Noise-induced Cochlear Synaptopathy with and Without Sensory Cell Loss

Highlights

• Loss of IHC synapses with cochlear neurons is ubiquitous after noise exposure.

• Synapse loss does not scale with TTS or PTS.

• Hair cell damage modifies synaptopathic outcomes.

• Threshold sensitivity measures dramatically underestimate noise risk.

Abstract

Prior work has provided extensive documentation of threshold sensitivity and sensory hair cell losses after noise exposure. It is now clear, however, that cochlear synaptic loss precedes such losses, at least at low-moderate noise doses, silencing affected neurons. To address questions of whether, and how, cochlear synaptopathy and underlying mechanisms change as noise dose is varied, we assessed cochlear physiologic and histologic consequences of a range of exposures varied in duration from 15 min to 8 h and in level from 85 to 112 dB SPL. Exposures delivered to adult CBA/CaJ mice produced acute elevations in hair cell- and neural-based response thresholds ranging from trivial (∼5 dB) to large (∼50 dB), followed by varying degrees of recovery. Males appeared more noise vulnerable for some conditions of exposure. There was little to no inner hair cell (IHC) loss, but outer hair cell (OHC) loss could be substantial at highest frequencies for highest noise doses. Synapse loss was an early manifestation of noise injury and did not scale directly with either temporary or permanent threshold shift. With increasing noise dose, synapse loss grew to ∼50%, then declined for exposures yielding permanent hair cell injury/loss. All synaptopathic, but no non-synaptopathic exposures produced persistent neural response amplitude declines; those additionally yielding permanent OHC injury/loss also produced persistent reductions in OHC-based responses and exaggerated neural amplitude declines. Findings show that widespread cochlear synaptopathy can be present with and without noise-induced sensory cell loss and that differing patterns of cellular injury influence synaptopathic outcomes.

Introduction

Noise can permanently elevate thresholds by permanently damaging outer hair cells (OHCs), the biological motors that amplify the sound-evoked cochlear mechanical response (Dallos, 2008). OHCs are among the cochlear structures most vulnerable to insult (see Kurabi et al., 2017 for review); however, the inner hair cell (IHC) synapses that provide for the communication of sensory information to cochlear nerve fibers are earlier targets in both the noise-exposed (Kujawa and Liberman, 2009, Lin et al., 2011) and the aging ear (Sergeyenko et al., 2013, Fernandez et al., 2015, Parthasarathy and Kujawa, 2018). Noise exposures causing large, but reversible/temporary threshold shifts (TTS) can nevertheless cause rapid (in minutes to hours) loss of up to ∼50% of the synapses between cochlear neurons and the IHCs they contact (Kujawa and Liberman, 2009, Fernandez et al., 2015). In comparison, cochlear synaptopathy in the aging ear is gradually progressive throughout the lifespan, with losses ultimately reaching a similar ∼50% maximum, at least in mice (Sergeyenko et al., 2013, Parthasarathy and Kujawa, 2018). Synapse loss with age is significant before the onset of threshold shifts and hair cell loss and can be exaggerated by even a single TTS- and synaptopathy-producing noise exposure as a young adult (Fernandez et al., 2015). Loss of the spiral ganglion cell bodies of these disconnected afferent neurons occurs slowly and with a delay for both etiologies; however, since the neuron is silenced with the loss of its synaptic connection to the IHC, ganglion cell counts can significantly underestimate the magnitude of the cochlear deafferentation, depending on when they are made.

Cochlear synaptic and neural loss has been observed in every mammalian model of noise- and age-related hearing loss studied thus far (see Liberman and Kujawa, 2017 for review). In humans, temporal bones recovered from individuals with clear noise exposure histories, some with audiometric notches of the type commonly seen after noise (McGill and Schuknecht, 1976, Liu et al., 2015), can show dramatic deafferentation (peripheral axon and/or ganglion cell loss) in cochlear regions without IHC loss. Additionally, age-progressive loss of peripheral afferent terminals, dramatically exceeding the loss of the IHCs they innervate, has been documented in temporal bones of individuals with no specific otologic disease (Viana et al., 2015, Wu et al., 2018).

Noise-exposure characteristics necessary to produce synaptic losses in humans are currently unknown, but cochlear damage appears to progress similarly (first IHC synapses, then stereocilia, later OHC loss, then IHC loss) across all mammalian species studied to date. This suggests that species differences in noise risk would largely reflect the noise dose required to progress from one type of damage to the next (Kujawa and Liberman, 2019 for review).

To date, cochlear synaptopathy and the neurodegeneration that follows have been studied most extensively using a noise exposure model in which the injury was produced by a single, relatively short duration, moderately intense noise producing large, but temporary, threshold elevations without hair cell loss in adult CBA/CaJ mice. This TTS model provided a powerful approach in initial studies because it allowed a clear separation of the functional deficits due to loss of IHC synapses from those due to hair cell loss or damage, and because, after threshold recovery, clues present in suprathreshold responses could be interpreted without a threshold shift confound.

Noise damage in humans may take many forms, however, and underlying mechanisms may differ for reversible vs. irreversible changes and for short vs. long exposures producing similar degrees of threshold shift. Here, we provide the first characterization of noise-induced injury to cochlear hair cells, synapses and their functions as noise dose was varied over a range from apparently non-pathological to a point where hair cells were permanently destroyed.