De novo Synthesis and Memory

项目摘要 记忆是我们最宝贵的财富，但我们仍然无法防止神经疾病造成的记忆丧失。 在这里，我们研究记忆的一个基本属性，这是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。博士 Worley的实验室率先发现和分析了细胞立即早期基因（IEG）作为效应子， 蛋白质合成依赖的记忆，并已描述的机制介导的IEGs弧，荷马1a和 NPTX2在兴奋性突触处增强活跃突触和减弱不活跃突触。新兴 概念将它们各自的分子和突触功能整合到一个时序程序中， 编码信息的蜂窝和电路适配。这一过程始于Arc和Homer1a， 细胞自主地控制AMPA型谷氨酸受体的突触表达。稍后的过程 由分泌的NPTX 2介导的非细胞自主作用，以加强特定类别的兴奋性突触 表达小清蛋白的抑制性神经元。来自小鼠模型的研究表明， NPTX 2导致神经活动增加，这可能会阻碍网络编码信息的能力， 以及活动依赖性病理学的倾向，包括癫痫发作和淀粉样蛋白生成。 值得注意的是，这种抑制性网络信息存储阶段的各个方面可以在活体人类中进行监测。 科目在人CSF中检测到分泌的NPTX 2，并且在神经系统中显著下调。 与认知功能衰退有关的疾病。我们假设NPTX 2下调提供了一个 人类神经系统疾病中认知状态的合理生物标志物，可能是某些记忆的原因 赤字基础研究将检查控制NPTX 2表达的不寻常的调节机制， 功能，并确定导致其在人脑中下调的过程。我们还将深入 深入了解IEG，特别是NPTX 2如何通过功能的获得和丧失来促进记忆 方法在体内模型的活动依赖性网络可塑性，包括海马重放。很稳定， 长期的支持将使我们能够建立一个多学科的研究计划，利用的优势， 约翰霍普金斯的神经科学社区进行基础研究， 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， 疾病研究。这些研究将为人类为什么会输建立一个新颖的、理性的、可翻译的概念 疾病的记忆功能。

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.