Prenatal Immune Programming of Sex Differences in Dysregulation of Emotion Processing in Midlife

项目总结/摘要 面对消极的生活经历，保持情绪稳定对健康老龄化至关重要。适应不良 对负性情感刺激的反应（“NAFecS”）与精神障碍有关，包括主要的 抑郁症（MDD）。事实上，有共同的大脑区域参与对NAFecS和MDD的反应。 病理生理学，包括：下丘脑（HYPO）、杏仁核（AMYG）、海马（HIPP）、前扣带回 大脑皮层（ACC），腹内侧和眶前额叶皮层（vmPFC，OFC），这些区域是高度性别化的区域。 二形的这一回路的活动在生理上与皮质醇反应、副交感神经系统的丧失有关。 心脏张力和免疫反应，包括TNF-α、IL-1β、IL-6，所有这些都因性别而异。我们将在这里测试 从胎儿发育开始的免疫途径异常与性别依赖性 影响HYPO，HIPP，AMYG和PFC，导致适应不良的负面情绪处理， 中年早期的MDD/抑郁情绪障碍，后者将加速该回路的老化 以及中年后期的负面情绪失调。我们将在2010年第一次对这一问题进行研究， 使用我们从妊娠第二/第三个三个月开始随访的55年前瞻性产前队列数据的人类 并在NIMH先前的研究中在44-50岁时进行评估。在4年内，我们将重新招募160名这样的后代 11年后，年龄将在55-61岁之间，与母亲产前免疫活性（TNF-α，IL-1β，IL-6，IL-10） 中年NAffec回路下降和负面情绪处理失调的性别差异， 抑郁症/严重心境障碍对中年早期影响我们将使用相同的多模式成像 与以前的方法（结构，功能成像（sMRI/fMRI））结合激素，自主神经和 免疫生理学和情绪调节措施。新的转录组学分析在后代的 外周血单核细胞（PBMC;测量先天免疫基因表达）将与 成人中年的结果。我们的生命周期观点是一种创新的方法， 维持健康情绪处理的免疫靶点是性别依赖的， 在功能衰退之前使用。这将有助于RDoC负面情绪和唤醒表型， 生理和基因型，以及情绪和性别的影响。

Project Summary/Abstract Maintaining emotional stability in the face of negative life experiences is critical for healthy aging. Maladaptive responses to negative affective stimuli (“NAffecS”) are implicated in psychiatric disorders, including major depressive disorder (MDD). In fact, there are shared brain regions involved in responses to NAffecS and MDD pathophysiology, including: hypothalamus (HYPO), amygdala (AMYG), hippocampus (HIPP), anterior cingulate cortex (ACC), and ventromedial and orbital prefrontal cortices (vmPFC, OFC), areas that are highly sexually dimorphic. Activity in this circuitry is physiologically associated with cortisol response, loss of parasympathetic cardiac tone, and immune responses, including TNF-α, IL-1β, IL-6, all of which differ by sex. We will test here that immune pathway abnormalities, beginning in fetal development, are associated with sex-dependent impacts on HYPO, HIPP, AMYG and PFC, resulting in maladaptive negative emotion processing and MDD/depressed mood symptomatology in early midlife, the latter of which will accelerate aging of this circuitry and negative emotion dysregulation in later midlife. We are uniquely poised to examine this for the first time in humans using data from our 55-year prospective prenatal cohort followed since 2nd/3rd trimesters of gestation and assessed at ages 44-50 in a previous NIMH study. Over 4 years, we will re-recruit 160 of these offspring who, 11 years later, will be ages 55-61, and relate maternal prenatal immune activity (TNF-α, IL-1β, IL-6, IL-10) to sex differences in midlife NAffec circuitry decline and negative emotion processing dysregulation and the impact of MDD/severe mood symptomatology in early midlife. We will use the same multimodal imaging approach as previously (structural, functional imaging (sMRI/fMRI)) coupled with hormones, autonomic and immune physiology, and emotion regulation measures. Novel transcriptomic analyses in the offspring's peripheral blood mononuclear cells (PBMCs; measuring innate immune gene expression) will be related to adult midlife outcomes. Our lifespan perspective is an innovative approach to identify potential immunotherapeutic targets for maintaining healthy emotion processing that are sex-dependent and can be applied prior to functional decline. This will contribute to RDoC Negative Affect and Arousal phenotypes, physiology and genotypes, and impact of mood and sex.