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The mechanisms by which neuronal circuits discriminate and encode the source of sensory signals remain elusive. To address this, we utilized as a model the posterior lateral line system of larval zebrafish, which is used to detect water currents. This system comprises a series of mechanosensory organs called neuromasts, which are innervated by neurons from the posterior lateral line ganglion. By combining single-neuromast optogenetic stimulation with whole-brain calcium imaging, we developed a novel approach to investigate how inputs from neuromasts are processed. Upon stimulating individual neuromasts, we observed that neurons in the brain of the zebrafish show diverse selectivity properties despite a lack of topographic organization in second-order circuits. We further demonstrated that complex combinations of neuromast stimulation are represented by sparse ensembles of neurons within the medial octavolateralis nucleus (MON) and found that neuromast input can be integrated nonlinearly. Our approach offers an innovative method for spatiotemporally interrogating the zebrafish lateral line system and presents a valuable model for studying whole-brain sensory encoding.<\/jats:p>","DOI":"10.1101\/2025.02.07.637118","type":"posted-content","created":{"date-parts":[[2025,2,9]],"date-time":"2025-02-09T00:55:20Z","timestamp":1739062520000},"source":"Crossref","is-referenced-by-count":2,"title":["Optogenetic interrogation of the lateral-line sensory system reveals mechanisms of pattern separation in the zebrafish brain"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8908-7768","authenticated-orcid":false,"given":"Nicolas","family":"Velez-Angel","sequence":"first","affiliation":[{"name":"Laboratory of Sensory Neuroscience, The Rockefeller University, New York, NY, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-3340-6502","authenticated-orcid":false,"given":"Sihao","family":"Lu","sequence":"additional","affiliation":[{"name":"Laboratory of Sensory Neuroscience, The Rockefeller University, New York, NY, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian","family":"Fabella","sequence":"additional","affiliation":[{"name":"Laboratory of Sensory Neuroscience, The Rockefeller University, New York, NY, USA"},{"name":"Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8304-1267","authenticated-orcid":false,"given":"Caleb C.","family":"Reagor","sequence":"additional","affiliation":[{"name":"Laboratory of Sensory Neuroscience, The Rockefeller University, New York, NY, USA"},{"name":"Tri-Institutional PhD Program in Computational Biology and Medicine, New York, NY, USA"},{"name":"Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8809-3384","authenticated-orcid":false,"given":"Holland R.","family":"Brown","sequence":"additional","affiliation":[{"name":"Sackler Institute of Developmental Psychobiology, Weill Cornell Medicine, New York, NY, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4198-1135","authenticated-orcid":false,"given":"Yuriria","family":"V\u00e1zquez","sequence":"additional","affiliation":[{"name":"Laboratory of Sensory Neuroscience, The Rockefeller University, New York, NY, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9381-6292","authenticated-orcid":false,"given":"Adrian","family":"Jacobo","sequence":"additional","affiliation":[{"name":"Chan Zuckerberg BioHub, San Francisco, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A. 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