Emotional learning-induced changes of neuronal representations in the hippocampal

描述(由申请者提供)：该应用程序的长期目标是了解情感体验如何改变前脑中记忆的获取和巩固过程。PI在开发最新的技术进步方面发挥了重要作用，这些技术进步允许在动物内部进行强大的实验设计，以成像多个大脑区域的大组神经元中可塑性相关基因的表达。应用这种方法(鲶鱼)，该提案概述了一系列实验，这些实验可以识别情绪诱导的表达Arc和H1a的神经元组的组成变化，这两个基因是巩固记忆所必需的活动调节基因。我们将检验一个由两部分组成的假说：7情绪空间学习改变了CA1中与长时记忆相关的信息处理，并向其投射到CA3、脑周围(PRH，第35区)和外侧内嗅皮层(LEC)的部分区域。7在情绪学习过程中杏仁基底外侧核(BLA)的激活使CA1的情绪体验引起的信息处理发生变化，并将CA3、PRH和LEC的部分投射到它。在实验1中，我们将操纵空间背景的情绪价位，并评估当空间背景在情感上是中性的，以及当它与厌恶事件(语境恐惧条件作用)配对时，该空间背景在海马体系统中诱导的Arc/H1a+神经元的重叠量。有证据表明，当一个地方是情绪中立的时候，不同的Arc/H1a表达神经元群被激活，当相同的地方与休克(低重叠)配对时，这表明在情绪学习过程中，海马体系统不仅仅是创建上下文表征，而是具有更一般的助记作用，与其参与非情绪学习类似。观察到海马区的低重叠，并向其投射部分周围和外侧内嗅觉皮质，将表明情绪学习在多个水平上调节海马体系统的信息处理。我们将结合脑内药物注射和鲶鱼方法进一步研究情绪学习过程中海马区的低重叠是否受到BLA激活的调节。在这一假说的第一个测试中，BLA将被灭活，重叠将像实验1中一样被评估。如果在情境恐惧条件反射之前使BLA失活，导致CA3和CA1高度重叠，则我们的假说将得到支持，类似于探索过两次背景但没有在其中受到足电击的大鼠。这项拟议的研究结果将通过回答两个基本问题显著促进我们的理解：1)情绪影响的空间记忆表征的变化是海马特有的，还是分布在海马体以及投射到它的周围和外侧内嗅皮层的区域？2)情绪影响的空间记忆表征的变化是否依赖于杏仁基底外侧核(BLA)的激活？公共卫生相关性这个基础科学项目建议调查情绪学习和由此产生的杏仁核基底外侧区激活如何影响海马体系统的信息处理。由此产生的发现肯定会在未来十年激励公共卫生领域的一个非常活跃的领域。情感影响过程的中断，包括记忆，在情绪和精神障碍中很常见，如创伤后应激障碍、焦虑、抑郁、精神分裂症、恐惧症和躁狂症。了解情绪是如何改变正在进行的信息处理和记忆巩固的，将使人们能够更有针对性地研究这些障碍中的异常机制，并将为测试遗传模型和设计成功的治疗方法提供一个框架。然而，这是一项基础科学建议，对公共卫生的直接适用性将取决于后续的应用研究。

DESCRIPTION (provided by applicant): The long-term objective of the application is to understand how emotional experiences alter memory acquisition and consolidation processes in the forebrain. The PI was instrumental in developing recent technological advances that allow powerful within-animal experimental designs in imaging plasticity-related genes expression in large groups of neurons across multiple brain regions. Applying this method (catFISH) the proposal outlines a series of experiments that can identify emotion-induced changes in the composition of neuronal groups expressing Arc and H1a, two activity-regulated genes that are necessary for memory consolidation. We will examine a two-part hypothesis: 7 Emotional spatial learning changes long term memory-related information processing in CA1 and projecting to it parts of CA3, perirhinal (PRh, area 35) and lateral entorhinal cortex (LEC). 7 Activation of the basolateral amygdala (BLA) during emotional learning enables changes in information processing induced by an emotional experience in CA1 and projecting to it parts of CA3, PRh and LEC. In Experiment 1 we will manipulate the emotional valence of a spatial context and assess the amount of overlap of Arc/H1a+ neurons in the hippocampal system induced by that spatial context when it is emotionally neutral, and when it is paired with an aversive event (contextual fear conditioning). Evidence that different Arc/H1a-expressing neuronal groups are activated when a place is emotionally-neutral and when the same place is paired with shock (low overlap) will suggest that during emotional learning the hippocampal system does not simply create contextual representation, but it has a more general mnemonic role that parallels its involvement in non-emotional learning. Observing low overlap in the hippocampus and projecting to it parts of perirhinal and lateral entorhinal cortex will indicate that emotional learning modulates information processing in the hippocampal system at multiple levels. We will combine intracranial drug infusions with the catFISH method to further investigate whether low overlap in the hippocampus during emotional learning is modulated by activation of the BLA. In a first test of this hypothesis the BLA will be inactivated and overlap will be assessed as in Experiment 1. Our hypothesis will be supported if inactivating the BLA before contextual fear conditioning results in high overlap in CA3 and CA1, similar to that of rats that have explored the context twice, but have not received footshock in it. The findings of the proposed research will significantly advance our understanding by answering two fundamental questions: 1) Are emotionally-influenced changes in spatial memory representations unique to the hippocampus, or are they distributed across the hippocampus and areas of perirhinal and lateral entorhinal cortex projecting to it? 2) Do emotionally-influenced changes in spatial memory representations depend on activation of the basolateral amygdala (BLA)? PUBLIC HEALTH RELEVANCE This basic science project proposes to investigate how emotional learning and resulting activation of the basolateral amygdala affects information processing in the hippocampal system. The resulting findings will be sure to inspire a very active area in public health in the coming decade. Disruption of emotion-influenced processes, including memory, are common in mood and psychiatric disorders such as post traumatic stress disorder, anxiety, depression, schizophrenia, phobias and manias. Understanding how emotion alters ongoing information processing and memory consolidation will enable more targeted studies of the mechanisms that are abnormal in these disorders and will provide a framework for testing genetic models and devising successful treatments. However, this is a basic science proposal and direct applicability to public health will depend upon follow-up applied studies.