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Correlative light and electron microscopy reveals the fine circuit structure underlying evidence accumulation in larval zebrafish

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  • Accumulating information is a critical component of most circuit computations in the brain across species, yet its precise implementation at the synaptic level remains poorly understood. Dissecting such neural circuits in vertebrates requires precise knowledge of functional neural properties and the ability to directly correlate neural dynamics with the underlying wiring diagram in the same animal. Here we combine functional calcium imaging with ultrastructural circuit reconstruction, using a visual motion accumulation paradigm in larval zebrafish. Using connectomic analyses of functionally identified cells and computational modeling, we show that bilateral inhibition, disinhibition, and recurrent connectivity are prominent motifs for sensory accumulation within the anterior hindbrain. We also demonstrate that similar insights about the structure-function relationship within this circuit can be obtained through complementary methods involving cell-specific morphological labeling via photo-conversion of functionally identified neuronal response types. We used our unique ground truth datasets to train and test a novel classifier algorithm, allowing us to assign functional labels to neurons from morphological libraries where functional information is lacking. The resulting feature-rich library of neuronal identities and connectomes enabled us to constrain a biophysically realistic network model of the anterior hindbrain that can reproduce observed neuronal dynamics and make testable predictions for future experiments. Our work exemplifies the power of hypothesis-driven electron microscopy paired with functional recordings to gain mechanistic insights into signal processing and provides a framework for dissecting neural computations across vertebrates.

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Author:Jonathan Boulanger-WeillORCiD, Florian KaempfORCiD, Richard L. Schalek, Mariela PetkovaORCiD, Sumit Kumar VohraORCiD, Jay H. SavaliyaORCiD, Yuelong Wu, Gregor F. P. SchuhknechtORCiD, Heike NaumannORCiD, Maren Eberle, Kim N. KirchbergerORCiD, Simone RenckenORCiD, Isaac H. BiancoORCiD, Daniel BaumORCiD, Filippo Del BeneORCiD, Florian EngertORCiD, Jeff W. LichtmanORCiD, Armin BahlORCiD
Document Type:Article
Parent Title (English):bioRxiv
Year of first publication:2025
DOI:https://doi.org/10.1101/2025.03.14.643363
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