Cochlear Nerve Degeneration

Behavioral/Systems/Cognitive Adding Insult to Injury: Cochlear Nerve Degeneration after “Temporary” Noise-Induced Hearing Loss Sha ron G. Kuj awa 1,2,3,4 and M. Cha rle s Liberman 1,2,4 1 Department of Otology and Laryngology, Harvard Medical School, Boston, Massachusetts 02115, 2 Eaton-Peabody Laboratory and 3 Department of Audiology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts 02114, and 4 Program in Speech and Hearing Bioscience and Technology, Division of Health Science and Technology, Harvard–Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 Ove rex pos ure to int ens e sou nd cancause tempor aryor per manent hea rin g loss. Pos tex pos ure rec ove ry of thr esh oldsensit ivi ty has been ass ume d to ind ica te revers al of damage to del ica te mec hano-sens ory and neu ral str uct ure s of the inner ear and no per sis tent or del aye d conseq uencesfor aud ito ry functi on.Here,we sho w, usi ng coc hle ar functi ona l ass aysand confoc al ima gin g of theinnerear in mou se,that acoustic overexposures causing moderate, but completely reversible, threshold elevation leave cochlear sensory cells intact, but cause acute loss of afferent nerve terminals and delayed degeneration of the cochlear nerve. Results suggest that noise-induced damage to the ear has progressive consequences that are considerably more widespread than are revealed by conventional threshold testing. This primary neurod egeneratio n shoul d add to diffi culties heari ng in noisy environmen ts, and could contr ibut e to tinni tus, hyper acusi s, and other perceptual anomalies commonly associated with inner ear damage. Introduction Noise-induced hearing loss (NIHL) is a major health problem (DHHS, 2009), because opportunities for overexposure abound, and exposures that damage hearing are not necessarily painful or even annoying. After overexposure, NIHL recovers with an ex- ponent ial time course (Mi lle r et al. , 19 63) for 2– 3 wee ks, dep end - ing on initi al sever ity. Thres holdsmay full y recov er (“temporary ” threshold shift) or stabilize at an elevated value (“permanent” threshold shift). Permanent NIHL is due to destruction of cochlear hair cells or damage to their mechano-sensory hair bun- dles (Liberman and Dodds, 1984). Hair cells normally transduce sound -evok ed mech anica l moti on into recep tor poten tial s, which lead to transmitter release at their glutamatergic synapses with cochlear afferent fibers (see Fig. 1). Hair cell damage can be vis ibl e wit hin min ute s aft er overex pos ure, and hai r cel l dea th can continue for days (Wang et al., 2002). In contrast, noise-induced loss of spi ral gan gli on cel ls (SGCs) , the cel l bodies of the coc hle ar aff ere nt neurons contac tin g the se hair cel ls, is del aye d by mon ths and can progress for years (Kujawa and Liberman, 2006). The re is no hai r cel l dea th in tempor aryNIHL;howev er,swell - ing of coc hle ar ner ve ter min als at the ir hai r-c ell syn aps es, sugges- tive of glu tamateexcito tox ici ty, is see n wit hin 24 h aft er exposure (Spoendlin, 1971; Lib erman and Mul roy , 1982; Robertson, 1983). Such sound-evoked excitotoxicity can be blocked by glutamate antagonists and mimicked by glutamate agonists in the absence of sound (Pujol et al., 1993; Sun et al., 2001; Puel et al., 2002; Ruel et al., 2007). Some noise or drug exposures can be followed by rapid postexposure recovery of cochlear synaptic ul- trastructure and audi tory thres holds , sugge sting that swoll en terminals have recovered or regenerated (Zheng et al., 1997; Puel et al., 1998; Zheng et al., 1999). Neuronal counts have not been made, however, and long survivals after apparently reversible noise exposures have not been evaluated. Here, we revisit the issue of neural degeneration in ears with tempo rary noise -indu ced thresh old shift s. We show rapid , exte n- sive, and irreversible loss of synapses within 24 h postexposure, and delayed and progressive loss of cochlear neurons over many months , alt hou gh hai r cel ls remain and rec ove r nor mal fun ction. Despite recovery of threshold sensitivity, the consequences of such primary neuronal loss on auditory processing of suprath- reshold sound s are likel y dramatic, espec iall y in difficul t liste ning environments. Mat eria ls and Met hods Animals and groups. Mice of the CBA/CaJ strain were used in this study, because they show excellent cochlear sensitivity and limited age-related ele vat ionin coch lea r thr esholds. Mal e CBA/CaJmice wer e nois e expose d at 16 weeks of age and held without further treatment for various postexposure times. Age-, strain-, and gender-matched animals held identi- cally, except for the exposure, served as controls. All procedures were approved by the Institutional Animal Care and Use Committee of the Massachusetts Eye and Ear Infirmary. Acoustic overexposures. The acoustic overexposure stimulus was an octave band of noise (8–16 kHz) at 100 dB SPL, for 2 h. During exposures, animals were unrestrained within small cells in a subdivided cage (1 animal/cel l). The cage was suspended directly below the horn of the sound-delivery loudspeaker in a small, reverberant chamber. Noise cali- bration to target SPL was performed immediately before each exposure session. Sound pressure levels varied by 1 dB across the cages. Physiological tests. Mice were anesthetized with ketamine (100 mg/kg, i.p.) and xylazine (10 mg/kg, i.p.). Acoustic stimuli were delivered via a Received June 16, 2009; revised Oct. 5, 2009; accepted Oct. 6, 2009. Research was supported by grants from the National Institute on Deafness and Other Communicative Disorders (R01 DC8577, RO1 DC0188, P30 DC5209) and by a generous donation from Steve and Andrea Kaneb. Correspondence should be addressed to Sharon G. Kujawa, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114-3096. E-mail: [email protected] . DOI:10.1523/JNEUROSCI.2845-09.2009 Copyright © 200 9 Societ y for Neuroscience 0270-6474/09/2914077-09$15.00 /0 The Journal of Neuroscience, November 11, 2009 • 29(45):14077–14085 • 14077

Cochlear Nerve Degeneration

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