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

中年短期使用雌二醇：对女性认知衰老的影响

• 批准号: 8771870
• 负责人: JILL M DANIEL
• 金额: $ 4.96万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8771870
• 关键词: Age; Age-associated memory impairment; Aging; Area; Biochemical; Brain; Cell Culture Techniques; Choline O-Acetyltransferase; Cognition; Cognitive; Cognitive aging; Data; Dementia; Estradiol; Estrogen Receptor alpha; Estrogen Therapy; Estrogens; Exposure to; Female; Gene Proteins; Gene Targeting; Genetic Transcription; Goals; Growth Factor; Health; Hippocampus (Brain); Hormones; Impaired cognition; Incidence; Insulin-Like Growth Factor I; Insulin-Like-Growth Factor I Receptor; Interferon Gamma Receptor Beta Chain; Intervention; Long-Term Effects; MAP Kinase Gene; Mediating; Memory; Menopausal Symptom; Menopause; Nature; Neurons; Ovarian; Ovary; Pathway interactions; Phosphorylation Site; Population; Proteins; Public Health; Rattus; Reporter Genes; Research; Response Elements; Risk; Signal Pathway; Signal Transduction Pathway; Site; System; Testing; Time; United States; Woman; Women' s Health; aged; aging brain; aging hippocampus; critical period; experience; middle age; prevent; receptor; research study

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.

描述（由申请人提供）：在接近绝经期的关键窗口期开始施用雌激素可以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，女性通常将雌激素疗法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。该研究的长期目标是确定中期短期接触雌激素对女性大脑和女性认知衰老的影响。年龄例如女性在更年期过渡期间使用的方法。要测试的中心假设是海马体内雌激素受体 α (ER¿) 和胰岛素样生长因子 - 1 (IGF-1) 系统的持久变化。由于中年时期卵巢功能停止后短期暴露于外源性雌二醇，永久改变了 ER¿衰老女性大脑海马体中的 IGF-1 系统导致 ER 水平升高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 IGF-1 和 ER 之间相互作用的性质。在海马神经元中；2)确定ER¿的各自贡献和 IGF-1 受体短期雌二醇暴露对海马体和海马依赖性记忆产生持久影响的能力；3) 确定 IGF-1 对海马体和海马依赖性记忆的影响程度；老年女性的记忆力取决于之前的激素经历，第一个目标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 ER 的能力。 -由雌激素反应元件驱动的报告基因介导的转录活性，并诱导 ER 上特定磷酸化位点的激活第二个目标下的实验将评估药物阻断大脑 IGF-1 受体 ER¿ ，或两者都影响中年卵巢切除大鼠短期雌二醇暴露对 ER 产生持久影响的能力¿第三个目标下的实验将确定集中施用的 IGF-1 对海马依赖性记忆、IGF-1 相关信号转导途径和 ER 的影响。这项研究有望对女性认知衰老的研究产生积极影响，通过阐明相对短期的机制。在卵巢功能停止后的关键时期暴露于外源性雌二醇会对海马体和认知产生持久影响。