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: 8110620
• 负责人: ALCINO J. SILVA
• 金额: $ 205.56万
• 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 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8110620
• 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在内的记忆中将如何取得进展？我们建议，重要的是，除了直接和短期内存之外，还要开始查看记忆阶段，而不是海马的最初参与。我们需要将重点从这些初始事件改变为长期过程，例如结构重组。我们的重新集中需要从控制受体修饰的分子过程转变为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到新皮层，因为大量证据暗示了遥不可及的新皮层。拟议的孔戴（Conte Centre for Conte Center of Conte Center for Cort遗传方法）的总体目标是确定在新皮层中起作用的神经可塑性的新型机制，对于远程记忆和皮质可塑性至关重要。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，包括一种新型的遗传筛查，旨在识别鼠标KOS和转基因，这些筛查和转基因会影响遥远的记忆，但不影响最近的记忆。以下是该中心框架的概述，它利用了其成员之间长期的（> 10年）的协作关系：1）Silva实验室将确定具有7--但没有为上下文调节的1天记忆缺陷的KOS和转基因，这是最受过研究的啮齿动物模型的情感记忆之一。重要的是，已经确定了两个突变体的试验屏幕，其中两个屏幕为正常的1天但缺乏7天的记忆。 2）选定的7天记忆突变体将筛选体感（FOX实验室）和视觉（Stryker实验室）皮质可塑性缺陷。在迄今为止在我们屏幕上选择的两个记忆突变体中，福克斯组对一个记忆突变体进行了研究，发现具有异常的体感可塑性！我们以前的协作工作还确定了具有相同特性（ACAMKII无效杂合突变）的另一个突变。 3）影响所有三种形式可塑性的突变体将由所有三个具有电生理学，体内成像和行为工具的实验室进行协作。 4）将在屏幕上鉴定出的关键基因会被鞭打，并将由中心详细研究所得的条件突变体。关键思想是利用可用于体感和视觉皮质可塑性的大量工具和信息，以了解新皮层网络中远程存储器存储的难度难以研究过程的可塑性机制。

项目成果

Synaptic tagging during memory allocation.

• DOI: 10.1038/nrn3667
• 发表时间: 2014-03
• 期刊: NATURE REVIEWS NEUROSCIENCE
• 影响因子: 34.7
• 作者: Rogerson, Thomas;Cai, Denise J.;Frank, Adam;Sano, Yoshitake;Shobe, Justin;Lopez-Aranda, Manuel F.;Silva, Alcino J.
• 通讯作者: Silva, Alcino J.

Distinctive features of adult ocular dominance plasticity.

• DOI: 10.1523/jneurosci.2451-08.2008
• 发表时间: 2008-10-08
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Sato M;Stryker MP
• 通讯作者: Stryker MP

The role of nitric oxide synthase in cortical plasticity is sex specific.

• DOI: 10.1523/jneurosci.3189-12.2012
• 发表时间: 2012-10-24
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Dachtler J;Hardingham NR;Fox K
• 通讯作者: Fox K

Molecular and cellular approaches to memory allocation in neural circuits.

• DOI: 10.1126/science.1174519
• 发表时间: 2009-10-16
• 期刊: Science (New York, N.Y.)
• 作者: Silva AJ;Zhou Y;Rogerson T;Shobe J;Balaji J
• 通讯作者: Balaji J

Experience-dependent plasticity acts via GluR1 and a novel neuronal nitric oxide synthase-dependent synaptic mechanism in adult cortex.

• DOI: 10.1523/jneurosci.1590-11.2011
• 发表时间: 2011-08-03
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Dachtler J;Hardingham NR;Glazewski S;Wright NF;Blain EJ;Fox K
• 通讯作者: Fox K