Social Imprinting in the Development of Major Depression

项目总结 这项申请寻求支持，以调查神经发育的起源和病因的严重抑郁障碍。具体地说，我们建议测试抑郁症的“胎儿程序化”模型，在该模型中，胎儿时期的不利条件--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--结合在一起，导致严重抑郁症的终生风险上升。该项目还解决了健康差距的挑战，这对抑郁症来说是显著和持久的，并且仍然是国家卫生研究院的优先领域。我们认为抑郁症的社会根源部分是神经发育。 在自然界中，了解抑郁症的发育途径不仅将产生对病因的重大见解，而且还将推动减少差异的目标。 这项建议的目的是：1)调查非典型胎儿应激反应途径和社会逆境的联合影响与严重抑郁障碍的终生风险；2)调查产前抑郁症发生过程中的基因-环境交互作用。以下假设将得到检验。1)产前风险的长期影响--如孕产妇保健所表明的那样 炎性细胞因子和母体HPA活性--在不利的社会条件下，对重度抑郁症的影响将会增强。假设1a是孕中期炎性细胞因子(IL-1、IL-6、TNF-)水平升高所表明的母胎应激和社会逆境的组合将与增加的终生风险和重大抑郁症的复发相关。假设1b孕中期HPA激素水平(CRH升高，DHEAS和hCG降低)将与终生风险和重大抑郁症的复发密切相关，在出生于社会逆境中的个体中最为明显2)怀孕和早期婴儿期间的社会逆境，与遗传因素相结合 易患抑郁症，与终生患抑郁症的风险增加有关。假设2是与HPA回路相关的基因的多态，以及先前有重复证据表明环境依赖对抑郁症的影响的基因的多态，将与抑郁症风险的增加最相关。 在出生于社会逆境背景下的儿童中尤为突出。 这项建议涉及了一项长达50年的研究数据，该研究对一个久负盛名的出生队列--新英格兰家庭研究--进行了调查，该研究是唯一能够解决精神疾病的产前决定因素的研究。 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严重抑郁症的发展途径，并确定可改变的途径，以减轻抑郁症的公共卫生负担。

PROJECT SUMMARY 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 proposal 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, 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 proposal 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.