Large-scale cellular-resolution read/write of activity enables discovery of cell types defined by complex circuit properties

bioRxiv 2025

Drinnenberg, Antonia and Attinger, Alexander and Raventos, Allan and Ramakrishnan, Charu and Gharagoz, Barsin Eshaghi and Cordero, Arjay and Jo, YoungJu and Siverts, La'Akea and Daigle, Tanya L. and Tasic, Bosiljka and Zeng, Hongkui and Giocomo, Lisa M. and Quirin, Sean and Ganguli, Surya and Deisseroth, Karl

Abstract

SUMMARY The complexity of the mammalian brain’s vast population of interconnected neurons poses a formidable challenge to elucidate its underlying mechanisms of coordination and computation. A key step forward will be technologies that can perform large-scale, cellular-resolution monitoring and interrogation of distributed brain circuit activity in behaving animals. Here, we present an all-optical strategy for precise optogenetic activity control of ∼10 3 neurons and simultaneous activity monitoring of ∼10 4 neurons within and across areas of mouse cortex—an order-of-magnitude leap beyond previous capabilities. Tracking population responses following delivery of precisely-defined widely-distributed activity patterns to the visual cortex of awake mice, we were surprised to identify neurons robustly responsive to stimulation of diverse ensembles, defying conventional like-to-like wiring rules. These cells were primarily deep L2/3 somatostatin-positive (SST) interneurons with functional properties distinct from other SST neurons, and appeared to play a role in brain dynamics that could only have been identified through broad cellular-resolution circuit interrogation. Our work reveals the value of measuring large-scale circuit-dynamical properties of functionally-resolved single cells, beyond genetic and anatomical classification, to define and explore the roles of cell types in brain function.

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