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

项目1概要。重度抑郁症（MDD）超过缺血性心脏病，成为第一大疾病 在全球范围内，女性的残疾风险是男性的两倍。虽然这是众所周知的，即使最近 与情绪失调和抑郁症本身相关的脑回路和基因的研究没有调查性别 甚至没有将目前的性别依赖知识纳入治疗的发展。这是 这是令人惊讶的，因为MDD与包括下丘脑在内的应激反应回路的异常有关 （HYPO）、杏仁核（AMYG）、海马体（HIPP）、前扣带皮层（ACC）和腹内侧和腹内侧皮质（Ventromedial and 眶前额叶皮质（vmPFC，OFC），是大脑中最具性别二态性的区域之一。HIPP， HYPO、AMYG和PFC在性类固醇和糖皮质激素受体与细胞因子受体偶联中密集， 特别是TNF-α、IL-1β、IL-6，它们是下丘脑垂体肾上腺（HPA）轴的主要共激活物。在 事实上，这些区域的活动与皮质醇反应有关， 副交感神经张力和免疫反应的丧失，我们之前已经证明了这一点在性别上是不同的。 此外，自主神经失调与心血管疾病本身显著相关，女性患者 MDD和心脏病同时发生的风险是女性的两倍，导致女性死亡风险增加3-5倍。 心脏病，通常是未被识别和未经治疗的MDD。这是一个全球性的公共卫生挑战， 因此，了解早期生物标志物在以后的生活中的共同发生将提供干预知识 之前利用一个难得的机会来研究胎儿的前驱因素对成人MDD的性别差异， 在人类体内研究中，我们将测试对中年早期中枢和外周生理学的相关影响， 在此，始于胎儿发育免疫途径异常与性别依赖性 对HYPO、HIPP、AMYG和PFC的影响，导致终身复发性MDD（rMDD），以及 对压力和自主神经功能紊乱的激素和免疫反应。成人受试者从我们 产前队列，产前血清存档，并已纳入我们的随访研究， 60岁，将重新招募（80例rMDD病例/50例健康对照，按性别平均分配，现在年龄为55- 61)对于拟议的研究。我们将测试这些产前免疫生物标志物是否与终身 中年早期MDD和ANS与神经血管失调（包括结构和功能脑 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由成年早期的严重抑郁症介导， 我们预测与母亲产前性别选择性先天免疫失调有关， exposure.先天免疫基因的新转录组学分析将为免疫途径提供线索， MDD和自主神经失调的性别差异。我们的生命周期观点是一种创新方法， 将确定潜在的治疗性性别依赖的早期干预目标，以减轻残疾以后的生活。

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.