Mechanisms in the Expression and Decay of Long-Term Habituation Memory

描述(由申请人提供)：学习会在行为、生理和基因表达方面产生长期的变化。尽管这一原理现在已经在整个动物界得到了很好的证明，但学习和记忆的基本方面仍然不清楚：1)支持长期记忆的生理和基因变化是如何跨神经回路整合的。2)如果遗忘代表长期记忆过程的衰退或活跃的擦除过程，以及3)记忆获得和保持的个体差异是如何产生的。为了解决学习和记忆中的这些基本问题，我们提出了一套简单的实验，使用海兔尾巴诱导的虹吸-撤退反射(T-SWR)的长期习服。各组动物将接受长期的习惯化训练(5组30个刺激施加在一侧的尾巴，30s的ISI，块之间90分钟)。这种训练可以使T-SWR行为得到长期的单边减少。为了确定LTH的生理相关性，训练的动物将被麻醉并减少到虹吸尾准备，从而能够在进行中的行为期间从T-SWR回路进行生理记录。通过比较每只动物训练侧和非训练侧的尾部诱发神经活动，将有可能确定LTH训练引起的长期神经可塑性的位置。在生理记录之后，来自T-SWR电路每一层的训练侧和非训练侧的神经元将被物理隔离。为了确定LTH的分子相关性，将从收获的细胞中提取RNA，反转录，并使用微阵列进行分析。通过对训练后1天和7天收获的动物重复同样的过程，将有可能确定记忆表达(1天)和衰退(7天)的生理和遗传相关性。此外，在群体内的分析将能够识别生理和转录因素，这些因素预测在长期习服的获得和衰退中明显存在的相当大的变异性。最后，用这种方法确定的LTH相关者将被实验操纵，以确定它们在LTH记忆的表达和衰退中的随意作用。这个项目提供了一种简单的方法，在为本科生参与提供极好机会的实验背景下，获得对长期记忆机制的基本洞察。 与公共健康相关：这个项目将探索调节习惯化长期记忆的遗传和神经变化，这是一种在整个动物界共享的简单形式的记忆。通过研究简单模式生物(Aplysia Calfornica)的习惯化机制，将有可能从根本上洞察记忆储存和随后衰退的过程。结果可能不仅对记忆障碍的治疗有影响，而且对被认为依赖于习惯化的各种注意力过程也有影响。

DESCRIPTION (provided by applicant): Learning produces long-term changes in behavior, physiology, and gene expression. Although this principle is now well-documented across the animal kingdom, fundamental aspects of learning and memory remain unclear: 1) how physiological and genetic changes supporting long-term memory are integrated across a neural circuit. 2) if forgetting represents the decay of long-term memory processes or an active erasure process, and 3) how individual differences in memory acquisition and retention arise. To address these fundamental issues in learning and memory, we propose a simple set of experiments using long-term habituation of the Aplysia tail-elicited siphon-withdrawal reflex (T-SWR). Groups of animals will be exposed to long-term habituation training (5 blocks of 30 stimuli applied to one side of the tail, 30s ISI, 90 min between blocks). This training produces a long-lasting and unilateral decrease in T-SWR behavior. To determine the physiological correlates of LTH, trained animals will be anesthetized and reduced to a siphon+tail preparation, enabling physiological recordings from the T-SWR circuit during ongoing behavior. By comparing tail-evoked neural activity from the trained and untrained side of each animal, it will be possible to identify sites of long- term neural plasticity elicited by LTH training. After physiological recordings, neurons from trained and untrained sides of each layer of the T-SWR circuit will be physically isolated. To determine the molecular correlates of LTH, RNA from harvested cells will be extracted, reverse-transcribed, and profiled using microarrays. By repeating this same procedure with animals harvested 1 and 7 days after training, it will be possible to determine physiological and genetic correlates of a memory expression (1 day) and decay (7 days). In addition, within group analyses will enable identification of physiological and transcriptional factors that predict the considerable variability evident in the acquisition and decay of long-term habituation. Finally, LTH correlates identified with this approach will be experimentally manipulated to determine their casual role in the expression and decay of LTH memory. This project provides a tractable means to gain fundamental insight into the mechanisms of long-term memory in an experimental context that offers excellent opportunities for undergraduate involvement. PUBLIC HEALTH RELEVANCE: This project will explore the genetic and neural changes that mediate long-term memory for habituation, a simple form of memory that is shared across the entire animal kingdom. By studying the mechanisms of habituation in a simple model organism (Aplysia californica), it will be possible to gain fundamental insight into the processes by memories are stored and subsequently decay. Results may have implications not only for the treatment of memory disorders, but also for a variety of attentional processes thought to depend on habituation.