The vestibular system is critical for maintaining balance reflexes, vital behaviors that are disturbed both in ag- ing and in several developmental disorders. While we know much about how the vestibular system functions we know considerably less about how it develops. To form functional circuits, neurons must adopt the correct identities and connect to appropriate partners. Many molecular mechanisms underlying these processes have been proposed but how these mechanisms work in the context of a specific system to generate behavior is not yet clear. We propose an innovative approach: to use the vestibulo-ocular reflex system of the larval zebrafish as a simple and tractable model to determine the origin of cues that specify vestibular interneuron identity. The vestibulo-ocular reflex circuit is a simple 3-neuron arc comprised of sensory neurons, interneurons, and motoneurons. Proper behavior requires that the right sensors (e.g. for upward tilts) be linked to the proper mo- toneurons (e.g. those that move the eyes down). Our lab has developed tools to determine interneuron identity anatomically and electrophysiologically. We can remove possible sources of identity cues (motoneurons and sensory neurons) either chronically, through genetic means, or acutely, through laser-mediated photoablation. Finally, we can collect and process neurons across development to profile their patterns of gene expression. This application proposes three Aims: To determine whether cues for interneuron identity arise from either (1) the motor neurons, (2) the sensory neurons, or (3) from local interactions between interneurons themselves. Completion of these experiments stands to make a significant contribution: to reveal the principles responsible for balance circuit development. As such, the work is a major step towards the long-term goal of using such an understanding to shed light on the mechanisms underlying vestibular and neurodevelopmental dysfunction.
The proposed research is relevant to public health because discovering the principles that permit normal de- velopment and function of balance circuits is expected to increase understanding of the mechanisms respon- sible for vestibular pathologies and associated balance dysfunction. Therefore, the proposed research is relevant to the part of the NIH?s mission to increase fundamental knowledge of the mechanisms of diseases, disorders, and dysfunctions that impair health.