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

项目 1 摘要。重度抑郁症（MDD）位居缺血性心脏病首位 造成全世界残疾的原因，女性的风险是男性的两倍。尽管这是众所周知的，即使是最近 对与情绪失调和重度抑郁症相关的大脑回路和基因的研究本身并不调查性别 影响甚至也没有将当前的性别依赖性知识纳入治疗方法的开发中。这是 令人惊讶的是，MDD 与应激反应回路（包括下丘脑）的异常有关 (HYPO)、杏仁核 (AMYG)、海马 (HIPP)、前扣带皮层 (ACC) 以及腹内侧和 眶前额皮质（vmPFC、OFC）是大脑中性别二态性最强的区域之一。 HIPP, HYPO、AMYG 和 PFC 富含性类固醇和糖皮质激素受体以及细胞因子受体， 特别是 TNF-α、IL-1β、IL-6，它们是下丘脑垂体肾上腺 (HPA) 轴的主要共激活剂。在 事实上，这些区域的活动与皮质醇反应、自主神经功能障碍有关 通过副交感神经张力的丧失和免疫反应，我们之前表明，这因性别而异。 此外，自主神经失调与心血管疾病本身显着相关，女性 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，通常伴有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，了解晚年同时发生的早期生物标志物将为干预提供知识 早些时候。利用难得的机会调查成人 MDD 和性别差异的胎儿前因 在人类体内研究中，我们将测试中年早期对中枢和外周生理学的相关影响 在此，从胎儿发育开始的免疫途径异常与性别依赖性有关 对 HYPO、HIPP、AMYG 和 PFC 的影响，导致终生复发性 MDD (rMDD) 和功能失调 中年早期对压力和自主神经功能障碍的激素和免疫反应。我们的成人主题 产前队列，其产前血清已存档，并已纳入我们的后续研究 60岁，将重新招募（80例rMDD/50名健康对照，按性别平均分配，现年龄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生相关。 中年早期的 MDD 和 ANS 以及神经血管失调（包括大脑结构和功能） 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，这 我们预测与母亲产前造成的先天免疫的性别选择性失调有关 曝光。先天免疫基因的新转录组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。我们的生命周期视角是一种创新方法 将确定潜在的性别依赖性治疗目标，进行早期干预，以减轻晚年的残疾。

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.