Short-term estradiol use in middle-age: implications for female cognitive aging

描述（由申请人提供）：假设在接近绝经的关键窗口期开始给予雌激素，以预防或延迟与年龄相关的认知能力下降。然而，由于潜在的健康风险，女性通常将雌激素治疗的使用限制在几年内以治疗更年期症状。短期使用雌激素对大脑的长期影响尚不清楚。这项研究的长期目标是确定中年妇女短期接触雌激素（如绝经过渡期妇女使用的雌激素）对女性大脑和女性认知老化的影响。有待检验的中心假设是，中年卵巢功能停止后短期暴露于外源性雌二醇导致海马中雌激素受体α（ER <$）水平和胰岛素样生长因子-1（IGF-1）系统的持续变化永久性地改变了ER <$1和IGF-1之间的相互作用。以及老年女性大脑海马体中的IGF-1系统，导致ER靶基因和蛋白质水平的增加，并增强海马体依赖性记忆。在初步数据的指导下，这一假设将通过三个具体目标进行检验：1）确定海马神经元中IGF-1和ER <$之间相互作用的性质; 2）确定ER <$和IGF-1受体在短期雌二醇暴露对海马和海马依赖性记忆产生持久影响的能力中的各自贡献;和3）确定IGF-1对老年女性海马体和海马体依赖性记忆的影响程度取决于先前的激素经验。第一个目标下的实验将使用原代海马细胞培养物来确定IGF-1及其信号通路诱导雌激素反应元件驱动的报告基因的ER <$介导的转录活性和诱导ER <$上特异性磷酸化位点的激活的能力。第二个目标下的实验将评估药物阻断脑IGF-1受体、ER <$或两者对中年卵巢切除大鼠短期雌二醇暴露对海马中ER <$靶基因和相关蛋白以及海马依赖性记忆产生持久影响的能力的影响。第三个目标下的实验将确定集中给药IGF-1对老年卵巢切除大鼠的海马依赖性记忆、IGF-1相关信号转导通路和ER靶基因及相关蛋白的影响，这些大鼠在中年期间已经和没有经历雌二醇暴露。这项研究有望对女性认知衰老的研究产生积极的影响，通过阐明在卵巢功能停止后的关键时期内相对短期暴露于外源性雌二醇对海马和认知产生持久影响的机制。

DESCRIPTION (provided by applicant): Estrogen administration begun during a critical window near menopause is hypothesized to prevent or delay age-associated cognitive decline. However, due to potential health risks women often limit use of estrogen therapy to a few years to treat menopausal symptoms. The long-term consequences for the brain of short-term use of estrogens are unknown. The long-term goal of the research is to determine the consequences for the female brain and for female cognitive aging of short-term exposure to estrogens during middle-age such as that used by women during the menopausal transition. The central hypothesis to be tested is that lasting changes in levels of estrogen receptor alpha (ER¿) and in the insulin-like growth factor-1 (IGF-1) system in the hippocampus resulting from short-term exposure to exogenously administered estradiol in middle-age following the cessation of ovarian function permanently alters the interaction between ER¿ and the IGF-1 system in the hippocampus of the aging female brain resulting in increases in levels of ER¿ target genes and proteins and in enhancement of hippocampus-dependent memory. Guided by preliminary data, this hypothesis will be tested by three specific aims: 1) Determine the nature of the interaction between IGF-1 and ER¿ in hippocampal neurons; 2) Determine the respective contributions of ER¿ and IGF-1 receptors in the ability of short-term estradiol exposure to exert lasting impacts on the hippocampus and on hippocampus-dependent memory; and 3) Determine the extent to which the effects of IGF-1 on the hippocampus and on hippocampus-dependent memory in aged females vary dependent upon previous hormone experience. Experiments under the first aim will use primary hippocampal cell cultures to determine the ability of IGF-1 and its signaling pathways to induce ER¿-mediated transcriptional activity from an estrogen response element driven reporter gene and to induce activation on of specific phosphorylation sites on ER¿. Experiments under the second aim will assess the impact of pharmacological blockage of brain IGF-1 receptors, ER¿, or both on the ability of short-term estradiol exposure in middle-aged ovariectomized rats to exert lasting impacts on ER¿ target genes and associated proteins in the hippocampus and on hippocampus-dependent memory. Experiments under the third aim will determine effects of centrally administered IGF-1 on hippocampus-dependent memory, IGF-1 associated signal transduction pathways, and ER¿ target genes and associated proteins in aged ovariectomized rats that have and have not undergone estradiol exposure during middle-age. This research is expected to have a positive impact on the study of female cognitive aging by providing elucidation of mechanisms by which a relatively short-term exposure to exogenously administered estradiol during a critical period following the cessation of ovarian function exerts lasting impacts on the hippocampus and on cognition.