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

描述（由申请人提供）：众所周知，童年逆境是成年情感障碍最有效的预测因素之一，尤其是在女性中。此外，有报道称，一组早期经历生活逆境但未出现成年疾病的妇女存在重要的分离，这表明在疾病保护或改善中可能存在重要的弹性因素。事实上，是否有一个关心和稳定的父母或监护人是区分受虐者的积极和消极结果的最重要的方面之一。我们提出，在特定的生殖时间点，女性患重度抑郁症（MOD）的风险增加以及其他情感障碍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）活性和卵巢类固醇反应性失调的编程效应。有充分的证据表明，从青春期到绝经后期，MOD和几种焦虑症在女性中比男性更常见。此外，女性一生中激素通量的周期与情感障碍的风险增加有关：经前（经前烦躁不安），产后（发作/复发双相情感障碍，MOD）和围绝经期（抑郁症状和重度抑郁症）。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，以及这如何与生命周期中动态激素通量的时期交叉，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在大脑成熟的这个敏感窗口期检查对应激反应的性别差异（项目III）。SCOR的资金将利用博士们各自的专业知识。Epperson和Bale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研究，以创建宾夕法尼亚大学行为健康中的性和性别研究中心。该中心将提供一个具有重要资源的知识平台，以鼓励知名研究人员及其学员将性别和社会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.