Translational implications of the interactions between hormones and age-related hearing loss.

Provocative research has revealed both positive and negative effects of hormones on hearing as we age; with in some cases, mis-regulation of hormonal levels in instances of medical comorbidities linked to aging, lying at the heart of the problem. Animal model studies have discovered that hormonal fluctuations can sharpen hearing for improved communication and processing of mating calls during reproductive seasons. Sex hormones sometimes have positive effects on auditory processing, as is often the case with estrogen, whereas combinations of estrogen and progesterone, and testosterone, can have negative effects on hearing abilities, particularly in aging subjects. Too much or too little of some hormones can be detrimental, as is the case for aldosterone and thyroid hormones, which generally decline in older individuals. Too little insulin, as in Type 1 diabetics, or poor regulation of insulin, as in Type 2 diabetics, is also harmful to hearing in our aged population. In terms of clinical translational possibilities, hormone therapies can be problematic due to systemic side effects, as has happened for estrogen/progestin combination hormone replacement therapy (HRT) in older women, where the HRT induces a hearing loss. As hormone therapy approaches are further developed, it may be possible to lower needed doses of hormones by combining them with supplements, such as antioxidants. Another option will be to take advantage of emerging technologies for local drug delivery to the inner ear, including biodegradeable, sustained-release hydrogels and micro-pumps which can be implanted in the middle ear near the round window. In closing, exciting research completed to date, summarized in the present report bodes well for emerging biomedical therapies to prevent or treat age-related hearing loss utilizing hormonal strategies.

Animal model studies yield translational solutions for cochlear drug delivery.

The field of hearing and deafness research is about to enter an era where new cochlear drug delivery methodologies will become more innovative and plentiful. The present report provides a representative review of previous studies where efficacious results have been obtained with animal models, primarily rodents, for protection against acute hearing loss such as acoustic trauma due to noise overexposure, antibiotic use and cancer chemotherapies. These approaches were initiated using systemic injections or oral administrations of otoprotectants. Now, exciting new options for local drug delivery, which opens up the possibilities for utilization of novel otoprotective drugs or compounds that might not be suitable for systemic use, or might interfere with the efficacious actions of chemotherapeutic agents or antibiotics, are being developed. These include interesting use of nanoparticles (with or without magnetic field supplementation), hydrogels, cochlear micropumps, and new transtympanic injectable compounds, sometimes in combination with cochlear implants.

Age-related hearing loss: GABA, nicotinic acetylcholine and NMDA receptor expression changes in spiral ganglion neurons of the mouse.

Age-related hearing loss - presbycusis - is the number one communication disorder and most prevalent neurodegenerative condition of our aged population. Although speech understanding in background noise is quite difficult for those with presbycusis, there are currently no biomedical treatments to prevent, delay or reverse this condition. A better understanding of the cochlear mechanisms underlying presbycusis will help lead to future treatments. Objectives of the present study were to investigate GABAA receptor subunit α1, nicotinic acetylcholine (nACh) receptor subunit ß2, and N-methyl-d-aspartate (NMDA) receptor subunit NR1 mRNA and protein expression changes in spiral ganglion neurons (SGN) of the CBA/CaJ mouse cochlea, that occur in age-related hearing loss, utilizing quantitative immunohistochemistry and semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) techniques. We found that auditory brainstem response (ABR) thresholds shifted over 40dB from 3 to 48kHz in old mice compared to young adults. DPOAE thresholds also shifted over 40dB from 6 to 49kHz in old mice, and their amplitudes were significantly decreased or absent in the same frequency range. SGN density decreased with age in basal, middle and apical turns, and SGN density of the basal turn declined the most. A positive correlation was observed between SGN density and ABR wave 1amplitude. mRNA and protein expression of GABAAR α1 and AChR ß2 decreased with age in SGNs in the old mouse cochlea. mRNA and protein expression of NMDAR NR1 increased with age in SGNs of the old mice. These findings demonstrate that there are functionally-relevant age-related changes of GABAAR, nAChR, NMDAR expression in CBA mouse SGNs reflecting their degeneration, which may be related to functional changes in cochlear synaptic transmission with age, suggesting biological mechanisms for peripheral age-related hearing loss.

Implantable micropump technologies for murine intracochlear infusions.

