Auditory function declines with age, as evidenced by communication difficulties in challenging listening environments for older adults. Declining auditory function may arise, in part, from an age-related loss and/or inactivity of low-spontaneous-rate (SR) auditory nerve (AN) fibers, a subgroup of neurons important for suprathreshold processing. Compared to high-SR fibers, low-SR fibers take longer to recover from prior stimulation. Taking advantage of this difference, the forward-masked recovery function paradigm estimates the relative proportions of low- and high-SR fibers in the AN by quantifying the time needed for AN responses to recover from prior stimulation (ΔTrecovery). Due to the slower recovery of low-SR fibers, ANs that need more time to fully recover (longer ΔTrecovery) are estimated to have a larger proportion of low-SR fibers than ANs that need less time (shorter ΔTrecovery). To test the hypothesis that low-SR fiber activity is reduced in older humans, the current study assessed recovery functions in 32 older and 16 younger adults using the compound action potential. Results show that ΔTrecovery is shorter for older adults than for younger adults, consistent with a theorized age-related loss and/or inactivity of low-SR fibers. ΔTrecovery did not differ between individuals with and without a prior history of noise exposure as assessed by self-report. This study is the first to successfully assess forward-masked recovery functions in both younger and older adults and provides important insights into the structural and functional changes occurring in the AN with increasing age.

Age-related hearing loss is a multifactorial condition with effects of aging and environmental exposures that contribute to cochlear pathologies. Metabolic hearing loss involves declines in the endocochlear potential, which broadly reduce cochlear amplification of low-level sounds. Sensory hearing loss involves damage to outer hair cells that may eliminate amplification, especially for high-frequency sounds. A novel approach was developed to estimate the extent of metabolic and sensory components (in dB) for an individual, by combining hearing loss profiles to optimally approximate their hearing thresholds (audiogram). This approach was validated using estimates of metabolic and sensory hearing loss from retrospective datasets including gerbils, cross-sectional and longitudinal audiograms from older adults, a measure of speech recognition in noise, and histopathology case reports. Simulation results showed that well-approximated audiograms can produce accurate metabolic and sensory estimates. Estimates of metabolic and sensory components of age-related hearing loss differentiated gerbils with known strial and/or sensory pathologies based on age and exposures. For older adults, metabolic estimates consistently increased with age and were associated with poorer speech recognition in noise, while sensory estimates were related to sex and noise exposure differences. Histopathology case reports (with audiograms) that described strial and outer hair cell pathology in temporal bones from older donors showed significant differences in metabolic and sensory estimates, respectively. The results support the view that audiograms include information that can be used to estimate the metabolic and sensory components of age-related hearing loss.

•Presbyacusis presents with metabolic, neural, and/or sensory phenotypes.•Reduced endocochlear potential is likely to be a key contributor to presbyacusis.•Genetic factors contribute to presbyacusis, including single-gene variants.•There appear to be downstream effects of presbyacusis on brain function and structure.

Acoustic communication between animals runs the gamut of simple to complex in its dynamic time and frequency structure. Narrow bandwidth codes are often used in noisy environments wherein simple filters can be used to recover the signal under poor signal to noise ratios. Tree frogs in the genus Eleutherodactylus use essentially single and double tones to attract mates in very noisy environments with many males calling mostly silent females. Over the last 40 years, Peter Narins has been studying these simple frog codes. He has shown that these frogs have evolved behaviors to avoid acoustic interference with their neighbors, both in time (by call suppression) and by changing their dominant frequencies across species. Radio amateurs using Morse code mimic frog behavior when trying to communicate with highly desired, weak-signal DX (distant) stations, where many strong signals are calling simultaneously. In this scenario, termed a “DX Pileup,” the calling operators use strategies similar to those of frogs to successfully contact the DX station. Peter (K2IXQ) has been an avid radio amateur for most of his life, using Morse code to chase DX around the world. Clearly, there is an overlap between his scientific research and his personal hobby.

