Median raphe input to dorsal CA1 shapes VIP interneuron recruitment and novelty-guided spatial memory

Luo, X.; Radhakrishnan, R.; Guet-McCreight, A.; Topolnik, D.; Bergeron, A.; Dulam, V.; Coulombe, L. D.; Besner, M.; Fortin-Houde, J.; Davies, J.; Michaud, F.; Amilhon, B.; Topolnik, L.

doi:10.64898/2026.09.17.752379

bioRxiv · 10.64898/2026.09.17.752379

Median raphe input to dorsal CA1 shapes VIP interneuron recruitment and novelty-guided spatial memory

Luo, X.·Radhakrishnan, R.·Guet-McCreight, A.·Topolnik, D.·Bergeron, A.·Dulam, V.·Coulombe, L. D.·Besner, M.·Fortin-Houde, J.·Davies, J.·Michaud, F.·Amilhon, B.·Topolnik, L.

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Abstract

Vasoactive intestinal peptide-expressing interneurons (VIP-INs) gate hippocampal inhibition during novel experience, but the long-range signals that engage these cells remain poorly understood. Here we identify median raphe (MnR) projections as a brainstem pathway that tunes dorsal CA1 VIP-IN recruitment through coordinated glutamatergic and serotonergic mechanisms. Anatomical mapping and optogenetic recordings showed that MnR axons innervate multiple VIP-IN subtypes, while transcriptomic and pharmacological analyses revealed fast glutamatergic excitation together with serotonin receptor-dependent modulation of synaptic and intrinsic responsiveness. In vivo calcium imaging showed that novelty preferentially recruited a speed-coupled VIP-IN ensemble, and inhibition of MnR input selectively reduced the magnitude of this response. A hippocampal circuit model linked this pathway to dendritic disinhibition and place-cell recruitment. Behaviorally, inhibition of MnR input preserved exploratory engagement but disrupted the organization of spatial sampling and impaired object-location memory. Thus, MnR input organizes hippocampal disinhibition to support novelty-guided exploration and memory encoding.

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Luo, X., Radhakrishnan, R., Guet-McCreight, A., Topolnik, D., Bergeron, A., Dulam, V., Coulombe, L. D., Besner, M., Fortin-Houde, J., Davies, J., Michaud, F., Amilhon, B., Topolnik, L.. 2026-09-18. Median raphe input to dorsal CA1 shapes VIP interneuron recruitment and novelty-guided spatial memory. https://doi.org/10.64898/2026.09.17.752379

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