Neuroendocrine Mechanisms of Reproductive Hormone Related Affective Dysfunction

描述（由申请人提供）：情感性障碍，如产后抑郁症（PPD）和其他与生殖相关的情绪障碍，是常见的，对妇女、儿童和社会构成了重大负担。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)提高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)可以预测PPD的高危人群。当前项目的目的是检查在基线和激素戒断沉淀条件下，与健康对照女性（无PPD病史）相比，过去有过PPD发作（复发的“高风险”）的女性在情绪唤醒和奖励处理领域是否表现出差异。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，这些神经回路是情绪唤醒和奖励处理的基础，并由此导致高风险女性的抑郁症状。这项研究的基本原理是，在高风险妇女中采用一个缩小比例的产褥期激素事件模型，可以识别出一组具有生殖相关情感功能障碍的个体，因此，这是将生殖激素引起的大脑功能特定变化与伴随的生殖激素诱发的情感功能障碍分开的最佳机会。此外，识别激素相关情感功能障碍的神经生理生物标志物，为研究各种障碍对情感功能障碍的易感性机制提供了一条清晰的途径。我们计划通过追求以下具体目标来实现该应用程序的目标：1)评估与基线相比，模拟产后生殖激素停药对高危和对照组妇女皮质边缘回路激活的影响；2)与基线相比，研究生殖激素戒断对高风险和对照组女性奖赏回路激活的影响。另一个探索性目标是确定以皮质边缘和奖励回路功能障碍为特征的神经生物标志物，可用于预测PPD的发病。这项拟议中的研究包括通过实验操纵生理健康的妇女体内的生殖激素，以创造出产褥期发生变化的缩小版。这种内分泌操纵范式将被用于研究基线和激素戒断沉淀条件下，预期经历激素相关情感失调的女性（n=15）和对照组（n=15）中情感和奖励处理调节的神经回路。预期的结果是识别神经回路潜在的易感性和调解激素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，并最终防止母亲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.