Due to the very small size of the mouse inner ear, 600 nL volume, developing effective, controlled infusion systems is quite challenging. Key technologies have been created to minimize both size and power for an implantable pump for murine intracochlear infusions. A method for coupling fine capillary tubing to microfluidic channels is presented which provides low volume, biocompatible interconnects withstanding pressures as high as 827 kPa (120 psi) and consuming less than 20 nL of volume exiting in-plane with the pump. Surface micromachined resistive bridges integrated into the flow channel for anemometry based flow rate measurement have been optimized for low power operation in the ultra-low flow rate regime. A process for creation of deformable diaphragms over pump chambers with simultaneous coating of the microfluidic channels has been developed allowing integration of a biocompatible fluid flow path. These advances represent enabling capabilities for a drug delivery system suitable for space constrained applications such as subcutaneous implantation in mice.

Expression patterns of estrogen receptors in the central auditory system change in prepubertal and aged mice.

Estrogens are important in the development, maintenance and physiology of the CNS. Several studies have shown their effects on the processing of hearing in both males and females, and these effects, in part, are thought to result from regulation of the transcription of genes via their classical estrogen receptor (ER) pathway. In order to understand the spatiotemporal changes that occur with age, we have studied the expression of ERs in the central auditory pathway in prepubertal and aged CBA mice with immunohistochemistry. In prepubertal mice a clear dichotomy was noted between the expression of ERα and ERß. ERß-positive neurons were found in the metencephalon whereas the majority of ERα was found in mesencephalon, diencephalon or the telencephalon. In the aged animals a different pattern of ER expression was found in terms of location and overall intensity. These age-induced changes in the expression pattern were generally not uniform, suggesting that region-specific mechanisms regulate the ERs' age-related expression. Neither the prepubertal nor the aged animals showed sex differences in any auditory structure. Our results demonstrate different age-dependent spatial and temporal changes in the pattern of expression of ERα and ERß, suggesting that each ER type may be involved in distinct roles across the central auditory pathway in different periods of maturation.

PET imaging of the normal human auditory system: responses to speech in quiet and in background noise.

The neural mechanisms involved in listening to sentences, and then detecting and verbalizing a specific word are poorly understood, but most likely involve complex neural networks. We used positron emission tomography to identify the areas of the human brain that are activated when young, normal hearing males and females were asked to listen to a sentence and repeat the last word from the Speech in Noise (SPIN) test. Listening conditions were (1) Quiet, (2) Speech, (3) Noise, and (4) SPIN with stimuli presented monaurally to either the left ear or the right ear. The least difficult listening task, Speech, resulted in bilateral activation of superior and middle temporal gyrus and pre-central gyrus. The Noise and SPIN conditions activated many of the same regions as Speech alone plus additional sites within the cerebellum, thalamus and superior/middle frontal gyri. Comparison of the SPIN condition versus Speech revealed additional activation in the right anterior lobe of the cerebellum and right medial frontal gyrus, near the cingulate. None of the left ear-right ear stimulus comparison revealed any significant differences except for the SPIN condition that showed greater activation in the left superior temporal gyrus for stimuli presented to the right ear. No gender differences were observed. These results demonstrate that repeating the last word in a sentence activates mainly auditory and motor areas of the brain when Speech is presented, whereas more difficult tasks, such as SPIN or multi-talker Noise, activate linguistic, attentional, cognitive, working memory, and motor planning areas.

Subcortical neural coding mechanisms for auditory temporal processing.

Biologically relevant sounds such as speech, animal vocalizations and music have distinguishing temporal features that are utilized for effective auditory perception. Common temporal features include sound envelope fluctuations, often modeled in the laboratory by amplitude modulation (AM), and starts and stops in ongoing sounds, which are frequently approximated by hearing researchers as gaps between two sounds or are investigated in forward masking experiments. The auditory system has evolved many neural processing mechanisms for encoding important temporal features of sound. Due to rapid progress made in the field of auditory neuroscience in the past three decades, it is not possible to review all progress in this field in a single article. The goal of the present report is to focus on single-unit mechanisms in the mammalian brainstem auditory system for encoding AM and gaps as illustrative examples of how the system encodes key temporal features of sound. This report, following a systems analysis approach, starts with findings in the auditory nerve and proceeds centrally through the cochlear nucleus, superior olivary complex and inferior colliculus. Some general principles can be seen when reviewing this entire field. For example, as one ascends the central auditory system, a neural encoding shift occurs. An emphasis on synchronous responses for temporal coding exists in the auditory periphery, and more reliance on rate coding occurs as one moves centrally. In addition, for AM, modulation transfer functions become more bandpass as the sound level of the signal is raised, but become more lowpass in shape as background noise is added. In many cases, AM coding can actually increase in the presence of background noise. For gap processing or forward masking, coding for gaps changes from a decrease in spike firing rate for neurons of the peripheral auditory system that have sustained response patterns, to an increase in firing rate for more central neurons with transient responses. Lastly, for gaps and forward masking, as one ascends the auditory system, some suppression effects become quite long (echo suppression), and in some stimulus configurations enhancement to a second sound can take place.

