Models of Signaling Mechanisms in LTP

描述(由申请人提供)：我们对学习和记忆所知或怀疑所知的大部分来自对长时程增强(LTP)的研究。LTP最先在海马体中发现，它是一种突触强度或重量的增加，可以由强大的高频动作电位序列诱导。尽管进行了多年的研究，但仍不清楚到达特定时间模式的突触的动作电位如何产生细胞信号，从而触发树突棘内的生化反应，从而导致突触强度的长期改变。这个项目将通过将建模和实验研究相结合来描述随着长时程增强的发展而发生的细胞信号过程，从而提供对这一过程的理解。 具体目标是：1)量化单个突触的多少变化才能解释LTP中观察到的增强量；2)系统地确定成功诱导LTP的刺激方案，以便识别特定方案可能激活的信号级联；3)表征突触故障在启动或阻止信号过程中的作用；4)确定在海马区CA1区NMDA依赖和NMDA非依赖形式的LTP所涉及的信号机制的差异；5)了解分子信号复合体如何在树突棘中发展和发挥功能。 模型和实验相结合的研究将为关于细胞信号在长时程增强中的机制的一些悬而未决的问题提供关键的见解。这些知识可以用来理解正常学习和记忆以及防止或破坏因酗酒而发生的学习和记忆的机制。所使用的方法可能对其他生理学领域的信号系统或基因调控具有普遍适用性。

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.