Estrogen and cognition over the lifespan

摘要 在易患与年龄有关的认知能力下降和老年疾病方面，性别差异很明显。雌二醇 (E2)对神经退行性疾病有保护作用，包括阿尔茨海默病， 激素对脆弱性性别差异的影响。然而，性类固醇治疗的障碍包括 观察到治疗窗的关闭，因为随着年龄的增长，E2治疗的有效性降低。 这项研究的目的是提供一个了解的机制，E2的影响， 记忆和治疗窗口的关闭。治疗窗的关闭以减少 在E2反应性转录中，E2处理不能增强N-甲基-D-天冬氨酸受体 （NMDAR）介导的突触传递。目标1将测试 假设E2治疗，测试前几天，具体影响NMDAR依赖性 情景记忆，这样它就可以挽救与年龄相关的情景记忆衰退， 迷宫和新物体识别任务。目的2将检验E2对记忆和记忆功能的影响这一假设， NMDAR功能通过NMDAR功能减退的逆转介导，通过NMDAR的氧化还原调节介导， 磷酸酶/激酶活性，类似于先前在老年男性中描述的。因此，据预测， 治疗窗的关闭（即在E2治疗改善认知并增加 NMDAR功能），E2治疗将促进抗氧化酶活性，减少氧化应激， 最小化氧化还原介导的CaMKII活性和NMDAR功能的降低。此外，在关闭 治疗窗（即对于E2不能挽救认知和NMDAR功能的动物），E2 治疗不会促进抗氧化酶活性或减少氧化应激， 并且CaMK II活性将由于氧化的氧化还原状态而降低。目标3将检验年龄- 对E2的转录反应性的相关变化至少部分是由于表观遗传调节 DNA甲基化。据预测，E2敏感基因的反应性降低将是一个重要的因素。 与DNA超甲基化相关，特别是在基因体区域（内含子），并且对CpG特异， 相对于非CpG甲基化位点。拟议中的研究将采用一种强大的行为组合， 对NMDAR功能敏感的测试，NMDAR突触反应的膜片钳记录，测量 氧化应激和酶活性，转录和DNA甲基化。

Abstract Sex differences are evident in vulnerability to age-related cognitive decline and diseases of aging. Estradiol (E2) is protective against neurodegenerative diseases, including Alzheimer’s disease, implicating sex hormone effects on sex differences in vulnerability. However, obstacles to sex steroid treatments include closing of the therapeutic window observed as decreased effectiveness of E2 treatment with advanced age. The goal of the proposed research is to provide an understanding of the mechanisms for E2 effects on memory and the closing of the therapeutic window. Closing of the therapeutic window is marked by a decrease in E2-responseive transcription and an inability of E2 treatment to enhance N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic transmission examined several days after treatment. Aim 1 will test the hypothesis that E2 treatment, several days prior to testing, specifically influences NMDAR-dependent episodic memory, such that it can rescue an age-related decline in episodic memory examined on the water maze and novel object recognition tasks. Aim 2 will test the hypothesis that E2 effects on memory and NMDAR function are mediated by reversal of NMDAR hypofunction, mediated by redox regulation of phosphatase/kinase activity, similar to that previously described in aging males. Thus, it is predicted that prior to closing of the therapeutic window (i.e. in animals in which E2 treatment improves cognition and increases NMDAR function), E2 treatment will promote antioxidant enzyme activity, reduce oxidative stress, and minimize redox-mediated decrease in CaMKII activity and NMDAR function. Further, following closing of the therapeutic window (i.e. for animals in which E2 does not rescue cognition and NMDAR function), E2 treatment will not promote antioxidant enzyme activity or reduce oxidative stress, and the NMDAR response and CaMKII activity will be decreased due to an oxidized redox state. Aim 3 will test the hypothesis that age- related changes in transcriptional responsiveness to E2 are due, at least in part, to epigenetic regulation through DNA methylation. It is predicted that decreased responsiveness of E2-sensitive genes will be associated with DNA hypermethylation, particularly in gene body regions (introns), and specific to CpG, relative to non-CpG methylation sites. The proposed studies will employ a powerful combination of behavioral tests that are sensitive to NMDAR function, patch-clamp recording of NMDAR synaptic responses, measures of oxidative stress and enzyme activity, transcription, and DNA methylation.