Urocortin 3 signalling in the auditory brainstem aids recovery of hearing after reversible noise-induced threshold shift.

KEY POINTS: Ongoing, moderate noise exposure does not instantly damage the auditory system but may cause lasting deficits, such as elevated thresholds and accelerated ageing of the auditory system. The neuromodulatory peptide urocortin-3 (UCN3) is involved in the body's recovery from a stress response, and is also expressed in the cochlea and the auditory brainstem. Lack of UCN3 facilitates age-induced hearing loss and causes permanently elevated auditory thresholds following a single 2 h noise exposure at moderate intensities. Outer hair cell function in mice lacking UCN3 is unaffected, so that the observed auditory deficits are most likely due to inner hair cell function or central mechanisms. Highly specific, rather than ubiquitous, expression of UCN3 in the brain renders it a promising candidate for designing drugs to ameliorate stress-related auditory deficits, including recovery from acoustic trauma. ABSTRACT: Environmental acoustic noise is omnipresent in our modern society, with sound levels that are considered non-damaging still causing long-lasting or permanent changes in the auditory system. The small neuromodulatory peptide urocortin-3 (UCN3) is the endogenous ligand for corticotropin-releasing factor receptor type 2 and together they are known to play an important role in stress recovery. UCN3 expression has been observed in the auditory brainstem, but its role remains unclear. Here we describe the detailed distribution of UCN3 expression in the murine auditory brainstem and provide evidence that UCN3 is expressed in the synaptic region of inner hair cells in the cochlea. We also show that mice with deficient UCN3 signalling experience premature ageing of the auditory system starting at an age of 4.7 months with significantly elevated thresholds of auditory brainstem responses (ABRs) compared to age-matched wild-type mice. Following a single, 2 h exposure to moderate (84 or 94 dB SPL) noise, UCN3-deficient mice exhibited significantly larger shifts in ABR thresholds combined with maladaptive recovery. In wild-type mice, the same noise exposure did not cause lasting changes to auditory thresholds. The presence of UCN3-expressing neurons throughout the auditory brainstem and the predisposition to hearing loss caused by preventing its normal expression suggests UCN3 as an important neuromodulatory peptide in the auditory system's response to loud sounds.

Slow oscillatory changes of DPOAE magnitude and phase after exposure to intense low-frequency sounds.

Sensitive sound detection within the mammalian cochlea is performed by hair cells surrounded by cochlear fluids. Maintenance of cochlear fluid homeostasis and tight regulation of intracellular conditions in hair cells are crucial for the auditory transduction process but can be impaired by intense sound stimulation. After a short, intense low-frequency sound, the cochlea shows the previously described "bounce phenomenon," which manifests itself as slow oscillatory changes of hearing thresholds and otoacoustic emissions. In this study, distortion product otoacoustic emissions (DPOAEs) were recorded after Mongolian gerbils were exposed to intense low-frequency sounds (200 Hz, 100 dB SPL) with different exposure times up to 1 h. After all sound exposure durations, a certain percentage of recordings (up to 80% after 1.5-min-long exposure) showed oscillatory DPOAE changes, similar to the bounce phenomenon in humans. Changes were quite uniform with respect to size and time course, and they were independent from sound exposure duration. Changes showed states of hypo- and hyperactivity with either state preceding the other. The direction of changes was suggested to depend on the static position of the cochlear operating point. As assessed with DPOAEs, no indication for a permanent damage after several or long exposure times was detected. We propose that sensitivity changes occur due to alterations of the mechanoelectrical transduction process of outer hair cells. Those alterations could be induced by different challenged homeostatic processes with slow electromotility of outer hair cells being the most plausible source of the bounce phenomenon. NEW & NOTEWORTHY Low-frequency, high-intensity sound can cause slowly cycling activity changes in the mammalian cochlea. We examined the effect of low-frequency sound duration on the degree of these alterations. We found that cochlear changes showed a stereotypical biphasic pattern independent of sound exposure duration, but the probability that significant changes occurred decreased with increasing sound duration. Despite exposure durations of up to 1 h, no permanent or transient impairments of the cochlea were detected.

A DPOAE assessment of outer hair cell integrity in ears with age-related hearing loss.

Distortion product otoacoustic emissions (DPOAEs) were used to assess outer hair cell (OHC) integrity in human ears with age-related hearing loss. Sound pressure measurements were made in the ear canal over the stimulus range 40-90 dB SPL (L2), with L1 = 0.45*L2 + 44 with F2 = 2 and 3 or 4 kHz. Model-generated DPOAE I/O functions were fit to DPOAE data to quantify the contribution of loss of nonlinearity (OHC loss) to the hearing loss. Results suggest OHC loss as a contributing cause of age-related hearing, regardless of audiogram configuration. It seems likely that OHC and strial pathology co-exist in ears with AHL.