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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疾病患者，但人们对记忆缺陷缺乏基本的认识