Modulation of Stress-Induced Anhedonia over the Menstrual Cycle: A Multi-Method Investigation of Stress and Reward Mechanisms

项目摘要/摘要。 严重抑郁障碍(MDD)是一种衰弱的临床疾病，与许多有害的 对个人和社会的影响，包括婚姻破裂、失业、教育程度低、 并增加自杀风险。此外，MDD对妇女的影响不成比例；MDD的发病率为 妇女比男子翻一番，特别是在育龄期间。2-3因此，必须 为了测试阐明女性MDD风险增加的病因的模型，以加速发展 育龄妇女MDD的最佳筛查工具和干预措施。快感缺乏症，或主观的 对愉悦刺激的反应性丧失是MDD的一种已知缺陷，4-7和急性和慢性应激源 被证明会抑制行为和神经对奖励的反应--一种被称为压力的现象 诱导性快感缺乏18与抑郁症状的增加有关。 由于他们的荷尔蒙特征，他们容易患上应激性快感缺失。孕酮(P4)和雌二醇(E2) 水平在典型的月经周期中波动，与两种压力都有相反的关系。 并奖励反应性。黄体中期的应激敏感性增加28，奖赏敏感性降低35 P4为高时的周期阶段。然而，这两种系统在卵泡周期的晚期表现出相反的作用。 当E2较高时的阶段，使得应力敏感性降低33并且奖励敏感性增强。 虽然先前的研究表明月经周期各阶段和卵巢激素影响应激反应和 奖励响应性分开来看，目前还没有研究表明压力是否会导致奖励减少 敏感度随着激素水平或月经周期阶段的不同而变化--这可能揭示出候选人 部分解释MDD风险性别差异的机制，并可能在未来的筛查和 对育龄妇女的干预努力。目前的研究利用重复测量设计来 测试新的假设，即应激性快感缺乏症的潜在系统是由卵巢调节的 荷尔蒙和周期阶段。具体地说，当前的提案旨在：1)审查急性社会危机的影响 应激源对神经奖赏反应的影响，2)比较与应激相关的神经奖赏反应的减少 在卵泡晚期和黄体中期，3)检查激素浓度和 与压力相关的奖赏反应的减少，以及4)检查假设的影响是否 通过生态瞬间测量的卵巢激素敏感度的个体差异 评估整个月经周期的情感和躯体症状。获得的培训经验 通过这项奖学金，申请者将为研究内分泌的独立研究生涯做好准备。 和神经标记物的情绪和焦虑的精神病理学。

Project Summary/Abstract. Major Depressive Disorder (MDD) is a debilitating clinical disorder that is associated with a host of deleterious impacts on individuals and society, including marital dissolution, unemployment, low educational attainment, and increased risk for suicide.46,47,76,77 Moreover, MDD disproportionately affects women; incidence of MDD is doubled in women as compared to men, specifically during their childbearing years.2-3 As such, it is imperative to test models elucidating the etiopathogenesis of women’s enhanced risk for MDD to expedite development of optimal screening tools and interventions for MDD in women of reproductive age. Anhedonia, or the subjective loss of reactivity to pleasurable stimuli, is a known deficit of MDD,4-7 and acute and chronic stressors have been shown to dampen behavioral and neural reactivity to rewards18-21—a phenomenon referred to as stress- induced anhedonia18 which has been linked to increased depressive symptoms.24,78 Women may be especially susceptible to stress-induced anhedonia due to their hormonal profiles. Progesterone (P4) and estradiol (E2) levels fluctuate over the course of the typical menstrual cycle and have opposing associations with both stress and reward reactivity. Stress sensitivity is increased28 and reward sensitivity is decreased35 in the mid-luteal phase of the cycle when P4 is high. However, both systems exhibit opposite effects in the late-follicular cycle phase when E2 is high, such that stress sensitivity is decreased33 and reward sensitivity is enhanced.35 Thus, while previous research suggests menstrual cycle phases and ovarian hormones impact stress reactivity and reward responsivity separately, no study has yet examined whether stress-related decreases in reward sensitivity vary as a function of hormone levels or menstrual cycle phase—which could reveal a candidate mechanism to partially explain sex differences in MDD risk and which could be targeted in future screening and intervention efforts for women of reproductive age. The current study leverages a repeated-measures design to test the novel hypothesis that systems underlying stress-induced anhedonia are modulated by ovarian hormones and cycle phases. Specifically, the current proposal aims to: 1) examine the effect of an acute social stressor on the neural reward response, 2) compare stress-related reductions in the neural reward response both in the late follicular and mid-luteal phases, 3) examine associations between hormone concentrations and stress-related reductions in the reward response, and 4) examine whether the hypothesized effects are moderated by individual differences in sensitivity to ovarian hormones as measured via ecological momentary assessment of affective and somatic symptoms across the menstrual cycle. The training experiences gained through this fellowship will prepare the applicant for an independent research career investigating endocrine and neural markers of risk for mood and anxiety psychopathology.