CAREER Molecular Basis of Synapse Specific Long-Term Memory Storage

突触特异性长期记忆存储的分子基础

• 批准号: 1453799
• 负责人: Sathyanarayanan Puthanveettil
• 金额: $ 60.98万
• 依托单位: The Scripps Research Institute
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2020-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1453799&HistoricalAwards=false
• 关键词: CAREER; Molecular; Basis; Synapse; Specific

One of the fundamental questions in neuroscience concerns memory-- how it works and why it goes wrong. Decades of research have identified that, at the cellular level, formation of new synaptic connections and remodeling of pre-existing synaptic connections are critical for memory formation. However, very little is known about how long-term memories are stored at specific synapses in the brain. To address this fundamental and unresolved problem, the investigators will take advantage of the large, identified neurons of the well-studied gill-withdrawal reflex circuitry of the sea snail Aplysia. The key components of this neural circuitry can easily be identified, isolated, and cultured to generate neural circuits in a dish that are amenable to investigation at the single-cell and subcellular level. Integrating synapse-specific physiological measurements with state-of-the-art live-cell imaging and tools for single-cell genomics analysis, the investigators will study the role of axonal transport in generating and maintaining synapse-specific long-term memory. The results from this work will yield novel insights into the molecular mechanisms that underlie the synapse-specific nature of long-term memories. As part of this project, high school and undergraduate students from diverse backgrounds will receive mentoring and be actively involved in various aspects of this study. Furthermore, a neuroscience inquiry-based lesson that involves the training of middle and high school students and middle school teachers will be developed and implemented. The proposed project investigates the molecular and cellular mechanisms underlying synapse-specific long-term memory storage. First, the project will assess whether and how gene products such as proteins and mRNAs are transported from the cell-body of neurons to specific synapses. Because the molecular motor protein kinesin mediates the transport of gene products from the cell-body, kinesin movement to synapses during memory formation and maintenance will be studied using advanced quantitative live-cell imaging microscopy. Second, mRNAs transported to specific synaptic compartments by kinesin will be identified using single-cell genomics tools. Third, whether and how the synapse communicates back to the cell-body during memory formation will be studied by characterizing the molecular motor protein dynein that moves from the synapse to the cell body. Taken together, these studies will bring novel molecular and mechanistic insights into understanding long-term memory storage and help identify specific mRNAs localized to specific synaptic compartments for storing long-term memories.

神经科学中的一个基本问题是关于记忆的--它是如何工作的，为什么会出错。 几十年的研究已经确定，在细胞水平上，新的突触连接的形成和预先存在的突触连接的重塑对于记忆的形成至关重要。然而，人们对长期记忆是如何储存在大脑中特定的突触上的知之甚少。为了解决这个根本的和未解决的问题，研究人员将利用大的，已确定的神经元的研究鳃回缩反射电路的海蜗牛。这种神经回路的关键组成部分可以很容易地识别，分离和培养，以在培养皿中产生神经回路，这些神经回路适合在单细胞和亚细胞水平上进行研究。 将突触特异性生理测量与最先进的活细胞成像和单细胞基因组学分析工具相结合，研究人员将研究轴突运输在产生和维持突触特异性长期记忆中的作用。这项工作的结果将产生新的见解的分子机制的基础突触特异性的长期记忆的性质。作为该项目的一部分，来自不同背景的高中和本科生将接受指导，并积极参与本研究的各个方面。此外，还将开发和实施一门涉及初中和高中学生以及中学教师培训的神经科学探究课。 该项目旨在研究突触特异性长期记忆存储的分子和细胞机制。首先，该项目将评估基因产物（如蛋白质和mRNA）是否以及如何从神经元的细胞体转运到特定的突触。由于分子马达蛋白驱动蛋白介导的基因产物从细胞体的运输，在记忆的形成和维护过程中，驱动蛋白运动到突触将使用先进的定量活细胞成像显微镜进行研究。其次，将使用单细胞基因组学工具鉴定由驱动蛋白转运到特定突触区室的mRNA。第三，在记忆形成过程中，突触是否以及如何与细胞体进行通信，将通过表征从突触移动到细胞体的分子马达蛋白动力蛋白来研究。总之，这些研究将为理解长期记忆存储带来新的分子和机制见解，并有助于识别定位于特定突触隔室的特定mRNA，用于存储长期记忆。