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Transcriptional responses to noise stress in mice

J.M.E. Cederholm,1 K.E. Froud,1 W.  Kaplan2 and G.D. Housley,1 1Translational Neuroscience Facility and Department of Physiology, School of Medical Sciences, University of New South Wales, NSW 2052, Australia and 2Peter Wills Bioinformatics Centre, Garvan Institute of Medical Research, Darlington, NSW 2010, Australia.

Exposure to excessive noise and the associated hearing loss is an increasing global problem in modern society. Following acoustic overstimulation a shift in hearing sensitivity is observed and depending on the intensity of the noise, a temporary (TTS), or permanent, threshold shift (PTS) will occur. In contrast to PTS, changes in hearing sensitivity after TTS-inducing noise are reversible. Many cochlear structures affected by noise overstimulation have been identified (e.g. Chen, 2006; Hirose & Liberman, 2003; Liberman & Dodds, 1984), and investigations into related changes in gene expression have been carried out. These studies focused on loud, PTS-inducing noise, in rats (e.g. Cho et al., 2004; Kirkegaard et al., 2006) and mice (e.g. Gratton et al., 2011; Tornabene et al., 2006). It is, however, also important to understand the possible transcriptional responses underlying TTS. Here we report the regulation of cochlear gene expression in C57Bl/6J mice in response to TTS-inducing noise.

Evoked auditory brainstem responses (ABR) were measured to broadband clicks, or 16 kHz tonepips, before and after 30 min noise exposure (86 dB or 95 dB, 4 – 32 kHz). Control mice underwent the same procedure, but were not exposed to noise. Experiments were conducted on mice anaesthetized with a ketamine/xylazine/acepromazine cocktail as previously described (Cederholm et al., 2012), and in accordance with University of New South Wales' Animal Care and Ethics Committee approval. That noise regime produced on average 12 ± 1.1 dB TTS for 86 dB noise, and on average 41 ± 3.0 dB for 96 dB noise. Separate experiments showed that these levels of TTS fully recovered within two weeks. Cochlea RNA extraction (RNeasy Plus Mini kit, Qiagen) was performed on tissue collected 1, 2, 4, 8 and 24 h after the noise exposure (pentobarbital overdose prior to tissue collection). cDNA template was hybridized to the Affymetrix® mouse gene array 1.1ST. Gene expression analysis was performed using GenePattern software ( Statistically significant changes in gene expression were identified as having a P-value of <0.001 and a minimum of a 2-fold up- or down-regulation.

We identified a number of genes that were up-regulated across all five times with TTS. The two most highly regulated genes after 86 dB noise exposure showed almost 20-fold up-regulation at 4 h. Up-regulation typically commenced two h after the noise exposure. We have shown, to our knowledge, for the first time transcriptional responses to TTS-inducing noise. The majority of the genes previously reported to be regulated after PTS-inducing noise was not observed to be responsive to TTS-level noise in our study. The TTS-regulated gene set we have identified here likely reflects cellular responses to noise stress that contribute to hearing adaptation and protection from noise-induced hearing loss.

Cederholm, J.M., Froud, K.E., Wong, A.C., Ko, M., Ryan, A.F., Housley, G.D. (2012) Differential actions of isoflurane and ketamine-based anaesthetics on cochlear function in the mouse. Hearing Research 292: 71-79.

Chen, G.D. (2006) Prestin gene expression in the rat cochlea following intense noise exposure. Hearing Research 222, 54-61.

Cho, Y., Gong, T.W., Kanicki, A., Altschuler, R.A., Lomax, M.I. (2004) Noise overstimulation induces immediate early genes in the rat cochlea. Brain Research Molecular Brain Research 130, 134-48.

Gratton, M.A., Eleftheriadou, A., Garcia, J., Verduzco, E., Martin, G.K., Lonsbury-Martin, B.L., Vazquez, A.E. (2011) Noise-induced changes in gene expression in the cochleae of mice differing in their susceptibility to noise damage. Hearing Research 277, 211-26.

Hirose, K., Liberman, M.C. (2003) Lateral wall histopathology and endocochlear potential in the noise-damaged mouse cochlea. Journal of the Association for Research in Otolaryngology 4, 339-52.

Liberman, M.C., Dodds, L.W. (1984) Single-neuron labeling and chronic cochlear pathology. III. Stereocilia damage and alterations of threshold tuning curves. Hearing Research 16, 55-74.

Kirkegaard, M., Murai, N., Risling, M., Suneson, A., Jarlebark, L., Ulfendahl, M. (2006) Differential gene expression in the rat cochlea after exposure to impulse noise. Neuroscience 142, 425-35.

Tornabene, S.V., Sato, K., Pham, L., Billings, P., Keithley, E.M. (2006) Immune cell recruitment following acoustic trauma. Hearing Research 222, 115-24.

This study was supported by the NH&MRC project grant APP 630618.