Interaction of Estrogen and Serotonin in Modulating Brain Activation in Menopause

描述(申请人提供)：在更年期过渡期间，许多女性报告她们的情绪恶化和记忆的主观损害。虽然卵巢雌激素分泌的减少显然与最常见的更年期症状有关，即潮热和生殖器萎缩，但雌激素影响更年期行为变化的机制尚不清楚，尽管人们对此很感兴趣。越来越多的临床前文献表明，雌激素可能与神经递质(如5-羟色胺)相互作用，5-羟色胺的功能被认为随着年龄的增长而下降。然而，在人类中，关于雌激素和5-羟色胺如何相互作用来调节情绪和认知的研究很少。我们的小组最近在填补这一空白方面取得了很大进展，证明了雌激素治疗(ET)调节了色氨酸(Trp)(5-羟色胺的前体)耗竭的绝经妇女的言语记忆表现(Amin等人)。2006b；EpPerson等人。2006)。与假耗竭相比，在ET之前的色氨酸耗竭(Trp-D)会恶化言语回忆，而在ET后10-12周则没有看到这种影响。这些初步发现表明，ET可能会保护个体免受由于5-羟色胺选择性减少而导致的言语回忆缺陷。本申请旨在通过在绝经妇女接受ET或安慰剂治疗之前和期间将功能磁共振成像(FMRI)添加到Trp-D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单独和交互影响。此外，这项研究的资金将使我们能够招募更年期不同阶段的女性，以确定更年期持续时间和ET对感兴趣的结果的交互影响。这一应用既新颖又及时，因为这项研究的结果可能会为正在进行的关于更年期妇女使用ET的风险和好处的讨论提供关键的信息。公共卫生相关性：这项研究的主要目的是进一步了解雌激素和神经递质5-羟色胺对年龄在48至60岁的更年期妇女认知和大脑激活的某些方面的个体和交互影响。女性在服用雌激素或安慰剂6周之前和之后都将接受认知测试和功能磁共振检查。我们将招募自上次月经以来的前10年的女性，这样我们就可以收集有关绝经以来的时间对我们感兴趣的结果的潜在影响的信息。我们期待这项研究的发现将帮助科学家和临床医生改进他们在更年期妇女中使用雌激素治疗的方法。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，以保护健康认知和/或治疗5-羟色胺是重要因素的痴呆症。这一应用既新颖又及时，因为这项研究的结果可能会为正在进行的关于更年期妇女使用ET的风险和好处的讨论提供关键的信息。

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.