Molecular and sensory foundations of vestibular reflex circuit assembly in the larval zebrafish

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PROJECT SUMMARY: Behavioral dysfunction in neurodevelopmental diseases often arises from aberrant neural circuit assembly. However, the developmental logic that dictates circuit organization, function, and ultimately behavior remains unresolved due to the complexity of most circuits. Gaze stabilization behavior in the larval zebrafish is an ideal model to understand the mechanisms that assemble functional neural circuits. Vertical gaze stabilization leverages simple architecture: all vertebrates use three cellular populations (peripheral sensory neurons, central vestibular projection neurons, and extraocular motor neurons) to transform nose-up or nose-down head movements into compensatory eye rotations. Among vertebrates, the zebrafish is particularly tractable for its genetic accessibility, transparency, and rapid external development. Previously, I discovered that the gaze stabilization circuit is topographically organized, and that this topography develops in a distinct temporal progression. I aim to leverage this organization to understand the contributions of motor and sensory partner populations to neural circuit development. With a genetic loss-of-function tool, I have already demonstrated that that motor partners are dispensable for gaze stabilization circuit development. The goal of the proposed research is twofold: 1) To define the developmental contributions of sensory partner populations to gaze stabilization circuit topography, function, and behavior (F99), and 2) To illuminate mechanisms by which specific molecules dictate functional circuit assembly (K00). In Aim 1 (F99), I will train to perturb subsets of peripheral vestibular sensory neurons during development. Following peripheral perturbations, I will use a validated optogenetically-evoked behavioral paradigm to assay changes in functional circuit topography and assembly. These data will provide insight into types of developmental signals (e.g., activity-dependent, trophic, or morphogenic) that assemble the gaze stabilization circuit. More broadly, the deliverables will speak to sensory contributions to neural circuit assembly. In Aim 2 (K00), I will select a postdoctoral lab to investigate the genetic foundations of functional neural circuit assembly using modern sequencing and computational approaches. I will integrate these molecular insights with anatomical, functional, and behavioral readouts of proper circuit assembly. Completion of this aim will train me to elucidate how genetically-defined developmental programs determine circuit organization, function, and behavior. Collectively, my training will strengthen my holistic approach to understanding mechanisms that govern typical neural circuit assembly and function. I will use this approach in my own lab to illuminate mechanisms of behavioral dysfunction in neurodevelopmental diseases.