In the mammalian cochlea, acoustic information is carried to the brain by the predominant (95%) large-diameter, myelinated type I afferents, each of which is postsynaptic to a single inner hair cell. The remaining thin, unmyelinated type II afferents extend hundreds of microns along the cochlear duct to contact many outer hair cells. Despite this extensive arbor, type II afferents are weakly activated by outer hair cell transmitter release and are insensitive to sound. Intriguingly, type II afferents remain intact in damaged regions of the cochlea. Here, we show that type II afferents are activated when outer hair cells are damaged. This response depends on both ionotropic (P2X) and metabotropic (P2Y) purinergic receptors, binding ATP released from nearby supporting cells in response to hair cell damage. Selective activation of P2Y receptors increased type II afferent excitability by the closure of KCNQ-type potassium channels, a potential mechanism for the painful hypersensitivity (that we term "noxacusis" to distinguish from hyperacusis without pain) that can accompany hearing loss. Exposure to the KCNQ channel activator retigabine suppressed the type II fiber's response to hair cell damage. Type II afferents may be the cochlea's nociceptors, prompting avoidance of further damage to the irreparable inner ear.type II cochlear afferents | ATP | acoustic trauma | hyperacusis | noxacusis T he mammalian cochlea is the most elaborate of vertebrate auditory organs. The elegantly coiled, mechanically tuned cochlear duct and functional differentiation between inner hair cells (IHCs) and outer hair cells (OHCs), afferent and efferent neuronal connections are among the features that enable the widest acoustic frequency range and most complex vocalizations among vertebrate species. This benefit, however, has been gained at a significant cost in the metabolic and mechanical vulnerability of cochlear hair cells and neurons. Loud sound progressively damages type I afferent neurons and OHCs (1). Once damaged beyond repair, these do not regenerate as they do in nonmammalian vertebrates, suggesting that protective mechanisms should exist to preserve cochlear function. Indeed, middle ear reflexes (2) and efferent inhibition of hair cells (3) can mitigate acoustic trauma to some extent. However, a more effective strategy is simply to avoid or withdraw from sources of trauma, by analogy to limb withdrawal triggered by C-fiber activation in skin.Here, we provide evidence that unmyelinated type II cochlear afferents can report cochlear trauma, a potential trigger for nocifensive behavior. Hyperactivity of type II neurons could contribute as well to the paradoxical hypersensitivity to loud sound that can accompany hearing loss, despite diminished type I afferent function. Hyperacusis is a comorbidity in 80% of tinnitus patients (4) suggesting common pathogenic mechanisms (5). In the most severe cases, hyperacusis is described as debilitating "ear pain" (6). The response to trauma by type II afferents may relate most directly to such ...

The distinctive planar polarity of auditory hair cells is evident in the polarized organization of the stereociliary bundle. Mutations in the core planar cell polarity gene Van Gogh-like 2 (Vangl2) result in hair cells that fail to properly orient their stereociliary bundles along the mediolateral axis of the cochlea. The severity of this phenotype is graded along the length of the cochlea, similar to the hair cell differentiation gradient, suggesting that an active refinement process corrects planar polarity phenotypes in Vangl2 knock-out (KO) mice. Because Vangl2 gene deletions are lethal, Vangl2 conditional knock-outs (CKOs) were generated to test this hypothesis. When crossed with Pax2-Cre, Vangl2 is deleted from the inner ear, yielding planar polarity phenotypes similar to Vangl2 KOs at late embryonic stages except that Vangl2 CKO mice are viable and do not have craniorachischisis like Vangl2 KOs. Quantification of planar polarity deficits through postnatal development demonstrates the activity of a Vangl2-independent refinement process that rescues the planar polarity phenotype within 10 d of birth. In contrast, the Pax2-Cre;Vangl2 CKO has profound changes in the shape and distribution of outer pillar cell and Deiters' cell phalangeal processes that are not corrected during the period of planar polarity refinement. Auditory brainstem response analyses of adult mice show a 10 -15 dB shift in auditory threshold, and distortion product otoacoustic emission measurements indicate that this mild hearing deficit is of cochlear origin. Together, these data demonstrate a Vangl2-independent refinement mechanism that actively reorients auditory stereociliary bundles and reveals an unexpected role of Vangl2 during supporting cell morphogenesis.

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