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: 7821476
• 负责人: ALCINO J. SILVA
• 金额: $ 208.25万
• 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/7821476
• 关键词: Forward; Genetic; Approaches; Mechanisms; Cortical

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.

在理解记忆（包括情绪记忆及其障碍）方面将如何取得进展？我们认为，重要的是开始研究超越即时记忆和短期记忆、超越海马体最初参与的记忆阶段。我们需要将重点从这些初始事件转向结构重组等长期进程。我们的重新关注需要从控制受体修饰的分子过程转向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向新皮质，因为大量证据表明新皮质与远程记忆有关。拟议的皮质可塑性正向遗传方法孔特中心的总体目标是确定在新皮质中运行的神经可塑性的新机制，并且对远程记​​忆和皮质可塑性都至关重要。为了实现这一目标，我们建议使用最先进的转基因、电生理学和成像方法，包括一种新颖的基因筛选，旨在识别影响远期记忆但不影响近期记忆的小鼠基因敲除和转基因。以下是该中心的框架概述，该框架利用了其成员之间长期（>10年）的合作关系： 1) Silva实验室将识别具有7天但没有1天的KO和转基因情境调节的记忆缺陷，这是研究最多的啮齿动物情绪记忆模型之一。重要的是，对 55 个突变体的初步筛选已经鉴定出其中两个具有正常的 1 天记忆，但缺乏 7 天记忆。 2）选定的7天记忆突变体将进行体感（Fox实验室）和视觉（Stryker实验室）皮质可塑性缺陷的筛选。迄今为止在我们的屏幕上选择的两种记忆突变体中，其中一种已被福克斯小组研究并发现具有异常的体感可塑性！我们之前的合作工作还发现了另一个具有相同特性的突变（aCaMKII 无效杂合突变）。 3) 影响所有三种可塑性形式的突变体将由所有三个实验室利用电生理学、体内成像和行为工具进行合作研究。 4) 筛选中确定的关键基因将被floxed，由此产生的条件突变体将由中心进行详细研究。关键思想是利用可用于体感和视觉皮层可塑性的丰富工具和信息来理解新皮层网络中较难研究的远程记忆存储过程背后的可塑性机制。