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

Abstract

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. AbstractEnvironmental 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.

Expression Patterns of the Neuropeptide Urocortin 3 and Its Receptor CRFR2 in the Mouse Central Auditory System

“…Expression patterns of UCN3 and CRFR2 in the cochlea and spiral ganglion neurons were reported in detail before (Graham et al, 2010;Fischl et al, 2019), so that here, we start with the description of UCN3 and CRFR2 expression in the CN. From there we proceed to the SOC, the LL, the IC, and the MGB.…”

“…We previously reported the expression of UCN3 in the auditory brainstem nuclei with respect to the protection of the auditory system from sound over-exposure ( Fischl et al, 2019 ). Surprisingly, this protective function was not accompanied by high numbers of UCN3-positive neuronal cell bodies in the SOC, but rather with an abundance of UCN3 expressing axons and synaptic terminals in this area ( Figures 2A,B ).…”

“…Besides the long-range endocrine signaling, some neuropeptides such as galanin (Freund-Mercier and Stoeckel, 1995) and oxytocin can also be released by dendrites and neuronal somata (Vila-Porcile et al, 2009). In invertebrates, The number of plus signs symbolizes the relative strength and a minus sign the lack of expression (Lewis et al, 2001;Li et al, 2002;Deussing et al, 2010;Graham et al, 2010;Basappa et al, 2012;Fischl et al, 2019).…”

“…That makes UCN3 the primary ligand for CRFR2. So far, UCN3 expression in the auditory system was reported in the cochlea and SOC ( Lewis et al, 2001 ; Li et al, 2002 ; Fischl et al, 2019 ). However, the physiological importance of UCN3 and its receptor CRFR2 for auditory function has been emphasized by knockout models of UCN3 and CRFR2, both showing enhanced vulnerability to noise trauma ( Graham et al, 2010 ; Fischl et al, 2019 ).…”

“…So far, UCN3 expression in the auditory system was reported in the cochlea and SOC ( Lewis et al, 2001 ; Li et al, 2002 ; Fischl et al, 2019 ). However, the physiological importance of UCN3 and its receptor CRFR2 for auditory function has been emphasized by knockout models of UCN3 and CRFR2, both showing enhanced vulnerability to noise trauma ( Graham et al, 2010 ; Fischl et al, 2019 ). Although noise trauma and systemic stress are two major causes of hearing loss in humans ( Masuda et al, 2012 ), our knowledge of the UCN3–CRFR2 contribution to auditory signal processing is rather limited.…”