Early bilateral deafening prevents calretinin up-regulation in the dorsal cortex of the inferior colliculus of aged CBA/CaJ mice.

This study was conducted to test the hypothesis that age-related calretinin (CR) up-regulation seen in the dorsal cortex of the inferior colliculus (ICdc) of old hearing CBA mice is dependent upon neural activity within the auditory pathway. We tested this hypothesis by bilaterally deafening young CBA/CaJ mice with kanamycin, and then aging them until 24 months. This manipulation mimics the lack of sound-evoked auditory activity experienced by old C57BL/6J mice, who are deaf and do not show CR up-regulation with age. Cell counts revealed that the density of CR+ cells in the ICdc of old hearing CBA mice was statistically different from old deafened CBA mice raised under identical conditions. Old hearing CBAs possessed an average of 27.54 more CR+ cells/100 microm2 than old deafened CBAs. When old deafened CBAs were compared to young hearing CBAs, young hearing C57s, and old deaf C57s, there was no significant difference in mean CR+ cell density in ICdc. Thus, only the old normal hearing CBAs showed an increase in CR+ cells with age, supporting the hypothesis that CR up-regulation depends upon sound-evoked activity. Moreover, these results demonstrate that up-regulation of CR expression was not simply due to a mouse strain difference.

HSV amplicon-mediated neurotrophin-3 expression protects murine spiral ganglion neurons from cisplatin-induced damage.

Ototoxicity is a major dose-limiting side effect of cisplatin (DDP) administration due to its propensity to induce destruction of hair cells and neurons in the auditory system. Previous studies demonstrated that TrkC-expressing spiral ganglion neurons (SGN) are protected from the cytotoxic effects of DDP by localized delivery of the trophic factor neurotrophin-3 (NT-3). Successful in vivo implementation of such a therapy requires the development of an efficient gene delivery vehicle for expression of NT-3 within the cochlea. To this end, we constructed a herpes simplex virus (HSV) amplicon vector that expressed a c-Myc-tagged NT-3 chimera (HSVnt-3myc). Helper virus-free vector stocks were initially evaluated in vitro for their capacity to direct expression of NT-3 mRNA and protein. Transduction of cultured murine cochlear explants with HSVnt-3myc resulted in production of NT-3 mRNA and protein up to 3 ng/ml as measured over a 48-h period in culture supernatants. To determine whether NT-3 overexpression could abrogate DDP toxicity, cochlear explants were transduced with HSVnt-3myc or a murine intestinal alkaline phosphatase-expressing control vector, HSVmiap, and then exposed to cisplatin. HSVnt-3myc-transduced cochlear explants harbored significantly greater numbers of surviving SGNs than those infected with control virus. These data demonstrate that amplicon-mediated NT-3 transduction can attenuate the ototoxic action of DDP on organotypic culture. The potency of NT-3 in protecting spiral ganglion neurons from degeneration suggests that in vivo neurotrophin-based gene therapy may be useful for the prevention and/or treatment of hearing disorders.

Age-related alteration in processing of temporal sound features in the auditory midbrain of the CBA mouse.

The perception of complex sounds, such as speech and animal vocalizations, requires the central auditory system to analyze rapid, ongoing fluctuations in sound frequency and intensity. A decline in temporal acuity has been identified as one component of age-related hearing loss. The detection of short, silent gaps is thought to reflect an important fundamental dimension of temporal resolution. In this study we compared the neural response elicited by silent gaps imbedded in noise of single neurons in the inferior colliculus (IC) of young and old CBA mice. IC neurons were classified by their temporal discharge patterns. Phasic units, which accounted for the majority of response types encountered, tended to have the shortest minimal gap thresholds (MGTs), regardless of age. We report three age-related changes in neural processing of silent gaps. First, although the shortest MGTs (1-2 msec) were observed in phasic units from both young and old animals, the number of neurons exhibiting the shortest MGTs was much lower in old mice, regardless of the presentation level. Second, in the majority of phasic units, recovery of response to the stimulus after the silent gap was of a lower magnitude and much slower in units from old mice. Finally, the neuronal map representing response latency versus best frequency was found to be altered in the old IC. These results demonstrate a central auditory system correlate for age-related decline in temporal processing at the level of the auditory midbrain.

