Higley, S. L. | bioRxiv Science

bioRxiv2024

Stress during puberty and adulthood pregnancy impact histone acetylation regulators in the hypothalamus

Undergoing stressful events during puberty puts women at risk for a variety of negative outcomes, and this risk is heightened if they become pregnant later in life. We previously demonstrated that stress during puberty combined with pregnancy in adulthood led to a blunted response of the hypothalamic-pituitary-adrenal stress axis in humans and mice. We have begun to understand the mechanisms underlying this effect by examining the paraventricular nucleus of the hypothalamus (PVN), a key regulator of the HPA axis. Prior studies uncovered an increase in chromatin openness within the PVN of the at-risk mice, with bioinformatic analyses implicating histone acetylation in this increased openness. Here, we measured the activity of histone acetyltransferase (HATs) and histone deacetylase (HDACs), the writers and erasers of histone acetylation, within the PVN to further characterize how stress during puberty and pregnancy may be interacting to produce a blunted stress response. We found that histone acetylation tone within the PVN is predictive of prior transcriptional and chromatin results, with pregnant, pubertally stressed females having a pro-acetylation tone within the PVN. These findings establish a role for regulators of acetylation in the open chromatin landscape characteristic in the PVN of pregnant, pubertally stressed females. Overall, this study provides insight into the epigenetic mechanisms underlying female-relevant risk for stress dysregulation, a central endophenotype of affective disorders.

neuroscience↗

bioRxiv2023

Immediate early genes as a molecular switch for lasting vulnerability following pubertal stress in mice

Why individuals suffer negative consequences following stress is a complex phenomenon that is dictated by individual factors, the timing of stress within the lifespan, and when in the lifespan the consequences are measured. Women who undergo adverse childhood experiences are at risk for lasting biological consequences, including affective and stress dysregulation. We have shown that pubertal adversity is associated with a blunted hypothalamic-pituitary-adrenal axis glucocorticoid response in peripartum humans and mice. In mice, our prior examination of the paraventricular nucleus (PVN) of the hypothalamus showed that pubertal stress led to an upregulation of baseline mRNA expression of six immediate early genes (IEGs) in the PVN of adult, pregnant mice. Separately, we showed that the pregnancy-associated hormone allopregnanolone is necessary and sufficient to produce the blunted stress response phenotype in pubertally stressed mice. In the current study, we further examined a potential mechanistic role for the IEGs in the PVN. We found that in pubertally stressed adult female, but not male, mice, intra-PVN allopregnanolone was sufficient to recapitulate the baseline IEG mRNA expression profile previously observed in pubertally stressed, pregnant mice. We also examined baseline IEG mRNA expression during adolescence, where we found that IEGs have developmental trajectories that showed sex-specific disruption by pubertal stress. Altogether, these data establish that IEGs may act as a key molecular switch involved in increased vulnerability to negative outcomes in adult, pubertally stressed animals. How the factors that produce vulnerability combine throughout the lifespan is key to our understanding of the etiology of stress-related disorders.

neuroscience↗