Age-related hearing loss (presbyacusis) has a complex etiology. Results from animal models detailing the effects of specific cochlear injuries on audiometric profiles may be used to understand the mechanisms underlying hearing loss in older humans and predict cochlear pathologies associated with certain audiometric configurations (“audiometric phenotypes”). Patterns of hearing loss associated with cochlear pathology in animal models were used to define schematic boundaries of human audiograms. Pathologies included evidence for metabolic, sensory, and a mixed metabolic + sensory phenotype; an older normal phenotype without threshold elevation was also defined. Audiograms from a large sample of older adults were then searched by a human expert for “exemplars” (best examples) of these phenotypes, without knowledge of the human subject demographic information. Mean thresholds and slopes of higher frequency thresholds of the audiograms assigned to the four phenotypes were consistent with the predefined schematic boundaries and differed significantly from each other. Significant differences in age, gender, and noise exposure history provided external validity for the four phenotypes. Three supervised machine learning classifiers were then used to assess reliability of the exemplar training set to estimate the probability that newly obtained audiograms exhibited one of the four phenotypes. These procedures classified the exemplars with a high degree of accuracy; classifications of the remaining cases were consistent with the exemplars with respect to average thresholds and demographic information. These results suggest that animal models of age-related hearing loss can be used to predict human cochlear pathology by classifying audiograms into phenotypic classifications that reflect probable etiologies for hearing loss in older humans.

Gerbils aged in quiet show a decline of the endocochlear potential (EP) and elevated auditory nerve compound action potential (CAP) thresholds. However, establishing a direct relationship between an age-related reduction in the EP and changes in the activities of primary auditory neurons is difficult owing to the complexity of age-related histological changes in the cochlea. To address this issue, we developed a young gerbil model of “metabolic” presbyacusis that uses an osmotic pump to deliver furosemide into the round window niche for 7 days, resulting in a chronically reduced EP. In this model, the only major histopathologic changes were restricted to the hook region of the cochlea and consisted of loss of strial intermediate cells and massive edema in the lateral wall. The morphological and physiological evidence suggests that the cochlea can adapt to furosemide application over time. The morphology of spiral ganglion cells and hair cells appeared normal throughout the cochlea. CAP responses and EP values in this model are similar to those of quiet-aged ears. The spontaneous activity of single auditory fibers (n = 188) was assessed in 15 young gerbils treated with furosemide for 7 days. The percentage of recorded low-spontaneous rate (SR) fibers at characteristic frequencies (CFs) ≥ 6 kHz was significantly lower in furosemide-treated than in control ears. Recovery function tests of CAP responses after prior stimulation also showed a decline in activity of the low-SR population with CFs ≥ 6 kHz in the treated cochleas. A similar loss in the activity of low-SR fiber has been previously shown in quiet-aged gerbils. These results suggest that dysfunction of the cochlear lateral wall and subsequent chronic reduction in the EP can directly affect the activity patterns of primary auditory neurons in a manner similar to that seen in aged gerbils.

The effects of pure aging on the physiology and morphology of the human peripheral auditory system are difficult to study given the variability inherent in genetics and the environment with which the system must cope. Environmental exposures accumulated over a lifetime often combine mild, continuous noise exposures occurring daily, with occasional punctate episodes of very high decibel trauma associated with loud music, power equipment, and small arms fire. Moreover, the human experience includes many drugs that often have unintended side effects on the auditory periphery. Some drugs have well-known ototoxic properties; others are more insidious, like the continuous high-level use of some narcotics. Noise and drug injuries tend to preferentially damage the hair cells in the cochlea. Genetics must then respond to an individual’s environment, resulting in the very large variability present in the hearing capabilities of elderly humans. It is clear that animal models of age-related hearing loss are required to tease out the effects of aging alone from the effects of environment and genetics. Yet up until ∼25 years ago, much of the research in presbycusis was accomplished by using human temporal bones and clinical data (Bredberg 1968; Schuknecht 1974; Gates et al. 1990; Schuknecht and Gacek 1993). Only in the last 30 years or so have animal models been established where the environment, diet, and genetics are strictly controlled (Keithley and Feldman 1979, 1982; Henry 1982; Keithley et al. 1989; Mills et al. 1990; Hequembourg and Liberman 2001; Ohlemiller and Gagnon 2004; for reviews see Willott 1991; Frisina and Walton 2001, 2006; Gates and Mills 2005; Canlon, Illing, and Walton, Chapter 3). Animals raised under these controlled conditions nonetheless show age-related declines in auditory function, consistent with the notion that presbycusis includes effects unique to aging and is not just the result of the combined effects of noise and other ototoxic factors over a lifetime.

