UC San Diego

Pavlovian fear conditioning, in which a neutral stimulus is paired with a shock, has been instrumental in uncovering the neural and molecular mechanisms underlying memory since the discovery that post-training lesions of the hippocampus disrupt contextual, but not cued, fear memory. Because of the paradigm’s relative simplicity, it has become the leading animal model of declarative memory. In contrast to post-training lesions, which produce severe amnesia of contextual fear, some studies have found that mice and rats with pre-training hippocampal lesions may acquire normal contextual memory, suggesting an alternative pathway for contextual fear learning. The prevailing theory proposes that the intact hippocampus uses a configural strategy, integrating environmental cues into a cohesive representation before it can be associated with shock, while a compromised hippocampus employs an elemental strategy, associating individual cues with shock. Despite the widespread use of contextual fear conditioning, it remains unclear what animals actually learn about static “elemental” environmental cues.This thesis introduces a novel within-subjects "context deconstruction" testing paradigm to systematically evaluate freezing responses to individual contextual components across three sensory modalities in mice. Chapter 1 reveals that intact mice exhibit an all-or-none response to the context, showing robust fear of the entire context, largely ignoring individual components, which aligns with the configural representation theory. This representation persists well into the systems consolidation period, despite repeated testing. Chapter 2 explores the protocol's utility by identifying distinct freezing patterns to contextual components following pharmacological manipulations known to impair context memory acquisition, highlighting the sensitivity of this approach. Under some dosing regimens, particularly those that produce amnesia, mice appear to use an elemental strategy. Chapter 3 directly tests whether hippocampal-lesioned mice acquire an elemental representation of the context. Results suggest an amalgamation of the configural and elemental hypotheses: there is evidence that mice respond to individual contextual cues, but freezing to the full training context remains more pronounced compared to freezing to partial contexts. This thesis emphasizes the need for more thorough fear conditioning protocols to elucidate subtle deficits in context learning, contributing to advancing our understanding of learning and memory processes in normal and compromised brain states.