Impact of Sex on Prenatal Stress-Immune Programming of Depression and Autonomic Dysregulation

项目1总结。严重抑郁障碍(MDD)超过缺血性心脏病成为第一大疾病 在全球范围内，这是残疾的主要原因，女性的患病风险是男性的两倍。尽管这是众所周知的，甚至是最近的 对与情绪失调和MDD相关的大脑回路和基因的研究本身并不调查性别 甚至也没有将当前的性别依赖知识纳入治疗学的发展中。这是 令人惊讶的是，MDD与包括下丘脑在内的应激反应回路的异常有关 下丘脑(Hypo)、杏仁核(AMYG)、海马体(Hipp)、前扣带回(ACC)、腹内侧部和 眼眶前额叶皮质(vmPFC，OFC)，这是大脑中性别差异最大的区域之一。希普， Hypo、AMYG和PFC的性激素和糖皮质激素受体与细胞因子受体结合在一起， 尤其是肿瘤坏死因子-α、白介素1-β、白介素6，它们是下丘脑-垂体-肾上腺轴的主要共同激活剂。在……里面 事实上，这些区域的活动与皮质醇反应有关，表现为自主神经功能障碍。 由于副交感神经心脏张力和免疫反应的丧失，我们之前展示的这些反应因性别而不同。 此外，自主神经失调与女性心血管疾病本身也有很大关系。 MDD和心脏病同时发生的风险是男性的两倍，导致女性死亡的风险是女性的3-5倍 由于心脏病，通常患有未被识别和治疗的MDD。这是一个世界性的公共卫生挑战， 因此，了解生命后期共同出现的早期生物标志物将为干预提供知识 早些时候。利用一个难得的机会来调查成年MDD和 在活体人体研究中，中年早期对中枢和外周生理的相关影响，我们将测试 在这里，从胎儿发育开始免疫途径异常与性别依赖有关 对Hypo、Hipp、AMYG和PFC的影响，导致终生复发的MDD(RMDD)，以及 中年早期对应激和自主神经功能障碍的激素和免疫反应。来自我们的成年受试者 产前队列，为他们存档产前血清，并已纳入我们对 60岁，将重新招募(80例rMDD患者/50名健康对照组，按性别平均，现在55岁- 61)用于拟议的研究。我们将测试这些产前免疫生物标志物是否与终生相关 MDD和ANS与中年早期(包括结构和功能脑)的神经血管失调 应激反应回路异常、生理失调)和神经血管功能障碍。我们 预测中年早期的性别差异将通过成年早期的严重抑郁来调节，这 我们预测与母体产前导致的性别选择性先天免疫失调有关 曝光。对先天免疫基因的新的转录分析将为研究免疫途径提供线索 MDD的性别差异与自主神经失调。我们的寿命视角是一种创新的方法， 将确定潜在的治疗性性别依赖的目标，以便在以后的生活中进行早期干预，以减轻残疾。

PROJECT 1 SUMMARY. Major depressive disorder (MDD) topped ischemic heart disease as the number one cause of disability worldwide, and women have twice the risk of men. Although this is well-known, even recent studies of brain circuitry and genes associated with mood dysregulation and MDD per se do not investigate sex effects nor incorporate even current sex-dependent knowledge into development of therapeutics. This is surprising since MDD is associated with abnormalities in stress response circuitry including hypothalamus (HYPO), amygdala (AMYG), hippocampus (HIPP), anterior cingulate cortex (ACC), and ventromedial and orbital prefrontal cortices (vmPFC, OFC), areas that are among the most sexually dimorphic in the brain. HIPP, HYPO, AMYG, and PFC are dense in sex steroid and glucocorticoid receptors coupled with cytokine receptors, in particular, TNF-α, IL-1β, IL-6, the major co-activators of the hypothalamic pituitary adrenal (HPA) axis. In fact, activity in these areas has been associated with cortisol response, autonomic dysfunction characterized by loss of parasympathetic cardiac tone, and immune responses, which we previously showed differed by sex. Furthermore, autonomic dysregulation is significantly associated with cardiovascular disease itself, with women at twice the risk of the co-occurrence of MDD and heart disease, leading to a 3-5-fold risk of death in women from heart disease, often with unrecognized and untreated MDD. This is a worldwide public health challenge, and thus understanding early biomarkers for the co-occurrence later in life will provide knowledge to intervene earlier. Leveraging a rare opportunity to investigate fetal antecedents to sex differences in adult MDD and associated impact on central and peripheral physiology in early midlife in human in vivo studies, 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 lifelong recurrent MDD (rMDD), and dysregulation of hormone and immune responses to stress and autonomic dysfunction in early midlife. Adult subjects from our prenatal cohort, for whom prenatal sera are archived and who have been included in our follow-up studies for 60 years, will be re-recruited (80 cases with rMDD/50 healthy controls, equally divided by sex, now ages 55- 61) for the proposed study. We will test whether these prenatal immune biomarkers are associated with lifelong MDD and ANS and neurovascular dysregulation in early midlife (including structural and functional brain abnormalities in stress response circuitry, physiologic dysregulation) and neurovascular dysfunction. We predict that the sex differences in early midlife will be mediated by major depression in earlier adulthood, which we predict is associated with sex-selective dysregulation of innate immunity resulting from maternal prenatal exposure. Novel transcriptomic analyses of innate immunity genes will provide clues to immune pathways to sex differences in MDD and autonomic dysregulation. Our lifespan perspective is an innovative approach that will identify potential therapeutic sex-dependent targets for early intervention to attenuate disability later in life.