Swept-sine noise-induced damage as a hearing loss model for preclinical assays

Abstract

Mouse models are key tools for studying cochlear alterations in noise-induced hearing loss (NIHL) and for evaluating new therapies. Stimuli used to induce deafness in mice are usually white and octave band noises that include very low frequencies, considering the large mouse auditory range. We designed different sound stimuli, enriched in frequencies up to 20 kHz (“violet” noises) to examine their impact on hearing thresholds and cochlear cytoarchitecture after short exposure. In addition, we developed a cytocochleogram to quantitatively assess the ensuing structural degeneration and its functional correlation. Finally, we used this mouse model and cochleogram procedure to evaluate the potential therapeutic effect of transforming growth factor β1 (TGF-β1) inhibitors P17 and P144 on NIHL. CBA mice were exposed to violet swept-sine noise (VS) with different frequency ranges (2–20 or 9–13 kHz) and levels (105 or 120 dB SPL) for 30 min. Mice were evaluated by auditory brainstem response (ABR) and otoacoustic emission tests prior to and 2, 14 and 28 days after noise exposure. Cochlear pathology was assessed with gross histology; hair cell number was estimated by a stereological counting method. Our results indicate that functional and morphological changes induced by VS depend on the sound level and frequency composition. Partial hearing recovery followed the exposure to 105 dB SPL, whereas permanent cochlear damage resulted from the exposure to 120 dB SPL. Exposure to 9–13 kHz noise caused an auditory threshold shift (TS) in those frequencies that correlated with hair cell loss in the corresponding areas of the cochlea that were spotted on the cytocochleogram. In summary, we present mouse models of NIHL, which depending on the sound properties of the noise, cause different degrees of cochlear damage, and could therefore be used to study molecules which are potential players in hearing loss protection and repair.

The effect of noise exposure during the developmental period on the function of the auditory system

“…Increased CAP thresholds were also observed by in adult chinchillas after a 5-day noise exposure, a 40-dB hearing threshold shift was reported by Noreña et al (2003) after a 1-h exposure of adult cats to pure tones at 120 dB. Sanz et al (2015) reported a shift of ABR and DPOAE thresholds in mice exposed for 30 min at the age of 2 months to a violet swept-sine stimulus at 105 or 120 dB SPL.…”

“…However, despite several pioneering works that showed the effects of developmental auditory deprivation (Silverman and Clopton, 1977;Clopton and Silverman, 1978;Coleman and O'Connor, 1979) and suggested that an experience-driven activity during ontogeny is necessary for normal development ConstantinePaton, 1983, 1985;Sanes and Tak acs, 1993), it was not until recently that the importance of proper stimulation and patterned neuronal activity was fully appreciated (e.g., Zhang et al, 2001Zhang et al, , 2002Bao et al, 2003;Chang and Merzenich, 2003;Kandler, 2004;Nakahara et al, 2004;Chang et al, 2005;Kandler and Gillespie, 2005;Zhang et al, 2008;Gr ecov a et al, 2009;Bure s et al, 2010Bure s et al, , 2014Bao et al, 2013). It appears that even a short-time detachment of the developing auditory system from natural and rich auditory experience, resulting from an impaired periphery or anomalous stimulation such as noise or clicks, will often result in altered structural and functional characteristics at various levels of the auditory system.…”

“…In particular, noise trauma in adulthood is assumed to result in a decrease of inhibition and an increased excitability of the auditory centers Wang et al, 1996;Salvi et al, 2000;Noreña et al, 2003;Sun et al, 2012), while a developmental noise exposure leads to lower maximum response magnitudes and presumably higher overall inhibitory strength (Gr ecov a et al, 2009;Bure s et al, 2010;Rybalko et al, 2011Rybalko et al, , 2015. It was thus suggested that an intervention during ontogeny disrupts normal development of, particularly, inhibitory connectivity, and the undeveloped circuits partly or completely retain their immature characteristics (Sanes and Tak acs, 1993;Gabriele et al, 2000;Rybalko and Syka, 2001;Kandler, 2004;Gr ecov a et al, 2009). Moreover, the developmental impairments may affect only certain tonotopical regions: Pierson and Snyder-Keller (1994) showed that adult rats which were transiently deafened on postnatal day 14 (P14) using an intense 8-min noise exposure present signs of improper development of the inferior colliculus (IC) only in the high-frequency regions.…”

“…Despite this volume of work, there still exists great uncertainty as to what effect a specific intervention will have: different interventions may have different consequences at various levels of the auditory system, depending also on the type of intervention, stimulus type, exposure levels, or age of exposure (e.g., Sanes and Constantine-Paton, 1985;Zhang et al, 2001;Chang et al, 2005;Gr ecov a et al, 2009;Insanally et al, 2009;Miyakawa et al, 2013). The duration of the insulting exposure plays an important role: for example, a brief intense exposure has often no influence on the hearing thresholds and neuronal excitatory thresholds (Gr ecov a et al, 2009;Kujawa and Liberman, 2009;Bure s et al, 2010;Rybalko et al, 2011;Sanz et al, 2015;Shi et al, 2015), while long-term exposure to moderate-level sounds results in elevated sound thresholds (Gao et al, 2009;Insanally et al, 2010;Lauer and May, 2011).…”

Aging, neurogenesis and neuroinflammation in hearing loss and protection

“…Laboratory animals are essential for generating accurate models of human hearing loss. One of the articles included in this eBook describes novel models for studying NIHL, based on the use of different sound stimuli, which provide solid ground on which to study potential therapeutic molecules (Sanz et al, 2015). Another important matter that must be addressed is the delivery of potential drugs to the cochlea.…”