The brain's vestibular neurons transform peripheral balance sensations into reflexive commands, stabilizing posture, gait, and gaze. Here we propose a series of experiments to test prevailing models of how developing central vestibular neurons come to properly relay sensory information to particular motoneurons, enabling gaze stabilization. Our proposal has three aims, each addressing a specific hypothesis about central neuron development: The current model in the field proposes that central vestibular neurons responsible for the vertical/torsional vestibuloocular reflex adopt one of two fates by responding to cues secreted from extraocular motoneurons that have wired to their target muscles. Our preliminary data suggests instead that vestibular neuron fate may instead proceed independently of such signals. We propose to leverage the optical accessibility, rapid external development, and molecular tractability of the zebrafish preparation. To directly quantify, in vivo, the spatiotemporal development of central vestibular neurons, we will use a birthdating technique we have previously optimized for motoneurons. We will do so both under normal conditions, as well as following optical lesions of oculomotor and trochlear nerves. Next, the current model of vestibular development proposes a vital role for the semicircular canals in determining the sensory selectivity of central vestibular neurons. However, our work in the larval zebrafish supports the idea that canal input is dispensable for a normal vertical/torsional VOR, suggesting the development of sensory selectivity is independent of canal in put. To define vestibular neuron tuning, we will directly measure the sensory selectivity of developing vestibular neurons using a novel electrophysiological preparation we have developed. We will provide vestibular stimuli (translation) to intact zebrafish while recording intracellularly from central vestibular neurons. Similarly, we will measure the response of the excitatory and inhibitory synaptic inputs to vestibular neurons to determine how the upstream vestibular signals shape the response of their target. Finally, most vertebrate vestibular neurons receive input from two end organs, the otoliths and the semicircular canals. The delayed emergence of functional semicircular canal input in the larval zebrafish provides a unique opportunity to determine whether or not sensory activity is required to establish proper connectivity. We will first measure the electrophysiological properties of canal afferent neurons as zebrafish develop to define emergent patterns of electrical activity. Next, we will determine when during development the canal and otolith afferents properly converge. We will do so by first expressing a light-sensitive channel in single canal afferents. We will then record from central vestibular neurons, defining their sensory tuning. We will then define the probability of connectivity between specific canal afferents, each tuned to a particular axis of rotation, with similarly and orthogonally tuned central vestibular neurons. Together, the impact of these experiments will be to define when and how anatomical specialization and sensory selectivity emerge in the vestibular neurons responsible for gaze stabilization. Such data are a prerequisite to evaluate and treat abnormal development, and to ameliorate acute central perturbations, such as follow stroke.
Our goal is to understand the normal mechanisms of central vestibular and ultimately sensorimotor maturation. Such data are a prerequisite to evaluate and treat abnormal development, and to ameliorate acute central perturbations, such as follow stroke.
| Bagnall, Martha W; Schoppik, David (2018) Development of vestibular behaviors in zebrafish. Curr Opin Neurobiol 53:83-89 |
