Effects of hormones and menopausal transitions on hippocampal structure and function

摘要 与荷尔蒙水平相关的变化在男性和女性中都有发生，但在女性中更为明显。 接近更年期，通常在45至52岁之间1。尽管先前的数据寻址 女性和男性的大脑老化差异，中年时期激素的变化如何影响大脑结构， 女性的认知仍不清楚。女性似乎更容易受到认知能力下降的影响， 围绝经期2，普遍认为女性在此期间会出现记忆缺陷。 时间段3-6。雌激素耗竭被广泛认为是围绝经期妇女认知功能障碍的可能原因7，但对雌激素水平下降如何影响认知功能的机械理解， 衰退和大脑的变化是相对知之甚少。在动物模型中， 在整个大脑中，但主要分布在边缘相关区域，这些区域在认知功能中起着至关重要的作用8。 具体地说，这些动物研究显示海马亚区角1、2和3密集 雌激素受体的聚集区域;这些雌激素受体的激活已被证明介导 雌激素对突触可塑性的有益作用以及在预防神经退行性变中发挥作用， 海马神经元9，10. 我们建议在此研究雌激素水平下降对海马结构的影响 作为我们与人类连接组项目合作的一部分， 老化（HCP-A）。该项目利用HCP-A正在使用的严格结构化的数据收集管道， 客观分期更年期数据点。虽然这里详细介绍的数据是作为 HCP-A项目，目前有103名受试者，预计将在2010年招募另外107名受试者。 未来2年，HCP-A不包括对后续研究的支持;研究 建议使用数据集回答科学问题必须由单独的研究资助 支持.具体来说，我们将分析高场磁共振成像（MRI）数据的 海马体，以评估记忆结构和功能的细节，并确定是否 较低的雌激素水平预示着围绝经期妇女记忆力较差。我们还将 研究激素替代疗法是否对调节 中年女性的雌激素水平我们希望这个项目的结果能阐明这个复杂的问题， 激素水平变化与海马结构后续效应之间的关系， 中年记忆功能

ABSTRACT Age-related changes in hormone levels occur in both men and women but are more pronounced in women approaching menopause, typically between the ages of 45 to 52 years old 1. Despite prior data addressing brain-aging differences in women and men, how hormone changes in midlife affect brain structure and cognition in women remains unclear. Women appear to be more vulnerable to cognitive decline during this peri-menopausal period 2, and there is general agreement that women experience memory deficits during this timeframe 3–6. Estrogen-depletion is widely regarded as a likely cause of cognitive impairment in peri-menopausal women 7 but the mechanistic understanding of how declining estrogen rates affect cognitive decline and brain changes is relatively poorly understood. In animal models, estrogen receptors are found throughout the brain, but predominate in limbic-related areas that play a crucial role in cognitive function 8. Specifically, these animal studies show hippocampal subfields Cornu Ammonis 1, 2, and 3 as densely populated regions of estrogen-receptors; activation of these estrogen-receptors has been shown to mediate estrogen's beneficial effect on synaptic plasticity as well as play a role in preventing neurodegeneration in hippocampal neurons 9,10. We propose here investigating the impact of declining estrogen levels on hippocampal structure and function in peri-menopausal women as part of our collaboration with the Human Connectome Project- Aging (HCP-A). This project makes use of the rigorously structured data collection pipeline HCP-A is using to objectively stage menopause data points. Although the data detailed here are being collected as part of the HCP-A project, with 103 subjects currently available and an additional 107 anticipated to be recruited over the coming 2 years, no support for subsequent investigations is included as part of the HCP-A; investigations proposing to answer scientific questions using the dataset must be funded with separate research support. Specifically, we will analyze high-field magnetic resonance imaging (MRI) data of the hippocampus in order to assess memory structures and function in fine detail and determine whether lower estrogen levels predict poorer memory performance in peri-menopausal women. We will also investigate whether hormone replacement therapy has a beneficial effect at mediating the effect of changes in estrogen levels in midlife women. We expect results from this project to shed light on the complex relationship between changes in hormone levels and subsequent effects on hippocampal structure and memory function in midlife.