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State-of-the-art multiphoton holographic optogenetics requires high-power illumination that only addresses relatively small populations of neurons in parallel. Conversely, one-photon holographic techniques can stimulate more neurons with two to three orders lower power, but with limited resolution or addressable volume. Perhaps most problematically, two-photon holographic optogenetic systems are extremely expensive and sophisticated which has precluded their broader adoption in the neuroscience community. To address this technical gap, we introduce a new one-photon light sculpting technique, three-dimensional multi-site random access photostimulation (3D-MAP), that overcomes these limitations by modulating light dynamically, both in the spatial and in the angular domain at multi-kHz rates. We use 3D-MAP to interrogate neural circuits in 3D and demonstrate simultaneous photostimulation and imaging of dozens of user-selected neurons in the intact mouse brain in vivo with high spatio-temporal resolution. 3D-MAP can be broadly adopted for high-throughput all-optical interrogation of brain circuits owing to its powerful combination of scale, speed, simplicity, and cost.<\/jats:p>","DOI":"10.7554\/elife.73266","type":"journal-article","created":{"date-parts":[[2022,1,20]],"date-time":"2022-01-20T08:15:20Z","timestamp":1642666520000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.73266","source":"Crossref","is-referenced-by-count":23,"title":["Three-dimensional multi-site random access photostimulation 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