Mechanisms underlying memory regulation by 17beta-estradiol, canonical Wnt signaling, and BDNF in male and female mice

雄性和雌性小鼠中 17β-雌二醇、经典 Wnt 信号传导和 BDNF 记忆调节的机制

基本信息

批准号：
9757819
负责人：
Karyn M Frick
金额：
$ 37.38万
依托单位：
UNIVERSITY OF WISCONSIN MILWAUKEE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-20 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9757819
关键词：
Acetylation Address Adult Alzheimer&apos s Disease Anxiety Disorders Behavioral Behavioral Sciences Biochemical Brain Brain-Derived Neurotrophic Factor Characteristics Complex Critical Pathways Data Dendritic Spines Development Disease Down Syndrome Epigenetic Process Epilepsy Estradiol Estrogen Receptor alpha Estrogen Receptor beta Estrogen Receptors Estrogens Etiology FRAP1 gene Family Female Foundations Functional disorder Generations Genetic Transcription Goals Gonadal Steroid Hormones Hippocampus (Brain)Histone Acetylation Impairment Ischemia Knowledge Lead Learning Mediating Memory Memory impairment Mental disorders Molecular Mus National Institute of Mental Health Neurodegenerative Disorders Neurodevelopmental Disorder Outcome Pathway interactions Patients Pharmaceutical Preparations Plague Prevalence Process Proteins Public Health Publishing Quality of life Regulation Research Research Design Role Severities Sex Differences Signal Pathway Signal Transduction Synaptic plasticity Testing Therapeutic Translations Vision WNT Signaling Pathway Wnt proteins Woman Work base brain behavior design effective therapy estrogenic improved innovation insight male memory consolidation memory process men neuromechanism neuropsychiatric disorder neuropsychiatry novel therapeutics promoter protein H(3)sex therapy development

项目摘要

Memory deficits plague patients with numerous mental disorders, yet a fundamental lack of knowledge about the neural mechanisms regulating memory formation has hampered the development of therapies to reduce this memory dysfunction. The sex steroid hormone 17β-estradiol (E2) is a potent modulator of hippocampal synaptic plasticity and memory, and likely contributes to sex differences in the prevalence, progression, and severity of many psychiatric and neurodegenerative diseases. However, the neural mechanisms through which E2 regulates memory are poorly understood. Thus, there is an urgent need to identify molecular mechanisms through which E2 regulates learning and memory processes in both sexes. Our long-term goal is to pinpoint the key neural mechanisms through which estrogens regulate hippocampal memory formation in males and females. The overall objective of this application, which is the next step toward attainment of our goal, is to determine the extent to which canonical Wnt signaling and BDNF contribute to the memory enhancing effects of E2. Our central hypothesis is that E2 enhances memory by promoting Wnt signaling, which then epigenetically regulates the transcription and translation of BDNF. These hypotheses were formulated on the basis of published data indicating that Wnt signaling increases BDNF expression6, and our own published data showing that canonical Wnt signaling is necessary for hippocampal memory consolidation in male mice7, histone acetylation is necessary for E2 to enhance hippocampal memory consolidation in female mice8, and that E2 increases hippocampal BDNF protein and H3 acetylation at Bdnf promoters in female mice7. Guided by our strong preliminary data, our hypothesis will be tested in three specific aims designed to: 1) determine the extent to which estrogenic regulation of canonical Wnt signaling facilitates hippocampal memory consolidation, 2) establish the extent to which canonical Wnt signaling and BDNF interact to regulate hippocampal memory consolidation, and 3) identify the molecular mechanisms through which E2 mediates BDNF expression and memory formation. This research is innovative because it utilizes a hypothesis-driven approach that integrates behavioral and biochemical analyses to identify mechanistic relationships among modulatory pathways that regulate hippocampal memory formation in both males and females. The proposed research is significant because it is the first step in a continuum of research designed to provide foundational knowledge about the molecular mechanisms through which E2 regulates memory formation. This work will provide sorely needed insights about estrogenic regulation of memory formation in both sexes that could lead to the generation of novel therapies specifically tailored to reduce memory dysfunction in patients of each sex. Such therapeutic advances would greatly improve the quality of life for millions of patients and their families.

记忆缺陷困扰着许多精神障碍患者，但他们对记忆缺乏基本了解调节记忆形成的神经机制阻碍了减少记忆形成的疗法的开发性类固醇激素 17β-雌二醇 (E2) 是海马体的有效调节剂。突触可塑性和记忆，并可能导致患病率、进展和记忆方面的性别差异然而，许多精神疾病和神经退行性疾病的严重程度是通过神经机制来实现的。人们对E2调节记忆知之甚少，因此迫切需要确定分子机制。 E2 通过它调节两性的学习和记忆过程。雌激素调节男性海马记忆形成的关键神经机制该应用程序的总体目标是实现我们目标的下一步。确定经典 Wnt 信号传导和 BDNF 对记忆增强效果的贡献程度我们的中心假设是 E2 通过促进 Wnt 信号传导来增强记忆，然后这些假设是基于表观遗传调控 BDNF 的转录和翻译。已发表的数据表明 Wnt 信号传导会增加 BDNF 表达6，以及我们自己已发表的数据表明经典 Wnt 信号传导对于雄性小鼠海马记忆巩固是必需的7，组蛋白乙酰化是 E2 增强雌性小鼠海马记忆巩固所必需的8，并且 E2 增加雌性小鼠海马 BDNF 蛋白和 Bdnf 启动子处的 H3 乙酰化7。根据我们强有力的初步数据，我们的假设将在三个具体目标中进行测试，旨在：1）确定典型 Wnt 信号传导的雌激素调节在多大程度上促进海马记忆巩固， 2) 确定经典 Wnt 信号传导和 BDNF 相互作用调节海马记忆的程度巩固，3) 确定 E2 介导 BDNF 表达的分子机制这项研究具有创新性，因为它采用了一种整合了假设驱动的方法。行为和生化分析，以确定调节途径之间的机制关系调节男性和女性的海马记忆形成。这项研究具有重要意义。因为这是旨在提供有关以下方面的基础知识的连续研究的第一步这项工作将提供我们迫切需要的 E2 调节记忆形成的分子机制。关于雌激素对两性记忆形成的调节的见解可能会导致记忆的产生专门针对减少每种性别患者的记忆功能障碍而设计的新疗法。进步将极大地改善数百万患者及其家人的生活质量。