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

 描述(申请人提供)：随着人口老龄化的大幅增加，完整的记忆功能是我们这个时代最重要的公共卫生和经济挑战之一。与年龄相关的记忆障碍与严重抑郁障碍(MDD)有关，两者在女性中的风险都是男性的两倍。然而，共同的病理生理学基础上的MDD和认知能力下降并不是很清楚。我们将检验这样一种假设，即这种共同的风险源于胎儿，涉及免疫应激和血管通路的异常，并导致性别依赖的后果。我们准备首次在人类中检验这一点，使用来自我们预期的成人产前队列的数据，从怀孕第二/第三个三个月开始跟踪，目前在MH090291上进行了年龄为47-54岁的测试，在此期间，我们调查了胎儿对记忆回路老化中性别差异的编程。我们跟踪了200名不和谐的兄弟姐妹(一名暴露于先兆子痫或胎儿生长受限，另一名未暴露)，我们证明产科并发症与母亲免疫激活异常的肿瘤坏死因子-、IL-1、IL-6和IL-10有关。为了这场竞争 为了更新，我们建议进一步跟踪这些兄弟姐妹，将他们分为患有MDD的人(n=80)和没有MDD的人(n=120)，并比较他们从47-54岁到55-62岁的中年记忆力下降和相关的生理障碍。我们将使用与MH090291相同的多模式脑成像和认知评估(结构(sMRI/dMRI)和功能(FMRI)成像以及言语学习/记忆的测量)，并结合新的神经血管功能测量(基于经颅多普勒超声)和一种新的遗传策略，使用对后代成年外周血单核细胞(PBMC)的转录分析，测量先天免疫基因的表达。在此过程中，我们将测试炎症分子通路中的基因表达是否与产前暴露、MDD和记忆回路下降有关。因此，我们的目标将共同检验这一假设，即产前炎症生物标记物与60年后性别依赖性记忆回路衰退有关，这是通过与MDD/情绪特征和神经血管功能障碍相关的共同性别依赖性免疫中断来实现的。我们的寿命视角是一种创新的方法，它将确定与抑郁症相关的、与性别相关的潜在治疗靶点，并可应用于记忆衰退之前的早期干预。

 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.