Memory traces bias new learning for hippocampal generalization

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bioRxiv. 2025 Nov 25;. doi: 10.1101/2025.11.24.690297

Qian FK, Li G, Lipshutz D, Romani S, Magee JC

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Abstract

The ability to use generalized prior experience to guide behavior in novel situations is a fundamental cognitive function. While recent evidence suggests that the hippocampus supports generalization how this is accomplished is poorly understood. Here we combined longitudinal optical imaging in head-fixed mice with computational modeling to examine generalization in hippocampal area CA1. We found that prior training accelerated behavioral adaptation to a novel environment and that this was accompanied by highly stable hippocampal representations. We identified putative memory traces from prior experience that enabled this generalization at multiple levels. At the population level, novel-context network dynamics rapidly aligned with low-dimensional neural subspaces established during prior experience. At the cellular level, spatially-informative weak "residual" activity reflecting generalizable information about the task structure appeared to bias which neurons form place fields (PFs) and where via behavioral timescale synaptic plasticity (BTSP). Finally, this was an active process as many PFs changed their reference frame in the novel environment to reflect the consistent task structure. In sum, the influence of memory traces on new PF formation may allow past experience to guide new learning such that representations are based on generalizable features, thus enabling rapid adaptive behavior in new contexts.

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bioRxiv preprint: https://www.biorxiv.org/content/early/2025/11/25/2025.11.24.690297

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Memory traces bias new learning for hippocampal generalization

Abstract

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