Determining the Neuroendocrine Contribution to Behavior & Cognition Across the Fe

描述(申请人提供)：指导我的研究努力、合作和培训机会的首要目标是确定性激素和神经类固醇与神经递质相互作用的机制，以调节女性的行为、情绪和认知。在我之前的两次导师K奖中，我能够开发出一个独特的临床研究计划，该计划在很大程度上依赖于从分子和基础神经科学获得的知识，为我们对经前焦虑症(PMDD)、产后抑郁症(PPD)以及围绝经期情绪和认知变化的发病机制的研究提供信息。为此，我采用了一系列研究范式和技术，目的是将临床前的发现转化为人体实验室。我在很大程度上依赖于使用质子磁共振波谱(1H-MRS)来探索性激素、神经类固醇和伽马氨基丁酸(GABA)在整个月经周期中功能之间的关系。在过去的一年里，我们已经转向使用激素和药物挑战范式来解决GABA浓度的变化，以及是否个别因素，如诊断、神经类固醇代谢和/或遗传多态，对观察到的反应变化负责。这是我建议在K24-Funding期间追求的模式。虽然1H-MRS是一种很好的工具，可以探索孕酮(通过别孕酮)和GABA之间的相互作用，但它不是与雌激素和5-羟色胺相互作用相关的问题的合适技术，因为雌激素和5-羟色胺相互作用可能对老年女性的情绪和认知至关重要。我们之前在更年期妇女中使用色氨酸耗竭范式的工作(Epson等人，2007b；Amin等人，2006b)使我对功能磁共振成像(FMRI)的用途越来越感兴趣。我的实验室最近得到了国家老龄化研究所的资助，研究雌激素和5-羟色胺对更年期女性认知和大脑激活的个体和交互影响。这笔赠款将为我提供重要的机会来磨练我的功能磁共振技能，并指导新的实习生。这些只是我希望在K24融资期间进行的两个方面的调查。我在这份申请中描述了正在进行的其他几个领域的工作，以及它们如何不仅为继续研究提供途径，而且为未来研究人员在以患者为导向的研究中的发展提供肥沃的土壤。我越来越注重指导初级调查人员，这促使我申请了K24，而不是为我的K02提交竞争续签。随着我的KO2即将结束(12/31/09)，及时资助这笔K24拨款将确保我能够专注于这里概述的研究职业发展计划和项目，并致力于促进初级研究人员的职业生涯。如果没有K24的资助，我将不得不在宾夕法尼亚大学新的终身副教授职位上承担额外的、与研究无关的活动，该职位将于2009年9月1日开始。在过去的9年里，我的翻译研究和教育努力确保了我能够以独特的姿态推动我们对神经内分泌对女性情绪和行为的影响的理解。在宾夕法尼亚大学精神病学系和妇产科的全力支持下，我身处一个智力丰富、相互支持的学术社区，这肯定会促进我和我所指导的个人的职业发展。 公共卫生相关性：这项研究的首要重要性是它关注与生殖内分泌相关的情绪障碍的神经内分泌基础，这种情绪障碍被称为经前焦虑症(PMDD)。以前的大多数研究都局限于中枢异常的外周指标，在加深我们对这种疾病的发病机制的了解方面并不成功。此外，我们有机会了解已知的有效治疗方法如何通过神经类固醇生成与内分泌系统相互作用，以调节大脑神经递质系统。此外，重要的是要考虑到，与生殖过程中发生的荷尔蒙变化相关的情绪障碍是司空见惯的。虽然PMDD只发生在3%-5%的妇女中，但更大比例的妇女经历的症状相对较轻(但仍具有临床意义)，而患有持续精神障碍的妇女经常在月经前经历疾病的恶化。通过对这一特定人群的进一步研究，我们将继续开发补充理论和方法，以研究患有经前恶化的持续精神情绪障碍的女性。到目前为止，我们研究这一妇女群体的能力一直受到限制，因为几个月来持有药物明显存在困难。然而，在PMDD中，前瞻性筛查妇女两个月是诊断评估的一部分。

DESCRIPTION (provided by applicant): The overarching objective that has guided my research endeavors, collaborations and training opportunities has been to determine the mechanism by which sex hormones and neurosteroids interact with neurotransmitters to modulate behavior, mood, and cognition in women. With my previous two mentored K awards, I was able to develop a unique clinical research program that relied heavily on knowledge gained from molecular and basic neuroscience to inform our investigations of the pathogenesis of premenstrual dysphoric disorder (PMDD), postnatal depression (PPD), and perimenopausal mood and cognitive changes. To this end, I have employed an array of research paradigms and technologies with the goal of translating preclinical findings to the human laboratory. I have relied heavily on the use of proton magnetic resonance spectroscopy (1H-MRS) to explore the relationship between sex hormones, neurosteroids and gamma-aminobutyric acid (GABA) function in women across the menstrual cycle. In the past year, we have moved towards the use of hormonal and pharmacologic challenge paradigms to address changes in GABA concentrations and whether individual factors such as diagnosis, neurosteroid metabolism, and/or genetic polymorphisms, are responsible for observed variations in response. It is this paradigm that I propose to pursue during K24-funding. While 1H-MRS as a tool is excellent for exploring the interaction between progesterone (via allopregnanolone) and GABA, it is not the appropriate technology for questions related to estrogen and serotonin interactions, which may be critical to mood and cognition in aging women. Our previous work using the tryptophan depletion paradigm in menopausal women (Epperson et al., 