Auditory Research publications

The systems-level mechanisms underlying loss of consciousness (LOC) under anesthesia remain unclear. General anesthetics suppress sensory responses within higher-order cortex and feedback connections, both critical elements of predictive coding hypotheses of conscious perception. Responses to auditory novelty may offer promise as biomarkers for consciousness. This study examined anesthesia-induced changes in auditory novelty responses over short (local deviant [LD]) and long (global deviant [GD]) time scales, envisioned to engage preattentive and conscious levels of processing, respectively. Electrocorticographic recordings were obtained in human neurosurgical patients (3 male, 3 female) from four hierarchical processing levels: core auditory cortex, non-core auditory cortex, auditory-related, and PFC. Stimuli were vowel patterns incorporating deviants within and across stimuli (LD and GD). Subjects were presented with stimuli while awake, and during sedation (responsive) and following LOC (unresponsive) under propofol anesthesia. LD and GD effects were assayed as the averaged evoked potential and high gamma (70–150 Hz) activity. In the awake state, LD and GD effects were present in all recorded regions, with averaged evoked potential effects more broadly distributed than high gamma activity. Under sedation, LD effects were preserved in all regions, except PFC. LOC was accompanied by loss of LD effects outside of auditory cortex. By contrast, GD effects were markedly suppressed under sedation in all regions and were absent following LOC. Thus, although the presence of GD effects is indicative of being awake, its absence is not indicative of LOC. Loss of LD effects in higher-order cortical areas may constitute an alternative biomarker of LOC. SIGNIFICANCE STATEMENT Development of a biomarker that indexes changes in the brain upon loss of consciousness (LOC) under general anesthesia has broad implications for elucidating the neural basis of awareness and clinical relevance to mechanisms of sleep, coma, and disorders of consciousness. Using intracranial recordings from neurosurgery patients, we investigated changes in the activation of cortical networks involved in auditory novelty detection over short (local deviance) and long (global deviance) time scales associated with sedation and LOC under propofol anesthesia. Our results indicate that, whereas the presence of global deviance effects can index awareness, their loss cannot serve as a biomarker for LOC. The dramatic reduction of local deviance effects in areas beyond auditory cortex may constitute an alternative biomarker of LOC.

Hyperbilirubinemia (jaundice) is caused by raised levels of unconjugated bilirubin in the blood. When severe, susceptible brain regions including the cerebellum and auditory brainstem are damaged causing neurological sequelae such as ataxia, hearing loss and kernicterus. The mechanism(s) by which bilirubin exerts its toxic effect have not been completely understood to date. In this study we investigated the acute mechanisms by which bilirubin causes the neurotoxicity that contributes to hearing loss. We developed a novel mouse model that exhibits the neurological features seen in human Bilirubin-Induced Neurological Dysfunction (BIND) syndrome that we assessed with a behavioural score and auditory brainstem responses (ABR). Guided by initial experiments applying bilirubin to cultured cells in vitro, we performed whole genome gene expression measurements on mouse brain tissue (cerebellum and auditory brainstem) following bilirubin exposure to gain mechanistic insights into biochemical processes affected, and investigated further using immunoblotting. We then compared the gene changes induced by bilirubin to bacterial lipopolysaccharide (LPS), a well characterized inducer of neuroinflammation, to assess the degree of similarity between them. Finally, we examined the extent to which genetic perturbation of inflammation and both known and novel anti-inflammatory drugs could protect hearing from bilirubin-induced toxicity. The in vitro results indicated that bilirubin induces changes in gene expression consistent with endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR). These gene changes were similar to the gene expression signature of thapsigargin-a known ER stress inducer. It also induced gene expression changes associated with inflammation and NF-κB activation. The in vivo model showed behavioural impairment and a raised auditory threshold. Whole genome gene expression analysis confirmed inflammation as a key mechanism of bilirubin neurotoxicity in the auditory pathway and shared gene expression hallmarks induced by exposure to bacterial lipopolysaccharide (LPS) a well-characterized inducer of neuroinflammation. Interestingly, bilirubin caused more severe damage to the auditory system than LPS in this model, but consistent with our hypothesis of neuroinflammation being a primary part of bilirubin toxicity, the hearing loss was protected by perturbing the inflammatory response. This was carried out genetically using lipocalin-2 (LCN2)-null mice, which is an inflammatory cytokine highly upregulated in response to bilirubin. Finally, we tested known and novel anti-inflammatory compounds (interfering with NF-κB and TNFα signalling), and also demonstrated protection of the auditory system from bilirubin toxicity. We have developed a novel, reversible, model for jaundice that shows movement impairment and auditory loss consistent with human symptoms. We used this model to establish ER-stress and inflammation as major contributors to bilirubin toxicity. Because of the rapid and reversible onset of toxicity in this novel model it represents a system to screen therapeutic compounds. We have demonstrated this by targeting inflammation genetically and with anti-inflammatory small molecules that offered protection against bilirubin toxicity. This also suggests that anti-inflammatory drugs could be of therapeutic use in hyperbilirubinemia.

