Anterograde Amnesia for Contextual Fear

描述（由申请人提供）：本提案探讨了多种交替的神经通路如何介导习得性恐惧记忆。我们的方法确定了4个关键假设：1)存在能够调解恐惧记忆的主要和替代途径。2)替代途径比主要途径效率低。3)更有效的主要途径主导了学习，排除了替代途径中的重要学习。4)当显性途径受损时，替代途径会进行补偿。具体的目标是使用行为和解剖学技术来指导情境恐惧条件反射的三个功能解剖阶段，以确定这些不同的途径是什么以及学习是如何在这些途径之间被调节的。这三个阶段分别是：1)Context Processing, 2) CS-US Association和3)Response Generation，这三个阶段通常分别由海马、基底外侧杏仁核和中央杏仁核介导。一个关键的发现是，虽然训练后对网络主要组成部分的损害严重损害了情境恐惧条件反射，但训练前的损害影响较小，因为替代途径弥补了破坏。这种补偿是由控制记忆形成的调节机制驱动的。通过使用行为测试、即时早期基因表达和通道追踪来确定一个区域的失活是否会导致替代途径中活性和行为重要性的增加，从而对该模型进行测试。在巴甫洛夫恐惧条件反射中，调节机制经常排除替代通路的作用。识别不同的恐惧通路，了解它们的功能以及它们是如何被招募的，对于理解恐惧条件反射的调节是至关重要的。从这个角度来看，当环境中的威胁和生物体的适应性反应之间缺乏平衡时，焦虑症就会出现。换句话说，焦虑症是恐惧和焦虑的正常调节机制的失败。一个关键的目标是发展对大脑如何维持“恐惧的内稳态”的理解，该模型的核心是在产生适应性行为的各种途径之间调节恐惧。

DESCRIPTION (provided by applicant): This proposal investigates how multiple alternate neural pathways mediate learned fear memories. Our approach identifies 4 key hypotheses: 1) There are primary & alternate pathways capable of mediating fear memory. 2) The alternate pathways are less efficient than the primary pathway. 3) The more efficient primary pathway dominates the learning, precluding significant learning in the alternate pathways. 4) The alternate pathways compensate when the dominant pathway is compromised. The specific aims are to use behavioral and anatomical techniques directed at 3 functional-anatomical stages of contextual fear conditioning, to determine what are these different pathways and how learning is being regulated between these pathways. These stages are: 1) Context Processing, 2) CS-US Association and 3) Response Generation, which are normally mediated by the hippocampus, basolateral amygdala and central amygdala, respectively. A key finding is that while posttraining lesions to a primary component of the network severely compromises contextual fear conditioning, pretraining lesions have lesser effects because alternate routes compensate for the disruption. This compensation is driven by regulatory mechanisms that control memory formation. This model is tested by determining if inactivating one region results in increased activity and behavioral importance in the alternate pathway using behavioral testing, immediate early gene expression and tract tracing. Regulatory mechanisms often preclude a role for the alternate pathways in Pavlovian fear conditioning. Identifying alternate fear pathways, understanding their function and how they are recruited, is essential for understanding the regulation of fear conditioning. From this perspective, anxiety disorders emerge when there is a lack of a balance between the threat in the environment and an organism's adaptive response. In other words, anxiety disorders are a failure of the normal regulatory mechanisms of fear and anxiety. A key goal is to develop an understanding of how the brain maintains a "homeostasis of fear," At the model's core is the regulation of fear between various pathways that generate adaptive behavior.