Anterograde Amnesia for Contextual Fear

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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.