Hair cell population integrity necessary to preserve vestibular function

Regeneration of hair cells is a primary target of gene therapy aimed at restoring vestibular and cochlear functions ¹ . Indeed, vestibular dysfunction constitutes a major medical concern, as one of its manifestation, dizziness, affects 15–35% of the general population, with a prevalence rate of 85% for those over 80 of age ^2,3 . Age-related alterations of both vestibular function ⁴ and the integrity of vestibular hair cells has been reported in humans ^5–8 . However, direct comparisons between structural pathology and vestibular dysfunctions quantifications are lacking in humans and rather limited in animal models ^4,9 , representing a significant gap in current knowledge.

Thus far, therapeutic trials in animal models targeting vestibular loss associated with genetic diseases have yielded varied and partial results ^1,10–12 , and the functional identity and quantity of hair cells sufficient to restore minimal or normal vestibular function remain undefined. Here, we further develop an innovative methodology ⁹ to bridge the gap between hair cells integrity and functional vestibular loss in individuals. Gradual vestibular deficits were induced through a dose-dependent ototoxic compound, 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 hair cells in different regions of ampulla and macula. Our findings reveal that the structure-function relationship is nonlinear, with lower bound of approximately 50% of hair cells 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 ¹³ the decisive role of type I, rather than type II, HC in the tested VOR functions.