Forward Genetic Approaches to Mechanisms of Cortical Plasticity

描述（由申请人提供）：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，重要的是要开始研究即时记忆和短期记忆之外的记忆阶段，以及海马体最初参与的记忆阶段。我们需要将重点从这些最初的事件转向结构重组等长期过程。我们的重新聚焦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移到新皮层，因为大量证据表明新皮层在远程记忆中起作用。Conte中心提出的皮质可塑性正向遗传方法的总体目标是确定在新皮层中运作的神经可塑性的新机制，这对远程记忆和皮质可塑性都是至关重要的。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，包括一种新的基因筛选，旨在识别小鼠KOs和影响远端但不影响近期记忆的转基因。以下是该中心利用其成员之间长期（bbbb10年）合作关系的框架概述：1)Silva实验室将识别有7天记忆缺陷的ko和转基因动物，但没有1天的记忆缺陷，这是研究最多的啮齿动物情绪记忆模型之一。重要的是，55个突变体的试点筛选已经确定了两个正常的1天记忆，但缺乏7天记忆。2)选取7天记忆突变体进行体感（Fox实验室）和视觉（Stryker实验室）皮质可塑性缺陷筛查。在我们筛选到目前为止选择的两个记忆突变体中，有一个已经被Fox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种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通过电生理学，体内成像和行为工具进行合作研究。4)筛选出的关键基因将被缠绕，中心将对产生的条件突变体进行详细研究。关键思想是利用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难以研究的远程记忆存储过程的可塑性机制。这里提出的研究不仅将阐明尚不清楚的远程记忆机制，还将为与精神分裂症、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治疗的发展提供重要见解。

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.