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

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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.

Introduction

Corticotropin-releasing factor (CRF) is a 41 amino acid peptide critically important to hypothalamic–pituitary–adrenal (HPA) axis function (Vale et al., 1981). While three receptors have been cloned (Grammatopoulos and Chrousos, 2002, Bale and Vale, 2004), only CRFR1 and CRFR2 are expressed in mammals. In addition to its role in HPA axis physiology, CRF and its receptors are expressed in the central nervous system (Sawchenko et al., 1993, Van Pett et al., 2000), suggesting functions for CRF beyond its classic hormonal role. CRF receptors are involved in sensitivity to stress and anxiety (Smith et al., 1998, Bale et al., 2000Bale et al., 2002, Kishimoto et al., 2000, Vetter et al., 2002), cellular stress responses of the skin (Slominski et al., 1998, Slominski et al., 1999, 2000, 2001), mood disorders (Nemeroff, 1988Nemeroff, 1992, Nemeroff et al., 1988, Bale and Vale, 2003), energy balance and metabolism (Pelleymounter et al., 2000), hemodynamics (Brown et al., 1986), vascularization (Bale et al., 2003) and differentiation of neuronal dendrites within the hippocampus (Chen et al., 2004).

Within the cochlea, hair cells are responsible for encoding auditory stimuli, while various support cells are important for homeostatic regulation of the endolymph, a specialized fluid of the scala media bathing the hair cell apices. Endolymph is an unusual extracellular fluid by virtue of its high potassium content, and relatively low calcium level. The exact ionic composition of the endolymph can be altered by acoustic overexposure (Marcus et al., 1998, Jentsch, 2000, Housley et al., 2006) and by other endogenous signals, that alter cochlear sensitivity, thereby serving a protective role against release of potentially excitotoxic levels of glutamate from the hair cells.

Because cochlear hair cells are spontaneously active, and are constantly stimulated by the environment, the cochlea is under constant physical and metabolic stress. Damage and subsequent loss of cochlear hair cells results in permanent hearing loss in mammals. Although noise-induced hearing loss is the most prevalent occupational injury reported in the United States, knowledge concerning mechanisms underlying susceptibility to noise-induced hearing loss, and general protein expression changes that take place within the cochlea in response to noise exposure, is incomplete. We have previously demonstrated the existence of urocortin, a CRF-related peptide, and CRFR1 and CRFR2 in the murine cochlea (Vetter et al., 2002) in regions involved with homeostatic regulatory functions of the inner ear, as well as neural processing of hair cell responses. Given that other systems such as the skin use local CRF signaling to maintain homeostasis and protect against physical damage, we hypothesized that the CRF system may play a similar role in the inner ear, and may serve to protect against pathologies such as noise-induced hearing loss. We therefore investigated whether CRF is expressed in the cochlea, determined the role of CRFR2 activity in cochlear function, and attempted to define some of the possible mechanisms by which CRFR2 may exert its protective effects using a CRFR2 null mouse line.

Section snippets

Animals, housing, and noise assessment

CRFR2-/- mice have been described previously (Bale et al., 2000). Mice were raised under standard vivarium conditions (12 h light/dark cycles) in ventilated Thoren cage racks. Alternatively, some mice were raised in an IAC acoustic chamber on static shelving. One octave filter measurements of sound intensities over a spectrum of frequencies from 63 to 16,000 Hz were measured in the standard vivarium to assess ambient sound levels. Two measures were taken; one on the actual shelf the cages are

CRF is expressed in the murine cochlea

The only CRF-like ligand previously reported in the cochlea is urocortin (Vetter et al., 2002). However, given the mismatch between the relatively restricted expression pattern of urocortin in the lateral olivocochlear terminals and the widespread distribution of its receptors, we hypothesized that other CRF-like ligands may also exist in the cochlea. Immunofluorescent labeling of adult mouse cochleae localized CRF to cells lining the lumen of the scala media, including lateral support cells

Discussion

Noise-induced hearing loss cuts across age, gender, ethnicity and profession, and is one of the most prevalent occupational injuries reported. It is especially prevalent in military veterans (Humes et al., 2005), and some estimates indicate that more than 30 million workers in the United States alone are exposed to hazardous noise levels (DHHS NIOSH pub. 96–115). Yet significant gaps exist in our understanding of the normal biochemical mechanisms underlying the ability of the cochlea to protect

Acknowledgments

This research was supported by NIHR01DC006258 (DEV) and The Tufts Center for Neuroscience Research Imaging Core, P30 NS047243. The authors are also indebted to Dr. M.C. Liberman of Mass. Eye and Ear Infirmary for granting access to his auditory physiology (ABR/DP) set-up. Drs. Wylie Vale and Kuo-Fen Lee of the Salk Institute for Biological Studies (La Jolla, CA) provided initial CRFR2 null and wild type mice from which the colony was generated at Tufts Univ. School of Medicine.

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    1

    These authors contributed equally to this work.

    2

    Present address: Univ. of Michigan School of Medicine, Ann Arbor, MI.

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