Neuroendocrine Mechanisms of Reproductive Hormone Related Affective Dysfunction

描述（由申请人提供）：情感障碍，如产后抑郁症（PPD）和其他生殖相关的情绪障碍，是常见的，并构成了妇女，儿童和社会的重大负担。然而，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症的触发和易感性的生物学机制的理解; 2）允许预测那些有患PPD风险的人。本项目的目的是检查那些过去的PPD发作（复发的“高风险”）是否显示出相对于健康对照女性（无PPD病史）在基线和激素戒断沉淀条件下的情绪唤醒和奖励处理域的差异。我们的中心假设是，生殖激素的变化与神经回路的失调有关，这些神经回路是高风险女性情绪唤起和奖励处理以及随之而来的抑郁症状的基础。拟议的研究的理由是，采用一个规模缩小的模型，产后激素事件的高危妇女允许识别一组个体同质的生殖相关的情感功能障碍，因此，最好的机会解开特定的变化，大脑功能由于生殖激素从那些伴随生殖激素沉淀的情感功能障碍。此外，确定一个神经生理学生物标志物的抑郁症相关的情感功能障碍提供了一个明确的途径，检查机制的易感性情感功能障碍的障碍。我们计划通过追求以下具体目标来实现本申请的目标：1）评估模拟产后生殖激素戒断与基线相比对高危和对照妇女皮质边缘回路激活的影响; 2）检查生殖激素戒断与基线相比对高危和对照妇女奖励回路激活的影响。另一个探索性目的是确定一种神经生物标志物，其特征在于皮质边缘和奖赏回路功能障碍，可用于预测PPD的发作。这项拟议中的研究涉及实验性地操纵正常女性的生殖激素，以创建产褥期发生的变化的缩小版本。这种内分泌操作范式将被用来检查神经回路的基础上的影响和奖励处理的调节下的基线和激素戒断沉淀的条件下，妇女谁预计将经历与情感失调（n=15）和控制（n=15）。预期的结果是识别潜在的神经回路的易感性和调解的情绪相关的情感功能障碍。了解这些神经生物学机制将随后提高我们识别PPD风险的能力，这可能会加强预防工作，并最终防止母体抑郁症对后代的有害影响。

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.