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

项目概要/摘要。 重度抑郁症（MDD）是一种使人衰弱的临床疾病，其与许多有害的 对个人和社会的影响，包括婚姻解体、失业、教育程度低， 46，47，76，77此外，抑郁症对女性的影响不成比例;抑郁症的发病率是 妇女的死亡率是男子的两倍，特别是在她们的生育年龄。 测试模型，阐明女性患抑郁症风险增加的病因，以加速抑郁症的发展 最佳的筛查工具和干预措施的MDD在育龄妇女。快感缺失，或主观的 对愉快刺激的反应性丧失是MDD的已知缺陷，4-7，急性和慢性应激源具有 已被证明会抑制行为和神经对奖励的反应18 -21-一种被称为压力的现象- 诱发性快感缺失18，这与抑郁症的增加有关。24，78女性可能尤其 由于他们的荷尔蒙状况，容易受到压力诱导的快感缺失的影响。孕酮（P4）和雌二醇（E2） 在典型的月经周期中，其水平会发生波动， 和奖励反应。在黄体中期，压力敏感性增加28，奖励敏感性降低35 当P4为高时，周期的相位。然而，这两个系统在卵泡周期后期表现出相反的作用 当E2高时，压力敏感性降低，奖励敏感性增强。 虽然先前的研究表明月经周期阶段和卵巢激素会影响应激反应， 奖励反应性，还没有研究探讨是否与压力有关的奖励减少 敏感性随激素水平或月经周期变化而变化--这可能揭示出一个候选人 部分解释MDD风险的性别差异的机制，可在未来的筛查中作为目标， 对育龄妇女的干预努力。目前的研究利用重复测量设计， 测试新的假设，即压力诱导的快感缺乏的系统是由卵巢调节的， 激素和周期阶段。具体而言，目前的建议旨在：1）研究急性社会事件的影响 压力源对神经奖励反应的影响，2）比较神经奖励反应中与压力相关的减少 在卵泡晚期和黄体中期，3）检查激素浓度和 与压力相关的奖励反应减少，以及4）检查假设的影响是否 通过对卵巢激素敏感性的个体差异（通过生态瞬时测量）调节 评估整个月经周期的情感和躯体症状。获得的培训经验 通过这个奖学金将准备申请人的一个独立的研究事业调查内分泌 以及情绪和焦虑精神病理学风险的神经标志物。

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.