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

描述（由申请人提供）：众所周知，童年逆境是成人情感障碍的最有效预测因素之一，特别是在女性中。此外，一个重要的解离已被报道为一个亚组的妇女经历早期生活的逆境，但不存在与成人疾病，这表明可能有重要的疾病保护或改善的弹性因素。事实上，一个关心和稳定的父母或监护人的可用性已被证明是区分虐待个人积极和消极结果的最重要方面之一。我们认为，一个重要的贡献者增加的风险，为重度抑郁症（MOD）的妇女，并倾向于其他情感障碍在特定的生殖时间点，是编程影响青春期前逆境失调的下丘脑垂体肾上腺（HPA）的活动和卵巢类固醇反应性在整个生命周期。据文献记载，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，女性一生中的激素波动期与情感障碍的风险增加有关：月经前期（经前焦虑障碍）、产后（双相情感障碍发作/复发，MOD）和围绝经期（抑郁症状和MDD）。SCOR建议中的科学项目的目标是确定青春期前逆境的经历如何重新编程大脑以应对压力失调，以及这如何与整个生命周期中的动态激素流量时期交叉，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检查在大脑成熟的敏感窗口期间对压力反应的性别差异（项目III）。SCOR的资金将利用Epperson博士和Bale博士在压力和生殖神经内分泌学，心理生理学和神经影像学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的性和性别研究中心。该中心将提供一个知识平台，提供重要的资源，鼓励已建立的调查人员及其学员将性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.