Neuroendocrine Mechanisms of Reproductive Hormone Related Affective Dysfunction

描述(申请人提供)：情感障碍，如产后抑郁(PPD)和其他与生殖有关的情绪障碍，很常见，对妇女、儿童和社会构成重大负担。然而，人们对女性抑郁症的神经生物学机制知之甚少。这项研究的长期目标是1)促进我们对女性抑郁障碍的触发和易感性背后的生物学机制的理解；2)允许预测那些有PPD风险的人。本项目的目的是检验在基线和激素撤除条件下，与健康对照组女性(没有PPD病史)相比，既往有PPD病史的患者(复发风险较高)是否在情绪唤醒和奖励处理领域表现出差异。我们的中心假设是，生殖激素的变化与高危女性情绪唤醒和奖励处理的神经回路失调以及随之而来的抑郁症状有关。这项拟议研究的基本原理是，在高危女性中使用产后荷尔蒙事件的缩小模型，可以识别一组与生殖相关的情感障碍同质的个体，因此，这是将生殖激素引起的大脑功能特定变化与伴随生殖激素引发的情感障碍的个体区分开来的最佳机会。此外，确定激素相关情感障碍的神经生理学生物标志物为研究跨障碍情感障碍的易感性机制提供了一条明确的途径。我们计划通过追求以下具体目标来实现这项应用的目标：1)与基线相比，评估模拟产后生殖激素停用对高危妇女和对照妇女皮质边缘回路激活的影响；以及2)与基线相比，检验生殖激素停用对高危妇女和对照妇女奖赏回路激活的影响。另一个探索性目标是确定一种神经生物标记物，其特征是皮质边缘和奖赏回路功能障碍，可以用来预测PPD的发病。这项拟议的研究涉及在实验中操纵情绪良好的女性的生殖荷尔蒙，以创建产褥期发生的变化的缩小版本。这一内分泌操作范例将被用来研究在基线和激素撤除沉淀条件下，可能经历与激素相关的情感失调(n=15)和对照(n=15)的女性的情绪和奖励处理调节的神经回路。预期的结果是确定与激素相关的情感功能障碍的易感性和介导性的神经回路。了解这些神经生物学机制将提高我们识别PPD高危人群的能力，这可能会加强预防努力，并最终防止母亲抑郁对后代的有害影响。

DESCRIPTION (provided by applicant): Affective disorders, such as postpartum depression (PPD) and other reproductive-related mood disorders, are common and constitute a significant burden for women, children, and society. However, little is known about the neurobiological mechanisms underlying depressive disorders in women. The long-term goal of this research is to 1) advance our understanding of the biological mechanisms underlying both the triggering of and susceptibility to depressive disorders in women; and 2) permit the prediction of those at risk for PPD. The objective of the current project is to examine whether those with a past episode of PPD (at "high risk" for recurrence) show differences in emotional arousal and reward processing domains relative to healthy control women (without a history of PPD) under baseline and hormone withdrawal-precipitated conditions. Our central hypothesis is that reproductive hormone changes are associated with dysregulation of the neural circuits underlying emotional arousal and reward processing and consequent depressive symptoms in high-risk women. The rationale for the proposed study is that employing a scaled down model of puerperal hormonal events in high-risk women permits the identification of a group of individuals homogeneous for reproductive related affective dysfunction and, hence, the best opportunity for disentangling the specific changes in brain function due to reproductive hormones from those accompanying reproductive hormone-precipitated affective dysfunction. Moreover, identifying a neurophysiologic biomarker for hormone-related affective dysfunction provides a clear pathway for examining mechanisms of susceptibility to affective dysfunction across disorders. We plan to accomplish the objectives of this application by pursuing the following specific aims: 1) to assess the effects of simulated postpartum reproductive hormone withdrawal, compared to baseline, on corticolimbic circuit activation in high-risk and control women; and 2) to examine the effects of reproductive hormone withdrawal, compared to baseline, on reward circuit activation in high-risk and control women. An additional exploratory aim is to identify a neural biomarker, characterized by corticolimbic and reward circuit dysfunction, that can be used to predict the onset of PPD. The proposed study involves experimentally manipulating reproductive hormones in euthymic women to create a scaled down version of the changes that occur at the puerperium. This endocrine manipulation paradigm will be used to examine the neurocircuitry underlying the regulation of affect and reward processing under baseline and hormone withdrawal-precipitated conditions among women who are expected to experience hormone-related affective dysregulation (n=15) and controls (n=15). The expected outcome is the identification of neural circuits underlying both the susceptibility to and mediation of hormone-related affective dysfunction. Understanding these neurobiological mechanisms will subsequently improve our ability to identify those at risk for PPD, which may strengthen prevention efforts and ultimately prevent the deleterious effects of maternal depression on offspring.