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，许多妇女报告情绪恶化，记忆力主观受损。虽然减少卵巢雌激素的产生显然与最常见的更年期症状有关，即潮热和泌尿生殖道萎缩，但雌激素可能影响更年期行为变化的机制尚不清楚，尽管非常感兴趣。越来越多的临床前文献表明，雌激素与神经递质如血清素的相互作用是可能的，血清素的功能被认为是随着年龄的增长而下降。然而，关于雌激素和5-羟色胺如何相互作用以调节情绪和认知的人类研究很少。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）可调节色氨酸（TRP）（5-羟色胺的前体）耗竭的绝经期女性的言语记忆表现（Amin et al. 2006 b; Epperson et al. 2006）。与假耗竭相比，ET前色氨酸耗竭（TRP-D）使言语回忆恶化，而ET后10-12周未见这种影响。这些初步的研究结果表明，ET可能会保护个人从赤字的口头回忆，由于选择性减少血清素。本申请试图通过在绝经期妇女中ET或安慰剂治疗之前和期间将功能性磁共振成像（fMRI）添加到TRP-D的范例中来确定雌激素和5-羟色胺对认知和情感处理以及脑激活的个体和交互作用。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对结果的相互影响。这项应用是新颖和及时的，因为这项研究的结果可能为正在进行的关于绝经期妇女使用ET的风险和获益的讨论提供关键信息。公共卫生相关性：本研究的首要目的是进一步了解激素雌激素和神经递质5-羟色胺对48至60岁更年期妇女认知和大脑激活某些方面的个体和相互作用。在雌激素或安慰剂给药6周之前和之后，女性将接受认知测试和fMRI检查。我们将招募自末次月经后前10年的女性，以便我们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结果将有助于科学家和临床医生改进绝经期妇女雌激素治疗的使用。此外，如果5-羟色胺的作用对于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/或治疗其中5-羟色胺是重要因素的痴呆症。这项应用是新颖和及时的，因为这项研究的结果可能为正在进行的关于绝经期妇女使用ET的风险和获益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.