The sense of hearing is remarkable for its auditory dynamic range, which spans more than 10 12 in acoustic intensity. The mechanisms that enable the cochlea to transduce high sound levels without damage are of key interest, particularly with regard to the broad impact of industrial, military, and recreational auditory overstimulation on hearing disability. We show that ATP-gated ion channels assembled from P2X 2 receptor subunits in the cochlea are necessary for the development of temporary threshold shift (TTS), evident in auditory brainstem response recordings as sound levels rise. In mice null for the P2RX2 gene (encoding the P2X 2 receptor subunit), sustained 85-dB noise failed to elicit the TTS that wild-type (WT) mice developed. ATP released from the tissues of the cochlear partition with elevation of sound levels likely activates the broadly distributed P2X 2 receptors on epithelial cells lining the endolymphatic compartment. This purinergic signaling is supported by significantly greater noise-induced suppression of distortion product otoacoustic emissions derived from outer hair cell transduction and decreased suprathreshold auditory brainstem response input/output gain in WT mice compared with P2RX2-null mice. At higher sound levels (≥95 dB), additional processes dominated TTS, and P2RX2-null mice were more vulnerable than WT mice to permanent hearing loss due to hair cell synapse disruption. P2RX2-null mice lacked ATP-gated conductance across the cochlear partition, including loss of ATP-gated inward current in hair cells. These data indicate that a significant component of TTS represents P2X 2 receptordependent purinergic hearing adaptation that underpins the upper physiological range of hearing.noise-induced hearing loss | acoustic overstimulation | permanent threshold shift | auditory neurotransmission | sound transduction S ensory systems are characterized by adaptation processes that sustain transduction as stimulus intensity increases. The mammalian auditory system operates across an acoustic power range of 120 dB, measured on the logarithmic decibel scale. The mechanism for the extraordinary acuity of the cochlea (recalling the ageold adage of "hearing a pin drop") arises from the commitment of 75% of the sensory hair cells, the outer hair cells, to electromechanical (reverse) transduction, driving a "cochlear amplifier." The nonlinear outer hair cell reverse transduction provides an ∼40-dB gain at hearing threshold, reducing to zero as sound levels rise (1). A major challenge for auditory physiology is to understand how hearing is preserved in the face of acoustic overstimulation, as noise can damage the cochlea and can greatly exacerbate hearing loss with aging (2). Given the recent propensity for direct delivery of high-level recreational sound to the ear canals by personal music players and, more broadly, the impact on our hearing of noise from industrial and military environments, there is an imperative to better understand the intrinsic mechanisms that enable the cochlea to accommodate lo...

The cochlear implant is the most successful bionic prosthesis and has transformed the lives of people with profound hearing loss. However, the performance of the "bionic ear" is still largely constrained by the neural interface itself. Current spread inherent to broad monopolar stimulation of the spiral ganglion neuron somata obviates the intrinsic tonotopic mapping of the cochlear nerve. We show in the guinea pig that neurotrophin gene therapy integrated into the cochlear implant improves its performance by stimulating spiral ganglion neurite regeneration. We used the cochlear implant electrode array for novel "close-field" electroporation to transduce mesenchymal cells lining the cochlear perilymphatic canals with a naked complementary DNA gene construct driving expression of brain-derived neurotrophic factor (BDNF) and a green fluorescent protein (GFP) reporter. The focusing of electric fields by particular cochlear implant electrode configurations led to surprisingly efficient gene delivery to adjacent mesenchymal cells. The resulting BDNF expression stimulated regeneration of spiral ganglion neurites, which had atrophied 2 weeks after ototoxic treatment, in a bilateral sensorineural deafness model. In this model, delivery of a control GFP-only vector failed to restore neuron structure, with atrophied neurons indistinguishable from unimplanted cochleae. With BDNF therapy, the regenerated spiral ganglion neurites extended close to the cochlear implant electrodes, with localized ectopic branching. This neural remodeling enabled bipolar stimulation via the cochlear implant array, with low stimulus thresholds and expanded dynamic range of the cochlear nerve, determined via electrically evoked auditory brainstem responses. This development may broadly improve neural interfaces and extend molecular medicine applications.

