Effects of Estradiol on Neural Reward System and Depression in the Perimenopause

 描述(由申请人提供)：尽管经过几十年的研究，情感障碍仍然很普遍，并与显著的发病率和死亡率有关。解开情感障碍的病理生理学一直是独一无二的挑战，因为抑郁综合征是异质性的，有不同的病因。我们建议通过研究围绝经期重度抑郁障碍(MDD)来解决这个问题，MDD是一种更同质的抑郁症亚型，具有既定的触发因素(即雌二醇戒断)。因此，关注围绝经期MDD将增加确定有意义的神经生物学标记物的可能性。了解MDD神经生物学介质的最有力工具之一是脑成像。先前的研究表明，额纹状体奖赏系统受雌二醇的调节，并与MDD有关。然而，围绝经期MDD的神经病理生理学从未被研究过。我们将使用功能磁共振成像(FMRI)在基线和雌激素治疗后1)测量围绝经期MDD患者额纹状体对奖励的反应，并测试雌激素对围绝经期妇女神经激活的影响；2)量化患有和不患有MDD的围绝经期妇女在基线和雌激素治疗后对奖励的行为反应；以及3)测量围绝经期MDD患者在基线和雌激素治疗后额纹状体对奖励的反应的心理相关性。这项研究设计将使我们能够探索围绝经期MDD的神经病理生理，雌二醇对神经奖赏系统的影响，以及神经奖赏系统功能障碍在多大程度上预测雌二醇的抗抑郁作用。这项研究将支持我的主要职业目标，成为一名独立资助的临床科学家，拥有必要的专业知识，对生殖情绪障碍的神经内分泌学进行最先进的机械研究。我的长期研究目标是1)增进我们对卵巢激素对大脑的影响的了解，以及这些影响如何导致生殖相关情绪障碍的触发和易感性；2)确定抑郁症风险的神经和内分泌标记物，从而提高我们预防女性情感性疾病的能力。这项建议中概述的培训和研究计划旨在用一个新颖的、与临床相关的研究计划来补充我以前的经验，该计划是在行为内分泌学和神经科学的交叉点上进行的。实现我的职业目标的具体目标是：1)获得神经科学和功能磁共振成像数据采集和分析方面的重点培训；2)发展神经内分泌学和激素管理方面的专业知识；3)获得在围绝经期妇女进行临床研究的经验；4)获得专业知识和试点数据，以支持主要由NIH R01拨款资助的跨学科研究计划。这份职业发展申请代表着我学术和研究培训的关键下一步。虽然成功培训的最终衡量标准将是在获奖期结束前获得独立资金，但用于确定我的培训和研究目标进展情况的基准包括参与者登记、数据分析渠道的创建、手稿准备、会议演示和拨款撰写。拟议的培训和研究活动将为我领导一个独立资助的研究项目做好准备，该项目专注于生殖情绪障碍的神经内分泌病理生理学。除了支持我的职业发展目标之外，这项拟议的研究还代表着表征围绝经期生殖激素相关情感障碍的神经机制的第一步。这项研究的影响预计将是对围绝经期MDD神经内分泌病理生理学的更好理解。这项工作的未来方向将包括识别预测生殖性情绪障碍易感性和对激素干预反应的神经生物标记物，以及探索可能有助于解释女性抑郁症优势的神经内分泌病因路径。

 DESCRIPTION (provided by applicant): Despite decades of research, affective disorders are prevalent and associated with significant morbidity and mortality. Unraveling the pathophysiology of affective disorders has been uniquely challenging because depressive syndromes are heterogeneous and have diverse etiologies. We propose to address this problem by studying perimenopausal major depressive disorder (MDD), a more homogeneous depression subtype with an established trigger (i.e., estradiol withdrawal). Focusing on perimenopausal MDD will therefore increase the likelihood of identifying meaningful neurobiological markers. One of the most powerful tools for understanding the neurobiological mediators of MDD is brain imaging. Prior research suggests that the frontostriatal reward system is regulated by estradiol and implicated in MDD. However, the neural pathophysiology of perimenopausal MDD has never been studied. We will use functional magnetic resonance imaging (fMRI) at baseline and following estradiol treatment to 1) measure the frontostriatal response to reward in perimenopausal MDD and test the effects of estradiol on neural activation in perimenopausal women; 2) quantify behavioral responses to reward at baseline and following estradiol administration in perimenopausal women with and without MDD; and 3) measure the psychological correlates of the frontostriatal response to reward in women with perimenopausal MDD at baseline and following estradiol administration. This study design will allow us to explore the neural pathophysiology of perimenopausal MDD, the effects of estradiol on the neural reward system, and the degree to which neural reward system dysfunction predicts the antidepressant effects of estradiol. This research will support my primary career goal to become an independently funded clinical scientist with the expertise necessary to conduct state-of-the-art mechanistic research on the neuroendocrinology of reproductive mood disorders. My long-term research objectives are to 1) advance our understanding of the effects of ovarian hormones on the brain and how these effects contribute to the triggering of and susceptibility to reproductive-related mood disorders; and 2) to identify neural and endocrine markers of depression risk, thereby improving our ability to prevent affective illness in women. The training and research plan outlined in this proposal are designed to supplement my previous experience with a novel, clinically relevant program of research at the intersection of behavioral endocrinology and neuroscience. The specific objectives to meet my career goal are to 1) obtain focused training in neuroscience and fMRI data acquisition and analysis; 2) develop expertise in neuroendocrinology and hormone administration; 3) gain experience with conducting clinical research in perimenopausal women; and 4) obtain expertise and pilot data to support an interdisciplinary research program principally funded by NIH R01 grants. This career development application represents the critical next step in my academic and research training. Although the ultimate measure of successful training will be the attainment of independent funding by the end of the award period, benchmarks that will be used to determine progress toward my training and research goals include participant enrollment, creation of a data analysis pipeline, manuscript preparation, conference presentations, and grant writing. The proposed training and research activities will prepare me to lead an independently funded research program focused on the neuroendocrine pathophysiology of reproductive mood disorders. In addition to supporting my career development objectives, the proposed research represents the first step in characterizing neural mechanisms of reproductive hormone-related affective dysfunction during the perimenopausal period. The impact of this research is expected to be an improved understanding of the neuroendocrine pathophysiology of perimenopausal MDD. Future directions for this work will include identifying neural biomarkers that predict reproductiv mood disorder susceptibility and response to hormonal interventions, and exploring neuroendocrine etiological pathways that may help to explain the preponderance of depression in women.