Hormone and enrichment effects on memory in aging mice

描述(申请人提供)：最近有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著增加更年期女性认知能力下降和痴呆症的风险。这些数据与在女性和啮齿动物身上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能力来缓解与年龄和激素相关的记忆丧失。突发奇想地发现孕激素对记忆有害，这一点甚至更令人惊讶，因为雌激素和黄体酮治疗已被证明对实验动物的记忆有益。这项拟议的研究旨在阐明黄体酮是否会减弱雌激素的有益影响，并确定雌激素和黄体酮对记忆巩固影响的神经机制。由于激素替代的副作用，如乳腺癌和中风风险的增加，使得在女性身上进行这些研究是不切实际的，因此拟议的研究将使用雌性小鼠模型。具体目标如下：1)确定雌激素和黄体酮是否单独或联合使用，增强年轻和老年女性海马区的记忆巩固和改变MAP激酶信号；2)确定记忆和海马区对雌激素和黄体酮的反应是否受环境因素的影响；3)比较不同持续时间(短期和长期)和类型(持续和周期性)的雌激素和黄体酮治疗对记忆力和神经的影响。为了实现这些目标，将使用去卵巢的雌性C57BL/6小鼠(4、17和24个月大)进行一系列9个实验。空间记忆将在空间水迷宫任务中被测试，非空间记忆将在物体识别任务中被测试。这项研究的目的是澄清Whims的发现，这项研究对数百万更年期女性的治疗产生了很大影响。Whims是一项有限的研究，重点是接受非周期性治疗的老年、受过高等教育的人群，其中包括一种有害的孕激素。确定治疗时的年龄、认知刺激程度、孕激素类型和治疗类型(即周期性和持续性)如何影响记忆力和神经对激素的反应将是未来激素替代使用的关键。我们的小鼠模型将使我们能够对这些因素进行比女性更有控制的研究。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，以防止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