A versatile, positive-going voltage indicator that enables accessible two-photon recordings in vivo
McDonald, A. J.; Land, M. A.; Yang, S.; Hakam, N.; Villette, V.; Zhu, J.; Galdamez, M.; Puebla, M. F. d. l.; Lu, X.; Foran, G.; Torne-Srivastava, T.; Campillo, B.; Liu, H.; Dong, X.; Lai, S.; Shorey, M.; Abdallah, H.; Banks, R.; Mamontova, A.; Shan, Y.-Y. Y.; Kroeger, R.; Law, R. G.; Hu, M.; Santos, D. G.; Bradley, J.; Lombardini, A.; Mathieu, B.; Ayon, A.; Natan, R. G.; Yuan, H.; Reimer, J.; Bourdieu, L.; Ji, N.; Zong, W.; St-Pierre, F.
Show abstract
Genetically encoded voltage indicators (GEVIs) enable cell-type-specific optical readout of membrane potential, but two-photon (2P) spike detection has been hampered by low signal-to-noise and ultrafast off-kinetics, restricting use to specialized microscopes. We introduce FORCE1s, a green, positive-going GEVI engineered to make robust 2P voltage imaging broadly accessible. FORCE1s brightens from a dark baseline during depolarization, reports spikes with [~]100% {Delta}F/F in awake mice, and displays repolarization kinetics that are tuned for reliable spike detection at sub-kilohertz frame rates. As a result, FORCE1s supports spike-resolved multi-cell recordings on standard resonant-scanning microscopes, and further scales to larger fields of view and neuron counts on advanced modalities. FORCE1s also enables multiplexed voltage-neurotransmitter imaging and extended recordings in freely moving mice using a compact, affordable MEMS-based 2P miniscope. Together, these advances establish FORCE1s as a community-ready tool that democratizes deep-tissue voltage imaging across platforms and experimental contexts.
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