Modulation of central vestibular processing for locomotor control - Project Summary Falls are the second leading cause of unintentional injury deaths worldwide and are driven in part by vestibular ataxia, a major health issue characterized by dizziness, vertigo, and difficulty maintaining an upright posture while walking. Balance issues can arise from dysfunction of vestibular nuclei (VN), structures in the brainstem that process sensations of motion arising during walking, and treatment for dysfunctional balance is hindered by limited understanding of brainstem motion processing. During walking and other forms of locomotion, animals must adapt their movements to an unpredictable world, but sensing while moving faces the problem of disentangling sensation generated by self-motion (reafference) from that generated externally (exafference). Appropriately processing reafference may be essential for maintaining balance during locomotion, enhancing sensitivity to unpredictable motion and suppressing inappropriate responses. Isolating and responding to exafference involves making a prediction of the predictable element, the reafference, computed based on an internal representation of the intended movement called ‘corollary discharge’ (CD). CD has been shown to cancel reafferent signals in the VN during voluntary neck movements, but is locomotion processed similarly? A likely source of CD to VN during locomotion is the cerebellum, which innervates the VN, because damage to this pathway can cause ataxia. However, predicting and disentangling locomotor motion feedback is challenging given the heterogeneity of VN neurons coupled with the technical challenge of manipulating motion sensation during locomotion. Here, we mitigate these challenges by leveraging the simple locomotion of larval zebrafish. These animals possess the key neural architecture of the VN and cerebellum, and their approachable behavior and optical transparency affords neural recordings during locomotion (swimming) with precise control over motion sensation. We have developed a behavioral assay suitable for intravital imaging that reliably evokes voluntary swimming with predictable motion sensation. Our general approach combines imaging neural activity while manipulating motion sensation in anatomically and genetically defined cell populations, in order to determine how the VN and cerebellum interact to process motion sensation and incorporate information about ongoing locomotion. This research will take place at the University of Wisconsin-Madison, home to leading experts in the fields of kinesiology, sensorimotor integration, and zebrafish neural function and development. I will have ample opportunities to train through research, coursework, seminars, and collaborations. I will also travel to national conferences and intensive training courses to grow as a scientist, communicator, and future mentor. Together, these efforts will help define how animals use expectation to refine motion processing during locomotion, advancing understanding of the basic neurobiology of balance that may ultimately inform human walking balance. I will perform this research while developing my career as a vestibular neuroscientist.
