Inhibitory tone in the dentate gyrus dynamically prioritizes memory flexibility or stability by tuning a sensitivity-consistency continuum

Elena Pérez-Montoyo, José María Caramés, Raquel Garcia-Hernandez, Mónica Peralta-Cañadas, Santiago Canals and Encarni Marcos

PLOS Biology, 2026, vol. 24, issue 8, 1-23

Abstract: A fundamental challenge for memory systems is balancing two opposing demands: sensitivity, which enables the encoding of subtle differences between similar experiences, and consistency, which preserves stable representations against interference. How the brain resolves this trade-off has remained unclear. Here, we identify inhibition in the dentate gyrus (DG) as a regulator of this balance, shifting hippocampal computation between sensitivity- and consistency-dominated regimes. Using an integrative approach that combines cell-type–specific pharmacogenetics in mice, behavioral assays, and computational modeling, we demonstrate that reducing inhibition during the encoding of overlapping experiences enhances later discrimination during recall. Computational modeling further predicted that, besides discrimination enhancement, disinhibition also increases susceptibility to interference, an effect that becomes particularly critical under high memory load, and compromises memory consistency across experiences. Conversely, increased inhibition stabilized memory representations, but reduced sensitivity, rendering similar experiences indistinguishable. These specific predictions were confirmed experimentally, showing that the DG inhibition tunes a sensitivity-consistency continuum. Together, our results uncover a systems-level principle by which hippocampal circuits dynamically prioritize flexibility or stability in memory formation depending on inhibitory tone. This framework advances our understanding of how the brain balances competing computational demands and has implications for neuropsychiatric and neurodegenerative disorders in which excitation–inhibition balance is disrupted.A fundamental challenge for memory systems is balancing sensitivity to similar experiences against the need for stable, interference-resistant representations. This study shows that dentate gyrus inhibition regulates this trade-off, with reduced inhibition enhancing discrimination but increasing interference, while increased inhibition stabilizes memories at the cost of sensitivity.

Date: 2026
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pbio00:3003956

DOI: 10.1371/journal.pbio.3003956

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