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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.

SUBMITTER: Morrison KE

PROVIDER: S-EPMC5326692 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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

Morrison Kathleen E KE Epperson C Neill CN Sammel Mary D MD Ewing Grace G Podcasy Jessica S JS Hantsoo Liisa L Kim Deborah R DR Bale Tracy L TL

Biological psychiatry 20160826 8

<h4>Background</h4>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 it ...[more]

PMID: 27776734

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Project description:IntroductionAntenatal depression is associated with a broad range of suboptimal outcomes in offspring, although the underlying mechanisms are not yet understood. Animal studies propose inflammation and glucocorticoids as mediators of the developmental programming effect of prenatal stress on offspring stress responses, but studies in humans are not yet at this stage. Indeed, to date no single study has examined the effects of a rigorously defined, clinically significant Major Depressive Disorder (MDD) in pregnancy on maternal antenatal inflammatory biomarkers and hypothalamic-pituitary (HPA) axis, as well as on offspring HPA axis, behavior and developmental outcomes in the first postnatal year.MethodsA prospective longitudinal design was used in 106 women (49 cases vs. 57 healthy controls) to study the effect of MDD in pregnancy and associated antenatal biology (inflammatory and cortisol biomarkers), on offspring stress response (cortisol response to immunization, at 8 weeks and 12 months), early neurobehavior (Neonatal Behavioral Assessment Scale, NBAS, at day 6), and cognitive, language and motor development (Bayley Scales of Infant and Toddler Development at 12 months).ResultsCompared with healthy controls, women with MDD in pregnancy had raised interleukin (IL) IL-6 (effect size (δ) = 0.53, p = 0.031), IL-10 (δ = 0.53, p = 0.043), tumor necrosis factor alpha (δ = 0.90, p = 0.003) and vascular endothelial growth factor (δ = 0.56, p = 0.008), together with raised diurnal cortisol secretion (δ = 0.89, p = 0.006), raised evening cortisol (δ = 0.64, p = 0.004), and blunted cortisol awakening response (δ = 0.70, p = 0.020), and an 8-day shorter length of gestation (δ = 0.70, p = 0.005). Furthermore, they had neonates with suboptimal neurobehavioral function in four out of five NBAS clusters measured (range of δ = 0.45-1.22 and p = 0.049-<0.001) and increased cortisol response to stress at one year of age (δ = 0.87, p < 0.001). Lastly, maternal inflammatory biomarkers and cortisol levels were correlated with infant stress response, suggesting a mechanistic link.ConclusionThis study confirms and extends the notion that depression in pregnancy is associated with altered offspring behavior and biological stress response, and demonstrates that changes in maternal antenatal stress-related biology are associated with these infant outcomes.

Dataset Information

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

Publications

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

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