Brain-Wide Circuitry Underlying Altered Auditory Habituation in Zebrafish Models of Autism

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 three genetic lines relevant to autism: fmr1, mecp2, and cntnap2. In free-swimming behavioral tests, we found each line had a unique profile of auditory hyperresponsiveness and/or reduced habituation compared with wild types. 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 repeated sound stimuli. 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, dopaminergic regions, and the locus ceruleus. Unique phenotypes include increased activity in auditory regions and excitatory/inhibitory imbalance in the cerebellum in fmr1 and differences in network activity over time in mecp2 and cntnap2. Comparing these distinct but overlapping brain-wide auditory networks suggests that diverse genetic factors may contribute to similar behavioral effects through a range of circuit- and network-scale mechanisms.