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

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 前额叶皮层（ACC）、腹内侧、腹外侧、背外侧和眶前额叶皮层（PFC）， 是最具性别差异的物种之一该回路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，以及免疫应答，包括TNF-α、IL-1β、IL-6， 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HYPO，HIPP，AMYG和PFC的性别依赖性影响相关，导致适应不良的负面影响 情绪处理和抑郁症。此外，NAffec电路的老化（即，下降）到中年后期 在中年早期会被MDD加速，导致在中年后期更大的负面情绪处理缺陷。 中年，我们预测将因性别而异，即女性比男性差。我们有独特的优势来研究这个问题 首次在人类中使用我们的产前队列数据，前瞻性地随访了自第2/第3个三个月以来的数据， 在之前的一项NIH研究中，我们调查了胎儿的性别编程， MDD的差异。我们将在5年内重新招募180名这些后代（按性别平均分配;一半 复发性MDD），11年后，年龄将为55-61岁。我们将母亲产前免疫活性（TNF-α） α，IL-1β，IL-6）与NAffec回路缺陷和适应不良的负性情绪调节的性别差异 年龄在55-61岁之间，从44-50岁开始下降。我们将使用与先前相同的多模态成像方法 （结构，功能成像（sMRI/fMRI））与激素，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组学分析 细胞将用于测量先天免疫基因表达的异常， 母体免疫暴露与成人中年结局相关。我们的生命周期观点是一种创新的 一种识别维持健康情绪处理的潜在免疫靶点的方法， 依赖于性别，可以在功能衰退之前应用。这将导致RDoC负面影响， 唤醒表型，生理学和基因型，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, 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.