; D055815:Young Adult
chemical_list: D003345:Corticosterone
keywords: Adolescence; HPA axis; Paraventricular nucleus; Postpartum; Pregnancy; Stress