Prepubertal Stress, Windows of Risk & Sex Bias for Affective Disturbance

青春期前的压力，风险之窗

• 批准号: 8522236
• 负责人: C. Neill NEILL EPPERSON
• 金额: $ 115.2万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-06 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8522236
• 关键词: Adrenal Glands; Adult; Affective; Aging; Anxiety Disorders; Autoimmune Diseases; Behavioral Model; Bipolar Disorder; Brain; Cardiovascular Diseases; Caring; Childhood; Disease; Dissociation; Epigenetic Process; Female; Funding; Gender; Goals; Gonadal Steroid Hormones; Hormonal; Hypothalamic structure; Individual; Life; Longevity; Maintenance; Major Depressive Disorder; Medical; Migraine; Molecular Models; Mood Disorders; Names; Obesity; Onset of illness; Outcome; Ovarian; Parents; Perimenopause; Pituitary Gland; Postpartum Period; Pregnancy; Psychophysiology; Puberty; Relapse; Reporting; Research; Research Personnel; Resources; Risk; Sex Bias; Sex Characteristics; Steroids; Stress; Subgroup; Substance Use Disorder; System; Time; Woman; behavioral health; biological adaptation to stress; depressive symptoms; early experience; experience; male; molecular modeling; neuroimaging; neuropsychiatry; premenstrual dysphoric disorder; prepuberty; programs; reproductive; reproductive neuroendocrinology; response; sex

DESCRIPTION (provided by applicant): It is well established that childhood adversity is one of the most potent predictors of adult affective disorders, particularly among women. Further, an important dissociation has been reported for a subgroup of women who experience early life adversity but do not present with adult disease, suggesting that there may be resiliency factors important in disease protection or amelioration. In fact, the availability of a caring and stable parent or guardian has been shown to be one of the most important aspects that distinguish between positive and negative outcomes in abused individuals. We propose that one vital contributor to the increased risk for major depressive disorder (MOD) in women, and propensity for other affective disturbances at specific reproductive time points, is the programming effect of prepubertal adversity on dysregulation of hypothalamic pituitary adrenal (HPA) activity and ovarian steroid responsiveness across the lifespan. It is well documented that from puberty to the late perimenopause, MOD and several anxiety disorders are more common in females than males. Moreover, periods of hormonal flux across the female lifespan are associated with increased risk for affective disturbance: the premenstrum (premenstrual dysphoric disorder), the postpartum (onset/relapse bipolar disorder, MOD), and the perimenopause (depression symptoms and MDD. The goal of the scientific Projects in this SCOR proposal is to determine how the experience of prepubertal adversity reprograms the brain toward stress dysregulation, and how this intersects with periods of dynamic hormonal flux across the life span, including pregnancy (Projects I & III) and aging (Projects II & III). In addition, mechanistic epigenetic studies will examine sex differences in response to stress during this sensitive window of brain maturation (Project III). SCOR funding would harness the respective expertise of Drs. Epperson and Bale in behavioral and molecular models of stress and reproductive neuroendocrinology, psychophysiology, and neuroimaging, to create the Penn Center for the Study of Sex and Gender in Behavioral Health. The Center would provide an intellectual platform with important resources to encourage established investigators, and their mentees, to consider sex and gender as crucial factors in their research.

描述（由申请人提供）：众所周知，童年逆境是成人情感障碍最有效的预测因素之一，尤其是在女性中。此外，据报道，经历早年逆境但未患成年疾病的女性亚群存在重要的分离，这表明可能存在对疾病保护或改善很重要的弹性因素。事实上，事实证明，是否有一个有爱心且稳定的父母或监护人是区分受虐待者的积极和消极结果的最重要方面之一。我们认为，女性患重度抑郁症（MOD）的风险增加以及在特定生育时间点出现其他情感障碍的倾向的一个重要因素是编程效应 青春期前的逆境对整个生命周期下丘脑垂体肾上腺（HPA）活性和卵巢类固醇反应性失调的影响。有充分证据表明，从青春期到围绝经期晚期，MOD 和几种焦虑症在女性中比男性更常见。此外，女性一生中荷尔蒙流动的时期与情感障碍的风险增加相关：经前（经前烦躁障碍）、产后（双相情感障碍发作/复发，MOD）和围绝经期（抑郁症状和 MDD）。本 SCOR 提案中科学项目的目标是确定青春期前逆境的经历如何使大脑重新编程以适应压力 失调，以及它如何与整个生命周期的动态荷尔蒙流动时期相交叉，包括怀孕（项目 I 和 III）和衰老（项目 II 和 III）。此外，机械表观遗传学研究将检查在大脑成熟的这个敏感窗口期间对压力反应的性别差异（项目 III）。 SCOR 资金将利用 Drs 各自的专业知识。 Epperson 和 Bale 在压力和分子行为模型中的研究 生殖神经内分泌学、心理生理学和神经影像学，创建宾夕法尼亚大学行为健康中的性和性别研究中心。该中心将提供一个拥有重要资源的知识平台，鼓励现有的研究人员及其受训者将性和社会性别视为其研究中的关键因素。