Interaction of Estrogen and Serotonin in Modulating Brain Activation in Menopause

描述（由申请人提供）：在更年期过渡期间，许多妇女报告她们的情绪恶化和主观记忆障碍。虽然卵巢雌激素分泌减少显然与最常见的更年期症状有关，即潮热和泌尿生殖系统萎缩，但雌激素影响更年期行为变化的机制尚不清楚，尽管引起了极大的兴趣。越来越多的临床前文献表明，雌激素可能与神经递质（如血清素）相互作用，而血清素的功能被认为会随着年龄的增长而下降。然而，关于雌激素和血清素如何相互作用来调节情绪和认知的人类研究缺乏。我们的研究小组最近在填补这一空白方面取得了进展，证明雌激素治疗（ET）可以调节色氨酸（TRP）（血清素的前体）消耗的绝经妇女的言语记忆表现（Amin ET al. 2006b; Epperson ET al. 2006）。与假耗损相比，ET前色氨酸耗损（TRP-D）使言语回忆恶化，而在ET治疗10-12周后没有发现这种影响。这些初步研究结果表明，ET可能保护个体免受由于血清素选择性减少而导致的言语回忆缺陷。本研究旨在确定雌激素和血清素对绝经妇女认知和情感加工以及大脑激活的个体和相互作用，方法是在ET或安慰剂治疗前和期间对TRP-D进行功能磁共振成像（fMRI）。此外，这项研究的资金将使我们能够招募处于更年期不同阶段的妇女，以确定更年期持续时间和ET对研究结果的相互作用。这项应用既新颖又及时，因为这项研究的结果可能为正在进行的关于绝经妇女使用ET的风险和益处的讨论提供关键信息。公共卫生相关性：本研究的主要目的是进一步了解雌激素和神经递质5 -羟色胺对48 - 60岁绝经妇女认知和大脑激活某些方面的个体和相互作用。女性将在服用雌激素或安慰剂6周前后分别接受认知测试和功能磁共振成像（fMRI）检查。我们将招募自最后一次月经后10年内的女性，这样我们就可以收集有关绝经后时间对我们感兴趣的结果的潜在影响的信息。我们期望这项研究的发现将有助于科学家和临床医生完善绝经期妇女雌激素治疗的使用。此外，如果5 -羟色胺的作用对维持健康认知至关重要，这些数据有助于未来的药物开发，以保持健康认知和/或治疗5 -羟色胺是重要因素的痴呆症。这项应用既新颖又及时，因为这项研究的结果可能为正在进行的关于绝经妇女使用ET的风险和益处的讨论提供关键信息。

DESCRIPTION (provided by applicant): During the menopause transition, many women report a worsening of their mood and a subjective impairment in memory. While dwindling ovarian production of estrogen is clearly related to the most common menopausal symptoms, namely hot flashes and genitourinary atrophy, the mechanism by which estrogen may influence behavioral changes during menopause is unclear, although of great interest. A growing preclinical literature indicates that estrogen interactions with neurotransmitters such as serotonin are likely, and serotonin function is believed to decline with age. However, there is a dearth of research in humans regarding how estrogen and serotonin may interact to modulate mood and cognition. Our group has recently made strides to fill this void by demonstrating that estrogen treatment (ET) modulates verbal memory performance in menopausal women undergoing depletion of tryptophan (TRP), the precursor of serotonin (Amin et al. 2006b; Epperson et al. 2006). Compared to sham depletion, tryptophan depletion (TRP-D) prior to ET worsened verbal recall, while no such effect was seen after 10-12 weeks of ET. These preliminary findings suggest that ET may protect individuals from deficits in verbal recall due to selective reduction in serotonin. The present application seeks to determine the individual and interactive effects of estrogen and serotonin on cognitive and affective processing and brain activation through the addition of functional magnetic resonance imaging (fMRI) to the paradigm of TRP-D before and during ET or placebo treatment in menopausal women. In addition, funding for this study will enable us to recruit women at varying stages of the menopause to determine the interactive effects of duration of menopause and ET on outcomes of interest. This application is both novel and timely as results from this study are likely to provide information critical to the on-going discussion regarding the risks and benefits of ET use in menopausal women. PUBLIC HEALTH RELEVANCE: The overarching purpose of this study is to further our understanding of the individual and interactive effects of the hormone estrogen and the neurotransmitter serotonin on certain aspects of cognition and brain activation in menopausal women ages 48 to 60 years. Women will undergo cognitive testing and fMRI sessions both before and after 6 weeks of either estrogen or placebo administration. We will recruit women who are across the first 10 years since their last menstrual period so that we can gather information regarding the potential impact of time since menopause on our outcomes of interest. We anticipate that findings from this study will help scientist and clinicians to refine their use of estrogen therapy in menopausal women. In addition, should the role of serotonin be of utmost importance for maintenance of healthy cognition, these data aid future drug development to preserve health cognition and/or to treat dementias in which serotonin is an important factor. This application is both novel and timely as results from this study are likely to provide information critical to the on-going discussion regarding the risks and benefits of ET use in menopausal women.