Vestibular dysfunction constitutes a major medical concern, and regeneration of hair cells (HC) is a primary target of gene therapy aimed at restoring vestibular functions. Thus far, therapeutic trials in animal models targeting vestibular loss associated with genetic diseases have yielded variable and partial results, and the functional identity and quantity of HCs required to restore minimal or normal vestibular function remain undefined. Indeed, direct comparisons between structural pathology and quantitative assessments of vestibular dysfunctions are lacking in humans and are rather limited in animal models, representing a significant gap in current knowledge. Here, we present an innovative methodology to bridge the gap between HC integrity and functional vestibular loss in individual mice of either sex. Gradual vestibular deficits were induced through a dose-dependent ototoxic lesion, quantified with canal or utricular-specific vestibulo-ocular reflex tests, and were then correlated in all individuals with the loss of type I and type II HCs in different regions of ampulla and macula. Our findings reveal that the structure-function relationship is nonlinear, with lower bound of approximately 50% of HCs necessary to retain minimal vestibular function, and threshold exceeding 80% to preserve normal function, thus shedding light on population coding mechanisms for vestibular response. Our data further support the decisive role of type I, rather than type II, HC in the tested VOR functions. Significance Statement: Vestibular dysfunction poses a major medical challenge, with significant consequences for balance, spatial orientation, and quality of life. While regenerative therapies targeting hair cell (HC) repair offer promise, the minimal structural requirements for restoring normal vestibular functions remain unclear. Through an innovative methodology that combines precise vestibulo-ocular reflex (VOR) quantification and region-specific analyses of HC loss in mice, we demonstrate a nonlinear relationship between structural integrity and functional recovery. Our findings establish critical thresholds of HC preservation, approximately 50% for minimal vestibular function and over 80% for normal function. These insights provide valuable benchmarks for translational research, refining therapeutic strategies for vestibular pathologies and advancing our understanding of population-coding mechanisms.
Schenberg et al. (Mon,) studied this question.