Forward Genetic Approaches to Mechanisms of Cortical Plasticity

描述(由申请人提供)：如何在理解记忆，包括情绪记忆及其障碍方面取得进展？我们认为，重要的是要开始研究记忆的各个阶段，超越即时和短期记忆，超越海马体的最初参与。我们需要将重点从最初的事件转移到更长期的进程，如结构重组。我们需要将重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大脑皮层，因为大量证据表明新大脑皮层与远程记忆有关。拟议的皮层可塑性正向遗传方法研究中心的总体目标是确定在新皮质中工作的神经可塑性的新机制，这些机制对远程记忆和皮质可塑性都是关键的。为了实现这一目标，我们建议使用最先进的转基因、电生理和成像方法，包括一种新的遗传屏幕，旨在识别影响远程但不影响最近记忆的小鼠KO和转基因。以下是该中心的框架，该中心利用其成员之间长期(&gt；10年)的合作关系：1)席尔瓦实验室将识别在情境条件作用下有7天但没有1天记忆缺陷的KO和转基因动物，这是研究最多的啮齿动物情感记忆模型之一。重要的是，55个突变体的试点筛选已经确定了两个1天正常但缺乏7天记忆的人。2)选择的7天记忆突变体将进行躯体感觉(Fox实验室)和视觉(Stryker实验室)皮质可塑性缺陷的筛查。到目前为止，在我们的屏幕上选择的两个记忆突变体中，有一个已经被福克斯研究小组研究，发现具有异常的躯体感觉可塑性！我们之前的合作工作也发现了另一个具有相同属性的突变(aCaMKII零杂合突变)。3)所有三个实验室将利用电生理学、活体成像和行为工具共同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筛选，由此产生的条件突变将由该中心详细研究。其关键思想是利用躯体感觉和视觉皮质可塑性可用的丰富工具和信息来了解新皮质网络中远程记忆存储过程背后的可塑性机制，这一过程很难研究。这里提出的研究不仅将阐明人们对远程记忆知之甚少的机制，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。

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.