Estrogen and cognition over the lifespan

雌激素与整个生命周期的认知

基本信息

批准号：
10370371
负责人：
THOMAS C FOSTER
金额：
$ 38.09万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-15 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10370371
关键词：
Address Aftercare Age-associated memory impairment Aging Alzheimer&apos s Disease Animals Attenuated Behavior Behavioral Body Regions Brain Cognition Cognition Disorders DNA DNA Methylation Data Dithiothreitol Effectiveness Elderly Episodic memory Equilibrium Estradiol Estrogen Receptor alpha Estrogen Receptor beta Estrogen Receptors Estrogens Exhibits Funding Gene Expression Gene Expression Profile Genes Genetic Transcription Genomics Goals Gonadal Steroid Hormones Hippocampus (Brain)Hormones Hour Hypermethylation Impaired cognition Injections Introns Link Long-Term Effects Longevity Measures Mediating Membrane Memory Methylation Mitochondria N-Methyl-D-Aspartate Receptors Neurodegenerative Disorders Oils Ontology Oxidation-Reduction Oxidative Stress Oxides Periodicity Phosphoric Monoester Hydrolases Phosphotransferases Physiology Proteins Reducing Agents Regulation Research Series Sex Differences Signal Transduction Site Stress Synapses Synaptic Receptors Synaptic Transmission Synaptic plasticity Testing Therapeutic Tissues Whole-Cell Recordings Work age related aged aging brain antioxidant enzyme behavior test calmodulin-dependent protein kinase II cognitive benefits deprivation differential expression enzyme activity epigenetic regulation improved juvenile animal male middle age neuroprotection novel object recognition patch clamp protein biomarkers receptor function response therapeutic effectiveness water maze

项目摘要

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.

抽象的性别差异是脆弱性与年龄相关的认知下降和衰老疾病的证据。雌二醇（E2）受到保护，包括包括阿尔茨海默氏病在内的神经退行性疾病，暗示性别马对脆弱性的性别差异的影响。但是，性类固醇治疗的障碍包括观察到的治疗窗口的结束是E2治疗随年龄的有效性降低。拟议研究的目的是提供对E2影响机制的理解记忆和治疗窗口的关闭。闭合治疗窗口以减少的标志在E2反应转录和E2治疗中无法增强N-甲基-D-天冬氨酸接收器（NMDAR）治疗几天后检查了介导的突触传播。 AIM 1将测试假设E2治疗在测试前几天，特别影响了NMDAR依赖性情节记忆，可以挽救在水上检查的情节记忆中与年龄相关的下降迷宫和新颖的对象识别任务。 AIM 2将检验以下假设：E2对记忆的影响和 NMDAR功能是由NMDAR功能功能率逆转介导的，由氧化还原调节介导磷酸酶/激酶活性，类似于先前在衰老雄性中描述的活性。那是预测的要结束治疗窗口（即在动物中，E2治疗改善认知并增加 NMDAR功能），E2治疗将促进抗氧化剂活性，减少氧化应激和最小化氧化还原介导的CAMKII活性和NMDAR功能的降低。此外，关闭治疗窗口（即E2不挽救认知和NMDAR功能的动物），E2 治疗不会促进抗氧化剂酶活性或减少氧化应激，而NMDAR反应由于氧化物氧化还原态，CAMKII活性将得到改善。 AIM 3将检验以下假设：对E2的转录反应性的相关变化至少部分归因于表观遗传调节通过DNA甲基化。可以预测，E2敏感基因的反应性降低将是与DNA高甲基化相关，特别是在基因体区域（内含子），特定于CpG，相对于非CPG甲基化位点。拟议的研究将采用强大的行为结合对NMDAR功能敏感的测试，NMDAR突触响应的贴片钳记录，测量氧化应激和酶活性，转录和DNA甲基化的作用。