With the exception of humans, the somata of type I spiral ganglion neurons (SGNs) of most mammalian species are heavily myelinated. In an earlier study, we used Ly5.1 congenic mice as transplant recipients to investigate the role of hematopoietic stem cells in the adult mouse inner ear. An unanticipated finding was that a large percentage of the SGNs in this strain were unmyelinated. Further characterization of the auditory phenotype of young adult Ly5.1 mice in the present study revealed several unusual characteristics, including 1) large aggregates of unmyelinated SGNs in the apical and middle turns, 2) symmetrical junction‐like contacts between the unmyelinated neurons, 3) abnormal expression patterns for CNPase and connexin 29 in the SGN clusters, 4) reduced SGN density in the basal cochlea without a corresponding loss of sensory hair cells, 5) significantly delayed auditory brainstem response (ABR) wave I latencies at low and middle frequencies compared with control mice with similar ABR threshold, and 6) elevated ABR thresholds and deceased wave I amplitudes at high frequencies. Taken together, these data suggest a defect in Schwann cells that leads to incomplete myelinization of SGNs during cochlear development. The Ly5.1 mouse strain appears to be the only rodent model so far identified with a high degree of the “human‐like” feature of unmyelinated SGNs that aggregate into neural clusters. Thus, this strain may provide a suitable animal platform for modeling human auditory information processing such as synchronous neural activity and other auditory response properties. J. Comp. Neurol. 518:3254–3271, 2010. © 2010 Wiley‐Liss, Inc.

Application of ouabain to the round window membrane of the gerbil selectively induces the death of most spiral ganglion neurons and thus provides an excellent model for investigating the survival and differentiation of embryonic stem cells (ESCs) introduced into the inner ear. In this study, mouse ESCs were pretreated with a neural-induction protocol and transplanted into Rosenthal's canal (RC), perilymph, or endolymph of Mongolian gerbils either 1-3 days (early post-injury transplant group) or 7 days or longer (late post-injury transplant group) after ouabain injury. Overall, ESC survival in RC and perilymphatic spaces was significantly greater in the early post-injury microenvironment as compared to the later post-injury condition. Viable clusters of ESCs within RC and perilymphatic spaces appeared to be associated with neovascularization in the early post-injury group. A small number of ESCs transplanted within RC stained for mature neuronal or glial cell markers. ESCs introduced into perilymph survived in several locations, but most differentiated into glia-like cells. ESCs transplanted into endolymph survived poorly if at all. These experiments demonstrate that there is an optimal time window for engraftment and survival of ESCs that occurs in the early post-injury period.

Degeneration of the spiral ganglion neurons (SGNs) of the auditory nerve occurs with age and in response to acoustic injury. Histopathological observations suggest that the neural degeneration often begins with an excitotoxic process affecting the afferent dendrites under the inner hair cells (IHCs), however, little is known about the sequence of cellular or molecular events mediating this excitotoxicity. Nuclear factor κB (NFκB) is a transcription factor involved in regulating inflammatory responses and apoptosis in many cell types. NFκB is also associated with intracellular calcium regulation, an important factor in neuronal excitotoxicity. Here, we provide evidence that NFκB can play a central role in the degeneration of SGNs. Mice lacking the p50 subunit of NFκB (p50−/−mice) showed an accelerated hearing loss with age that was highly associated with an exacerbated excitotoxic-like damage in afferent dendrites under IHCs and an accelerated loss of SGNs. Also, as evidenced by immunostaining intensity, calcium-buffering proteins were significantly elevated in SGNs of the p50−/−mice. Finally, the knock-out mice exhibited an increased sensitivity to low-level noise exposure. The accelerated hearing loss and neural degeneration with age in the p50−/−mice occurred in the absence of concomitant hair cell loss and decline of the endocochlear potential. These results indicate that NFκB activity plays an important role in protecting the primary auditory neurons from excitotoxic damage and age-related degeneration. A possible mechanism underlying this protection is that the NFκB activity may help to maintain calcium homeostasis in SGNs.

