Emotional learning-induced changes of neuronal representations in the hippocampal

描述（由申请人提供）：该应用程序的长期目标是了解情绪体验如何改变前脑中的记忆获取和巩固过程。PI在开发最新技术进步方面发挥了重要作用，这些技术进步允许强大的动物内实验设计在多个大脑区域的大群神经元中成像可塑性相关基因表达。应用这种方法（catFISH），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H1 a的神经元群组成的变化，Arc和H1 a是记忆巩固所必需的两种活动调节基因。我们将研究一个两部分的假设：7情绪空间学习改变长期记忆相关的信息处理在CA 1和投射到它的部分CA 3，嗅周（PRh，区35）和外侧内嗅皮层（LEC）。[7]在情绪学习过程中，基底外侧杏仁核（BLA）的激活能够改变由CA 1中的情绪体验引起的信息处理，并将CA 3、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效价，并评估当空间背景是情绪中性时，以及当空间背景与厌恶事件（背景恐惧条件反射）配对时，由空间背景诱导的海马系统中Arc/H1 a+神经元的重叠量。当一个地方情绪中性时以及当同一个地方与电击配对时（低重叠），不同的Arc/H1 a表达神经元群被激活的证据表明，在情绪学习期间，海马系统不仅仅创建上下文表征，而且它具有更普遍的记忆作用，与其参与非情绪学习相似。观察海马的低重叠，并将部分嗅周和外侧内嗅皮层投射到海马，将表明情绪学习在多个层面上调节海马系统的信息处理。我们将结合联合收割机颅内药物输注与catFISH方法，进一步研究情绪学习过程中海马的低重叠是否受到BLA激活的调节。在该假设的第一次测试中，BLA将被灭活，并将如实验1中那样评估重叠。如果在情境恐惧条件反射之前使BLA失活会导致CA 3和CA 1的高度重叠，那么我们的假设将得到支持，这与已经探索了两次情境但没有接受过足电击的大鼠的情况类似。拟议研究的结果将通过回答两个基本问题来显著推进我们的理解：1）受情绪影响的空间记忆表征变化是海马体独有的，还是分布在海马体以及投射到海马体的嗅周和外侧内嗅皮层区域？2)受情绪影响的空间记忆表征变化是否依赖于基底外侧杏仁核（BLA）的激活？公共卫生相关性这一基础科学项目旨在研究情绪学习和基底外侧杏仁核的激活如何影响海马系统的信息处理。由此产生的发现必将在未来十年激发公共卫生领域的一个非常活跃的领域。受情绪影响的过程（包括记忆）的中断在情绪和精神疾病中很常见，如创伤后应激障碍、焦虑、抑郁、精神分裂症、恐惧症和躁狂症。了解情绪如何改变正在进行的信息处理和记忆巩固将使这些疾病中异常机制的研究更具针对性，并将为测试遗传模型和设计成功的治疗方法提供框架。然而，这是一项基础科学建议，能否直接应用于公共卫生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.