The role of extracellular matrix in estradiol regulation of hippocampal memory consolidation

项目摘要 记忆障碍是许多神经精神疾病的定义特征，然而我们的理解是， 记忆功能障碍的神经生物学机制以及治疗这些问题的能力 症状仍然不足。性类固醇激素17 β-雌二醇（E2）是一种强大的学习调节剂 并且对海马体有深远的影响，海马体是记忆形成的关键区域。e2诱发的 海马体内的信号传导对于记忆巩固是必要的，但分子机制 产生这种效果的原因还没有完全确定。因此，我们研究的长期目标是确定 E2调节海马记忆形成的分子机制。的总体目标 本申请旨在确定ECM分子MMP-9和β 1-整联蛋白的必要程度 E2增强雄性和雌性小鼠的海马记忆。根据之前的数据显示， MMP-9和β 1-整合素作为海马可塑性的重要调节因子共同发挥作用，我们的中心假设是： E2通过增加MMP-9修饰ECM增强海马记忆巩固 酶活性和随后的细胞表面β 1-整联蛋白受体活化。这项工作的基本原理是 通过揭示E2在调节海马可塑性和记忆中的作用的新机制，我们将 提高我们的理解和能力，治疗目标，雌激素调节海马 功能障碍我们的中心假设将在两个特定的目标进行测试：1）确定在多大程度上， MMP-9的雌激素调节有助于海马记忆增强，和2）确定 雌二醇和β 1-整联蛋白受体相互作用产生海马记忆增强的程度。 这两个目标都将使用生物化学和行为方法的组合来表征机制， E2调节海马ECM的结果。首先，将E2直接注入背侧 研究了MMP-9和β 1-整合素在雄性和雌性小鼠海马中的表达和活性， 评估。然后，使用一次性学习任务和颅内灌注药理学抑制剂，我们将 确定MMP-9和β 1-整合素影响记忆巩固的雌激素调节的程度。 这项工作是创新的，因为它代表了一个根本性的转变，从传统的重点放在细胞内 信号传导机制，以考虑ECM在雌激素调节中的潜在重要作用， 记忆巩固。通过直接评估ECM对雌激素记忆调节的作用， 将推进海马中E2信号传导的现有模型，以整合细胞外和细胞内 信号处理。这一贡献是重要的，因为它将提供必要的基础知识 关于雌二醇调节男性和女性大脑记忆形成的机制， 其将用于产生记忆功能障碍的新的假定治疗靶点。

PROJECT SUMMARY Memory impairment is a defining characteristic of many neuropsychiatric disorders, however our understanding of the neurobiological mechanisms of memory dysfunction and ability to therapeutically address these symptoms remain inadequate. The sex steroid hormone 17β-estradiol (E2) is a powerful regulator of learning and memory and has profound effects in the hippocampus, a region critical to memory formation. E2-induced signaling within the hippocampus is necessary for memory consolidation, but the molecular mechanisms producing this effect are still not fully defined. Therefore, the long-term goal of our research is to determine the molecular mechanisms through which E2 regulates hippocampal memory formation. The overall objective of this application is to determine the extent to which the ECM molecules MMP-9 and β1-integrin are necessary for E2 to enhance hippocampal memory in both male and female mice. Based on previous data showing that MMP-9 and β1-integrin work together as critical regulators of hippocampal plasticity, our central hypothesis is that E2 enhances hippocampal memory consolidation through modification of the ECM via increased MMP-9 enzymatic activity and subsequent activation of cell-surface β1-integrin receptors. The rationale for this work is that by uncovering novel mechanisms of E2 action in regulating hippocampal plasticity and memory, we will improve our understanding, and ability to therapeutically target, estrogenic regulation of hippocampal dysfunction. Our central hypothesis will be tested in two specific aims: 1) determine the extent to which estrogenic regulation of MMP-9 contributes to hippocampal memory enhancement, and 2) determine the extent to which estradiol and β1-integrin receptors interact to produce hippocampal memory enhancement. Both aims will use a combination of biochemical and behavioral methods to characterize the mechanisms and outcomes of E2 regulation of the hippocampal ECM. First, E2 will be directly infused into the dorsal hippocampus of male and female mice and the effects on MMP-9 or β1-integrin expression and activity will be assessed. Then, using one-trial learning tasks and intracranial infusion of pharmacological inhibitors, we will determine the extent to which MMP-9 and β1-integrin influence estrogenic regulation of memory consolidation. This work is innovative in that it represents a fundamental shift from the conventional focus on intracellular signaling mechanisms to consider the potentially important contribution of the ECM in estrogenic regulation of memory consolidation. By directly assessing the contributions of the ECM to estrogenic memory regulation, we will advance the existing model of E2 signaling in the hippocampus to integrate extracellular and intracellular signaling processes. This contribution is significant because it will provide essential foundational knowledge about the mechanisms through which estradiol regulates memory formation in the male and female brain, which will serve to generate new putative therapeutic targets for memory dysfunction.