Unmyelinated type II afferent neurons report cochlear damage

Abstract

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 ...

Recent advances in the development and function of type II spiral ganglion neurons in the mammalian inner ear

“…This strongly supports the idea that type II SGNs, but not type I SGNs, can serve a role in pain sensation within the auditory system. A second study by Liu et al revealed that the function of type II SGNs in auditory nociception is mediated by extracellular ATP mainly released by SCs after HC damage [80]. In this study, the authors mechanically ablated HCs and detected slow activation of type II SGNs, which was dependent on both ATP-gated P2X receptors and G-protein-coupled P2Y receptors.…”

“…Immunostaining studies show that the ATP-gated ion channel P2X 2 is present in the synaptic regions of type I and type II SGNs beneath IHCs and OHCs [78, 79], suggesting that SGNs may respond to extracellular ATP. Application of ATP to dissected cochleae not only depolarizes OHCs and indirectly evokes EPSCs in type II afferents, but also evokes an inward current to depolarize type II afferents [72, 80]. Upon mechanical trauma, ATP is released by damaged HCs, generating intracellular calcium increase and ATP release among surrounding HCs and SCs (Fig.…”

“…3B) [80, 87]. In one study, Flores et al made use of Vglut3 (vesicular glutamate transporter 3) null mice, in which IHCs fail to release glutamate and thus cannot activate type I SGNs [87].…”

Postnatal maturation of auditory-nerve heterogeneity, as seen in spatial gradients of synapse morphology in the inner hair cell area

“…3 and 8). In light of this developmental timeline, synaptic physiology of type-II terminals obtained from rats at P5-P10 (Liu et al, 2015; Weisz et al, 2014) could differ in significant ways from the mature state.…”

Tyrosine Hydroxylase Expression in Type II Cochlear Afferents in Mice

“…Despite this extended dendritic arbor, type II afferents are only weakly activated by hair cell glutamate release (Weisz et al 2009;Weisz et al 2012) and are insensitive to sound Robertson 1984;Robertson et al 1999), although they project centrally in parallel with neighboring type I afferents (Berglund and Brown 1994;Brown et al 1988;Brown and Ledwith 1990;Morgan et al 1994). Emerging evidence suggests that type II afferents instead respond to tissue damage (Flores et al 2015;Liu et al 2015) perhaps to serve as cochlear nociceptors. Further insight into type II function will require knowledge of their central connectivity, as well as animal models in which type II function can be altered selectively.…”