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

基本信息

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
项目类别：
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

项目摘要

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.

总体总结。重度抑郁症（MDD）位居心脏病首位，成为导致抑郁症的首要原因在全世界范围内，女性患残疾的风险是男性的两倍。 MDD 与压力异常有关反应回路，是大脑中性别二态性最强的区域。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，这些领域的活动与皮质醇反应、自主神经功能障碍和免疫反应有关，我们证明了这一点因性别而异。这很重要，因为自主神经失调与心血管显着相关疾病。事实上，女性同时出现重度抑郁症、自主神经失调和心脏病的风险是女性的两倍导致女性死于心脏病的风险增加 3 至 5 倍，而且往往未得到识别和诊断未经治疗的MDD。因此，了解MDD和自主神经性别差异的早期生物标志物失调将为早期干预提供知识，减轻晚年生活残疾，特别是对于风险较高的女性。该 SCORE 的科学使命是确定压力免疫途径从胎儿发育开始的异常，对大脑的性别差异有共同的影响调节情绪和终生复发性MDD的电路以及激素和免疫反应的失调中年早期的压力、自主神经和神经血管功能障碍。我们的目标是促进跨学科、基础研究人员和临床研究人员之间的转化合作，以增强我们对影响的理解性对 MDD 以及中枢和外周自主神经功能的影响，并为翻译这一点提供基础性别选择性疗法的知识。此外，我们的目标是作为跨学科资源来培训并向科学界传播有关 MDD 和自主神经失调的性别差异的发现医学界、政策制定者和公众。为了实现这一目标，提出了三项综合研究： 1) 一项临床群体神经科学研究，将产前风险生物标志物与大脑回路的性别差异联系起来中年早期 MDD 对压力的生理缺陷； 2) 直接使用临床研究经皮神经调节刺激迷走神经、耳支（或 taVNS）以靶向与应激免疫功能相关的电路，并绘制其神经解剖学、生理学和临床效应图按性别划分的 MDD，与项目 1 中的主题相同； 3）啮齿动物模型研究，将绘制出中心项目 1 和 2 涉及的机制路径。此外，三个核心将有助于该项目的成功得分：1) 领导管理核心，负责管理和监督行政整合研究和核心； 2) 资源核心，提供跨研究共享的技术专业知识； 3) 职业生涯增强核心，以补充初级教师和其他人员有关我们 SCORE 主题的培训，以及成为科学界、医学界和公共界关于性别差异的教育大使抑郁症和普通医学合并症是一个具有全球公共卫生影响的话题。