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
• 负责人: Karyn M Frick
• 金额: $ 51.61万
• 依托单位: UNIVERSITY OF WISCONSIN MILWAUKEE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-15 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735271
• 关键词: 26S proteasome; Actins; Address; Adult; Alzheimer' s Disease; Anxiety Disorders; Automobile Driving; Brain; Characteristics; Complex; Data; Dendritic Spines; Development; Dorsal; Estradiol; Estrogen Receptors; Etiology; Female; Functional disorder; Generations; Glutamate Receptor; Goals; Gonadal Steroid Hormones; Hippocampus; Ion Channel; Knowledge; Mass Spectrum Analysis; Measures; Mediating; Memory; Memory impairment; Mental Depression; Mental disorders; Mission; Molecular; Mus; National Institute of Neurological Disorders and Stroke; Nervous System; Neurons; Nuclear; Outcome; Pathway Analysis; Patients; Persons; Pharmacology; Play; Polymers; Polyubiquitination; Proteasome Inhibition; Protein Biosynthesis; Proteins; Proteomics; Public Health; Publishing; Regulation; Report (document); Research; Rodent; Role; Sex Differences; Signal Transduction; Slice; Synapses; Synaptic plasticity; System; Testing; Tissues; Ubiquitin; Vertebral column; Woman; Work; behavioral outcome; calmodulin-dependent protein kinase II; density; effective therapy; estrogenic; hormone regulation; in vivo; innovation; insight; male; memory consolidation; men; multicatalytic endopeptidase complex; nervous system disorder; neuromechanism; neuropsychiatric disorder; neuropsychiatry; novel; novel therapeutics; pharmacologic; polymerization; protein degradation; receptor; sex; ubiquitin mediated proteasome degradation

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.

项目概要 记忆障碍是许多神经精神疾病的一个决定性特征，然而，理解 调节海马记忆形成的复杂神经机制仍然难以捉摸。性类固醇 17β-雌二醇 (E2) 是男性和女性海马可塑性和记忆力的强大调节剂， 然而，人们对发生这种情况的神经机制知之甚少。因此，长期目标 我们研究的目的是查明 E2 调节海马记忆的神经机制 男性和女性的巩固。该应用程序的总体目标是确定机制 E2 通过其调节泛素蛋白酶体系统 (UPS) 的活性以及调节的程度 蛋白酶体蛋白降解有助于记忆巩固和海马的雌激素调节 两性的树突棘密度。尽管 UPS 介导的海马蛋白降解是 UPS 活动在调节 E2 的过程中发挥的作用对于突触重塑和记忆巩固至关重要 对两性记忆形成和脊柱重塑的调节作用仍然完全未被探索。我们的 中心假设是 DH 中 UPS 介导的蛋白质降解是由 E2 作用于雌激素和 谷氨酸受体，是 E2 促进记忆巩固和 CA1 的主要机制 脊柱密度。该假设基于先前的工作，表明 E2 通过重叠机制 UPS 活动有助于海马体的可塑性和记忆力。我们的中心假设将在 以下三个具体目标：1）确定E2激活海马的细胞机制 UPS 活性，2) 识别 E2 诱导的跨亚细胞区室 UPS 激活的蛋白质靶标，3) 确定蛋白酶体活性在 E2 诱导的记忆巩固和 CA1 脊柱促进过程中的关键作用 密度。将使用区域和时间特定的药理学操作来建立受体 背侧海马 E2-UPS 相互作用的潜在机制，以及结构和行为 这些相互作用的结果。基于泛素特异性质谱的尖端蛋白质组学也将 用于识别 E2 降解的新蛋白质。这项工作的创新之处在于它代表了 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 调节蛋白质降解作为同等和相反的对应物的新考虑 海马可塑性和记忆的雌激素调节。这一贡献意义重大，因为它将提供 有关 E2 调节记忆巩固机制的重要基础知识 两种性别，这可能会导致开发新的针对性别的治疗方法来解决记忆问题 在许多精神障碍中观察到功能障碍。