Hormone and enrichment effects on memory in aging mice

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，长期使用雌激素和雌激素显著增加更年期妇女认知能力下降和痴呆的风险。这些数据与在女性和啮齿动物中进行的研究形成鲜明对比，这些研究表明雌激素具有明显的缓解年龄和死亡相关记忆丧失的能力。WHIMS的发现是，雌激素和孕激素治疗对实验室动物的记忆力有益，因此更令人惊讶的是，雌激素和孕激素治疗对记忆力有害。拟议的研究旨在阐明孕激素是否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作用的神经机制。由于激素替代的不良副作用，如乳腺癌和中风的风险增加，使得在女性中进行这些研究变得不切实际，因此拟议的研究将利用雌性小鼠模型。具体目标如下：1）查明雌激素和孕激素单独或组合是否增强年轻和老年女性海马体中的记忆巩固并改变MAP激酶信号传导，2）确定记忆和海马体对雌激素和孕激素的反应是否受环境因素的影响，比较雌激素和孕激素治疗在持续时间（短期与长期）和类型（持续与周期性）方面的记忆和神经效应。为了实现这些目标，卵巢切除雌性C57 BL/6小鼠（4、17和24月龄）将用于一系列9项实验。空间记忆将在空间水迷宫任务中测试，非空间记忆将在物体识别任务中测试。这项研究的目的是澄清WHIMS的发现，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，重点是接受非周期性治疗的老年人，受过高等教育的人群，包括一种有害的类胡萝卜素。确定治疗时的年龄、认知刺激程度、抗抑郁素的类型和治疗类型（即，周期性与持续性）对记忆和神经对激素的反应的影响将是未来使用激素替代品的关键。我们的小鼠模型将使这些因素的研究比女性更可控。阐明这些问题可能最终导致开发更安全，更有效的治疗方法，以预防女性认知能力下降和痴呆症

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