Fetal Hormonal Programming of Sex Differences in Aging of the Memory Circuitry (Phase II)

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 DESCRIPTION (provided by applicant): With the substantial increase in aging of the population, intact memory function is one of the most important public health and economic challenges of our time. Age-related memory disorders are associated with major depressive disorder (MDD), and both have twice the risk in women than men. However, the shared pathophysiology that underlies MDD and cognitive decline is not well known. We will test the hypothesis that this shared risk has fetal origins that involve abnormalities in immune-stress and vascular pathways with sex- dependent consequences. We are uniquely poised to examine this for the first time in humans using data from our prospective prenatal cohort of adults, followed since 2nd/3rd trimesters of gestation and tested currently at ages 47-54 in MH090291, during which we investigated the fetal programming of sex differences in memory circuitry aging. We followed 200 discordant siblings (one exposed to preeclampsia (PE) or fetal growth restriction (FGR) and one unexposed), obstetric complications we demonstrated were associated with maternal immune activation abnormalities in TNF-, IL-1, IL-6, and IL-10. For this competitive renewal, we propose to follow these siblings further, separating them into those who had MDD (n=80) and those who did not (n=120), and compare them with respect to later midlife memory decline and associated physiologic disruptions from ages 47-54 to 55-62 years. We will use the same multimodal brain imaging and cognitive assessments, as in MH090291 (structural (sMRI/dMRI) and functional (fMRI) imaging and measures of verbal learning/memory), coupled with new measures of neurovascular function (based on transcranial Doppler ultrasound) and a novel genetic strategy, using transcriptomic analyses of the offspring's adult peripheral blood mononuclear cells (PBMCs), measuring innate immune gene expression. In so doing, we will test whether gene expression within inflammatory molecular pathways is related to prenatal exposure, MDD and memory circuitry decline. Thus, together, our aims will test the hypothesis that prenatal inflammatory biomarkers are related to sex-dependent memory circuitry decline 60 years later through shared sex-dependent immune disruptions associated with MDD/mood traits and neurovascular dysfunction. Our lifespan perspective is an innovative approach that will identify potential therapeutic targets associated with depression that are sex- dependent, and can be applied to early periods for intervention prior to memory decline.