Measuring neuronal input-output operations in vivo with random access projection microscopy

Xie, M. E.; Seyedolmohadesin, M.; He, M.; Li, L.; Hao, Y. A.; Flickinger, D.; Gibiser, R.; King, J.; Driessen, K.; Park, J.; Peene, R. C.; Loeffler, H.; Nguyen, K.; Tom, M.; Williford, A.; Swapp, J.; Tononi, G.; Cirelli, C.; Lin, M. Z.; Kimmel, B. E.; Glaser, J.; Golub, M. D.; Charles, A. S.; Svoboda, K.; Jaindl, G.; Podgorski, K.

doi:10.64898/2026.11.05.764682

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bioRxiv · 10.64898/2026.11.05.764682

Measuring neuronal input-output operations in vivo with random access projection microscopy

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Abstract

Neurons transform thousands of synaptic inputs into spiking output, and understanding this transformation requires measuring many submicron synapses at millisecond timescales in vivo. Here we present SLAP2, a two-photon random access projection microscope with no per-target access time cost, yielding over 5-fold faster imaging than existing methods, and performant real-time hardware motion correction. Flexible scanning modes enable measurement of hundreds of synapses at ~200 Hz, >800 synapses volumetrically at 50-100 Hz, and compartment-resolved dendritic voltage at 2-10 kHz in behaving mice. Simultaneous dendritic glutamate and somatic calcium imaging in visual cortex pyramidal neurons revealed nonlinear input-output amplification of stimulus onset and preferred stimulus orientation responses. Amplified features are associated with spatially organized inputs and stronger trial-to-trial coupling between synaptic activity and somatic output. These measurements establish SLAP2 as a powerful tool for recording intricate patterns of subcellular fluorescence dynamics in behaving animals.

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Xie, M. E., Seyedolmohadesin, M., He, M., Li, L., Hao, Y. A., Flickinger, D., Gibiser, R., King, J., Driessen, K., Park, J., Peene, R. C., Loeffler, H., Nguyen, K., Tom, M., Williford, A., Swapp, J., Tononi, G., Cirelli, C., Lin, M. Z., Kimmel, B. E., Glaser, J., Golub, M. D., Charles, A. S., Svoboda, K., Jaindl, G., Podgorski, K.. 2026-11-06. Measuring neuronal input-output operations in vivo with random access projection microscopy. https://doi.org/10.64898/2026.11.05.764682

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