Sex Differences in Major Depression: Impact of Prenatal Stress-Immune and Autonomic Dysregulation

重度抑郁症的性别差异：产前压力免疫和自主神经失调的影响

• 批准号: 10089485
• 负责人: JILL M GOLDSTEIN
• 金额: $ 162.33万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10089485
• 关键词: Adrenal Glands; Adult Children; Amygdaloid structure; Anterior; Anxiety; Area; Attenuated; Autonomic Dysfunction; Autonomic nervous system; Basic Science; Biological Markers; Brain; Brain Diseases; Brain imaging; CRH gene; Cardiac; Cardiovascular Diseases; Centers of Research Excellence; Clinical; Clinical Investigator; Clinical Research; Collaborations; Communities; Corticotropin-Releasing Hormone; Coupled; Cytokine Receptors; Data Analytics; Development; Devices; Disease; Early Intervention; Elderly; Faculty; Fetal Development; Functional disorder; Genes; Glucocorticoid Receptor; Glucocorticoids; Gonadal Steroid Hormones; Health; Heart; Heart Diseases; Hippocampus (Brain); Hormone secretion; Hormones; Hydrocortisone; Hypothalamic structure; Immune; Immune response; Interleukin-1; Interleukin-6; Knowledge; Leadership; Life; Longevity; Major Depressive Disorder; Maps; Medical; Medicine; Mental Depression; Mission; Moods; Myocardial Ischemia; Nerve; Neurons; Neurosciences; Outcome; Pathway interactions; Peripheral; Physiological; Physiology; Pituitary Gland; Policy Maker; Population; Prefrontal Cortex; Public Health; Receptor Activation; Recurrence; Resources; Risk; Rodent Model; Scientist; Series; Sex Differences; Sexual Dysfunction; Specialized Center; Steroid Receptors; Stress; Study models; TNF gene; Technical Expertise; Technology; Testing; Therapeutic; Training; Translating; Translations; Woman; biological adaptation to stress; brain circuitry; career; cingulate cortex; clinical effect; comorbid depression; cytokine; depressive symptoms; disability; early detection biomarkers; effective therapy; heart function; high risk; immune function; in utero; men; middle age; mortality risk; neuroregulation; neurovascular; next generation; novel therapeutics; paraventricular nucleus; pedagogy; prenatal; prenatal stress; respiratory; response; sex; sexual dimorphism; stress reactivity; success; therapeutic development; translational study; vagus nerve stimulation

OVERALL SUMMARY. Major depressive disorder (MDD) topped heart disease as the number one cause of disability worldwide, and women have twice the risk of men. MDD is associated with abnormalities in the stress response circuitry, areas that are among the most sexually dimorphic in the brain. These areas are dense in sex steroid and glucocorticoid receptors coupled with cytokine receptors. Further, activity in these areas has been associated with cortisol response, autonomic dysfunction, and immune responses, which we showed differed by sex. This is important since autonomic dysregulation is significantly associated with cardiovascular disease. In fact, women are at twice the risk for the co-occurrence of MDD, autonomic dysregulation and heart disease, leading to a 3-5-fold risk of death in women from heart disease, often with unrecognized and untreated MDD. Thus, understanding early biomarkers for sex differences in MDD and autonomic dysregulation will provide knowledge for early intervention, attenuating later life disability, in particular for women who are at higher risk. The scientific mission of this SCORE is to identify stress-immune pathway abnormalities, beginning in fetal development, that have shared consequences for sex differences in brain circuitry regulating mood and lifelong recurrent MDD and dysregulation of hormone and immune responses to stress, and autonomic and neurovascular dysfunction in early midlife. We aim to facilitate transdisciplinary, translational collaboration among basic and clinical investigators to enhance our understanding of the impact of sex on MDD and central and peripheral autonomic function and provide the groundwork for translating this knowledge into sex-selective therapeutics. Further, we aim to serve as an interdisciplinary resource to train and disseminate findings about sex differences in MDD and autonomic dysregulation to the scientific and medical communities, policy makers, and the public. To accomplish this, three integrated studies are proposed: 1) a clinical population neuroscience study relating prenatal risk biomarkers to sex differences in brain circuitry and physiologic deficits in response to stress in MDD in early midlife; 2) clinical study using direct transcutaneous neuromodulatory stimulation of the vagus nerve, auricular branch (or taVNS) to target the circuitry associated with stress-immune function and map its neuroanatomic, physiologic and clinical effects in MDD by sex, in the same subjects as in project 1; and 3) rodent model studies that will map out the central mechanistic pathways involved in projects 1 and 2. In addition, three cores will contribute to the success of this SCORE: 1) Leadership Administration Core to administer and oversee the administrative integration of the studies and cores; 2) Resources Core to provide shared technical expertise across studies; and 3) Career Enhancement Core, to supplement the training of junior faculty and others on the topic of our SCORE, and become pedagogical ambassadors to the scientific, medical and public communities about sex differences in depression and comorbidities with general medicine, a topic with global public health implications.

总结。重度抑郁症（MDD）是心脏病，这是第一名 全世界的残疾人，妇女的风险是男性的两倍。 MDD与压力异常有关 响应电路，是大脑中性最多态的区域。这些区域密集 性类固醇和糖皮质激素受体与细胞因子受体结合。此外，这些领域的活动有 与皮质醇反应，自主神经功能障碍和免疫反应有关，我们表明 与性别不同。这很重要，因为自主性失调与心血管显着相关 疾病。实际上，妇女的同时发生，自主神经失调和心脏的同时存在风险的两倍 疾病，导致女性因心脏病的死亡风险3-5倍，通常没有被认为 未经处理的MDD。因此，了解MDD和自主教的性别差异的早期生物标志物 失调将为早期干预提供知识，削弱以后的生活障碍，特别是 面临更高风险的妇女。该分数的科学任务是确定压力免疫途径 从胎儿发育开始，对大脑的性别差异产生后果，异常 调节情绪和终身复发性MDD的电路和激素的失调和免疫反应 中年早年的压力以及自主神经和神经血管功能障碍。我们旨在促进跨学科， 基本和临床研究人员之间的翻译合作，以增强我们对 在MDD和中央和外围自主功能上进行性别，并为翻译这一点提供了基础 了解性选择性治疗学。此外，我们旨在作为训练的跨学科资源 并传播有关MDD性别差异和对科学和自主性失调的发现的发现 医疗社区，政策制定者和公众。为此，提出了三项综合研究： 1）一项临床人群神经科学研究将产前风险生物标志物与性别差异有关 和生理缺陷，以应对中年早期MDD的压力； 2）使用直接研究 迷走神经，耳神经分支（或TAVN）的经牙神经调节刺激以靶向 与应力免疫功能相关的电路，并绘制其神经解剖学，生理和临床效应 与项目1相同的主题中的MDD； 3）将绘制中央的啮齿动物模型研究 项目1和2中涉及的机械途径。此外，三个核心将有助于成功的成功 得分：1）领导管理核心以管理和监督的行政整合 研究和核心； 2）资源核心，以在研究之间提供共同的技术专长； 3）职业 增强核心，以补充初级教师和其他人在我们的分数主题上的培训，以及 成为有关性别差异的科学，医学和公共社区的教学大使 通用医学的抑郁症和合并症，这是全球公共卫生影响的主题。