Anterograde Amnesia for Contextual Fear

描述(由申请者提供)：这项提案调查了多条交替的神经通路如何调节获得性恐惧记忆。我们的方法确定了四个关键假设：1)存在能够调节恐惧记忆的主要途径和替代途径。2)替代途径的效率低于主要途径。3)更有效的初级路径支配了学习，排除了在替代路径上的显著学习。4)当主导途径受到损害时，替代途径会起到补偿作用。具体目标是使用针对情境恐惧条件作用的三个功能解剖阶段的行为和解剖学技术，以确定这些不同的路径以及这些路径之间的学习是如何受到调节的。这些阶段是：1)语境加工，2)CS-US联想和3)反应生成，通常分别由海马体、杏仁基底外侧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伤会严重影响情境恐惧条件反射，但训练前的损伤影响较小，因为替代路径弥补了这种干扰。这种补偿是由控制记忆形成的调节机制驱动的。通过行为学测试、即刻早期基因表达和轨迹追踪来确定灭活一个区域是否会导致替代路径中活动和行为重要性的增加，从而对该模型进行测试。调节机制通常排除了替代通路在巴甫洛夫恐惧条件反射中的作用。识别替代的恐惧途径，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。一个关键的目标是了解大脑是如何维持“恐惧的动态平衡”的，该模型的核心是调节产生适应性行为的各种途径之间的恐惧。

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.