Hidden hearing loss (HHL), a recently described auditory disorder, has been proposed to affect auditory neural processing and hearing acuity in subjects with normal audiometric thresholds, particularly in noisy environments. In contrast to central auditory processing disorders, HHL is caused by defects in the cochlea, the peripheral auditory organ. Noise exposure, aging, ototoxic drugs and peripheral neuropathies are some of the known risk factors for HHL. Our knowledge of the causes and mechanisms of HHL are based primarily on animal models. However, recent clinical studies have also shed light on the etiology and prevalence of this cochlear disorder and how it may affect auditory perception in humans. Here, we review the current knowledge regarding the causes and cellular mechanisms of HHL, summarize information on available noninvasive tests for differential diagnosis, and discuss potential therapeutic approaches for treatment of HHL.

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The auditory system detects and encodes sound information with high precision to provide a high-fidelity representation of the environment and communication.In mammals, detection occurs in the peripheral sensory organ (the cochlea) containing specialized mechanosensory cells (hair cells) that initiate the conversion of sound-generated vibrations into action potentials in the auditory nerve. Neural activity in the auditory nerve encodes information regarding the intensity and frequency of sound stimuli, which is transmitted to the auditory cortex through the ascending neural pathways. Glial cells are critical for precise control of neural conduction and synaptic transmission throughout the pathway, allowing for the precise detection of the timing, frequency, and intensity of sound signals, including the sub-millisecond temporal fidelity is necessary for tasks such as sound localization, and in humans, for processing complex sounds including speech and music. In this review, we focus on glia and glia-like cells that interact with hair cells and neurons in the ascending auditory pathway and contribute to the development, maintenance, and modulation of neural circuits and transmission in the auditory system. We also discuss the molecular mechanisms of these interactions, their impact on hearing and on auditory dysfunction associated with pathologies of each cell type.

Age-related hearing loss (ARHL) is the most prevalent sensory deficit in the elderly.This progressive pathology often has psychological and medical comorbidities, including social isolation, depression, and cognitive decline. Despite ARHL's enormous societal and economic impact, no therapies to prevent or slow its progression exist. Loss of synapses between inner hair cells (IHCs) and spiral ganglion neurons (SGNs), a.k.a. IHC synaptopathy, is an early event in cochlear aging, preceding neuronal and hair cell loss. To determine if age-related IHC synaptopathy can be prevented, and if this impacts the time-course of ARHL, we tested the effects of cochlear overexpression of neurotrophin-3 (Ntf3) starting at middle age. We chose Ntf3 because this neurotrophin regulates the formation of IHC-SGN synapses in the neonatal period. We now show that triggering Ntf3 overexpression by IHC supporting cells starting in middle age rapidly increases the amplitude of sound-evoked neural potentials compared with age-matched controls, indicating that Ntf3 produces a positive effect on cochlear function when the pathology is minimal. Furthermore, near the end of their lifespan, Ntf3-overexpressing mice have milder ARHL, with larger sound-evoked potentials along the ascending auditory pathway and reduced IHC synaptopathy compared with age-matched controls. Our results also provide evidence that an age-related decrease in cochlear Ntf3 expression contributes to ARHL and that Ntf3 supplementation could serve as a therapeutic for this prevalent disorder. Furthermore, these findings suggest that factors that regulate synaptogenesis during development could prevent age-related synaptopathy in the brain, a process involved in several central nervous system degenerative disorders.

Hearing impairment without threshold elevations can occur when there is damage to high‐threshold auditory nerve fibre synapses with cochlear inner hair cells. Instead, cochlear synaptopathy produces suprathreshold deficits, especially in older patients, which affect conversational speech. Given that listening in noise at suprathreshold levels presents significant challenges to the ageing population, we examined the effects of synaptopathy on tone‐in‐noise coding on the central recipients of auditory nerve fibres, i.e. the cochlear nucleus neurons. To induce synaptopathy, guinea pigs received a unilateral sound overexposure to the left ears. A separate group received sham exposures. At 4 weeks post‐exposure, thresholds had recovered but reduced auditory brainstem response wave 1 amplitudes and auditory nerve synapse loss remained on the left side. Single‐unit responses were recorded from several cell types in the ventral cochlear nucleus to pure‐tone and noise stimuli. Receptive fields and rate–level functions in the presence of continuous broadband noise were examined. The synaptopathy‐inducing noise exposure did not affect mean unit tone‐in‐noise thresholds, nor the tone‐in‐noise thresholds in each animal, demonstrating equivalent tone‐in‐noise detection thresholds to sham animals. However, synaptopathy reduced single‐unit responses to suprathreshold tones in the presence of background noise, particularly in the cochlear nucleus small cells. These data demonstrate that suprathreshold tone‐in‐noise deficits following cochlear synaptopathy are evident in the first neural station of the auditory brain, the cochlear nucleus neurons, and provide a potential target for assessment and treatment of listening‐in‐noise deficits in humans. Key points Recording from multiple central auditory neurons can determine tone‐in‐noise deficits in animals with quantified cochlear synapse damage. Using this technique, we found that tone‐in‐noise thresholds are not altered by cochlear synaptopathy, whereas coding of suprathreshold tones‐in‐noise is disrupted. Suprathreshold deficits occur in small cells and primary‐like neurons of the cochlear nucleus. These data provide important insights into the mechanisms underlying difficulties associated with hearing in noisy environments.