Estrogenic regulation of the hippocampal ubiquitin-proteasome system and its role in memory and structural plastcity

项目摘要 然而，记忆障碍是许多神经精神障碍的一个明显特征，然而，一种理解 调控海马体记忆形成的复杂神经机制仍然难以捉摸。性激素 17雌二醇(17β-estadiol，E_2)对男性和女性的海马可塑性和记忆都有很强的调节作用。 然而，人们对这种情况发生的神经机制知之甚少。因此，长期目标是 我们研究的重点是确定雌激素调节海马体记忆的神经机制 男性和女性的巩固。本应用程序的总体目标是确定机制 E2通过什么来调节泛素蛋白酶体系统(UPS)的活性以及在多大程度上 蛋白酶体蛋白降解参与记忆巩固和海马区的雌激素调节 树突棘密度在两性中均较高。尽管UPS介导的海马区蛋白质降解 突触重构和记忆巩固所必需的UPS活性在介导E_2‘S中的作用 无论男女，对记忆形成和脊柱重塑的调节作用仍完全不清楚。我们的 中心假说是UPS介导的蛋白质降解是由E2作用于雌激素和雌激素而触发的。 谷氨酸受体，是E2促进记忆巩固和CA1的主要机制 脊椎密度。这一假说是基于之前的工作，即E2通过重叠的机制 UPS活性参与了海马区的可塑性和记忆功能。我们的中心假设将在#年评估 以下三个具体目标：1)确定雌激素激活海马体的细胞机制 UPS活性，2)确定雌激素诱导的UPS跨细胞亚区激活的蛋白质靶点，3) 蛋白酶体活性在E2诱导的记忆巩固和CA1脊椎易化中的关键作用 密度。将使用区域和时间特定的药理操作来建立受体 背侧海马区E2-UPS相互作用的机制以及结构和行为 这些互动的结果。基于尖端泛素特定质谱学的蛋白质组学也将 用于识别E2靶向降解的新蛋白质。这项工作具有创新性，因为它代表了一种 从传统的关注蛋白质合成作为雌激素记忆的主要贡献者的根本转变 对蛋白质降解这一新的考虑进行了调整，认为这是蛋白质降解所必需的对等和相反的对应关系 雌激素对海马可塑性和记忆的调节。这一贡献意义重大，因为它将提供 关于E2调节记忆巩固的机制的基本基础知识 两性，这可能导致开发针对性别的新治疗方法来解决记忆问题 在许多精神障碍中观察到的功能障碍。

Project Summary Memory impairment is a defining characteristic of many neuropsychiatric disorders, however, an understanding of the complex neural mechanisms regulating hippocampal memory formation remains elusive. The sex steroid 17β-estradiol (E2) is a powerful modulator of hippocampal plasticity and memory in both males and females, however the neural mechanisms through which this occurs are poorly understood. Therefore, the long-term goal of our research is to pinpoint the neural mechanisms through which E2 regulates hippocampal memory consolidation in males and females. The overall objectives of this application are to determine the mechanisms through which E2 regulates activity of the ubiquitin proteasome system (UPS) and the extent to which proteasomal protein degradation contributes to estrogenic regulation of memory consolidation and hippocampal dendritic spine density in both sexes. Although UPS-mediated protein degradation in the hippocampus is essential for synaptic remodeling and memory consolidation, the role that UPS activity plays in mediating E2’s modulatory effects on memory formation and spine remodeling in either sex remains completely unexplored. Our central hypothesis is that UPS-mediated protein degradation in the DH is triggered by E2 acting at estrogen and glutamate receptors and is a principal mechanism through which E2 promotes memory consolidation and CA1 spine density. This hypothesis is based on previous work suggesting overlapping mechanisms through which E2 and UPS activity contribute to hippocampal plasticity and memory. Our central hypothesis will be evaluated in the following three specific aims: 1) determine the cellular mechanisms through which E2 activates hippocampal UPS activity, 2) identify protein targets of E2-induced UPS activation across subcellular compartments, 3) establish a key role for proteasome activity in E2-induced facilitation of memory consolidation and CA1 spine density. Regionally- and temporally- specific pharmacological manipulations will be used to establish receptor mechanisms underlying E2-UPS interactions in the dorsal hippocampus, as well as the structural and behavioral outcomes of these interactions. Cutting edge ubiquitin-specific mass spectrometry-based proteomics will also be used to identify novel proteins targeted by E2 for degradation. This work is innovative in that it represents a fundamental shift from a conventional focus on protein synthesis as a primary contributor to estrogenic memory modulation to a novel consideration of protein degradation as an equal and opposite counterpart necessary for estrogenic regulation of hippocampal plasticity and memory. This contribution is significant because it will provide essential foundational knowledge about the mechanisms through which E2 regulates memory consolidation in both sexes, which could lead to the development of novel sex-specific treatments to address the memory dysfunction observed in numerous mental disorders.