Forward Genetic Approaches to Mechanisms of Cortical Plasticity

皮质可塑性机制的正向遗传学方法

• 批准号: 7138204
• 负责人: ALCINO J. SILVA
• 金额: $ 160.29万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7138204
• 关键词: Forward; Genetic; Approaches; Mechanisms; Cortical

Description (Provided by Applicant): How is progress going to be made in understanding memory, including emotional memory and its disorders? We propose that it is important to start looking at phases of memory beyond immediate and short-term memory, beyond the initial involvement of the hippocampus. We need to alter the focus from these initial events to longer-term processes such as structural reorganization. Our refocus needs to switch from the molecular processes controlling receptor modification to those controlling synaptic and dendritic structure. Furthermore, our attention should also change from hippocampus to neocortex, as a wealth of evidence implicates neocortex in remote memory. The overall goal of the proposed Conte Center for Forward Genetic Approaches to Cortical Plasticity is to identify novel mechanisms of neural plasticity that operate in the neocortex and are critical for both remote memory and cortical plasticity. To accomplish this goal we propose to use state-of-the-art transgenic, electrophysiological and imaging approaches, including a novel genetic screen designed to identify mouse KOs and transgenics that affect remote, but not recent memory. The following is an outline of the framework of the Center that takes advantage of the long-standing (>10 years) collaborative relationship among its members: 1) The Silva laboratory will identify KOs and transgenics that have 7-, but no 1-day memory deficits for contextual conditioning, one of the most studied rodent models of emotional memory. Importantly, a pilot screen of 55 mutants already identified two with normal 1-day, but deficient 7-day memory. 2) The selected 7-day memory mutants will be screened for somatosensory (Fox Laboratory) and visual (Stryker Laboratory) cortical plasticity deficits. Out of the two memory mutants selected so far in our screen, one has been studied by the Fox group and found to have abnormal somatosensory plasticity! Our previous collaborative work also identified another mutation with the same properties (aCaMKII null heterozygous mutation). 3) Mutants that affect all three forms of plasticity will be studied collaboratively by all three laboratories with electrophysiology, in vivo imaging and behavioral tools. 4) Key genes identified in the screen will be floxed and the resulting conditional mutants will be studied in detail by the Center. The key idea is to leverage the wealth of tools and information available for somatosensory and visual cortical plasticity to understand the plasticity mechanisms underlying the harder-to- study process of remote memory storage in neocortical networks. The studies proposed here will not only shed light on poorly understood mechanisms of remote memory, they will also provide important insights for the development of treatments for memory disorders associated with psychiatric and neurologic conditions such as schizophrenia, depression and Alzheimer's disease.

描述（申请人提供）：在理解记忆，包括情绪记忆及其障碍方面将取得哪些进展？我们认为，重要的是要开始关注即时和短期记忆之外的记忆阶段，超越海马体的最初参与。我们需要将重点从这些初始事件转移到结构重组等长期进程。我们需要将焦点从控制受体修饰的分子过程转移到控制突触和树突结构的分子过程。此外，我们的注意力也应该从海马体转移到新皮层，因为大量证据表明新皮层与远程记忆有关。拟议的康特中心的总体目标是向前遗传方法的皮质可塑性是确定新的神经可塑性机制，在新皮层中运作，是至关重要的远程记忆和皮层可塑性。为了实现这一目标，我们建议使用国家的最先进的转基因，电生理和成像方法，包括一种新的遗传屏幕，旨在确定小鼠科斯和转基因影响远程，但不是最近的记忆。以下是利用其成员之间的长期（>10年）合作关系的中心框架的概述：1）席尔瓦实验室将识别科斯和转基因动物，这些动物具有7天但没有1天的情境条件反射记忆缺陷，这是研究最多的情绪记忆啮齿动物模型之一。重要的是，对55个突变体的试验性筛选已经确定了两个具有正常的1天记忆，但缺乏7天记忆。2)筛选选定的7天记忆突变体的体感（Fox Laboratory）和视觉（斯特赖克实验室）皮质可塑性缺陷。在我们筛选出的两个记忆突变体中，福克斯小组已经研究了其中一个，发现它具有异常的躯体感觉可塑性！我们之前的合作工作还鉴定了另一种具有相同性质的突变（aCaMKII无效杂合突变）。3)所有三个实验室将利用电生理学、体内成像和行为工具合作研究影响所有三种形式可塑性的突变体。4)在筛选中确定的关键基因将被floxed，产生的条件突变体将由该中心详细研究。关键的想法是利用丰富的工具和信息可用于躯体感觉和视觉皮层可塑性，以了解可塑性机制的基础上更难研究的远程记忆存储过程中的新皮层网络。这里提出的研究不仅将揭示远程记忆的机制知之甚少，它们还将为开发与精神分裂症，抑郁症和阿尔茨海默病等精神和神经疾病相关的记忆障碍的治疗方法提供重要的见解。