When stimuli from different sensory modalities are received, they may be combined by the brain to form a multisensory percept. One key mechanism for multisensory binding is the unity assumption under which multisensory stimuli that share certain physical properties like temporal and/or spatial correspondence are grouped together as deriving from one object. In humans, evidence for a role of the unity assumption has been found in spatial tasks and also in temporal tasks using stimuli that share physical properties (speech-related stimuli, musical and synesthetically congruent stimuli). In our study, we investigate the role of the unity assumption in an animal model in a temporal order judgment task. When subjects are asked to indicate which of two spatially separated visual stimuli appeared first in time, performance improves when the visual stimuli are paired (in time) with spatially non-informative acoustic cues, a phenomenon known as the temporal ventriloquism effect. Here, we show that European starlings perform better when one singleton acoustic cue is paired with the first visual stimulus as compared to pairing with the second visual stimulus. This shows, in combination with our previous study, that a non-informative singleton acoustic cue, when temporally paired with the first visual stimulus, triggers alerting while, when temporally pairing with the second visual stimulus, it prevents a temporal ventriloquism effect because the unity assumption is violated. Thus, the unity assumption influences sensory perception not only in humans but also in an animal model. The importance of the unity assumption in this task supports the idea that the temporal ventriloquism effect, similar to the spatial ventriloquism effect, is based on multisensory binding and integration but not on alerting effects.

Recent work has demonstrated that transmembrane channel-like 1 protein (TMC1) is an essential component of the sensory transduction complex in hair cells of the inner ear. A closely related homolog, TMC2, is expressed transiently in the neonatal mouse cochlea and can enable sensory transduction in Tmc1 -null mice during the first postnatal week. Both TMC1 and TMC2 are expressed at adult stages in mouse vestibular hair cells. The extent to which TMC1 and TMC2 can substitute for each other is unknown. Several biophysical differences between TMC1 and TMC2 suggest these proteins perform similar but not identical functions. To investigate these differences, and whether TMC2 can substitute for TMC1 in mature hair cells, we generated a knock-in mouse model allowing Cre -inducible expression of Tmc2 . We assayed for changes in hair cell sensory transduction and auditory and vestibular function in Tmc2 knockin mice ( Tm [ Tmc2 ]) in the presence or absence of endogenous Tmc1 , Tmc2 or both. Our results show that expression of Tm[TMC2] restores sensory transduction in vestibular hair cells and transiently in cochlear hair cells in the absence of TMC1. The cellular rescue leads to recovery of balance but not auditory function. We conclude that TMC1 provides some additional necessary function, not provided by TMC2.

Significance Early linguistic experience affects perception and cortical processing of speech, even in infants. The current study examined whether linguistic effects extend to brainstem speech encoding, where responses are rapid, automatic, and preattentive. We focused on transient consonants and measured perception behaviorally and the corresponding complex auditory brainstem response (cABR) onset using simultaneous electroencephalography/magnetoencephalography (EEG/MEG) in native Spanish and English speakers. We demonstrate that the latency of an EEG-cABR onset peak predicts consonant perception and that the perception differs according to language background. MEG-cABR analysis demonstrates deep sources for the onset, providing complimentary support for a brainstem origin. Effects of early linguistic experience on speech perception can be observed at the earlier stage of speech encoding at the brainstem.

Tonal working memory (WM) refers to the maintenance and the online manipulation of tonal information and has been suggested to involve different mechanisms than verbal WM. Previous research has suggested that verbal WM performance is determined by the duration instead of the number of verbal materials. We investigated in the present study to what degree that the number and the duration of notes in a sequence influence the tonal WM in participants with or without professional musical training. The forward tonal discrimination task in Experiment 1 tested the maintenance of the tonal information and the backward N-back tonal task in Experiment 2 probed the running memory span of tonal information. Results show that the number of notes, but not the duration of notes in a tone sequence significantly affects tonal WM performance for both musicians and non-musicians. In addition, within a minimum musical context, musicians outperformed non-musicians in the N-back tonal task but not the forward tone sequence discrimination task. These findings indicate that the capacity of tonal WM is determined by the number of notes but not the duration of notes in a sequence to be memorized, suggesting a different mechanism underlying tonal WM from verbal WM. Furthermore, the present study demonstrated that N-back tonal task is a quantitative and sensitive measure of the effect of musical training on tonal WM.