Bone marrow (BM)-derived stem cells have shown plasticity with a capacity to differentiate into a variety of specialized cells. To test the hypothesis that some cells in the inner ear are derived from BM, we transplanted either isolated whole BM cells or clonally expanded hematopoietic stem cells (HSCs) prepared from transgenic mice expressing enhanced green fluorescent protein (EGFP) into irradiated adult mice. Isolated GFP(+) BM cells were also transplanted into conditioned newborn mice derived from pregnant mice injected with busulfan (which ablates HSCs in the newborns). Quantification of GFP(+) cells was performed 3-20 months after transplant. GFP(+) cells were found in the inner ear with all transplant conditions. They were most abundant within the spiral ligament but were also found in other locations normally occupied by fibrocytes and mesenchymal cells. No GFP(+) neurons or hair cells were observed in inner ears of transplanted mice. Dual immunofluorescence assays demonstrated that most of the GFP(+) cells were negative for CD45, a macrophage and hematopoietic cell marker. A portion of the GFP(+) cells in the spiral ligament expressed immunoreactive Na, K-ATPase, or the Na-K-Cl transporter (NKCC), proteins used as markers for specialized ion transport fibrocytes. Phenotypic studies indicated that the GFP(+) cells did not arise from fusion of donor cells with endogenous cells. This study provides the first evidence for the origin of inner ear cells from BM and more specifically from HSCs. The results suggest that mesenchymal cells, including fibrocytes in the adult inner ear, may be derived continuously from HSCs.

No AccessPerspectives on Hearing and Hearing Disorders: Research and DiagnosticsArticle1 Dec 2006Mechanisms of Age-Related Hearing Loss John H. Mills, Richard A. Schmiedt, Bradley A. Schulte and Judy R. Dubno John H. Mills Medical University of South Carolina, Department of Otolaryngology-Head and Neck SurgeryCharleston, SC Google Scholar More articles by this author , Richard A. Schmiedt Medical University of South Carolina, Department of Otolaryngology-Head and Neck SurgeryCharleston, SC Google Scholar More articles by this author , Bradley A. Schulte Medical University of South Carolina, The Department of Pathology and Laboratory MedicineCharleston, SC Google Scholar More articles by this author and Judy R. Dubno Medical University of South Carolina, Department of Otolaryngology-Head and Neck SurgeryCharleston, SC Google Scholar More articles by this author https://doi.org/10.1044/hhd10.2.2 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationTrack Citations ShareFacebookTwitterLinked In References Boettcher, F. A., Gratton, M. A., & Schmiedt, R. A. (1995). Effects of age and noise on the auditory system.Occupational Medicine, 10, 577–591. Google Scholar Boettcher, F. A., Mills, J. H., & Norton, B. L. (1993). Age-related changes in auditory evoked potentials of ger–bils. I. Response amplitudes.Hearing Research, 71, 137–145. Google Scholar Cruickshanks, K. J., Klein, R., Klein, B. E., Wiley, T. L., Nondahl, D. M., & Tweed, T. S. (1998). Cigarette smoking and hearing loss: The epidemiology of hearing loss study.Journal of the American Medical Association, 279, 1715–1719. CrossrefGoogle Scholar Davis, H. (1983). An active process in cochlear mechanics.Hearing Research, 9, 79–90. 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One of the most significant results from animal and human studies of age-related hearing loss involves degeneration of the lateral wall (stria vascularis and spiral ligament) of the cochlea, which is responsible for generating electrochemical gradients and regulating ion homeostasis. Accompanying this degeneration is a decrease in the endocochlear potential (EP), which is an 80- to 100-mV dc resting potential located in scala media. Reductions in the magnitude of the EP affect the function of the cochlear amplifier, which provides a gain of ~20 dB at low frequencies, increasing to ~60 dB or greater as frequency increases from ~1 to 8 kHz. Indeed, age-related threshold shifts observed in animals and humans can be accounted for almost totally by age-related degeneration of the stria vascularis/spiral ligament with attendant reductions in the EP and in the gain of the cochlear amplifier. Although considerable support exists for the involvement of strial vasculature in degeneration of the stria vascularis and the associated declines in EP and cochlear amplifier, the question of what constitutes the initial injury remains unclear. It is tempting to speculate that atrophy of strial marginal or intermediate cells, or both, occurs secondarily to vascular insufficiency resulting from capillary necrosis; however, the reverse could also be true. In gerbil and human, age-related degeneration of the auditory nerve may be the second most distinctive feature of age-related hearing loss. Strikingly absent in gerbil data and in some human data are age-related losses of outer and inner hair cells, except in the most basal and apical regions of the cochlea. These results and others suggest that age-related hearing loss should be viewed as a vascular, metabolic, neural hearing loss rather than a sensory hearing loss.

