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

记忆回路老化中性别差异的胎儿激素编程（第二阶段）

• 批准号: 9325823
• 负责人: JILL M GOLDSTEIN
• 金额: $ 25万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9325823
• 关键词: Adult; Adult Children; Age; Age-Related Memory Disorders; Aging; Anisotropy; Biological Markers; Blood Vessels; Brain; Brain imaging; Cardiac; Cognitive; Communities; Coupled; Data; Diffusion; Diffusion Magnetic Resonance Imaging; Discipline of obstetrics; Doppler Ultrasound; Fascicle; Female; Fetal Growth Retardation; Functional Magnetic Resonance Imaging; Functional disorder; Gene Expression; Genetic; Genotype; Gonadal Hormones; Health; Hippocampus (Brain); Homeostasis; Hormonal; Human; Hyperactive behavior; Image; Immune; Immune system; Impaired cognition; Individual; Inferior; Inflammatory; Interleukin-1; Interleukin-1 beta; Interleukin-10; Interleukin-6; Intervention; Link; Longevity; Major Depressive Disorder; Measures; Memory; Memory Loss; Mental Depression; Molecular; Moods; Multimodal Imaging; Outcome; Parietal; Parietal Lobe; Pathway interactions; Perinatal Exposure; Peripheral Blood Mononuclear Cell; Phase; Phenotype; Physiological; Physiology; Pre-Eclampsia; Pregnancy; Public Health; Rest; Risk; Sex Characteristics; Short-Term Memory; Siblings; Stress; Stress Tests; TNF gene; Testing; Time; Verbal Learning; Water; White Matter Hyperintensity; Woman; aging population; base; blood oxygen level dependent; cognitive testing; cohort; experience; extracellular; fetal; fetal programming; functional decline; gray matter; health economics; healthy aging; high risk; hypercortisolemia; immune activation; in utero; indexing; innovation; memory encoding; men; middle age; neuroinflammation; neurovascular; neurovascular coupling; novel; offspring; prenatal; prenatal exposure; programs; prospective; response; risk sharing; sex; therapeutic target; trait; transcriptomics; white matter

 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.

 描述（由申请人提供）：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。与抑郁症相关的记忆障碍与重度抑郁症（MDD）有关，女性的风险是男性的两倍。然而，共同的病理生理学基础的MDD和认知能力下降是不为人所知。我们将检验这一假设，即这种共同的风险有胎儿的起源，涉及异常的免疫应激和血管通路与性别依赖的后果。我们将首次在人类中使用来自我们的前瞻性产前成人队列的数据来研究这一点，随后从妊娠的第二/第三个三个月开始，目前在MH 090291中的47-54岁进行测试，在此期间，我们研究了记忆电路老化中性别差异的胎儿编程。我们跟踪了200个不一致的兄弟姐妹（一个暴露于先兆子痫（PE）或胎儿生长受限（FGR），另一个未暴露），我们证明产科并发症与TNF-α、IL-1 β、IL-6和IL-10的母体免疫激活异常相关。对于这种竞争性 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），并比较他们在47-54岁至55-62岁的中年记忆衰退和相关生理中断方面。我们将使用与MH 090291相同的多模式脑成像和认知评估（结构（sMRI/dMRI）和功能（fMRI）成像和言语学习/记忆的措施），加上神经血管功能的新措施（基于经颅多普勒超声）和一种新的遗传策略，使用后代成年外周血单核细胞（PBMC）的转录组学分析，测量先天免疫基因的表达。在这样做的过程中，我们将测试炎症分子通路内的基因表达是否与产前暴露、MDD和记忆回路下降有关。因此，我们的目标将共同测试这样的假设：产前炎症生物标志物与60年后的性别依赖性记忆回路下降有关，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干扰实现的。我们的寿命视角是一种创新的方法，将确定与抑郁症相关的潜在治疗靶点，这些靶点具有性别依赖性，并可应用于记忆衰退之前的早期干预。