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Biol Psychiatry. 2017 Apr 15;81(8):693-701. doi: 10.1016/j.biopsych.2016.08.027. Epub 2016 Aug 26.

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

Author information

1
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.
2
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.
3
Penn PROMOTES Research on Sex and Gender in Health, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania.
4
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.
5
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.

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:

Adolescence; HPA axis; Paraventricular nucleus; Postpartum; Pregnancy; Stress

PMID:
27776734
PMCID:
PMC5326692
DOI:
10.1016/j.biopsych.2016.08.027
[Indexed for MEDLINE]
Free PMC Article

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