De novo Synthesis and Memory

项目摘要 记忆是我们最宝贵的财富，但我们仍然无法阻止它在神经系统疾病中的丧失。 在这里，我们研究记忆的一个基本属性，即它对快速从头蛋白的依赖 合成，并找出有助于正常记忆和导致人类记忆丧失的途径。Dr。 沃利的实验室率先发现和分析了细胞即刻早期基因(IEGs)作为效应器 并描述了IEGS Arc，Hmer 1a和IEGS Arc，Hmer 1a和 NPTX2位于兴奋性突触，加强活跃的突触，削弱不活跃的突触。新兴 概念将它们各自的分子和突触功能集成到序列的时间程序中 编码信息的细胞和电路适配。这一过程始于Arc和Hmer 1a，它们起作用 细胞-自主控制AMPA型谷氨酸受体的突触表达。稍后的流程 由分泌的NPTX2介导的非细胞自主作用增强特定类别的兴奋性突触 表达小白蛋白的抑制神经元。来自小鼠模型的研究表明，向下调节 NPTX2导致神经活动增加，这可能会阻止网络编码信息的能力，因为 以及活动依赖的病理倾向，包括癫痫发作和淀粉样蛋白的生成。 值得注意的是，可以在活人身上监测到信息存储的这种抑制网络阶段的各个方面 研究对象。在人的脑脊液中检测到分泌型NPTX2，并在神经系统中显著下调 与认知退化有关的疾病。我们假设NPTX2下调提供了一个 人类神经系统疾病认知状态的合理生物标记物，可能是某些记忆的原因 赤字。基础研究将研究控制NPTX2表达和 功能，并确定导致其在人脑中下调的过程。我们还将获得更深的 深入了解IEG，特别是NPTX2是如何通过功能的获得和丧失来促进记忆的 活体模型中活动依赖的网络可塑性的方法，包括海马体回放。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 约翰霍普金斯大学神经科学界的基础研究，以及 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学，翻译方面 疾病研究。这些研究将建立一个新的、合理的、可翻译的概念来解释为什么人类会输 疾病中的记忆功能。

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.