Hypothesis: Mitomycin C is ototoxic when applied topically to the structures of the middle ear. Background: Mitomycin C is a topically applied medication widely used in a variety of surgical procedures to prevent excessive scar tissue formation. Its safety for use during otologic procedures has not been fully evaluated. Methods: A laboratory study was undertaken using the Mongolian gerbil as an animal model. Both acute and chronic effects on cochlear function of mitomycin C were assessed with measurements of compound action potential (CAP) thresholds of the auditory nerve, CAP input/output functions, distortion product otoacoustic emissions, and endocochlear potentials. Morphologic changes were assessed with light microscopy using hematoxylin-eosin staining as well as transmission electron microscopy. Results: Five-minute applications of mitomycin C (0.5 mg/ml) to the entire surface of the middle ear adversely affected CAP thresholds, input/output functions, distortion product otoacoustic emissions, and the endocochlear potential. Ninety-minute exposures of mitomycin C solely to the round window produced similar changes. Histologic evaluation of animals 1 week after treatment showed damage to cochlear hair cells, the stria vascularis, and spiral ganglion neurons when compared with controls. Conclusion: Mitomycin C can produce substantial sensorineural hearing loss when applied topically to the gerbil middle ear for even brief periods. Consequently, its safety for topical use in the human middle ear is highly questionable.

Application of ouabain to the intact round-window (RW) membrane of the gerbil cochlea induces apoptosis in most spiral ganglion neurons (SGNs), leaving a few neurons intact (Schmiedt et al. 2002 ). Here, physiological measures and immunostaining were used to examine the process of SGN degeneration at 3, 6, 12, and 24 h, 4 days, and 1 and 5 months after ouabain treatment. The few remaining neurons surviving up to 5 months after ouabain treatment were immunoreactive for peripherin, a type II neuron marker. Peripherin-positive cell counts indicate that about 7% of the SGNs in the gerbil cochlea are type II neurons, and these neurons survive intact after ouabain treatment. Ouabain exposure had little effect on the outer hair cell and lateral wall systems, even after a 5 month loss of auditory-nerve function. The cellular locations of cytochrome c , poly (ADP-ribose) polymerase (PARP), and activated caspase 3 were examined in control and ouabain-treated cochleas. A redistribution of cytochrome c in peripherin-negative (type I) neurons was observed at 3 h after ouabain exposure. Degraded PARP and activated caspase 3 were also detected in peripherin-negative SGNs at 6 and 24 h after treatment, respectively. These results suggest that the redistribution of cytochrome c is an early event during apoptosis in type I SGNs and that activation of PARP and caspase 3 are associated with apoptosis in these cells. Calcineurin and NF-κB are two important signaling pathways that may modulate cell survival in the central nervous system. Here, we found that calcineurin and NF-κB selectively labeled type II neurons. It is speculated that the high levels of calcineurin and NF-κB in type II SGNs, as compared with type I SGNs, may play protective roles in enhancing the survival of type II neurons exposed to ouabain.

Auditory characteristics of metabolic or strial presbycusis were investigated using an animal model in which young adult Mongolian gerbils (Meriones unguiculates) were implanted with an osmotic pump supplying furosemide continuously to the round window. This model causes chronic lowering of the endocochlear potential (EP) and results in auditory responses very similar to those seen in quiet-aged gerbils (Schmiedt et al., J. Neurosci. 22:9643–9650, 2002). Auditory function was examined up to one week post-implant by measurement of auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs). Emission “threshold” was defined as the stimulus level required to reach a criterion emission amplitude. Comparing all responses on a “threshold-shift diagram,” where emission threshold increases were plotted versus ABR threshold increases, the following results were obtained: (1) On average, the increase of the emission threshold was about 55% of the increase in ABR threshold, with comparatively little scatter. (2) The main dysfunction in metabolic presbycusis appears to be a decrease in the gain of the cochlear amplifier, combined with an additional, smaller increase in neural threshold, both effects caused by a chronically low EP. (3) For ABR threshold increases over 20 dB, the points for the chronic low-EP condition were largely separate from those previously found for permanent acoustic damage. The threshold-shift diagram therefore provides a method for noninvasive differential diagnosis of two common hearing dysfunctions.

