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Scribble signalosome and active forgetting

涂鸦信号体和主动遗忘

基本信息

批准号：
9884818
负责人：
Isaac Cervantes Sandoval
金额：
$ 14.92万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-02 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9884818
关键词：
AMPA Receptors Affect Animals Architecture Area Behavioral Binding Brain Cells Cognitive Cyclic AMP Decision Making Dendrites Dopamine Receptor Drosophila genus Elements Environment Equilibrium Functional Imaging Future Genes Genetic Genetic study Goals Human Immunoprecipitation Impairment Intelligence Learning Light Lobe Logic Mediating Memory Memory Loss Mental disorders Molecular Molecular Genetics Monitor Monomeric GTP-Binding Proteins Mushroom Bodies N-Methyl-D-Aspartate Receptors Nature Neuronal Plasticity Neurons Neurosciences Output Pathway interactions Process Protein Isoforms Proteins Proteomics Regulation Research Rewards Role Scaffolding Protein Signal Transduction Stimulus Structure Synapses System Weight approach behavior avoidance behavior base classical conditioning cofilin conditioning dopaminergic neuron experience experimental study fitness flexibility forgetting interest memory acquisition memory consolidation memory process neural circuit neural correlate neurotransmitter release presynaptic protein protein interaction rac1 GTP-Binding Protein scaffold virtual

项目摘要

PROJECT SUMMARY/ABSTRACT Mechanisms for memory formation and consolidation have been intensely studied for decades. Surprisingly, the process of forgetting, presumably of equal importance, has been virtually ignored. Fortunately, this focus is shifting and recent neuroscience-based interest in understanding how memories are forgotten has emerged. It is thought that forgetting enhances memory flexibility, by reducing the influence of obsolete information. In addition, forgetting may remove specific details of previous experiences, thereby promoting generalization. Thus, forgetting allows intelligent decision-making in an ever-changing and noisy environment. Research on forgetting is important not only because it will increase our understanding of how memories are processed by the brain but also because many psychiatric disorders may be associated with deficits in forgetting. This is a fledgling field in the study of learning and memory that will take great importance in the future years. Molecular, cellular and systems neuroscience studies using Drosophila have uncovered several major tenets that reveal the logic by which olfactory memories are formed, consolidated and retrieved. The first is that modulation of mushroom body (MB) Kenyon cell (KC) synaptic activity underlies associative learning. A second tenet is that the modulation of KC plasticity employs cAMP signaling. A third is that the mushroom body output neurons (MBOn) receive input from the KC and their activation influences approach or avoidance behavior. A fourth tenet is that dopamine neurons (DAn) are activated by aversive or rewarding stimuli to provide the US input during classical conditioning. Most recently, studies have started to shed some light on the antagonist process to memory acquisition and consolidation, i.e., memory forgetting. Recent molecular genetic studies have identified a role for the small G protein Rac1 in forgetting of olfactory memories. In addition, the dopamine receptor Damb, mediates the process of forgetting and this dopaminergic activity is modulated with the behavioral state of the animal. The current project seeks to build on our current understanding of memory loss by exploring a relatively new role for multidomain scaffolding protein, Scribble. The long-term goal is to define the molecular and functional nature of this scaffolding protein and its interacting proteins. Aim 1 will increase our basic understanding of how Scribble regulates forgetting by untangling the complexity of its gene and the multidomain protein as well as by revealing its subcellular localization. Aim 2 will dissect the molecular architecture of the forgetting signalosome. We will identify Scribble’s protein-protein interactions with the likelihood that we will find additional molecules involved in the regulation of forgetting. Aim 3 will explore the neural correlates of memory forgetting, by following the progression of the neuronal plasticity observed in MBOn and how is this plasticity affected by Scribble and other forgetting regulators like Rac. The significance of the current proposal resides in our poor current understanding of how memories are forgotten.

项目概要/摘要几十年来，人们对记忆形成和巩固的机制进行了深入研究。出奇，遗忘的过程大概同样重要，但实际上却被忽视了。幸运的是，这个重点是最近，人们对理解记忆如何被遗忘产生了基于神经科学的兴趣。它人们认为遗忘可以通过减少过时信息的影响来增强记忆的灵活性。在此外，遗忘可能会消除以前经历的具体细节，从而促进概括。因此，遗忘可以在不断变化和嘈杂的环境中做出明智的决策。研究遗忘很重要，不仅因为它会增加我们对记忆如何处理的理解还因为许多精神疾病可能与遗忘缺陷有关。这是一个学习和记忆研究中的一个新兴领域，在未来几年将变得非常重要。使用果蝇进行的分子、细胞和系统神经科学研究揭示了几个主要原理揭示了嗅觉记忆形成、巩固和检索的逻辑。第一个是蘑菇体（MB）凯尼恩细胞（KC）突触活动的调节是联想学习的基础。一秒钟其原理是 KC 可塑性的调节采用 cAMP 信号传导。第三个是蘑菇体产量神经元 (MBOn) 接收来自 KC 的输入，它们的激活会影响接近或回避行为。一个第四个原则是多巴胺神经元（DAn）被厌恶或奖励刺激激活，以提供美国经典条件作用期间的输入。最近，研究开始揭示拮抗剂的一些情况记忆获取和巩固的过程，即记忆遗忘。最近的分子遗传学研究已经确定了小 G 蛋白 Rac1 在嗅觉记忆遗忘中的作用。此外，多巴胺受体 Damb，介导遗忘过程，这种多巴胺能活性受动物的行为状态。当前的项目旨在建立在我们目前对记忆丧失的理解之上通过探索多结构域支架蛋白 Scribble 的一个相对较新的作用。长期目标是定义该支架蛋白及其相互作用蛋白的分子和功能性质。目标1将会增加我们对 Scribble 如何通过解开其基因的复杂性和多结构域蛋白以及揭示其亚细胞定位。目标 2 将剖析分子遗忘信号体的结构。我们将确定 Scribble 与蛋白质之间的相互作用我们很可能会发现更多参与遗忘调节的分子。目标 3 将探索记忆遗忘的神经相关性，通过跟踪观察到的神经元可塑性的进展 MBOn 以及 Scribble 和 Rac 等其他遗忘调节因子如何影响这种可塑性。当前提案的重要性在于我们目前对记忆如何运作的理解还很有限。忘记了。