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:
- 金额:$ 37.38万
- 依托单位:
- 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:
- 关键词:AcetylationAddressAdultAlzheimer&aposs DiseaseAnxiety DisordersBehavioralBehavioral SciencesBiochemicalBrainBrain-Derived Neurotrophic FactorCharacteristicsComplexCritical PathwaysDataDendritic SpinesDevelopmentDiseaseDown SyndromeEpigenetic ProcessEpilepsyEstradiolEstrogen Receptor alphaEstrogen Receptor betaEstrogen ReceptorsEstrogensEtiologyFRAP1 geneFamilyFemaleFoundationsFunctional disorderGenerationsGenetic TranscriptionGoalsGonadal Steroid HormonesHippocampus (Brain)Histone AcetylationImpairmentIschemiaKnowledgeLeadLearningMediatingMemoryMemory impairmentMental disordersMolecularMusNational Institute of Mental HealthNeurodegenerative DisordersNeurodevelopmental DisorderOutcomePathway interactionsPatientsPharmaceutical PreparationsPlaguePrevalenceProcessProteinsPublic HealthPublishingQuality of lifeRegulationResearchResearch DesignRoleSeveritiesSex DifferencesSignal PathwaySignal TransductionSynaptic plasticityTestingTherapeuticTranslationsVisionWNT Signaling PathwayWnt proteinsWomanWorkbasebrain behaviordesigneffective therapyestrogenicimprovedinnovationinsightmalememory consolidationmemory processmenneuromechanismneuropsychiatric disorderneuropsychiatrynovel therapeuticspromoterprotein H(3)sextherapy 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.
记忆定义了患有多种精神障碍的瘟疫患者,但根本缺乏有关
调节记忆形成的神经元机制阻碍了疗法的发展
此内存功能障碍。性别立体声马酮17β-雌二醇(E2)是海马的有效调节剂
突触可塑性和记忆力,可能导致患病率,进展和
许多精神病和神经退行性疾病的严重程度。但是,神经力学通过
E2调节记忆的理解很少。这是迫切需要识别分子机制
E2通过它调节两个性别的学习和记忆过程。我们的长期目标是确定
雌激素调节男性海马记忆形成的关键神经元机制
该应用程序的总体目标,这是实现我们目标的下一步,是
确定规范的Wnt信号传导和BDNF在多大程度上有助于增强内存效应
E2。我们的中心假设是E2通过促进Wnt信号来增强内存,然后
表观遗传调节BDNF的转录和翻译。这些假设是在
已发表的数据的依据,表明Wnt信号增加了BDNF表达式6,而我们自己已发布的数据
表明规范Wnt信号对于雄性小鼠的海马记忆巩固是必需的。
E2需要组蛋白乙酰化以增强雌性小鼠的海马记忆巩固和
该E2增加了雌性小鼠BDNF启动子的海马BDNF蛋白和H3乙酰化。指导
我们强大的初步数据,我们的假设将以三个特定目的进行检验:1)确定
规范Wnt信号传导设施海马记忆巩固的雌激素调节的程度
2)确定规范Wnt信号传导和BDNF相互作用以调节海马记忆的程度
巩固,3)确定E2介导BDNF表达和的分子机制
内存形成。这项研究具有创新性,因为它利用了一种假设驱动的方法来整合
行为和生化分析,以确定调节途径之间的机械关系
调节男性和女性的海马记忆形成。拟议的研究很重要
因为这是持续研究的第一步,旨在提供有关有关的基础知识
E2通过其调节记忆形成的分子机制。这项工作将非常需要
关于两个性别中记忆形成的雌激素调节的见解,这可能导致产生
专门针对每种性别患者的记忆功能障碍而定制的新型疗法。这种疗法
进步将大大改善数百万患者及其家人的生活质量。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Karyn M Frick其他文献
Karyn M Frick的其他文献
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{{ truncateString('Karyn M Frick', 18)}}的其他基金
UW-Milwaukee Promoting Equity, Diversity, and Academic Success Through Aging Research Program (UWM STAR)
威斯康星大学密尔沃基分校通过老龄化研究项目促进公平、多样性和学业成功 (UWM STAR)
- 批准号:
10626597 - 财政年份:2023
- 资助金额:
$ 37.38万 - 项目类别:
Estrogenic regulation of the hippocampal ubiquitin-proteasome system and its role in memory and structural plastcity
海马泛素-蛋白酶体系统的雌激素调节及其在记忆和结构可塑性中的作用
- 批准号:
10735271 - 财政年份:2023
- 资助金额:
$ 37.38万 - 项目类别:
Hormone and enrichment effects on memory in aging mice
激素和浓缩对衰老小鼠记忆力的影响
- 批准号:
7255624 - 财政年份:2005
- 资助金额:
$ 37.38万 - 项目类别:
Hormone and enrichment effects on memory in aging mice
激素和浓缩对衰老小鼠记忆力的影响
- 批准号:
6979946 - 财政年份:2005
- 资助金额:
$ 37.38万 - 项目类别:
Hormone and enrichment effects on memory in aging mice
激素和浓缩对衰老小鼠记忆力的影响
- 批准号:
7646244 - 财政年份:2005
- 资助金额:
$ 37.38万 - 项目类别:
Hormone and enrichment effects on memory in aging mice
激素和浓缩对衰老小鼠记忆力的影响
- 批准号:
7122783 - 财政年份:2005
- 资助金额:
$ 37.38万 - 项目类别:
Hormone and enrichment effects on memory in aging mice
激素和浓缩对衰老小鼠记忆力的影响
- 批准号:
7474011 - 财政年份:2005
- 资助金额:
$ 37.38万 - 项目类别:
Estrogenic-cholinergic interactions in memory modulation
记忆调节中的雌激素-胆碱能相互作用
- 批准号:
6574123 - 财政年份:2002
- 资助金额:
$ 37.38万 - 项目类别:
Estrogenic-cholinergic interactions in memory modulation
记忆调节中的雌激素-胆碱能相互作用
- 批准号:
6686809 - 财政年份:2002
- 资助金额:
$ 37.38万 - 项目类别:
HORMONE EFFECTS ON MEMORY AND NEUROBIOLOGY IN AGING MICE
激素对衰老小鼠记忆和神经生物学的影响
- 批准号:
2865456 - 财政年份:1999
- 资助金额:
$ 37.38万 - 项目类别:
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