Inputs to a physiologically characterized region of the inferior colliculus of the young adult CBA mouse.

Presbycusis is a sensory perceptual disorder involving loss of high-pitch hearing and reduced ability to process biologically relevant acoustic signals in noisy environments. The present investigation is part of an ongoing series of studies aimed at discerning the neural bases of presbycusis. The purpose of the present experiment was to delineate the inputs to a functionally characterized region of the dorsomedial inferior colliculus (IC, auditory midbrain) in young, adult CBA mice. Focal, iontophoretic injections of horseradish peroxidase were made in the 18-24 kHz region of dorsomedial IC of the CBA strain following physiological mapping experiments. Serial sections were reacted with diaminobenzidine or tetramethylbenzidine, counterstained and examined for retrogradely labeled cell bodies. Input projections were observed contralaterally from: all three divisions of cochlear nucleus; intermediate and dorsal nuclei of the lateral lemniscus (LL); and the central nucleus, external nucleus and dorsal cortex of the IC. Input projections were observed ipsilaterally from: the medial and lateral superior olivary nuclei; the superior paraolivary nucleus; the dorsolateral and anterolateral periolivary nuclei; the dorsal and ventral divisions of the ventral nucleus of LL; the dorsal and intermediate nuclei of LL; the central nucleus, external nucleus and dorsal cortex of the IC outside the injection site; and small projections from central gray and the medial geniculate body. These findings in young, adult mice with normal hearing can now serve as a baseline for similar experiments being conducted in mice of older ages and with varying degrees of hearing loss to discover neural changes that may cause age-related hearing disorders.

Calbindin D-28k immunoreactivity in the medial nucleus of the trapezoid body declines with age in C57BL/6, but not CBA/CaJ, mice.

This study compared calbindin D-28k immunoreactivity in the medial nucleus of the trapezoid body (MNTB) in young (3-4 month old) and old (24-26 month old) CBA/CaJ mice, and young (3-4 month old), middle-aged (6.5-8.5 month old), and old (24-29 month old) C57BL/6 mice. C57BL/6 mice exhibit progressively more severe peripheral (sensorineural) hearing loss between 4 and 12 months of age, whereas CBA/CaJ mice show little change in peripheral sensitivity until very late in life. We obtained auditory brainstem response audiograms on all subject mice. Old CBA mice were selected for study whose audiograms matched those of young CBA and C57 controls. Middle-aged C57 mice showed elevated thresholds indicative of peripheral degeneration. Brain sections were reacted with anti-calbindin D-28k (CB). Staining patterns in Nissl and anti-CB material were characterized and cells were counted. We found no significant change in the number of CB+ cells or the total number of cells in the MNTB of old CBA mice compared to young controls. However, the mean number of CB+ cells decreased by 11% in middle-aged, and by 14.8% in old C57 mice. Since the decline in C57 mice was significant by 6.5-8.5 months of age, the decrease could be the consequence of a loss of input from the cochlear nucleus where cell numbers are known to decline by this age in this strain. The total number of neurons in MNTB assessed from Nissl material showed a more modest 7.1% decline with age in C57 mice, implying that the greater loss of CB immunoreactive cells with age cannot be completely attributed to a reduction in the total number of cells.

Age-related changes in calbindin D-28k and calretinin immunoreactivity in the inferior colliculus of CBA/CaJ and C57Bl/6 mice.

This study examines calbindin D-28k and calretinin immunoreactivity in the inferior colliculus (IC) of young and old mice of two strains. The CBA/CaJ mouse maintains good hearing until very late in life, whereas the C57Bl/6 strain exhibits severe sensorineural hearing loss at an early age. Young and old mice of both strains were selected with matching auditory brainstem response audiograms and gap detection thresholds. Brain sections were reacted with anti-calbindin D-28k (CB) and anti-calretinin (CR). Staining patterns were characterized and cell counts performed. CB immunoreactivity was high only in the nucleus of the commissure (NCO); counts revealed a 22.3% decrease in the number of CB+ cells in old CBA mice and a 25.1% decrease in old C57 mice. Calretinin immunoreactivity was high in the pericentral regions of the IC, but the central nucleus was devoid of CR+ cells. The dorsal cortex, lateral nucleus, and NCO showed increases of 42.3, 49.0, and 61%, respectively, in the number of CR+ cells, but only in the old CBA mice. No significant change was observed in the old C57 mice. Whereas decreases in CB immunoreactivity are common with age, this study is the first to report an age-related increase in CR immunoreactivity in the auditory system. The increase in CR+ cells is a possible compensatory adaptation to the decrease in CB+ cells. That the number of CR+ cells remains constant with age in C57 mice suggests this compensation may depend upon stimulus-driven activity, but this requires further study.

