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，目前的基因技术不足以剖析NMDA受体在记忆形成的不同阶段中的作用。这项建议侧重于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NMDA受体活性在前两个阶段：学习和记忆巩固中起作用，但在记忆提取中不起作用。为了验证这一假设，一种新开发的基因敲除技术将被用于培育一种突变小鼠，在该突变小鼠中，NMDA受体功能的丧失是可诱导的、可逆的，并且具有区域特异性。第一组主要的实验将集中在这些条件突变的分子、生化和电生理特性上。第二组主要的实验将检验在记忆巩固期间，在初始学习之后，是否需要依次激活海马区和/或皮质区域的NMDA受体。新基因技术可行性的证明应该会导致在解剖其他基因在不同大脑功能的多个过程中的精确功能方面得到广泛应用。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的潜在治疗干预提供新的策略。

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.