GENETIC ANALYSIS OF PHASES OF MEMORY CONSOLIDATION

经典的神经学和心理学研究表明，记忆过程包括学习、巩固/储存和提取。很明显，目前的遗传技术不足以解剖NMDA受体在记忆形成的各个阶段的作用。本文介绍了一种新的基因技术及其在记忆巩固分子机制研究中的应用。假设海马和/或皮层的NMDA受体活性在学习和记忆巩固的前两个阶段起作用，但在记忆提取中不起作用。为了验证这一假设，将采用一种新开发的基因敲除技术来产生一种突变小鼠，其中NMDA受体功能的丧失是可诱导的、可逆的和亚区域特异性的。第一组主要的实验将集中在这些条件突变体的分子、生化和电生理特征上。第二组主要的实验将检验在记忆巩固期间，是否需要在初始学习后海马和/或皮层区域的NMDA受体的顺序激活。新的基因技术的可行性证明，将导致在解剖其他基因在各种脑功能的多个过程中的精确功能的广泛应用。此外，了解记忆巩固和储存的分子机制也可能为治疗记忆障碍提供新的潜在治疗干预策略。

Classic neurological and psychological studies have indicated that memory process consists of learning, consolidation/storage, and retrieval. It is obvious that the present genetic technologies are inadequate for dissecting the role of NMDA receptors in various stages of memory formation. This proposal focuses on a new genetic technology and its application in the study of the molecular mechanisms of memory consolidation. It is hypothesized that the NMDA receptor activity in the hippocampus and/or cortex plays a role in the first two stages: learning and the memory consolidation, but not in memory retrieval. To test this hypothesis, a newly developed gene knockout technology will be employed to produce a mutant mouse in which the loss of NMDA receptor function is inducible, reversible, and subregion- specific. The first major set of experiments will be focused on molecular, biochemical, and electrophysiological characterizations of on these conditional mutants. The second major set of experiments will be conducted to examine whether the sequential activation of NMDA receptors in the hippocampus and/or cortical regions after initial learning is required during the period of memory consolidation. Demonstration of feasibility of new genetic technology should lead to a broad application in dissecting the precise functions of other genes in multiple-processes of various brain functions. Moreover, understanding the molecular mechanisms of memory consolidation and storage may also reveal new strategy for potential therapeutic interventions for the treatment of memory disorders.