Neural correlates of behavioral gap detection in the inferior colliculus of the young CBA mouse.

The gap detection paradigm is frequently used in psychoacoustics to characterize the temporal acuity of the auditory system. Neural responses to silent gaps embedded in white-noise carriers, were obtained from mouse inferior colliculus (IC) neurons and the results compared to behavioral estimates of gap detection. Neural correlates of gap detection were obtained from 78 single neurons located in the central nucleus of the IC. Minimal gap thresholds (MGTs) were computed from single-unit gap functions and were found to be comparable, 1-2 ms, to the behavioral gap threshold (2 ms). There was no difference in MGTs for units in which both carrier intensities were collected. Single unit responses were classified based on temporal discharge patterns to steady-state noise bursts. Onset and primary-like units had the shortest mean MGTs (2.0 ms), followed by sustained units (4.0 ms) and phasic-off units (4.2 ms). The longest MGTs were obtained for inhibitory neurons (x = 14 ms). Finally, the time-course of behavioral and neurophysiological gap functions were found to be in good agreement. The results of the present study indicate the neural code necessary for behavioral gap detection is present in the temporal discharge patterns of the majority of IC neurons.

Quantitative measures of hair cell loss in CBA and C57BL/6 mice throughout their life spans.

The CBA mouse shows little evidence of hearing loss until late in life, whereas the C57BL/6 strain develops a severe and progressive, high-frequency sensorineural hearing loss beginning around 3-6 months of age. These functional differences have been linked to genetic differences in the amount of hair cell loss as a function of age; however, a precise quantitative description of the sensory cell loss is unavailable. The present study provides mean values of inner hair cell (IHC) and outer hair cell (OHC) loss for CBA and C57BL/6 mice at 1, 3, 8, 18, and 26 months of age. CBA mice showed little evidence of hair cell loss until 18 months of age. At 26 months of age, OHC losses in the apex and base of the cochlea were approximately 65% and 50%, respectively, and IHC losses were approximately 25% and 35%. By contrast, C57BL/6 mice showed approximately a 75% OHC and a 55% IHC loss in the base of the cochlea at 3 months of age. OHC and IHC losses increased rapidly with age along a base-to-apex gradient. By 26 months of age, more than 80% of the OHCs were missing throughout the entire cochlea; however, IHC losses ranged from 100% near the base of the cochlea to approximately 20% in the apex.

Efferent projections of a physiologically characterized region of the inferior colliculus of the young adult CBA mouse.

The present investigation is part of an ongoing series of studies aimed at discerning the neural bases of presbycusis. Presbycusis is a sensory perceptual disorder involving loss of high-pitch hearing and reduced ability to process biologically relevant acoustic signals in noisy environments. The purpose of the present experiment was to delineate the efferent projections of a functionally characterized region of the dorsomedial inferior colliculus (IC, auditory midbrain) in young, adult CBA mice. The CBA strain's progressive loss of hearing over its lifespan approximates many aspects of the mild-to-moderate hearing loss experienced by a significant number of humans suffering from presbycusis. Focal, iontophoretic injections of HRP were made in the 18-24 kHz region of dorsomedial IC of the CBA strain following physiological mapping experiments. Serial sections were reacted with a chromagen, counterstained and examined for anterogradely labeled fibers and boutons. Efferent projections were observed ipsilaterally in: medial and ventral divisions of the medial geniculate body (MGB); middle layers of the superior colliculus; central gray; and external nucleus (E), dorsal cortex (DC) and central nucleus of IC. Contralaterally, labeled fibers and boutons were seen in the IC at a location homologous to the injection site, as well as in E and DC. A small projection was noted in contralateral MGB. These findings in young, adult mice with normal hearing can now serve as a baseline for similar experiments being conducted in mice and animals of other species of older ages and with varying degrees of hearing loss.

