TY - JOUR

T1 - Altered brain-wide auditory networks in a zebrafish model of fragile X syndrome

AU - Constantin, Lena

AU - Poulsen, Rebecca E.

AU - Scholz, Leandro A.

AU - Favre-Bulle, Itia A.

AU - Taylor, Michael A.

AU - Sun, Biao

AU - Goodhill, Geoffrey J.

AU - Vanwalleghem, Gilles C.

AU - Scott, Ethan K.

N1 - Publisher Copyright: © 2020 The Author(s).

PY - 2020/9/16

Y1 - 2020/9/16

N2 - Background: Loss or disrupted expression of the FMR1 gene causes fragile X syndrome (FXS), the most common monogenetic form of autism in humans. Although disruptions in sensory processing are core traits of FXS and autism, the neural underpinnings of these phenotypes are poorly understood. Using calcium imaging to record from the entire brain at cellular resolution, we investigated neuronal responses to visual and auditory stimuli in larval zebrafish, using fmr1 mutants to model FXS. The purpose of this study was to model the alterations of sensory networks, brain-wide and at cellular resolution, that underlie the sensory aspects of FXS and autism. Results: Combining functional analyses with the neurons' anatomical positions, we found that fmr1 -/- animals have normal responses to visual motion. However, there were several alterations in the auditory processing of fmr1 -/- animals. Auditory responses were more plentiful in hindbrain structures and in the thalamus. The thalamus, torus semicircularis, and tegmentum had clusters of neurons that responded more strongly to auditory stimuli in fmr1 -/- animals. Functional connectivity networks showed more inter-regional connectivity at lower sound intensities (a - 3 to - 6 dB shift) in fmr1 -/- larvae compared to wild type. Finally, the decoding capacities of specific components of the ascending auditory pathway were altered: the octavolateralis nucleus within the hindbrain had significantly stronger decoding of auditory amplitude while the telencephalon had weaker decoding in fmr1 -/- mutants. Conclusions: We demonstrated that fmr1 -/- larvae are hypersensitive to sound, with a 3-6 dB shift in sensitivity, and identified four sub-cortical brain regions with more plentiful responses and/or greater response strengths to auditory stimuli. We also constructed an experimentally supported model of how auditory information may be processed brain-wide in fmr1 -/- larvae. Our model suggests that the early ascending auditory pathway transmits more auditory information, with less filtering and modulation, in this model of FXS.

AB - Background: Loss or disrupted expression of the FMR1 gene causes fragile X syndrome (FXS), the most common monogenetic form of autism in humans. Although disruptions in sensory processing are core traits of FXS and autism, the neural underpinnings of these phenotypes are poorly understood. Using calcium imaging to record from the entire brain at cellular resolution, we investigated neuronal responses to visual and auditory stimuli in larval zebrafish, using fmr1 mutants to model FXS. The purpose of this study was to model the alterations of sensory networks, brain-wide and at cellular resolution, that underlie the sensory aspects of FXS and autism. Results: Combining functional analyses with the neurons' anatomical positions, we found that fmr1 -/- animals have normal responses to visual motion. However, there were several alterations in the auditory processing of fmr1 -/- animals. Auditory responses were more plentiful in hindbrain structures and in the thalamus. The thalamus, torus semicircularis, and tegmentum had clusters of neurons that responded more strongly to auditory stimuli in fmr1 -/- animals. Functional connectivity networks showed more inter-regional connectivity at lower sound intensities (a - 3 to - 6 dB shift) in fmr1 -/- larvae compared to wild type. Finally, the decoding capacities of specific components of the ascending auditory pathway were altered: the octavolateralis nucleus within the hindbrain had significantly stronger decoding of auditory amplitude while the telencephalon had weaker decoding in fmr1 -/- mutants. Conclusions: We demonstrated that fmr1 -/- larvae are hypersensitive to sound, with a 3-6 dB shift in sensitivity, and identified four sub-cortical brain regions with more plentiful responses and/or greater response strengths to auditory stimuli. We also constructed an experimentally supported model of how auditory information may be processed brain-wide in fmr1 -/- larvae. Our model suggests that the early ascending auditory pathway transmits more auditory information, with less filtering and modulation, in this model of FXS.

KW - Auditory perception

KW - Autism spectrum disorder

KW - Brain/physiopathology

KW - Calcium imaging

KW - CGaMP

KW - Fragile X syndrome

KW - Graph theory

KW - Light-sheet microscopy

KW - Sensory systems

KW - Zebrafish

UR - http://www.scopus.com/inward/record.url?scp=85091128929&partnerID=8YFLogxK

U2 - 10.1186/s12915-020-00857-6

DO - 10.1186/s12915-020-00857-6

M3 - Journal article

C2 - 32938458

AN - SCOPUS:85091128929

VL - 18

JO - B M C Biology

JF - B M C Biology

SN - 1741-7007

IS - 1

M1 - 125

ER -