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

说明(由申请人提供)：在接近绝经的关键时间段开始服用雌激素被认为是为了预防或延缓与年龄相关的认知能力下降。然而，由于潜在的健康风险，女性经常将雌激素疗法的使用限制在几年内来治疗更年期症状。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期间短期接触雌激素对女性大脑和女性认知老化的影响，比如女性在更年期过渡期间使用的雌激素。有待测试的中心假设是，在卵巢功能停止后，中年时短期暴露于外源性雌激素导致的海马区雌激素受体α(ER？)和胰岛素样生长因子-1(IGF-1)系统水平的持久变化，永久性地改变了老化女性大脑海马区ER？和IGF-1系统之间的相互作用，导致ER？靶基因和蛋白质水平的增加，并增强了对海马体的依赖记忆。在初步数据的指导下，这一假说将受到三个特定目标的检验：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受体在短期雌激素暴露对海马区和海马区依赖记忆施加持久影响的能力中各自的贡献；以及3)确定IGF-1对海马区和老年女性海马区依赖记忆的影响在多大程度上取决于先前的激素经验。在第一个目标下的实验将使用原代培养的海马细胞来确定IGF-1及其信号通路从雌激素反应元件驱动的报告基因中诱导ER介导的转录活性的能力，以及诱导ER上特定的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或两者兼而有之对中年去卵巢大鼠短期雌二醇暴露的影响，以对海马区ER靶基因和相关蛋白产生持久影响，并对海马区依赖记忆产生影响。第三个目标下的实验将确定集中应用IGF-1对老年去卵巢大鼠的海马区依赖记忆、IGF-1相关信号转导通路以及ER？靶基因和相关蛋白的影响。这项研究有望对女性认知老化的研究产生积极影响，阐明在卵巢功能停止后的关键时期相对短期地暴露于外源性雌激素对海马体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.