2007b; Amin et al., 2006b) led me to become increasingly interested in the utility of functional magnetic resonance imaging (fMRI). My lab recently received funding from the National Institute on Aging to study the individual and interactive effects of estrogen and serotonin on cognition and brain activation in menopausal women. This grant will provide important opportunities for me to hone my skills with fMRI and to mentor new trainees. These are just two lines of investigations that I wish to pursue during K24 funding. I have described in this application several other areas of on-going work and how they will not only provide avenues for continued research, but fertile ground for the development of future investigators in patient-oriented research. It is my increasing focus on mentoring junior investigators that motivates me to apply for a K24 instead of submitting a competitive renewal for my K02. As my KO2 is drawing to an end (12/31/09), timely funding of this K24 grant will insure that I can focus on both the research career development plans and project outlined herein, as well as commit substantial effort to fostering the careers of junior researchers. Without K24 funding, I will have to assume additional, non-research related activities in my new Tenured Associate Professor position at the University of Pennsylvania, which is beginning September 1, 2009. My translational research and educational endeavors over the past 9 years have insured that I am uniquely poised to advance our understanding of neuroendocrine contribution to mood and behavior in women. With the full support of both the Departments of Psychiatry and Obstetrics/Gynecology at Penn, I am situated in an intellectually rich and supportive academic community that is certain to further my career development as well as that of individuals I mentor. PUBLIC HEALTH RELEVANCE: The primary importance of this study is its focus on the neuroendocrine basis for a reproductive endocrine related mood disorder known as Premenstrual Dysphoric Disorder (PMDD). Most previous studies have been limited to peripheral indicators of central abnormalities, and have been less than successful at furthering our knowledge of the pathogenesis of this disorder. In addition, we have the opportunity to understand how a known effective treatment interacts with the endocrine system via neurosteroidogenesis to modulate brain neurotransmitter systems. Furthermore, it is important to consider that mood disorders associated with the hormonal changes occurring in the context of reproductive processes are commonplace. While PMDD occurs in only 3-5% of women, a greater percentage of women experience relatively less severe (but still clinically meaningful) symptoms, while women with ongoing psychiatric disorders frequently experience exacerbation of their illness in the premenstruum. By further studying this specific population we will continue to develop supplementary rationales and methods for studying women with premenstrual exacerbations of ongoing psychiatric mood disorders. Thus far, we have been limited in our ability to study this population of women due to obvious difficulties of with holding medications for several months. Whereas, in PMDD it is part of the diagnostic assessment to prospectively screen women for two months.