Subchronic alteration of vestibular hair cells in mice: implications for multisensory gaze stabilization

Background

Balance and gaze stabilization are directed by the vestibular system, which begins with organs in the inner ear. Injury to these structures can lead to vertigo, disorientation, and falls as well as poor quality of life. Remarkably, the central vestibular system maintains plasticity throughout life and is able to recuperate after trauma in a process known as vestibular compensation. Other sensory systems such as the visual and proprioceptive systems provide feedback to guide recalibration. While many labs have begun investigating vestibular compensation, our knowledge of the involved mechanisms remains limited, especially since previous studies utilize complete suppression of the vestibular periphery.

A large number of patients experience fluctuating or incomplete vestibular dysfunction, warranting further study of compensation to transient or partial loss. Previous work has established 3,3ʹ-iminodiproprionitrile (IDPN) delivered subchronically as a model for fluctuating inner ear function in rodents with a treatment period followed by a washout period. Exposure to IDPN in drinking water has adverse effects on posture and locomotion, but its influence on gaze stabilization is currently unknown. As vestibulo-ocular circuits are used as the primary readout for clinical diagnostic testing, these results will be informative for clinicians as well as basic scientists.

Using IDPN exposure, the authors tested its effects on the two subclasses of peripheral organs—the semicircular canals and otolith organs—in mice with both histological and behavioral measures. Due to the multisensory nature of vestibular function, the authors additionally studied the integration of visual and vestibular systems during incomplete injury to the periphery.

Research questions: Does subchronic ototoxic exposure induce functional changes of the vestibular periphery? And if so, does visual information relieve transient and partial vestibular injury?

Results

Short-term ototoxic treatment reduces vestibulo-ocular reflexes temporarily

Testing of the canal-dependent and otolith-dependent vestibulo-ocular reflex (VOR) revealed significant dysfunction at the end of IDPN treatment. Interestingly, responses due to canal stimulation partially recovered by the end of the washout period, while those derived from otolith activation completely recovered. Despite reaching different levels of restoration, results of both tests followed a similar time course. Individual variability was similar between canal and otolith tests, such that functional changes were proportional at the end of treatment and washout periods. Therefore, the IDPN treatment affects gaze stabilization similarly for canal and otolith organ circuits.

IDPN affects type I hair cells specifically, which are restored after washout

To better understand the changes in function observed, histology of vestibular epithelium was performed. Although type II hair cell markers were unaffected in all organs, type I hair cell labeling was significantly reduced at treatment completion and recovered to control levels at the end of washout. Markers for type I hair cells of each organ type correlated with gain for their respective test; type II markers were not related to behavioral performance. This implies that type I hair cells are altered by brief IDPN exposure, though they do not seem to be killed by this compound, and that changes to these cells impact gaze stabilization.

Visual reflex is recruited at vestibular-dominated frequencies of motion

The optokinetic reflex (OKR) was also affected after IDPN treatment, with higher gain that persisted throughout the washout period; differences were significant specifically at higher frequencies. Phase, however, was unchanged in both temporal and stimulation frequency variables. Examining vestibular weight across frequencies suggested visual substitution in high frequencies specifically, which are driven by vestibular stimulation rather than visual. This reweighting of signals is most effectively accomplished with reliable vestibular responses, such that noisy and low-reproducible responses have additional adverse effects on gaze stabilization.

Significance 

This preprint from the Beraneck lab expands our understanding of vestibular compensation by addressing transient and partial dysfunction, and provides insight into visual reflexes during recovery. Visuo-vestibular integration is not only informed by the experimental results, but also through computational modeling. The approach translates to various patient experiences, generating interest from vestibular clinicians and scientists as well as those studying multisensory integration. 

Questions for the Authors

1. Do you imagine type I hair cell function is permanently affected, even after the return of markers?
2. How do you think aVOR results would differ at low and high frequencies over time?

References

Schenberg, L., Palou, A., Simon, F., Bonnard, T., Barton, C.-E., Fricker, D., … Beraneck, M. (2023). Subchronic alteration of vestibular hair cells in mice: implications for multisensory gaze stabilization. BioRxiv, 2023.04.19.535725. https://doi.org/10.1101/2023.04.19.535725

Tags: balance, plasticity, translational

doi: https://doi.org/10.1242/prelights.35022

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