Social Imprinting in the Development of Major Depression

重度抑郁症发展中的社会印记

• 批准号: 7938877
• 负责人: Stephen E Gilman
• 金额: $ 32.7万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7938877
• 关键词: Address; Adrenal Glands; Adrenal hormone preparation; Area; Biogenesis; Birth; CRH gene; Child; Data; Development; Epidemiologist; Etiology; Exposure to; Family Study; Genes; Genetic Polymorphism; Genetic Predisposition to Disease; Human Chorionic Gonadotropin; Hypothalamic structure; Individual; Inflammatory; Interleukin-1; Interleukin-6; Investigation; Major Depressive Disorder; Mental Depression; Mental disorders; Modeling; Nature; New England; Pathway interactions; Perinatal Exposure; Pituitary Gland; Pregnancy; Public Health; Recurrence; Risk; Risk Factors; Social Conditions; Social Environment; TNF gene; Testing; United States National Institutes of Health; biological adaptation to stress; career; cohort; cytokine; fetal; fetal programming; gene environment interaction; health disparity; imprint; infancy; insight; lifetime risk; prenatal; prenatal stress; social

DESCRIPTION (provided by applicant): This application seeks support to investigate the neurodevelopmental origins and etiology of major depressive disorder. Specifically, we propose to test a "fetal programming" model of depression in which adverse conditions during the fetal period-as indicated by exposure to maternal hypothalamic-pituitary- adrenal (HPA) hormones, elevated maternal pro-inflammatory cytokines; early social adversity; and genetic susceptibility, combine to contribute to a trajectory of elevated lifetime risk for major depression. This project also addresses the challenge of health disparities, which for depression are marked and persistent, and which remain an NIH priority area. We propose that the social origins of depression are, in part, neurodevelopmental in nature, and that understanding the developmental pathways to depression will not only yield significant insights into etiology, but will also advance the objective of reducing disparities. The aims of this application are: 1) to investigate the combined influences of atypical fetal stress- response pathways and social adversity in relation to the lifetime risk of major depressive disorder; and 2) to investigate gene-environment interactions during the prenatal period in the development of depression. The following hypotheses will be tested. 1) The long-term impact of prenatal risks-as indicated by maternal pro- inflammatory cytokines and maternal HPA activity-for major depression will be heightened under adverse social conditions. Hypothesis 1a is that the combination of maternal-fetal stress, as indicated by elevated levels of inflammatory cytokines (IL-1, IL-6, and TNF-) during mid-gestation, and social adversity will be associated with an increased lifetime risk and recurrence of major depression. Hypothesis 1b is that levels of HPA hormones (increased CRH and decreased DHEAS and hCG) during mid-gestation will be associated with the lifetime risk and recurrence of major depression most strongly among individuals born in the context of social adversity 2) Social adversity during pregnancy and early infancy, in combination with genetic susceptibility to depression, with be associated with an elevated lifetime risk of depression. Hypothesis 2 is that polymorphisms in genes associated with HPA circuitry and in genes with prior replicated evidence of environmentally dependent effects on depression, will be associated with an increased risk of depression most strongly among children born in the context of social adversity. This application involves data from a 50-year investigation of a well-established birth cohort, the New England Family Study, which is uniquely capable of addressing the prenatal determinants of mental illness. The applicant is a social epidemiologist whose long-term career objectives are to discover the developmental pathways leading to major depression, and to identify modifiable pathways in order to reduce the public health burden of depression.

描述（由申请人提供）：本申请旨在研究重度抑郁症的神经发育起源和病因学。具体来说，我们建议测试一种“胎儿编程”抑郁症模型，其中胎儿期的不利条件-如暴露于母体下丘脑-垂体-肾上腺（HPA）激素，母体促炎细胞因子升高；早期社会逆境；和遗传易感性，结合起来会增加患重度抑郁症的终生风险。该项目还解决了健康差距的挑战，这对于抑郁症来说是明显和持久的，并且仍然是NIH的优先领域。我们认为抑郁症的社会起源在一定程度上是神经发育的，理解抑郁症的发育途径不仅会对病因产生重要的见解，而且还会促进减少差异的目标。本应用的目的是：1)研究非典型胎儿应激反应途径和社会逆境对重度抑郁症终生风险的综合影响；2)探讨产前抑郁发生过程中基因与环境的相互作用。以下假设将被检验。1)在不利的社会条件下，产前风险（如母体促炎因子和母体HPA活性）对重度抑郁症的长期影响将会增强。假设1a认为，妊娠中期炎症细胞因子（IL-1、IL-6和TNF-）水平升高所表明的母胎压力和社会逆境的结合，将增加重度抑郁症的终生风险和复发。假设1b认为妊娠中期的HPA激素水平（CRH升高，DHEAS和hCG降低）与重度抑郁症的终生风险和复发相关，这在社会逆境环境中出生的个体中最为明显。2)妊娠期和婴儿期的社会逆境，加上抑郁症的遗传易感性，与抑郁症的终生风险升高相关。假设2是，与HPA回路相关的基因的多态性，以及先前有重复证据表明环境依赖于抑郁症影响的基因，将与在社会逆境中出生的儿童患抑郁症的风险增加联系在一起。这一应用程序涉及的数据来自于一项建立良好的出生队列的50年调查，即新英格兰家庭研究，该研究具有解决精神疾病的产前决定因素的独特能力。申请人是一名社会流行病学家，其长期职业目标是发现导致重度抑郁症的发展途径，并确定可改变的途径，以减轻抑郁症的公共卫生负担。