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

Abstract

Background Adverse childhood experiences (ACEs) are one of the greatest predictors for 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 (PVN). 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 PVN 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.

Childhood adversity impact on gut microbiota and inflammatory response to stress during pregnancy

“…Our previous translational study found that high ACE postpartum women exhibited a blunted cortisol response to acute stress, mirroring hyporesponsive HPA function in postpartum female mice exposed to ELS (Morrison et al, 2017). However, in the present sample there was no main effect of ACE on proinflammatory cytokine response to stress.…”

“…Scores range from 0–10 and reflect the occurrence(s) of event(s), not their frequency or severity. An ACE score >=2 is associated with increased risk of preterm birth (Christiaens et al, 2015) and altered HPA axis function during pregnancy (Bowers et al, 2018) and postpartum (Morrison et al, 2017). Thus, participants scoring 2 or greater were considered “high ACE” while subjects with ACE score of <2 were considered “low ACE.”…”

“…While recent research from our laboratory indicates dysregulated HPA response among high ACE women postpartum (Morrison et al, 2017), ACE impact on inflammatory response to stress has not been studied during pregnancy. Maternal ACE history is associated with lower offspring gestational age and weight at delivery (Smith et al, 2016), and recent work suggests maternal cortisol (Gillespie et al, 2017) or elevated baseline interleukin (IL)-6 (Miller et al, 2017) may mediate this.…”

“…Those who have experienced ACEs show an exaggerated inflammatory response to acute laboratory stress (Trier Social Stress Test; TSST) (Carpenter et al, 2010), larger IL-6 response to daily stressors (Gouin et al, 2012), and larger ex vivo cytokine responses to microbial challenge or lipopolysaccharide (LPS) stimulation (Miller et al, 2011) compared with those without a history of childhood adversity. Individuals with exposure to childhood adversity also evidence dysregulated HPA axis function (Bunea et al, 2017), including blunted cortisol response to the TSST or Montreal Imaging Stress Task (MIST) (Carpenter et al, 2007; Lovallo, 2013; Suzuki et al, 2014; Voellmin et al, 2015), blunted cortisol awakening response (CAR) (Kumsta et al, 2017), greater heterogeneity in diurnal cortisol patterns (Gonzalez et al, 2009), low hair cortisol (Kalmakis et al, 2015), and blunted cortisol response to a separation stressor at six months postpartum (Morrison et al, 2017). During pregnancy specifically, high ACE women show lower baseline cortisol (Shea et al, 2007), greater hair cortisol levels (Schreier et al, 2015), increased cortisol response to daily stress (Bublitz and Stroud, 2012), elevated CAR in the context of poor current perceived family function (Bublitz et al, 2014), and greater hair cortisol associated with depressive or somatic symptoms (Bowers et al, 2018).…”

The Nature of Nurture: How Developmental Experiences Program Adult Stress Circuitry

“…(10) describe the impact that stress in the preadolescent period has on adult HPA regulation. They demonstrate that in both mice and human women, exposure to stress during the preadolescent period leads to dysregulated stress responses that emerged only during pregnancy and the peripartum period, suggesting that these long-lasting behavioral and endocrine effects emerge only within the hormonal milieu of pregnancy.…”