PROJECT SUMMARY / ABSTRACT Perinatal depression affects 6.5%-12.9% of mothers, with comorbid perinatal anxiety occurring in as many as 50% of cases. In low-income people of color, rates of these perinatal affective disorders (PNAD) are even higher. PNAD are associated with adverse effects on both maternal and infant health and can contribute to preterm birth and low birth weight. It is important to further our understanding of the etiology of PNAD to more efficaciously identify and treat patients, especially in at-risk populations. Levels of progesterone, and its metabolites allopregnanolone (ALLO) and pregnanolone (PA) fluctuate drastically during pregnancy and have been implicated in the pathogenesis of PNAD. These neuroactive steroids (NAS) act via the inhibitory GABAA receptors to alter neural circuitry and modulate affective symptoms. Postpartum withdrawal from NAS provokes affective symptoms and modifies GABAA receptor subunit expression. Our initial published work suggests that acute surges in NAS early in pregnancy (1st and 2nd trimesters) are also associated with affective symptoms in low-income perinatal people of color. To our knowledge PNAD symptoms have not been studied in relation to NAS withdrawal and surges in the same cohort. Further, our preclinical work links acute alterations in NAS to changes in the composition of the α4, γ2, and δ GABAA receptor subunit expression, but this work has not been translated to humans. We have developed methods to measure GABAA receptor subunit expression in peripheral mononuclear blood cells (PBMCs). We propose to recruit 50 pregnant participants from MoMent, a longstanding cohort comprised primarily of racial and ethnic minorities. We will measure NAS (ALLO and PA), GABAA receptor subunit expression (α4, γ2, and δ) and affective symptoms (depression and anxiety) at four time points, once per trimester and postpartum. Overall, we hypothesize that protracted stress common in PNAD, particularly in people of color, may lead to exaggerated perinatal changes in NAS (Aim 1) and insufficient adaptation of GABAAR subunits (Aim 2) contributing to high rates of PNAD. These mechanisms can occur independently or interactively such that in some individuals, the dramatic increases in or withdrawal from NAS in the perinatal period contribute to PNAD symptoms, especially when GABAAR do not functionally adapt to NAS. The specific aims are to investigate (1) the association between the rate of specific perinatal NAS changes (early-pregnancy surges, postpartum withdrawal) and affective symptoms; and (2) the association between degree of dynamic perinatal changes in GABAA receptor subunit expression and affective symptoms, as well as to explore the interactive effects of these two factors. By studying affective symptoms in relation to both rate of NAS surges/withdrawal and GABAA receptor subunit expression in the same at-risk perinatal cohort, this study will have a meaningful impact on our understanding of PNAD pat...