Brain-wide circuitry underlying altered auditory habituation in zebrafish models of autism

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 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 hyper-responsiveness and/or reduced habituation compared to 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 coeruleus. 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. Significance statement Wilde et al. compare auditory habituation phenotypes in three genetic zebrafish models of autism. Of particular interest, several lines had overlapping behavioral phenotypes despite distinct patterns of brain-wide activity and network organization. Rather than pointing to a single mechanism underlying altered sensory responses, the data instead suggest there may be multiple neural routes to superficially similar sensory behaviors. This fits with growing discussions in human research that auditory processing in autism is unlikely to reflect one unified phenotype, but instead a diverse set of sensory profiles and underlying neural processes. Comparing across multiple genetic models and levels of neural organization may therefore help strengthen links between mechanistic animal work and the variability described in human sensory research in autism.