De novo Synthesis and Memory

从头合成和记忆

• 批准号: 10307140
• 负责人: PAUL F WORLEY
• 金额: $ 57.31万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10307140
• 关键词: Amyloid; Amyloid beta-Protein; Biological Markers; Brain; Cells; Clinical; Cognitive; Communities; Dependence; Deterioration; Disease; Down-Regulation; Excitatory Synapse; Failure; Generations; Glutamate Receptor; Hippocampus (Brain); Homer 1a; Human; Immediate-Early Genes; Individual; Information Storage; Interdisciplinary Study; Laboratories; Mediating; Memory; Memory Loss; Memory impairment; Messenger RNA; Molecular; Monitor; Neurology; Neurosciences; Parvalbumins; Pathology; Pathway interactions; Phase; Process; Property; Protein Biosynthesis; Psychiatry; Research; Seizures; Synapses; human subject; in vivo Model; inhibitory neuron; insight; loss of function; mouse model; nervous system disorder; neuropathology; novel; prevent; programs; relating to nervous system; response; synaptic function

Project Summary Memory is our most precious possession, yet we remain unable to prevent its loss in neurological diseases. Here we examine a fundamental property of memory, which is its dependence on rapid de novo protein synthesis, and identify pathways that contribute to normal memory and that underlie human memory loss. Dr. Worley's laboratory pioneered the discovery and analysis of cellular immediate early genes (IEGs) as effectors of protein synthesis-dependent memory, and has described mechanisms mediated by IEGs Arc, Homer 1a and NPTX2 at excitatory synapses that strengthen active synapses and weaken inactive synapses. Emerging concepts integrate their individual molecular and synaptic functions into a temporal program of sequential cellular and circuit adaptations that encode information. The process begins with Arc and Homer1a, which act cell-autonomously to control the synaptic expression of AMPA type glutamate receptors. A later process mediated by secreted NPTX2 acts non cell-autonomously to strengthen excitatory synapses on a specific class of inhibitory neurons that express parvalbumin. Studies from mouse models indicate that down regulation of NPTX2 results in increased neural activity that may occlude the ability of networks to encode information, as well as a propensity for activity-dependent pathology including seizures and Aß amyloid generation. Remarkably, aspects of this inhibitory network phase of information storage can be monitored in living human subjects. Secreted NPTX2 is detected in human CSF and is prominently down-regulated in neurological diseases in association with cognitive deterioration. We hypothesize that NPTX2 down-regulation provides a rational biomarker of cognitive status in human neurological disease and may be is causal for certain memory deficits. Basic studies will examine the unusual regulatory mechanisms that control NPTX2 expression and function, and identify processes that result in its down-regulation in human brain. We will also gain deeper insight into how IEGs, and NPTX2 in particular, contribute to memory using gain and loss of function approaches in in vivo models of activity-dependent network plasticity including hippocampal replay. Stable, long-term support will allow us to establish a multidisciplinary research program that leverages the strengths of the Neuroscience community at Johns Hopkins for basic studies, and the Clinical Departments of Neuropathology and Psychiatry at Johns Hopkins and Neurology at UC San Diego for translational aspects of disease research. These studies will establish a novel, rational, and translatable concept for why humans lose memory function in disease.

项目概要 记忆是我们最宝贵的财富，但我们仍然无法阻止神经系统疾病导致的记忆丧失。 在这里，我们研究了记忆的一个基本特性，即它对快速从头蛋白质的依赖 合成，并确定有助于正常记忆和人类记忆丧失的途径。 Worley 的实验室率先发现并分析了作为效应子的细胞立即早期基因 (IEG) 蛋白质合成依赖性记忆，并描述了 IEG Arc、Homer 1a 和 NPTX2 作用于兴奋性突触，可增强活跃突触并削弱非活跃突触。 概念将其各自的分子和突触功能整合到顺序的时间程序中 编码信息的细胞和电路适应过程始于 Arc 和 Homer1a，它们起作用。 细胞自主地控制 AMPA 型谷氨酸受体的突触表达。 由分泌的 NPTX2 介导，非细胞自主地作用，以增强特定类别的兴奋性突触 小鼠模型的研究表明表达小白蛋白的抑制性神经元的下调。 NPTX2 导致神经活动增加，可能会阻碍网络编码信息的能力，如 以及活动依赖性病理倾向，包括癫痫发作和 Aß 淀粉样蛋白生成。 值得注意的是，信息存储的抑制网络阶段的各个方面可以在活人中进行监控 在人类脑脊液中检测到分泌的 NPTX2，并且在神经系统中显着下调。 我们勇敢地认为 NPTX2 下调提供了一种与认知恶化相关的疾病。 人类神经系统疾病认知状态的合理生物标志物，可能与某些记忆有关 基础研究将检查控制 NPTX2 表达和的异常调节机制。 功能，并确定导致其在人脑中下调的过程。我们还将获得更深入的了解。 深入了解 IEG，尤其是 NPTX2 如何利用功能的获得和丧失来促进记忆 活动依赖性网络可塑性的体内模型的方法，包括稳定的海马重放。 长期支持将使我们能够建立一个多学科研究计划，利用以下方面的优势： 约翰·霍普金斯大学的神经科学界进行基础研究，以及临床部门 约翰霍普金斯大学的神经病理学和精神病学以及加州大学圣地亚哥分校的神经病学的转化方面 这些研究将为人类为何失败建立一个新颖、合理且可转化的概念。 疾病中的记忆功能。