Regeneration of Vestibular Otolith Afferents after Ototoxic Damage

Abstract

Regeneration of receptor cells and subsequent functional recovery after damage in the auditory and vestibular systems of many vertebrates is well known. Spontaneous regeneration of mammalian hair cells does not occur. However, recent approaches provide hope for similar restoration of hearing and balance in humans after loss. Newly regenerated hair cells receive afferent terminal contacts, yet nothing is known about how reinnervation progresses or whether regenerated afferents finally develop normal termination fields. We hypothesized that neural regeneration in the vestibular otolith system would recapitulate the topographic phenotype of afferent innervation so characteristic of normal development. We used an ototoxic agent to produce complete vestibular receptor cell loss and epithelial denervation, and then quantitatively examined afferent regeneration at discrete periods up to 1 year in otolith maculas. Here, we report that bouton, dimorph, and calyx afferents all regenerate slowly at different time epochs, through a progressive temporal sequence. Furthermore, our data suggest that both the hair cells and their innervating afferents transdifferentiate from an early form into more advanced forms during regeneration. Finally, we show that regeneration remarkably recapitulates the topographic organization of afferent macular innervation, comparable with that developed through normative morphogenesis. However, we also show that regenerated terminal morphologies were significantly less complex than normal fibers. Whether these structural fiber changes lead to alterations in afferent responsiveness is unknown. If true, adaptive plasticity in the central neural processing of motion information would be necessitated, because it is known that many vestibular-related behaviors fully recover during regeneration.

Maintained Expression of the Planar Cell Polarity Molecule Vangl2 and Reformation of Hair Cell Orientation in the Regenerating Inner Ear

“…In the vestibular organs, regenerated hair cells reacquire the same orientations and physiological sensitivities as their counterparts in the undamaged ear (Dye et al 1999;Zakir and Dickman 2006), but the molecular signals that regulate hair cell structure and orientation during regeneration are not known. Recent developmental studies of the mammalian ear have demonstrated that molecules of the planar cell polarity (PCP) pathway play a critical role in the establishment of hair cell orientation (Montcouquiol et al , 2006aWang et al 2006;Deans et al 2007).…”

Recovery of otoacoustic emissions after high-level noise exposure in the American bullfrog

“…There have been surprisingly few studies of the afferent innervation of regenerated hair cells (Duckert and Rubel, 1990;Duckert and Rubel, 1993;Haque et al, 2009;Ryals and Westbrook, 1994;Xiang et al, 2000;Zakir and Dickman, 2006). New synaptic endings are seen on repairing and regenerating hair cells soon after their appearance, but normal innervation is not restored for much longer periods (Haque et al, 2009;Ryals and Westbrook, 1994;Whitlon and Sobkowicz, 1991;Zakir and Dickman, 2006).…”

“…New synaptic endings are seen on repairing and regenerating hair cells soon after their appearance, but normal innervation is not restored for much longer periods (Haque et al, 2009;Ryals and Westbrook, 1994;Whitlon and Sobkowicz, 1991;Zakir and Dickman, 2006). Rapid functional recovery after sound trauma may be associated with processes involving the surviving hair cells -rather than with the regeneration of lost hair cells (Reng et al, 2001).…”

Recovery of Gaze Stability During Vestibular Regeneration

“…We then directly characterized the functional recovery of gaze stability during vestibular regeneration based on our previously established morphologic landmarks of receptor recovery (Dickman and Lim 2004;Dye et al 1999;Zakir and Dickman 2006). Finally, we demonstrate links between component mechanisms of gaze stability and vestibular receptor function in birds.…”

“…In birds, reptiles, and amphibians, the occurrence of spontaneous regeneration of vestibular receptors following inner ear damage is now well established (Corwin and Cotanche 1988;Cruz et al 1987;Weisleder and Rubel 1993). Although much of the inner ear morphology returns to normal phenotypic patterns (reviewed in Matsui et al 2005), significant differences persist in vestibular afferent innervation following complete regeneration (Zakir and Dickman 2006). The effects of vestibular receptor loss on the central neuronal processing of motion information that govern gaze and postural stability are not yet fully understood.…”