CREB IN DECLARATIVE AND NON-DECLARATIVE MEMORY IN MOUSE

小鼠声明性和非声明性内存中的 CREB

基本信息

批准号：
6293963
负责人：
Christopher John Pittenger
金额：
$ 2.23万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-02-07 至 2001-08-31
项目状态：
已结题

项目摘要

Different forms of memory employ different logical, serve different behavioral roles, and are associated with different neuroanatomical structures, but appear to use similar mechanisms of information storage. Specifically, memories are believed to e stored in plastic change in the connections between neurons. Abnormalities of synaptic plasticity have been suggested in the etiology of retardation, drug addiction, depression, and other pathological states. Synaptic plasticity, as well as many forms of learning, has an early and late phase; the late phase requires gene activation. The transcription CREB has been implicated as a major player in the induction of the genes required for long-lasting, late-phase plasticity. I have generated transgenic mice which expressing a dominant- negative allele of CREB, which interferes with its function in the induction of downstream genes. In one transgenic line, expression of the transgene is largely restricted to the CA1 region of the dorsal hippocampus; plasticity in this region has been strongly implicated in the learning of behavioral tasks. I have shown that mice of the line are deficient in the acquisition of spatial memory but not in a control task. A second line of mice expresses the transgene exclusively in the dorsal striatum, a structure that is required for the learning of certain habit-based tasks. These mice are deficient in two such tasks but not in hippocampus- dependent learning. Future studies under this fellowship will further explore the behavioral phenotype of these two lines of mice further characterize the molecular consequences of interfering with CREB function, and (in collaboration with others) investigate the electrophysiological correlates of these observed behavioral deficits. These studies will lead to an increased understanding of the mechanisms of different forms of learning in normal and pathological conditions.

不同形式的记忆采用不同的逻辑，扮演不同的行为角色，并与不同的神经解剖结构相关联，但似乎使用了相似的信息存储机理。具体而言，记忆被认为是在神经元之间的连接中存储在塑性变化中的。在迟钝，药物成瘾，抑郁症和其他病理状态的病因学病因中已经提出了突触可塑性的异常。突触可塑性以及许多形式的学习，具有早期和晚期。晚期需要基因激活。转录CREB被认为是诱导长期持久，后期可塑性所需的基因的主要参与者。我已经产生了表达CREB的显性阴性等位基因的转基因小鼠，该等位基因在下游基因的诱导中干扰了其功能。在一个转基因线中，转基因的表达在很大程度上仅限于背侧海马的CA1区域。该地区的可塑性与学习行为任务有关。我已经表明，该线的小鼠在获取空间内存方面不足，而不是在控制任务中。第二行小鼠在背纹状体中仅表示转基因，这是学习某些基于习惯的任务所需的结构。这些小鼠在两个这样的任务中缺乏，但在海马依赖性学习中没有。在该奖学金下的未来研究将进一步探索这两条小鼠的行为表型，进一步表征了干扰CREB功能的分子后果，并（与他人合作）研究了这些观察到的行为缺陷的电生理相关性。这些研究将导致人们对在正常和病理条件下不同形式学习的机制的理解增加。