Exposure of mice to total body irradiation induces nuclear factor kappaB (NFkappaB) activation in a tissue-specific manner. In addition to the spleen, lymph nodes, and bone marrow, the tissues that exhibit NFkappaB activation now include the newly identified site of the intestinal epithelial cells. NFkappaB activated by total body irradiation mainly consists of NFkappaB p50/RelA heterodimers, and genetically targeted disruption of the NFkappaB p50 gene in mice significantly decreased the activation. By comparing tissue damage and lethality in wild-type and NFkappaB p50 knockout (p50-/-) mice after they were exposed to increasing doses of total body irradiation, we additionally examined the role of NFkappaB activation in total body irradiation-induced tissue damage. The results show that p50-/- mice are more sensitive to total body irradiation-induced lethality than wild-type mice (LD50/Day 7: wild-type = 13.12 Gy versus p50-/- = 7.75 Gy and LD50/Day 30: wild-type = 9.31 Gy versus p50-/- = 7.81 Gy). The increased radiosensitivity of p50-/- mice was associated with an elevated level of apoptosis in intestinal epithelial cells and decreased survival of the small intestinal crypts compared with wild-type mice (P < 0.01). In addition, RelA/TNFR1-deficient (RelA/TNFR1-/-) mice also exhibited a significant increase in intestinal epithelial cell apoptosis after they were exposed to total body irradiation as compared with TNFR1-deficient (TNFR1-/-) mice (P < 0.01). In contrast, no significant increase in total body irradiation-induced apoptosis or tissue injury was observed in bone marrow cells, spleen lymphocytes, and the liver, heart, lung, and kidney of p50-/- mice in comparison with wild-type mice. These findings indicate that activation of NFkappaB selectively protects the small intestine against ionizing radiation-induced damage.

Dr. Joe Zwislocki served as my dissertation advisor during those tumultuous years in cochlear physiology when our understanding of outer hair cell (OHC) function was evolving from that of a sensory cell to that of a mechanical amplifier. Spoendlin had recently demonstrated that 90%–95% of auditory-nerve afferents originated from inner hair cells (IHCs), but the characteristics of IHC receptor potentials remained an enigma. Otoacoustic emissions and OHC electromotility were terms yet to be defined. Theories relating auditory-nerve activity to basilar-membrane mechanics included concepts of second filters, basilar-membrane nonlinearities, and phase opposition. It was a fertile time for theories and experiments attempting to describe a black-box system that did not yield its mysteries easily. Around 1977, IHC receptor potentials were found to be as sharply tuned as auditory-nerve responses, and the era of cochlear micromechanics began. Joe Zwislocki, as usual, has played a primary role in defining this new era, utilizing the relationships between the OHC stereocilia and the tectorial membrane as his modeling clay.

Hearing loss can have multiple causes. The outer and middle ears are conductive pathways for acoustic energy to the inner ear (cochlea) and help shape our spectral sensitivity. Conductive hearing loss is mechanical in nature such that the energy transfer to the cochlea is impeded, often from eardrum perforations or middle ear fluid buildup. Beyond the middle ear, the cochlea comprises three interdependent systems necessary for normal hearing. The first is that of basilar-membrane micromechanics including the outer hair cells. This system forms the basis of the cochlear amplifier and is the most vulnerable to noise and drug exposure. The second system comprises the ion pumps in the lateral wall tissues of the cochlea. These highly metabolic cells provide energy to the cochlear amplifier in the form of electrochemical potentials. This second system is particularly vulnerable to the effects of aging. The third system comprises the inner hair cells and their associated sensory nerve fibers. This system is the transduction stage, changing mechanical vibrations to nerve impulses. New treatments for hearing loss are on the horizon; however, at present the best strategy is avoidance of cochlear trauma and the proper use of hearing aids. [Work supported by NIA and MUSC.]