Functional development of interneurons that mediate the vestibulo-ocular reflex

New York University School Of Medicine, New York NY

Investigators

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Abstract

Project Summary / Abstract of Supplemental Research The vestibular system is critical for maintaining stable gaze. The simple, well­understood system responsible for stable gaze has served as a means to understand fundamental principles of neural circuits. The parent R01 focuses on using the vestibulo­ocular reflex system of the larval zebrafish as a simple and tractable model to determine the origin of cues that specify vestibular interneuron identity. Completion of the parent R01 stands to make a significant contribution: to reveal the principles responsible for balance circuit development. Therefore the parent work is a major step towards the long­term goal of using such an understanding to shed light on the mechanisms underlying vestibular and neurodevelopmental dysfunction. Together with our collaborator, we have validated a new transgenic reagent that allows us to selectively express human 4R­Tau in vestibular brainstem neurons. We have observed pronounced postural and balance defects in these fish, motivating us to apply for supplemental funding. We propose to supplement our R01 by examining the behavioral and molecular consequences of human 4R­Tau protein on the vestibulo­ocular reflex circuit. We will compare vestibulo­ocular reflex behavior longitudinally in fish that do / do not express human 4R­Tau pro­ tein in neurons responsible for gaze stabilization. Next, we will compare the transcriptional profiles of neurons from fish that do / do not express human 4R­Tau protein in central vestibular neurons. First, we will assay the vestibular neurons themselves, and then, to understand the circuit­level consequences of 4R­Tau expression, we will compare the downstream population of extraocular motor neurons. Our work will serve to evaluate the suitability of the zebrafish gaze­stabilization system as a means to evaluate the basic behavioral and molecu­ lar mechanisms of human 4R­Tau expression. As Tau protein is closely linked to Alzheimer’s disease and its related dementias (e.g. progressive supranuclear palsy), our work is an important step towards understanding these debilitating disorders.