CREB regulation of gene expression in spatial and contextual memory

这项建议的总体目标是描述啮齿动物大脑在获得和巩固空间记忆和语境记忆过程中转录水平的变化。空间记忆在本质上与个体在空间中的方位和运动有关，与周围环境中物体的位置有关。语境记忆在周围环境线索和特定事件之间建立认知联系。对空间和背景记忆是如何形成的基本了解，将有助于为各种神经和神经精神疾病设计适当的治疗和预防策略，这些疾病表现出记忆处理的变化，如阿尔茨海默病、中风和创伤后应激障碍。越来越多的证据揭示了基因转录调控在记忆获得和巩固中的作用。CAMP反应元件结合蛋白(CREB)编码基因的定点突变和几个基因的原位杂交研究为基因转录在长期记忆获得和巩固中的作用提供了强有力的证据。我们的总体假设是，CREB功能是在记忆获得和巩固过程中调节基因转录变化所必需的。我们认为，学习和记忆过程伴随着大脑不同区域特定基因转录的积累和下调。此外，我们假设，在Morris Water迷宫和洞板食物搜索任务中，调控基因的一个子集在获得和巩固空间记忆时使用CREB基因敲除小鼠和可诱导的CREB突变体。含有数千个小鼠cDNA的DNA微阵列将用于杂交实验，使用从动物脑中提取的、处于空间记忆获得和巩固不同阶段的33P标记的cDNAs探针。特定目的2将监测CREB基因敲除和可诱导突变小鼠中数千个小鼠基因的表达，以确定CREB调控下与恐惧相关的长期记忆中的转录本。最后，特定目标3将研究CREB突变小鼠在海马片诱导长期潜伏期后基因表达的变化。拟议中的一系列实验将提供新的基础知识，涉及大脑中信息存储的分子机制。

The overall goal of this proposal is to characterize the changes in transcript levels which occur in the rodent brain during acquisition and consolidation of spatial and contextual memory. Spatial memory is associative in nature and relatives to the orientation and movement of an individual in space in relationship to the location of objects in the surrounding environment. Contextual memory establishes cognitive associations between surrounding environmental cues and specific events. A basic understanding of how spatial and contextual memories are formed will enable the design of appropriate treatment and prevention strategies for the various neurologic and neuropsychiatric conditions that display alterations in memory processing, such as Alzheimer's disease, stroke and post-traumatic-stress disorder. An expanding body of evidence reveals a role for the regulation of gene transcription in acquisition and consolidation of memory. Targeted mutation of the gene encoding the cAMP Responsive Element Binding protein (CREB) and in situ hybridization studies of several genes provide strong evidence in support of a role of gene transcription in long-term memory acquisition and consolidation. Our overall hypothesis is that CREB function is necessary to mediate changes in gene transcription throughout acquisition and consolidation of memory. We propose that learning and memory processes are accompanied by accumulation and down regulation of specific gene transcripts within different regions of the brain. Moreover, we hypothesize that a subset of the genes regulated during acquisition and consolidation of spatial memory in the Morris Water maze and the hole board food search task using both CREB knockout mice and inducible CREB mutants. DNA microarrays containing thousands of mouse cDNAs will be used in hybridization experiments using 33P labeled cDNA probes prepared from mouse brain mRNA extracted from animals at different stages of acquisition and consolidation of spatial memory. Specific Aim 2 will monitor the expression of thousands of mouse genes in CREB knockout and inducible mutant mice to identify transcripts under CREB regulation in long-term memory associated with fear. Finally, Specific Aim 3 will study the changes in gene expression which occur in CREB mutant mice following induction of long-term potential in hippocampal slices. The proposed set of experiments will provide new and fundamental knowledge which concerns the molecular mechanisms subserving information storage in the brain.