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

项目摘要/摘要 面对消极的生活经历，保持情绪稳定是健康衰老的关键。适应不良 对负面情感刺激的反应(“NaffecS”)与精神障碍有关，包括严重的 抑郁障碍(MDD)。事实上，对NaffecS和MDD的反应涉及到共享的大脑区域 病理生理学，包括：下丘脑(Hypo)、杏仁核(AMYG)、海马体(Hipp)、前扣带回 皮质(ACC)，以及腹内侧额叶皮质和眶前额叶皮质(vmPFC，OFC)，这是性行为高度集中的区域 双态的。这一回路的活动在生理上与皮质醇反应、副交感神经丧失 心脏张力和免疫反应，包括肿瘤坏死因子-α、IL-1β、IL-6，所有这些都在性别上有所不同。我们将在这里进行测试 从胎儿发育开始的免疫途径异常与性别依赖有关 对Hypo、Hipp、AMYG和PFC的影响，导致不适应的负面情绪处理和 中年早期的MDD/抑郁情绪症状，后者会加速这一回路的老化 以及中年后期的负性情绪失调。我们独一无二地做好了准备，将在 人类使用我们55年的前瞻性产前队列的数据，从怀孕的第二/第三个三个月开始跟踪 并在之前的NIMH研究中评估了年龄在44-50岁之间。在4年内，我们将重新招募160名这样的后代 11年后，世卫组织将年满55-61岁，与母体产前免疫活动(肿瘤坏死因子-α、IL-1β、IL-6、IL-10)有关 中年性别差异对NAffec回路衰退和负性情绪加工障碍的影响 MDD/严重情绪症状对中年早期的影响。我们将使用相同的多模式成像 方法与以前一样(结构、功能成像(sMRI/fMRI))结合激素、自主神经和 免疫生理学，情绪调节措施。后代基因中的新转录组分析 外周血单核细胞(PBMCs；测量先天免疫基因表达)将与 成人中年结局。我们的寿命视角是一种发现潜力的创新方法 维持健康情绪处理的免疫治疗靶点是性别依赖的，可以 在功能衰退之前应用。这将有助于RDoC的负面影响和唤醒表型， 生理和基因类型，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.