Social Imprinting in the Development of Major Depression

重度抑郁症发展中的社会印记

• 批准号: 8089557
• 负责人: Stephen E Gilman
• 金额: $ 32.37万
• 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/8089557
• 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）：本申请寻求支持，以调查神经发育的起源和重性抑郁症的病因。具体来说，我们建议测试一个“胎儿编程”抑郁症模型，其中胎儿期的不良条件-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，联合收割机相结合，以提高终身患抑郁症的风险。该项目还解决了健康差距的挑战，这对抑郁症是显着的和持久的，这仍然是NIH的优先领域。我们认为，抑郁症的社会起源，在某种程度上，神经发育的性质，并了解抑郁症的发展途径不仅会产生显着的病因学的见解，但也将推进减少差距的目标。本申请的目的是：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身风险的综合影响; 2）研究产前抑郁症发生过程中的基因-环境相互作用。将检验以下假设。1)在不利的社会条件下，产前风险对重度抑郁症的长期影响--如母体促炎细胞因子和母体HPA活性所示--将得到加强。假设1a是母胎压力，如妊娠中期炎性细胞因子（IL-1，IL-6和TNF-α）水平升高所示，与社会逆境的组合将与终身风险增加和抑郁症复发相关。假设1b：妊娠中期HPA激素水平（CRH升高，DHEAS和hCG降低）与抑郁症的终生风险和复发相关，在社会逆境背景下出生的个体中最强2）妊娠期和婴儿早期的社会逆境，与抑郁症的遗传易感性相结合，与抑郁症的终生风险升高相关。假设2是，与HPA回路相关的基因多态性以及先前复制的证据表明环境依赖性对抑郁症有影响的基因多态性，将与在社会逆境背景下出生的儿童的抑郁症风险增加最密切相关。本申请涉及的数据来自一个50年的调查，一个完善的出生队列，新英格兰家庭研究，这是唯一能够解决产前决定因素的精神疾病。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，以减少抑郁症的公共卫生负担。