Aging of Emotion Circuitry: Impact of Sex, Depression, and Fetal Immune Origins

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、腹外侧、背外侧和眼眶前额叶皮质(PFC)，这些区域是 最具两面性的人之一。该回路中的活动在生理上与皮质醇反应有关， 副交感神经心脏张力丧失，以及免疫反应，包括肿瘤坏死因子-α，IL-1β，IL-6，反应 性别不同。我们将在这里测试免疫途径异常，从胎儿发育开始 与性别依赖对Hypo、Hipp、AMYG和PFC的影响相关，导致不良适应负面 中年早期的情绪加工与MDD。此外，NAffec电路老化(即衰退)到中年后期 会在中年早期被MDD加速，导致在以后的负面情绪处理上有更大的缺陷 中年，我们预测的中年会因性别而异，即女性比男性更糟糕。我们做好了独特的准备来研究这一点 首次在人类中使用来自我们的产前队列的数据，从第二/第三个三个月开始进行前瞻性跟踪 在NIH之前的一项研究中，我们调查了胎儿对性别的编程，并在44-50岁之间进行了评估 MDD的差异。我们将在5年内重新招募180名这样的后代(按性别平均；一半为 复发性MDD)，11年后，他们将达到55-61岁。我们将与母体产前免疫活动(肿瘤坏死因子-2) α、IL-1β、IL-6)与NAffec回路缺陷和不良适应负性情绪调节的性别差异 年龄55-61岁，44-50岁下降。我们将使用与之前相同的多模式成像方法 (结构、功能成像(sMRI/fMRI))结合激素、自主神经和免疫生理学，以及 情绪调节措施。子代外周血单核细胞中新的转录分析 细胞将被用来测量先天免疫基因表达的异常，以回应产前 母体免疫暴露并与成人中年结局有关。我们的寿命视角是一种创新 识别维持健康情绪处理的潜在免疫治疗靶点的方法 与性别有关，可在功能衰退之前使用。这将导致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, ventrolateral, dorsolateral, and orbital prefrontal cortices (PFC), areas that are among the most 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, responses that 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 in early midlife. Further, aging of NAffec circuitry (i.e., decline) into later midlife will be accelerated by MDD in early midlife, resulting in greater deficits in negative emotion processing in later midlife, that we predict will differ by sex, i.e. women worse than men. We are uniquely poised to examine this for the first time in humans using data from our prenatal cohort prospectively followed since 2nd/3rd trimesters and assessed at ages 44-50 in a previous NIH study, in which we investigated fetal programming of sex differences in MDD. We will re-recruit over 5 years 180 of these offspring (equally divided by sex; half with recurrent MDD) who, 11 years later, will be ages 55-61. We will relate maternal prenatal immune activity (TNF- α, IL-1β, IL-6) to sex differences in NAffec circuitry deficits and maladaptive negative emotion regulation at ages 55-61 and decline from ages 44-50. 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 will be used to measure abnormalities in innate immune gene expression in response to prenatal maternal immune exposures and 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.