Determining the Neuroendocrine Contribution to Behavior & Cognition Across the Fe

描述（由申请人提供）：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以调节女性行为、情绪和认知的机制。凭借我之前的两次指导K奖，我能够开发一个独特的临床研究项目，该项目严重依赖于从分子和基础神经科学中获得的知识，以告知我们对经前焦虑症（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调查。为此，我采用了一系列研究范式和技术，目的是将临床前研究结果转化为人类实验室。我在很大程度上依赖于使用质子磁共振波谱（1H-MRS）来探索女性在月经周期中性激素、神经类固醇和γ -氨基丁酸（GABA）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理学挑战范式来解决GABA浓度的变化，以及个体因素（如诊断、神经类固醇代谢和/或遗传多态性）是否对观察到的反应变化负责。这就是我在k24资助期间所要追求的模式。虽然1H-MRS作为一种工具对于探索孕酮（通过异孕酮）和GABA之间的相互作用是很好的，但它不是与雌激素和血清素相互作用相关的问题的合适技术，而雌激素和血清素相互作用可能对衰老女性的情绪和认知至关重要。我们之前在绝经期妇女中使用色氨酸消耗范式的工作（Epperson等人，2007b； Amin等人，2006b）使我对功能磁共振成像（fMRI）的实用性越来越感兴趣。我的实验室最近得到了国家老龄化研究所的资助，用于研究雌激素和血清素对更年期妇女认知和大脑活动的个体和相互作用。这项资助将为我提供重要的机会来磨练我的功能磁共振成像技术，并指导新的学员。这只是我希望在K24资助期间进行的两项调查。我在本应用程序中描述了正在进行的工作的其他几个领域，以及它们如何不仅为继续研究提供途径，而且为未来以患者为导向的研究人员的发展提供肥沃的土壤。正是我越来越关注指导初级调查员，促使我申请K24，而不是提交K02的竞争性续期。由于我的KO2即将结束（2009年12月31日），及时获得这笔K24资助将确保我能够专注于研究生涯发展计划和项目，并致力于培养初级研究人员的职业生涯。没有K24的资助，我将不得不承担额外的，非研究相关的活动，我在宾夕法尼亚大学的新终身副教授职位，从2009年9月1日开始。在过去的9年里，我的转化研究和教育努力确保了我在推进我们对神经内分泌对女性情绪和行为的影响的理解方面具有独特的优势。在宾夕法尼亚大学精神病学和妇产科的全力支持下，我身处一个知识丰富、支持我的学术社区，这肯定会促进我和我所指导的个人的职业发展。

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.