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

基本信息

批准号：
7255624
负责人：
Karyn M Frick
金额：
$ 25.42万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
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/7255624
关键词：
Acute Adverse effects Affect Age Aging Attenuated Brain C57BL/6 Mouse Choline O-Acetyltransferase Chronic Cognitive Controlled Study Cyclic AMP-Responsive DNA-Binding Protein Data Dementia Development Dorsal Educational Background Environmental Risk Factor Estrogens Extracellular Signal Regulated Kinases Female Future Goals Hippocampus (Brain)Hormonal Hormones Impaired cognition Injection of therapeutic agent Laboratory Animals Lead Learning Length MAP Kinase Gene Measures Memory Memory Loss Menopause Mitogen-Activated Protein Kinases Molecular Mus Population Progesterone Progestins Rattus Recommendation Research Risk Rodent Series Signal Transduction Standards of Weights and Measures Stroke Synaptophysin Testing Training Treatment Protocols Water Woman Women&apos s Health Work age related aged base design experience hormone therapy malignant breast neoplasm mouse model neuromechanism object recognition prevent protein activation relating to nervous system research study response treatment duration

项目摘要

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）：最近备受争议的女性健康倡议记忆研究（WHIMS）表明，长期使用雌激素和孕激素治疗会显着增加更年期女性认知能力下降和痴呆的风险。这些数据与针对女性和啮齿动物的研究形成鲜明对比，这些研究表明雌激素具有明显的减轻与年龄和激素相关的记忆丧失的能力。 WHIMS 发现孕激素对记忆有害的发现更令人惊讶，因为雌激素和孕激素治疗已被证明对实验动物的记忆有益。拟议的研究旨在阐明孕激素是否会减弱雌激素的有益作用，并确定雌激素和孕激素对记忆巩固影响的神经机制。由于激素替代的不良副作用（例如乳腺癌和中风风险增加）使得在女性中进行这些研究不切实际，因此拟议的研究将使用雌性小鼠模型。具体目标如下：1) 查明雌激素和孕激素单独或组合是否能增强记忆巩固并改变年轻和老年女性海马中的 MAP 激酶信号传导，2) 确定记忆和海马对雌激素的反应是否和黄体酮受环境因素的影响，以及 3) 比较不同持续时间（短时间）的雌激素和黄体酮治疗对记忆和神经的影响。与长期）和类型（持续与周期性）。为了实现这些目标，切除卵巢的雌性 C57BL/6 小鼠（4、17 和 24 个月大）将用于一系列九个实验。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更年期妇女的治疗。 WHIMS 是一项有限的研究，重点关注接受非周期性治疗且含有有害类型孕激素的老年、受过高等教育的人群。确定治疗年龄、认知刺激程度、孕激素类型和治疗类型（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。我们的小鼠模型将能够比女性模型对这些因素进行更受控的研究。对这些问题的阐明最终可能会导致开发出更安全、更有效的治疗方法，以预防女性认知能力下降和痴呆症