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: 7646244
• 负责人: Karyn M Frick
• 金额: $ 24.92万
• 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 2010-12-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7646244
• 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; Stroke; Synaptophysin; Testing; Training; Treatment Protocols; Water; Woman; Women' s Health; Work; age related; aged; base; design; effective therapy; environmental enrichment for laboratory animals; experience; hormone therapy; malignant breast neoplasm; mouse model; neuromechanism; object recognition; prevent; protein activation; relating to nervous system; research study; response; treatment duration

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计划记忆研究（WHIMS）意味着，雌激素和孕激素的长期治疗显着增加了绝经女性认知能力下降和痴呆症的风险。这些数据与对女性和啮齿动物的研究形成鲜明对比，这些研究表明雌激素能够减轻与年龄和激素相关的记忆丧失的能力。人们发现，孕激素对记忆有害的想法更加令人惊讶，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减弱了雌激素的有益作用，并确定雌激素和孕激素对记忆巩固作用的神经机制。由于替代激素的不利副作用，例如增加乳腺癌和中风的风险增加，因此在女性中进行这些研究是不切实际的，因此拟议的研究将利用雌性小鼠模型。具体目的如下：1）确定是否单独或组合雌激素和孕激素会增强记忆巩固并改变女性和衰老女性的海马中的MAP激酶信号传导，2）确定Mnemonic和Hippocal对雌激素和孕激素对环境因素的影响以及对环境因素的影响以及对环境因素的影响以及对环境的影响是否影响。持续时间（短期与长期）和类型（持续与环状）有所不同。为了实现这些目的，将在一系列九个实验中使用卵巢切除的雌性C57BL/6小鼠（4、17和24个月大）。空间内存将在空间迷宫任务中进行测试，并将在对象识别任务中测试非空间内存。这项研究的目的是阐明异想天开的发现，这项研究极大地影响了数百万个更年期妇女的治疗。 WHIMS是一项有限的研究，重点是较老，受过良好教育的人群接受治疗，该治疗方法不是循环的，其中包括有害类型的孕激素。确定治疗年龄，认知刺激程度，孕激素类型以及治疗类型（即环状与持续性）等因素如何影响激素对激素的助记符和神经反应对于未来对激素替代的使用至关重要。与女性相比，我们的小鼠模型将对这些因素进行更控制的研究。阐明这些问题可能最终导致发展更安全，更有效的治疗方法，以防止女性认知能力下降和痴呆

项目成果

The progesterone-induced enhancement of object recognition memory consolidation involves activation of the extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin (mTOR) pathways in the dorsal hippocampus.

• DOI: 10.1016/j.yhbeh.2012.01.004
• 发表时间: 2012-04
• 期刊: HORMONES AND BEHAVIOR
• 影响因子: 3.5
• 作者: Orr, Patrick T.;Rubin, Amanda J.;Fan, Lu;Kent, Brianne A.;Frick, Karyn M.
• 通讯作者: Frick, Karyn M.

The effects of acute 17beta-estradiol treatment on gene expression in the young female mouse hippocampus.

• DOI: 10.1016/j.nlm.2008.09.017
• 发表时间: 2009-03
• 期刊: NEUROBIOLOGY OF LEARNING AND MEMORY
• 影响因子: 2.7
• 作者: Pechenino, Angela S.;Frick, Karyn M.
• 通讯作者: Frick, Karyn M.

Post-training progesterone dose-dependently enhances object, but not spatial, memory consolidation.

• DOI: 10.1016/j.bbr.2008.07.014
• 发表时间: 2008-12-12
• 期刊: Behavioural brain research
• 影响因子: 2.7
• 作者: Harburger LL;Pechenino AS;Saadi A;Frick KM
• 通讯作者: Frick KM

Estradiol-induced object memory consolidation in middle-aged female mice requires dorsal hippocampal extracellular signal-regulated kinase and phosphatidylinositol 3-kinase activation.

• DOI: 10.1523/jneurosci.4333-09.2010
• 发表时间: 2010-03-24
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Fan L;Zhao Z;Orr PT;Chambers CH;Lewis MC;Frick KM
• 通讯作者: Frick KM

Dorsal hippocampal progesterone infusions enhance object recognition in young female mice.

• DOI: 10.1016/j.pbb.2009.05.012
• 发表时间: 2009-08
• 期刊: PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR
• 影响因子: 3.6
• 作者: Orr, Patrick I.;Lewis, Michael C.;Frick, Karyn M.
• 通讯作者: Frick, Karyn M.