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: 10747460
• 负责人: JILL M GOLDSTEIN
• 金额: $ 6.22万
• 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/10747460
• 关键词: 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; Gonadal Steroid Hormones; Health; Heart Diseases; Hippocampus; Hormone secretion; Hormones; Hydrocortisone; Hypothalamic structure; Immune; Immune response; Interleukin-6; Knowledge; Leadership; Life; Longevity; Major Depressive Disorder; Maps; Medical; Medicine; Mental Depression; Mission; Moods; Myocardial Ischemia; Nerve; Neuroanatomy; Neurons; Neurosciences; Outcome; Pathway interactions; Peripheral; Physiological; Physiology; 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; comorbidity; depressive symptoms; disability; early detection biomarkers; effective therapy; heart function; high risk; hypothalamic-pituitary-adrenal axis; immune function; in utero; men; middle age; mortality risk; neuroregulation; neurovascular; next generation; novel therapeutics; paraventricular nucleus; 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.

总体总结。严重抑郁障碍(MDD)是心脏病的头号原因 在全世界范围内，残疾的风险是女性的两倍。MDD与应激异常有关 反应回路是大脑中性别差异最大的区域之一。这些地区是密集的 性激素和糖皮质激素受体与细胞因子受体偶联。此外，这些领域的活动已经 与皮质醇反应、自主神经功能障碍和免疫反应有关，我们发现 性别不同。这一点很重要，因为自主神经失调与心血管疾病密切相关 疾病。事实上，女性同时发生MDD、自主神经失调和心脏疾病的风险是女性的两倍 疾病，导致妇女死于心脏病的风险是前者的3-5倍，通常是未被认识到的和 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 调节失调将为早期干预提供知识，减轻晚年的残疾，特别是 风险较高的女性。这项评分的科学任务是确定应激免疫途径。 从胎儿发育开始的异常，对大脑性别差异有共同的后果 调节情绪的回路与终生反复发作的MDD和激素调节失调以及免疫反应 压力，以及中年早期的自主神经和神经血管功能障碍。我们的目标是促进跨学科、 基础和临床研究人员之间的翻译合作，以增强我们对 关于MDD的性行为以及中枢和外周自主神经功能，并为翻译这一点提供了基础 将知识转化为性别选择疗法。此外，我们的目标是作为一个跨学科的资源进行培训 并将有关MDD的性别差异和自主神经失调的研究结果传播给科学和 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)一项临床人群神经科学研究，将产前风险生物标记物与大脑回路中的性别差异联系起来 和中年早期MDD对应激反应的生理缺陷；2)使用DIRECT 经皮神经调制刺激迷走神经、耳支(或taVNS)以靶向 与应激免疫功能相关的回路及其在神经解剖学、生理学和临床中的作用 按性别划分的MDD，与项目1相同的受试者；以及3)啮齿动物模型研究，将绘制出 项目1和2中涉及的机械性途径。此外，三个核心将有助于这一项目的成功 得分：1)领导管理核心，负责管理和监督 研究和核心；2)资源核心，提供跨专业共享的技术专长；以及3)职业 增强核心，以补充初级教员和其他人关于我们分数的主题的培训，以及 成为科学、医学和公共社区关于性别差异的教育大使 抑郁症和与普通医学的共病，这是一个具有全球公共卫生影响的话题。