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A transcriptomic axis aligns with in vivo functional dynamics in hippocampal inhibitory circuits

Yong, H. C.; Herrlinger, S. A.; Conde Paredes, M. E.; O'Toole, C. K.; Yoo, J.; Rao, B. Y.; Mihaila, T. S.; Shi, J.; Dey, S.; Varol, E.; Losonczy, A.

2026-04-08 neuroscience
10.64898/2026.04.07.716935 bioRxiv
Show abstract

Linking molecular identity to function in vivo at single-cell resolution remains an outstanding challenge in neuroscience. Here, we bridge this gap in the mouse hippocampus with an end-to-end pipeline of cell-resolved two-photon imaging and spatial transcriptomics. CA1 interneurons exhibiting heterogeneous physiological responses during a virtual-reality navigation task were post hoc clustered by gene expression into 5 GABAergic subclasses and 14 types. Physiological responses of individual cells aligned with a transcriptomic axis, and a classifier trained on physiological features alone recovered the same ordered organization. Our approach establishes a direct, scalable framework for linking in vivo circuit dynamics to constituent cell identity, revealing a transcriptomic axis that encompasses the structural and functional diversity of hippocampal inhibitory neurons. One-Sentence SummaryTracking neurons from behavior to spatial transcriptomics links in vivo function to molecular identity in the hippocampus.

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