A corticotropin-releasing factor system expressed in the cochlea modulates hearing sensitivity and protects against noise-induced hearing loss

Abstract

Noise-induced hearing loss is a highly prevalent occupational injury, yet little is known concerning the signals controlling normal cochlear sensitivity and susceptibility to noise-induced trauma. While the corticotropin-releasing factor (CRF) system is involved in activation of the classic hypothalamic-pituitary-adrenal axis, it is also involved in local physiological responses to stress in many tissues, and is expressed in the inner ear. We demonstrate that mice lacking the CRF receptor CRFR2 exhibit a significantly lower auditory threshold than wild type mice, but this gain of function comes at the price of increased susceptibility to acoustic trauma. We further demonstrate that glutamatergic transmission, purinergic signaling, and activation of Akt (PKB) pathways within the cochlea are misregulated, which may underlie the enhanced sensitivity and trauma susceptibility observed in CRFR2-/- mice. Our data suggest that CRFR2 constitutively modulates hearing sensitivity under normal conditions, and thereby provides protection against noise-induced hearing loss.

The Cochlear CRF Signaling Systems and their Mechanisms of Action in Modulating Cochlear Sensitivity and Protection Against Trauma

“…CRF and both CRF receptors (Fig. 1, 3, and Table 1) are expressed within the mouse cochlea (Graham et al, 2010; Graham and Vetter, 2011). The role of cochlear CRF signaling (and by extension HPA-equivalent signaling within the cochlea) has begun to be revealed using transgenic mice lacking CRFR1 or CRFR2 (CRFR1 and CRFR2 null respectively).…”

“…The role of cochlear CRF signaling (and by extension HPA-equivalent signaling within the cochlea) has begun to be revealed using transgenic mice lacking CRFR1 or CRFR2 (CRFR1 and CRFR2 null respectively). These mouse models were used to examine in vivo the structural and functional consequences induced by constitutive loss of each CRF receptor gene (Graham et al, 2010; Graham and Vetter, 2011), as well as through pharmacological activation of CRFR2 in an in vitro model (Basappa et al, 2010). …”

“…In contrast to the lower auditory sensitivity of the CRFR1 null mice, CRFR2 null mice exhibit ABR thresholds that are 20–25dB lower than wild type mice and distortion product otoacoustic emission thresholds that are 10–15dB lower than wild types (Graham et al, 2010). The lower distortion product thresholds suggest that enhanced cochlear amplification (via increased outer hair cell activity) contributes to some, but not all, of the hypersensitivity observed in these mice (since the increase in distortion product emissions is about half of the ABR threshold change).…”

“…Since activity of the classic CRF-induced HPA axis maintains system-wide homeostasis in response to stress, we have investigated whether this system plays a role in modulating the cochlea via an influence over various factors, including afferent function (i.e. setting sensitivity) (Graham et al, 2010; Graham and Vetter, 2011) and cellular response to metabolic insult (Basappa et al, 2010), thereby protecting the cochlea from damaging exposures to loud sounds. This review will cover the cochlear HPA-equivalent signaling system, and suggest possible functions and mechanisms of action of this system based on what is known of similar systems expressed by other organs/tissues of the body.…”

Loss of Myh14 Increases Susceptibility to Noise-Induced Hearing Loss in CBA/CaJ Mice

“…Noise-induced hearing loss (NIHL) has now become one of the most prevalent occupational injuries reported [1]. Long-term exposure to high intensity noise can cause this sensorineural hearing disorder.…”