CAREER Molecular Basis of Synapse Specific Long-Term Memory Storage

神经科学的一个基本问题与记忆有关——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，新突触连接的形成和原有突触连接的重塑对记忆的形成至关重要。然而，对于长期记忆是如何储存在大脑中特定的突触中，我们知之甚少。为了解决这个根本的、尚未解决的问题，研究人员将利用已经被充分研究过的海蜗牛鳃退缩反射回路中的大型、已确定的神经元。这种神经回路的关键组成部分可以很容易地被识别、分离和培养，从而在培养皿中产生神经回路，从而可以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。这项工作的结果将对长期记忆的突触特异性本质的分子机制产生新的见解。作为该项目的一部分，来自不同背景的高中生和本科生将接受指导，并积极参与本研究的各个方面。此外，还将开发和实施以初高中学生和初高中教师为培训对象的神经科学探究式课程。该项目旨在研究突触特异性长期记忆储存的分子和细胞机制。首先，该项目将评估诸如蛋白质和mrna等基因产物是否以及如何从神经元的细胞体运输到特定的突触。由于分子运动蛋白激酶介导基因产物从细胞体的运输，激酶在记忆形成和维持过程中向突触的运动将使用先进的定量活细胞成像显微镜进行研究。其次，mrna通过激酶转运到特定的突触区室，将使用单细胞基因组学工具进行鉴定。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运动蛋白dynein来研究。综上所述，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区室的特定mrna，以存储长期记忆。

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.