Abstract

How the brain encodes, stores, and retrieves memories is a central question in neuroscience. Memory is a fundamental cognitive process that allows us to retain and recall past experiences but also enables us to learn, adapt, and navigate an ever-changing environment. At the heart of memory processing is the hippocampus, a brain region essential for contextualizing memories and guiding behavior accordingly, yet the neural and behavioral mechanisms underlying context-sensitive memory expression remain incompletely understood.

Freezing behavior, a rodent defensive response to threats, is a well-established model for studying context-dependent fear memory retrieval. Freezing expression adapts between robust responses to threat-associated contexts (context-specific fear) and generalization to similar contexts (context-generalized fear), influenced by multiple factors affecting memory processing. Its value as a memory indicator makes the accurate identification of freezing crucial and highlights the importance of refining its analysis methods. However, conventional freezing analysis overlooks nuanced features that could illuminate memory processing regulation, such as the behavioral mechanisms driving freezing adaptation in different contexts. Further, the hippocampal activity dynamics underlying context-sensitive freezing responses, especially the role of inhibitory neurons, are not fully described.

This thesis addresses these gaps by combining advanced behavioral analysis with real-time neural fiber photometry recordings and proposing new approaches for studying freezing. We develop and validated a protocol to optimize freezing detection thresholds, enhancing objective and accurate identification of memory-related freezing. We also reveal how freezing features —bout count and duration and temporal-spatial dynamics— are influenced by experimental factors (shock intensity, number, location and memory age) and differ between context-specific and generalized fear. Incorporating these features into principal component analysis highlighted their distinct contributions to context discrimination. Finally, we identify that PV⁺ and SST⁺ inhibitory populations in hippocampal CA1 and dentate gyrus subregions modulate their activity during freezing, with SST⁺ neurons showing subregion-specific roles and context-sensitive modulation.

Overall, this thesis introduces innovative approaches for analyzing freezing and provides new insights into the behavioral and neural mechanisms regulating context-appropriate fear responses, advancing our understanding of context-sensitive memory.