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

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.