Sensory circuit development in a zebrafish model of fragile X syndrome

  • Awarded: 2018
  • Award Type: Pilot
  • Award #: 569051

Autism spectrum disorders (ASDs) have traditionally been thought of as primarily disorders of cognition. However, increasing evidence also points to deficits in lower-level sensory processing. Sensory changes predictive of a subsequent ASD diagnosis are measurable by six months of age in humans, but little is known about how ASD alters the very early developmental pathway for sensory circuits and what implications this has for the design of therapies. Understanding these processes requires an animal model in which the activity of large populations of central neurons can be recorded over development at single-neuron resolution and in which simple, sensory-driven behaviors can be easily measured. Geoffrey Goodhill proposes to exploit the unique advantages afforded by calcium imaging in a zebrafish model of fragile X syndrome (FX) that lacks fmr1 to examine how the detailed temporal dynamics of sensory circuit development are altered in an ASD model and how this correlates with changes in behavior.

Goodhill’s laboratory will use high-speed imaging of larval zebrafish to quantitatively characterize how visually driven behavior differs between FX and wild type (WT) fish. Further, using GCaMP6 2-photon calcium imaging of large-scale patterns of spontaneous activity, combined with novel graph theoretical tools, his group aims to reveal how the development of the functional circuit architecture of the tectum differs between FX and WT fish. The team will also examine alterations in the development of sensory processing between FX and WT fish, by imaging neural activity evoked by sensory (ie., visual) stimuli. Quantitative changes in visually driven behaviors will then be correlated with changes in any circuit-level properties identified. Findings from these studies are expected to reveal key changes in early sensory circuit processing caused by loss of fmr1. This project will also provide an animal model system which can subsequently be used for rapidly screening possible interventions.

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