Hormone and enrichment effects on memory in aging mice

激素和浓缩对衰老小鼠记忆力的影响

• 批准号: 6979946
• 负责人: Karyn M Frick
• 金额: $ 26.81万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6979946
• 关键词: behavior test; biological signal transduction; cAMP response element binding protein; combination chemotherapy; disease /therapy duration; drug adverse effect; drug screening /evaluation; enzyme activity; enzyme linked immunosorbent assay; estrogens; female; hormone regulation /control mechanism; hormone therapy; laboratory mouse; mature animal; memory disorders; mitogen activated protein kinase; nonhuman therapy evaluation; progesterone; proteomics; statistics /biometry; western blottings

DESCRIPTION (provided by applicant): The recent controversial Women's Health Initiative Memory Study (WHIMS) implies that long-term treatment with estrogen and progestin significantly increases the risk of cognitive decline and dementia in menopausal women. These data sharply contrast with studies in women and rodents that have demonstrated a clear ability of estrogen to alleviate age- and hormone-related memory loss. The WHIMS finding that progestin is detrimental to memory is even more surprising because estrogen and progesterone treatment have been shown to be beneficial to memory in laboratory animals. The proposed studies were designed to clarify whether progesterone attenuates the beneficial effects of estrogen and to identify the neural mechanisms underlying the effects of estrogen and progesterone on memory consolidation. Because adverse side effects of hormone replacement such as increased risks of breast cancer and stroke make it impractical to conduct these studies in women, the proposed studies will utilize a female mouse model. The specific aims are as follows: 1) To pinpoint if estrogen and progesterone, alone or in combination, enhance memory consolidation and alter MAP kinase signaling in the hippocampus in young and aging females, 2) To determine if the mnemonic and hippocampal response to estrogen and progesterone is influenced by environmental factors, and 3) To compare the mnemonic and neural effects of estrogen and progesterone treatments that vary in duration (short- vs. long-term) and type (sustained vs. cyclic). To achieve these aims, ovariectomized female C57BL/6 mice (4, 17, and 24 months old) will be used in a series of nine experiments. Spatial memory will be tested in a spatial water maze task and non-spatial memory will be tested in an object recognition task. The goal of this research is to clarify the findings of WHIMS, a study which has greatly impacted the treatment of millions of menopausal women. WHIMS was a limited study, focusing on an older, highly educated population receiving treatment that was not cyclic and included a detrimental type of progestin. Establishing how factors such as age at treatment, degree of cognitive stimulation, type of progestin, and type of treatment (i.e., cyclic vs. sustained) influence the mnemonic and neural response to hormones will be critical to future use of hormone replacement. Our mouse model will enable a more controlled study of these factors than is possible with women. Elucidation of these issues may ultimately lead to the development of safer and more effective treatments to prevent cognitive decline and dementia in women

描述（由申请人提供）：最近有争议的妇女健康倡议记忆研究（WHIMS）表明，长期使用雌激素和黄体酮治疗会显著增加绝经妇女认知能力下降和痴呆的风险。这些数据与对女性和啮齿动物的研究形成鲜明对比，这些研究已经证明了雌激素明显能够减轻与年龄和激素相关的记忆丧失。WHIMS发现黄体酮对记忆有害，这更令人惊讶，因为在实验动物中，雌激素和黄体酮治疗已被证明对记忆有益。这些研究旨在阐明黄体酮是否会减弱雌激素的有益作用，并确定雌激素和黄体酮对记忆巩固作用的神经机制。由于激素替代的副作用，如增加乳腺癌和中风的风险，使得在女性身上进行这些研究不切实际，因此拟议的研究将利用雌性小鼠模型。具体目标如下：1)确定雌激素和孕激素单独或联合使用是否能增强年轻和老年女性的记忆巩固并改变海马中MAP激酶信号；2)确定记忆和海马对雌激素和孕激素的反应是否受环境因素的影响；3)比较不同持续时间（短期vs长期）和类型（持续vs循环）的雌激素和孕激素治疗的记忆和神经效应。为了实现这些目标，将在4、17和24个月大的雌性C57BL/6小鼠中进行一系列的9个实验。空间记忆将在空间水迷宫任务中进行测试，非空间记忆将在物体识别任务中进行测试。这项研究的目的是澄清WHIMS的研究结果，这项研究极大地影响了数百万绝经妇女的治疗。WHIMS是一项有限的研究，重点关注接受非循环治疗的高学历老年人，其中包括一种有害的黄体酮。确定诸如治疗年龄、认知刺激程度、黄体酮类型和治疗类型（即循环与持续）等因素如何影响对激素的记忆和神经反应，对于未来使用激素替代疗法至关重要。与女性相比，我们的小鼠模型将能够对这些因素进行更可控的研究。对这些问题的阐明可能最终导致开发出更安全、更有效的治疗方法，以预防妇女的认知能力下降和痴呆