Female hormone influences on auditory system aging are not completely understood. Because of widespread clinical use of hormone replacement therapy (HRT), it is critical to understand HRT effects on sensory systems. The present study retrospectively analyzed and compared hearing abilities among 124 postmenopausal women taking HRT, treated with estrogen and progestin (E؉P; n ‫؍‬ 32), estrogen alone (E; n ‫؍‬ 30), and a third [non-hormone replacement therapy (NHRT; n ‫؍‬ 62)] control group. Subjects were 60 -86 years old and were matched for age and health status. All had relatively healthy medical histories and no significant noise exposure, middle-ear problems, or major surgeries. Hearing tests included pure-tone audiometry, tympanometry, distortion-product otoacoustic emissions (DPOAEs), transient otoacoustic emissions, and the hearing-in-noise test (HINT). The HINT tests for speech perception in background noise, the major complaint of hearing-impaired persons. Pure-tone thresholds in both ears were elevated (poorer) for the E؉P relative to the E and control groups. For DPOAEs, the E؉P group presented with lower (worse) levels than the E and control groups, with significant differences for both ears. For the HINT results, the E؉P group had poorer speech perception than the E and control groups across all background noise speaker locations and in quiet. These findings suggest that the presence of P as a component of HRT results in poorer hearing abilities in aged women taking HRT, affecting both the peripheral (ear) and central (brain) auditory systems, and it interferes with the perception of speech in background noise.estrogen ͉ hearing loss ͉ hormone replacement therapy ͉ presbycusis ͉ progesterone A ge-related hearing loss (presbycusis) is the number one communication disorder, and it is one of the top three chronic medical conditions of elderly persons. Because of the widespread prescription of hormone replacement therapy (HRT), it is critical to determine the effects of HRT on sensory systems in postmenopausal females. Sensory function declines with age, yet the effects of HRT on hearing, balance, vision, and the chemical senses are not assessed in HRT drug development.Estrogen (E) and progestin (P) actions have been linked to key sensory and CNS processes and disorders such as cognition, memory, dementia (Alzheimer's disease), epilepsy, depression, and others. For instance, Rice et al.(1) reported differences between E alone and EϩP in rates of cognitive decline, showing E alone as beneficial and the presence of P as detrimental. Shumaker et al. (2) reported that the use of EϩP increased the risk for dementia in elderly females. Klaiber et al. (3,4) demonstrated that the effects of P seem opposed to those of E for mood changes. Stein and Hoffman (5) reported opposite effects of E and P in the treatment of acute brain trauma, attributing to P overall qualities of a neuroprotection agent. Klein et al. (6) suggested a protective effect of E on eye-lens opacities.The effects of sex hormones on hearing and ...

To understand possible causative roles of apoptosis gene regulation in age-related hearing loss (presbycusis), apoptotic gene expression patterns in the CBA mouse cochlea of four different age and hearing loss groups were compared, using GeneChip and real-time (qPCR) microarrays. GeneChip transcriptional expression patterns of 318 apoptosis-related genes were analyzed. Thirty eight probes (35 genes) showed significant differences in expression. The significant gene families include Caspases, B-cell leukemia/lymphoma2 family, P53, Cal-pains, Mitogen activated protein kinase family, Jun oncogene, Nuclear factor of kappa light chain gene enhancer in B-cells inhibitorrelated and tumor necrosis factor-related genes. The GeneChip results of 31 genes were validated using the new TaqMan ® Low Density Array (TLDA). Eight genes showed highly correlated results with the GeneChip data. These genes are: activating transcription factor3, B-cell leukemia/ lymphoma2, Bcl2-like1, caspase4 apoptosis-related cysteine protease 4, Calpain2, dual specificity phosphatase9, tumor necrosis factor receptor superfamily member12a, and Tumor necrosis factor superfamily member13b, suggesting they may play critical roles in inner ear aging.

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