Speech recognition in noise and presbycusis: relations to possible neural mechanisms.

This study is part of ongoing efforts to characterize and determine the neural bases of presbycusis. These efforts utilize humans and animals in sets of overlapping hypotheses and experiments. Here, 50 young adult and elderly subjects, with normal audiometric thresholds or high-frequency hearing loss, were presented three types of linguistic materials at suprathreshold levels to determine speech recognition performance in noise. The study sought to determine how peripheral and central auditory system dysfunctions might be implicated in the speech recognition problems of elderly humans. There were four main findings. (1) Peripheral auditory nervous system pathologies, manifested as reduced sensitivity for speech-frequency pure tones and speech materials, contribute to elevated speech reception thresholds in quiet, and to reduced speech recognition in noise. (2) Good cognitive ability was demonstrated in the old subjects who took advantage of supportive context as well or better than young subjects, strongly indicating that the cortical portions of the speech/language nervous system did not account for the speech understanding dysfunctions of the old subjects. (3) When audibility and cognitive functioning were not affected, the demonstrated speech-recognition in-noise dysfunction remained in old subjects. This implicates auditory brainstem or auditory cortex temporal-resolution dysfunctions in accounting for the observed differences in speech processing. (4) Performance differences between young and elderly subjects with elevated thresholds illustrate the effects of age plus hearing loss and thereby implicate both peripheral and central dysfunctions in presbycusics. This is because the differences in performance between young and elderly subjects with normal peripheral sensitivity identified a central auditory dysfunction.

Preservation of amplitude modulation coding in the presence of background noise by chinchilla auditory-nerve fibers.

Sound envelope temporal fluctuations are important for effective processing of biologically relevant acoustic information including speech, animal vocalizations, sound-source location, and pitch. Amplitude modulation (AM) of sound envelopes can be encoded in quiet with high fidelity by many auditory neurons including those of the auditory nerve (AN) and cochlear nucleus. From both neurophysiological and clinical perspectives, it is critical to understand the effects of background masking noise on the processing of AM. To further this goal, single-unit recordings were made from AN fibers in anesthetized chinchillas. Units were classified according to spontaneous firing rate (SR) and threshold. Best frequency (BF) pure-tone bursts and AM (10-500 Hz) tone bursts were employed as stimuli at several sound levels, both in quiet and in the presence of a continuous wideband noise. It was found that (1) in quiet, low SR AN fibers show the strongest AM coding, followed in order by medium SR and high SR fibers, respectively. (2) AN units of all three classes generally preserve their AM coding even in the presence of loud (0 or +6 dB S/N) background noise and at high sound levels (over 75 dB SPL). (3) This preservation is usually achieved by lowering the average firing rate proportionately to decreases in the synchronous (fundamental frequency) response. (4) For a few AN fibers, the AM coding increases or is reduced in the presence of the background noise. These findings suggest that AN preservation of AM coding in the presence of a continuous masking noise results from shifts in the operating ranges and firing rates of AN fibers resulting from cochlear nonlinearities and adaptive mechanisms.

Sensorineural hearing loss alters recovery from short-term adaptation in the C57BL/6 mouse.

Several strains of laboratory mouse (Mus musculus) have a pattern of hearing loss which resembles that found in humans. The C57BL/6 strain of mouse has a genetic defect that results in degeneration of the organ of Corti, originating in the basal, high-frequency region and then proceeding apically over time. The end result is a severe-to-profound sensorineural hearing loss (SNHL) by 14 months of age. In contrast, auditory function of the CBA strain remains normal through its early life span then slowly declines later in life, much like that typified by human presbycusis. The purpose of the present study was to compare ABR (peak 5) forward masking recovery functions in young, normal-hearing CBA and C57BL/6 mice to hearing-impaired C57BL/6 mice. ABR audiograms were obtained prior to collecting the tone-on-tone forward masking data. Masking was defined as a 50% reduction in the P5 component of the ABR, elicited and masked by 12 kHz tone bursts, using masker/probe time delays from 0 to 100 ms. Time constants were computed from an exponential model fit to the recovery functions (masker level vs. time delay). In hearing-impaired animals there was a significant increase in recovery from short-term adaptation as measured by the time constants, as well as a significant latency shift in the P5 component. The effects of SNHL on the recovery of the P5 component from short-term adaptation was comparable to that reported behaviorally for human hearing-impaired listeners and physiologically from the inferior colliculus (IC) of chinchillas suffering permanent threshold shifts.