Project II focuses on the menopause as a critical window in the hormonal life of women, a period of increased risk for new onset affective disorders and cognitive complaints. Consistent with the overarching theme of this SCOR application, we propose that prepubertal adversity contributes not only to the sex bias for affective disorders in women, but their heightened risk for these disturbances during periods of dynamic hormonal change. Prepubertal stress certainly contributes to adverse outcomes in men, as well as women. However, menopausal women provide the ideal population for the investigation of eariy life adversity effects on the estrogen-serotonin interaction as it relates to affect and cognition. Preclinical and human studies highlight the lasting impact of prepubertal adversity on serotonin function at the gene, enzyme, neurotransmitter, and receptor levels. Pertinent to menopausal women, stress and estradiol (E2) share many of the same serotonergic targets with early and chronic adversity leading to sub-optimal serotonergic response to E2. Could stress modify the estrogen x serotonin relationship and be responsible for suboptimal affect regulation and cognition during periods of dwindling estrogen? Our hypotheses are explored through an observational evaluation of women over the menopausal transition. We will select a subgroup of these women in early postmenopause, with and without significant childhood adversity, who will undergo experimentally-induced serotonin reduction with the tryptophan depletion paradigm and fMRI pre and post short-term E2 treatment. We will investigate the impact of prepubertal adversity and these experimental manipulations on brain activation during performance of affective processing and working memory tasks. Additionally, we will examine adversity effects on basal hypothalamic pituitary adrenal HPA axis function using the Cortisol awaking response and relate these data to our main outcomes of interest. Like Project I, Project II utilizes the Adverse Childhood Events (ACE) Questionnaire to consider prepubertal adversity not from the standpoint of one particular kind of stressor or trauma, but from a more holistic appreciation of early life 'adversity' as a potent predictor of HPA axis dysregulation and disease risk.
Prepubertal trauma is one of the greatest predictors of affective disorder onset in women, and the menopause transition is a period of heightened risk. The growing animal and human data indicating a persistent impact of early life adversity on serotonin function and estrogen responsiveness highlights the importance of examining this stage of life with respect to our proposed outcomes of interest.
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