Functional maturation of interneurons that mediate the vestibulo-ocular reflex - Renewal - Resubmission - 1

PROJECT SUMMARY / ABSTRACT Deficits in vestibular function severely impact quality of life for 5% of children, 1/3 of Americans over 40, and lead to falls, a major cause of death among the elderly. Understanding how vestibular reflexes develop and function is therefore profoundly important. Vertebrates stabilize their gaze with a highly conserved neural cir- cuit consisting of 1) sensory afferents that sense instability, 2) projection interneurons that relay and transform corrective commands to 3) extraocular motor neurons. Vestibular interneurons show considerable heterogene- ity in their responses to instability. Correlative studies of functionally-defined interneuron subtypes have shaped our understanding of vestibular signal processing, motor learning, and recovery after injury. However, we know comparably little about how vestibular interneurons develop. In cortex, thalamus, and spinal cord, molecular characterization of development enabled subtype-specific targeting, loss-, and gain-of-function experiments. These tools revolutionized our understanding of neural circuit function. Here we propose a similar approach to understand interneurons responsible for the vestibulo-ocular reflex. In the past period, we discovered that vestibular interneuron birthdate anticipates identity (i.e. nose- up/nose- down sensitivity and eyes-up/eyes-down connectivity). Here, we will use birthdate as a handle to differentiate subtypes of vestibulo-ocular reflex interneurons. Specifically, we will determine if/how birthdate and sensory experience shape an interneuron’s transcriptional identity, sensory selectivity, and influence on behavior. By illuminating how fundamental properties of vestibular interneuron subtypes emerge, our work stands to make a significant contribution to our understanding of normal and disrupted balance circuit development.