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

记忆缺陷困扰着患有许多精神障碍的患者，但对此缺乏基本的了解 调节记忆形成的神经机制阻碍了治疗方法的发展 这种记忆障碍。性激素17雌二醇(17β-estadiol，E_2)是一种强有力的海马区调节剂 突触的可塑性和记忆，并可能有助于性别差异的患病率，进展和 许多精神疾病和神经退行性疾病的严重性。然而，神经机制通过它 人们对E2对记忆的调节知之甚少。因此，迫切需要确定分子机制。 雌二醇通过它来调节两性的学习和记忆过程。我们的长期目标是找出 雌激素调节男性和大鼠海马区记忆形成的关键神经机制 女性。此应用程序的总体目标是实现我们的目标的下一步，即 确定规范的Wnt信号和脑源性神经营养因子在多大程度上促进记忆增强 雌二醇组。我们的中心假设是，E2通过促进Wnt信号来增强记忆，然后 表观遗传学调控BDNF的转录和翻译。这些假说是在 已发表的数据表明Wnt信号增加了BDNF的表达，我们自己的已发表的数据也是如此 表明规范的Wnt信号对雄性小鼠的海马区记忆巩固是必要的， 组蛋白乙酰化是雌二醇增强雌性小鼠海马区记忆巩固所必需的。 雌二醇增加雌性小鼠海马区BDNF蛋白和BDNF启动子上的H3乙酰化。指导原则 我们强大的初步数据，我们的假设将在三个特定的目标中进行测试：1)确定 经典Wnt信号的雌激素调节促进海马区记忆巩固的程度， 2)建立规范的Wnt信号和BDNF相互作用的程度，以调节海马记忆 以及3)确定E2介导BDNF表达的分子机制和 记忆的形成。这项研究具有创新性，因为它利用了一种假设驱动的方法， 行为和生化分析，以确定调控途径之间的机制关系 调节男性和女性的海马体记忆形成。这项拟议的研究具有重要意义 因为这是一系列研究的第一步，旨在提供关于 E2调节记忆形成的分子机制。这项工作将提供急需的 关于雌激素性调节记忆形成的洞察可能导致 专门为减少男女患者记忆障碍而量身定做的新疗法。这样的治疗方法 进步将极大地改善数百万患者及其家人的生活质量。

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.