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

Louise Schenberg, Aïda Palou, François Simon, Tess Bonnard, Charles-Elliot Barton, Desdemona Fricker, Michele Tagliabue, Jordi Llorens, Mathieu Beraneck

Preprint posted on 19 April 2023

When mice receive unreliable information from their ears, how do they use their eyes? 🐭 Schenberg et al. show that visual reflexes are altered and can supplement info during vestibular stimulation

Selected by Samantha Davis


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?


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.


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?


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.

Tags: balance, plasticity, translational

Posted on: 13 July 2023 , updated on: 14 July 2023


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Author's response

The author team shared

1. Do you imagine type I hair cell function is permanently affected, even after the return of markers?

Certainly, some type I hair cells may suffer a permanent loss of function, but our hypothesis is that most of them will recover function in parallel with the recovery in marker expression. More precisely, a recovery in type I hair cell function is the simplest explanation for the observed recovery in reflex gains during the washout period.

The question of cell function recovery is a very interesting one. Our previous studies on the subchronic IDPN model (Sedó-Cabezón et al., Dis. Model. Mech. 2015; Greguske et al., Arch. Toxicol., 2019) provide robust evidence that enduring toxic stress can cause a loss of function that is still reversible. The loss of vestibular function during continuous ototoxic exposure and its recovery during a subsequent washout period clearly associated with histological alterations and their posterior repair. While the initial observations focused on the loss of markers in the contact between the type I hair cell and its postsynaptic afferent, data in the present article and other unpublished data reveal that many molecular changes occur in the hair cell under toxic stress. We are now working to understand the relationship between these alterations and their reversion with the function loss and recovery. Importantly, we have obtained evidence that these phenomena are also relevant to the ototoxicity caused by the clinically relevant aminoglycoside antibiotics (Maroto et al., Arch. Toxicol. 2023).
On the other hand, the ototoxicity literature provides plenty of evidence for the persistence of damaged hair cells in vestibular epithelia after ototoxic insults. For instance, many images show hair cells with abnormal stereocilia that probably cannot accomplish proper mechanotrasduction. What determines that a hair cell shows reversible or persistent damage? What are the physiological consequences of the presence of damaged hair cells in the sensory epithelium? Are there molecular targets that can be stimulated to accelerate or induce hair cell repair? These are questions whose answers have clear therapeutic implications.

2. How do you think aVOR results would differ at low and high frequencies over time?

aVOR gain loss during the IDPN sub-chronic exposition is significantly present in all frequencies we tested (0.2 to 2Hz). However, we observed a gain loss at higher frequencies earlier during the protocol than at lower frequencies, concurring with data indicating that type I hair cells are better suited to detecting high frequencies stimulations than type II hair cells. As a six-week long exposure to IDPN leads to a decrease of the aVOR gain for both low and high frequencies, a longer exposition time should amplify the loss for all frequencies as both type I and type II hair cells have been showed to be damaged during a longer (8 weeks) exposure (Greguske et al, 2019).

Conversely, we observed during the washout period an earlier aVOR recovery of the lowest frequency compared to the highest frequencies. While the aVOR gain at these highest tested frequencies remained significantly decreased after 6 weeks of washout, a longer period might allow for further recovery. Whether a complete reversal of IDPN toxicity could ultimately be observed  remains an open question.

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