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

描述(由申请人提供)：众所周知，童年的逆境是成人情感障碍最有效的预测因素之一，特别是在女性中。此外，据报道，在经历早期生活逆境但没有成年疾病的女性亚群中，有一个重要的分离，这表明可能存在在疾病保护或改善方面重要的弹性因素。事实上，有一个关爱和稳定的父母或监护人已经被证明是区分受虐待个人的积极和消极后果的最重要方面之一。我们认为，女性患严重抑郁障碍(MOD)的风险增加以及在特定生殖时间点发生其他情感障碍的倾向的一个重要因素是青春期前逆境对下丘脑-垂体-肾上腺(HPA)活动和卵巢类固醇反应的编程效应。有充分的证据表明，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，女性一生中荷尔蒙波动的时期与情感障碍的风险增加有关：经前(经前焦虑症)、产后(发病/复发双相情感障碍，MOD)和围绝经期(抑郁症状和MDD)。这个SCOR提案中的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，以及这如何与整个生命周期中荷尔蒙的动态变化时期相交，包括怀孕(项目I和III)和衰老(项目II和III)。此外，机械论表观遗传学研究将检验在大脑成熟的敏感窗口期间应激反应的性别差异(项目III)。SCOR Funding将利用Epson和Bale博士在压力和生殖神经内分泌学、心理生理学和神经成像的行为和分子模型方面的各自专业知识，创建宾夕法尼亚大学行为健康中性和性别研究中心。该中心将提供一个拥有重要资源的智力平台，鼓励已有的研究人员及其指导对象将性别和性别视为其研究中的关键因素。

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.