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Preadolescent Adversity Programs a Disrupted Maternal Stress Reactivity in Humans and Mice

  • Kathleen E. Morrison
    Affiliations
    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
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  • C. Neill Epperson
    Affiliations
    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
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  • Mary D. Sammel
    Affiliations
    Penn PROMOTES Research on Sex and Gender in Health, University of Pennsylvania, Philadelphia, Pennsylvania

    Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania
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  • Grace Ewing
    Affiliations
    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
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  • Jessica S. Podcasy
    Affiliations
    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
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  • Liisa Hantsoo
    Affiliations
    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
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  • Deborah R. Kim
    Affiliations
    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
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  • Tracy L. Bale
    Correspondence
    Address correspondence to: Tracy L. Bale, Ph.D., University of Pennsylvania, Department of Animal Biology, 410F Hill Pavilion, 380 South University Avenue, Philadelphia, Pennsylvania 19104-6046; .
    Affiliations
    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
    Search for articles by this author

      Abstract

      Background

      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.

      Methods

      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.

      Results

      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.

      Conclusions

      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.

      Keywords

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      Linked Article

      • The Nature of Nurture: How Developmental Experiences Program Adult Stress Circuitry
        Biological PsychiatryVol. 81Issue 8
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          For thousands of years humans have attempted to reduce complex phenomena—including thoughts, feelings, and behavior—to more simplistic, manageable explanations. Arguments have long existed about the relative importance of nature versus nurture—are a patient’s difficulties primarily the result of the genes he or she was born with or the impact of his or her early experiences? It is clear, at this point, that the answer is usually both: a complicated interplay of genes and environment that develops over time.
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