
==== Front
bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.09.04.611137
preprint
1
Article
Brain-wide circuitry underlying altered auditory habituation in zebrafish models of autism
Wilde Maya http://orcid.org/0000-0002-5762-8427

Ghanbari Anahita http://orcid.org/0000-0002-8364-6266

Mancienne Tessa http://orcid.org/0009-0007-2947-7119

Moran Ailís http://orcid.org/0000-0002-8706-9777

Poulsen Rebecca E. http://orcid.org/0000-0002-6669-520X

Constantin Lena http://orcid.org/0000-0003-1492-3845

Lee Conrad http://orcid.org/0000-0003-4838-8502

Scholz Leandro Aluisio http://orcid.org/0000-0002-2411-0429

Arnold Joshua http://orcid.org/0000-0002-7262-9436

Qin Wei http://orcid.org/0000-0001-7062-380X

Karle Timothy J. http://orcid.org/0000-0003-0817-6425

Petrou Steven http://orcid.org/0000-0002-4960-6375

Favre-Bulle Itia http://orcid.org/0000-0003-3118-356X

Hoffman Ellen J. http://orcid.org/0000-0002-5083-1369

Scott Ethan K. http://orcid.org/0000-0003-3150-9216

05 9 2024
2024.09.04.611137https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://biorxiv.org/lookup/doi/10.1101/2024.09.04.611137
nihpp-2024.09.04.611137.pdf
Abstract

Auditory processing is widely understood to occur differently in autism, though the patterns of brain activity underlying these differences are not well understood. The diversity of autism also means brain-wide networks may change in various ways to produce similar behavioral outputs. We used larval zebrafish to investigate auditory habituation in four genetic lines relevant to autism: fmr1 , mecp2 , scn1lab and cntnap2 . In free-swimming behavioral tests, we found each line had a unique profile of auditory hypersensitivity and/or delayed habituation. Combining the optical transparency of larval zebrafish with genetically encoded calcium indicators and light-sheet microscopy, we then observed brain-wide activity at cellular resolution during auditory habituation. As with behavior, each line showed unique alterations in brain-wide spontaneous activity, auditory processing, and adaptation in response to repetitive acoustic stimuli. We also observed commonalities in activity across our genetic lines that indicate shared circuit changes underlying certain aspects of their behavioral phenotypes. These were predominantly in regions involved in sensory integration and sensorimotor gating rather than primary auditory areas. Overlapping phenotypes include differences in the activity and functional connectivity of the telencephalon, thalamus, dopaminergic regions, and the locus coeruleus, and excitatory/inhibitory imbalance in the cerebellum. Unique phenotypes include loss of activity in the habenula in scn1lab , increased activity in auditory regions in fmr1, and differences in network activity over time in mecp2 and cntnap2 . Comparing these distinct but overlapping brain-wide auditory networks furthers our understanding of how diverse genetic factors can produce similar behavioral effects through a range of circuit- and network-scale mechanisms.
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