De novo Synthesis and Memory

从头合成和记忆

• 批准号: 10056993
• 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/10056993
• 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.

项目摘要 记忆是我们最宝贵的潜力，但我们仍然无法防止其神经系统疾病的丧失。 在这里，我们检查了记忆的基本特性，这是对快速蛋白的依赖 合成并确定有助于正常记忆和人类记忆丧失构成的途径。博士 沃利（Worley）的实验室率先发现和分析细胞立即的早期基因（IEG）作为生效者 蛋白质合成依赖性记忆，并描述了由IEGS ARC，Homer 1a和 兴奋性突触中的NPTX2，可以增强主动突触和弱非活性突触。新兴 概念将其个体分子和突触功能整合到顺序的临时程序中 编码信息的蜂窝和电路适应。该过程始于Arc和Homer1a，该过程 细胞自主，以控制AMPA型谷氨酸受体的突触表达。以后的过程 由分泌的NPTX2介导的无自动细胞自动起作用以增强特定类别的兴奋性突触 表达白蛋白的抑制性神经元。来自小鼠模型的研究表明，调节 NPTX2导致神经活动增加，这可能会阻止网络编码信息的能力，例如 以及对活动依赖性病理的希望，包括癫痫发作和Aß淀粉样蛋白产生。 值得注意的是，可以在活着的人类中监视信息存储的这种抑制网络阶段 主题。分泌的NPTX2在人CSF中检测到，在神经系统中显着下调 与认知定义相关的疾病。我们假设NPTX2下调提供了 人类神经疾病的认知状况的理性生物标志物可能是某些记忆的原因 缺陷。基础研究将研究控制NPTX2表达和 功能并确定导致其在人脑下调的过程。我们还将更深入 深入了解IEGS和NPTX2如何使用功能的增益和丧失有助于记忆 在活动依赖性网络可塑性的体内模型中接近包括海马重放的。稳定的， 长期支持将使我们能够建立一个多学科研究计划，以利用 约翰·霍普金斯（Johns Hopkins）基础研究的神经科学社区，以及 约翰·霍普金斯（Johns Hopkins）的神经病理学和精神病学和圣地亚哥加州大学神经病学的转化方面 疾病研究。这些研究将建立一个新颖，理性和可翻译的概念 疾病的记忆功能。