Models of Signaling Mechanisms in LTP

描述（由申请人提供）：我们所知道的，或怀疑我们知道的，关于学习和记忆的大部分来自长时程增强（LTP）的研究。LTP首先在海马中发现，是可以由强高频动作电位序列诱导的突触强度或重量的增加。尽管多年的研究，它仍然不知道确切的动作电位到达突触在特定的时间模式可以产生细胞信号，触发树突棘内的生化反应，导致突触强度的长期修改。该项目将通过结合建模和实验研究来描述随着长时程增强的发展而发生的细胞信号传导过程，从而提供对这一过程的理解。 具体目标是：1）为了量化在单个突触处需要多少变化来解释在LTP中观察到的增强量，2）为了系统地确定成功地引发LTP的刺激方案，以允许识别特定方案可以激活的信号级联，3）为了表征突触故障在启动或阻碍信号传导过程中的作用，4）确定海马CA 1区NMDA依赖型和NMDA非依赖型LTP信号机制的差异; 5）了解分子信号复合物在树突棘中的发育和功能。 结合建模和实验研究将提供关键的见解，一些悬而未决的问题，细胞信号的机制，在长时程增强。这些知识可用于了解正常学习和记忆以及预防或破坏酒精滥用时发生的学习和记忆的机制。所使用的方法可能具有普遍适用性的信号系统在其他领域的生理学或基因调控。

DESCRIPTION (provided by applicant): Much of what we know, or suspect we know, about learning and memory comes from the study of long-term potentiation (LTP). LTP, first discovered in the hippocampus, is an increase in the strength or weight of synapses that can be induced by strong high frequency trains of action potentials. Despite years of study, it is still not known precisely how action potentials arriving al synapses in particular temporal patterns can generate cellular signals that trigger the biochemical reactions within dendritic spines that lead to long-term modifications of synaptic strength. This project will provide an understanding of this process by combining modeling and experimental studies to characterize the cellular signaling processes that occur with the development of long-term potentiation. Specific aims are: 1) To quantify how much of a change at individual synapses is necessary to account for the amount of potentiation observed in LTP, 2) To determine systematically stimulation protocols that are successful in eliciting LTP to allow identification of signaling cascades that particular protocols may activate, 3) To characterize the role of synaptic failures in initiating or hindering signaling processes, 4) To identify the differences in signaling mechanisms involved in NMDA-dependent and NMDA-independent forms of LTP in hippocampal area CA1, 5) To understand how molecular signaling complexes develop and function in dendritic spines. The combined modeling and experimental studies will provide critical insights into some of the outstanding questions about the mechanisms of cellular signaling in long-term potentiation. This knowledge can be used to understand mechanisms involved both in normal learning and memory and in the prevention or disruption of learning and memory that occurs with alcohol abuse. The methods used could have general applicability to signaling systems in other areas of physiology or for gene regulation.