Dynamic shifts between pattern separation and reinstatement in human CA3 and dentate gyrus

Distinguishing similar memories is thought to require hippocampal pattern separation, the orthogonalization of overlapping neural representations. Here, high-resolution 7-Tesla fMRI during one-shot encoding of similar target-lure pairs demonstrated that pattern separation and reinstatement are modulated by stimulus domain, similarity, and hippocampal long-axis position. Univariate novelty responses during successful object and scene discrimination were found across medial temporal lobe cortex and hippocampal subfields. Multivariate neural pattern similarity was reduced for correctly rejected low-similarity lures across domains throughout all medial temporal regions, consistent with pattern separation. Increasing target-lure similarity resulted in more hippocampal than cortical pattern separation. An exception were high-similarity scene lures which elicited greater hippocampal pattern similarity, indicating reinstatement. In dentate gyrus and CA3, reduced pattern similarity predicted better object, increased similarity better scene memory, depending on hippocampal long-axis position. Pattern separation and reinstatement are therefore not fixed computational properties of specific subregions but shift dynamically during fast episodic learning.