Cisplatin, a small platinum-containing molecule, is a widely used, highly effective anticancer drug. However, severe side effects have been found in cancer patients treated with cisplatin, including nephrotoxicity, neurotoxicity, and ototoxicity. These cisplatin-induced side effects can have a major impact on patient quality of life, including social development problems in pediatric patients that develop hearing loss. Previous studies have suggested that the major cause of cisplatin-induced ototoxicity is abnormal accumulation of reactive oxygen species (ROS) and oxidative stress. Alpha-lipoic acid (ALA), one of the most effective antioxidants, is known to be involved in the cellular antioxidant system and may have a protective effect on cisplatin-induced ototoxicity. However, the therapeutic effect of ALA on damaged hearing function and its detailed mechanism of action are not fully understood. This study focused on determining whether ALA has a potential as a protective and/or therapeutic agent for cisplatin-induced ototoxicity. Histological and physiological analyses were performed using cisplatin-treated mouse cochlea and HEI-OC1 culture cells in pre- and post-treatment with ALA in vitro and in vivo. We found that ALA contributes to protecting mitochondrial function by preventing ROS accumulation and inhibiting apoptotic cell death. Importantly, post-treatment with ALA consistently showed an almost equal restorative effect to pretreatment, in vitro and in vivo, supporting the possible use of ALA as a therapeutic agent for cisplatin-induced ototoxicity. This study is the first report on a strong therapeutic potential of ALA to rescue ototoxic hearing loss caused by cisplatin, and our data provide key evidence that ALA may act as a reducing agent for glutathione disulfide to increase glutathione levels on behalf of glutathione reductase. This result was consistent in both cultured cells and the mouse model, which improves the clinical value of ALA for therapy of cisplatin-induced ototoxicity.

The ventriloquism aftereffect (VAE) refers to a shift in auditory spatial perception following exposure to a spatial disparity between auditory and visual stimuli. The VAE has been previously measured on two distinct time scales. Hundreds or thousands of exposures to a an audio-visual spatial disparity produces enduring VAE that persists after exposure ceases. Exposure to a single audio-visual spatial disparity produces immediate VAE that decays over seconds. To determine if these phenomena are two extremes of a continuum or represent distinct processes, we conducted an experiment with normal hearing listeners that measured VAE in response to a repeated, constant audio-visual disparity sequence, both immediately after exposure to each audio-visual disparity and after the end of the sequence. In each experimental session, subjects were exposed to sequences of auditory and visual targets that were constantly offset by +8° or -8° in azimuth from one another, then localized auditory targets presented in isolation following each sequence. Eye position was controlled throughout the experiment, to avoid the effects of gaze on auditory localization. In contrast to other studies that did not control eye position, we found both a large shift in auditory perception that decayed rapidly after each AV disparity exposure, along with a gradual shift in auditory perception that grew over time and persisted after exposure to the AV disparity ceased. We modeled the temporal and spatial properties of the measured auditory shifts using grey box nonlinear system identification, and found that two models could explain the data equally well. In the power model, the temporal decay of the ventriloquism aftereffect was modeled with a power law relationship. This causes an initial rapid drop in auditory shift, followed by a long tail which accumulates with repeated exposure to audio-visual disparity. In the double exponential model, two separate processes were required to explain the data, one which accumulated and decayed exponentially and the other which slowly integrated over time. Both models fit the data best when the spatial spread of the ventriloquism aftereffect was limited to a window around the location of the audio-visual disparity. We directly compare the predictions made by each model, and suggest additional measurements that could help distinguish which model best describes the mechanisms underlying the VAE.

Age-related hearing decline typically includes threshold shifts as well as reduced wave I auditory brainstem response (ABR) amplitudes due to cochlear synaptopathy/neuropathy, which may compromise precise coding of suprathreshold speech envelopes. This is supported by findings with older listeners, who have difficulties in envelope and speech processing, especially in noise. However, separating the effects of threshold elevation, synaptopathy, and degradation by noise on physiological representations may be difficult. In the present study, the effects of notched, low- and high-pass noise on envelope-following responses (EFRs) in aging were compared when sound levels (aged: 85-dB SPL; young: 60- to 80-dB SPL) were matched between groups peripherally, by matching wave I ABR amplitudes, or centrally by matching EFR amplitudes. Low-level notched noise reduced EFRs to sinusoidally amplitude-modulated (SAM) tones in young animals for notch widths up to 2 octaves. High-pass noise above the carrier frequency reduced EFRs. Young animals showed EFR reductions at lower noise levels. Low-pass noise did not reduce EFRs in either young or aged animals. High-pass noise may affect EFR amplitudes in young animals more than aged by reducing the contributions of high-frequency-sensitive inputs. EFRs to SAM tones in modulated noise (NAM) suggest that neurons of young animals can synchronize to NAM at lower sound levels and maintain dual AM representations better than older animals. The overall results show that EFR amplitudes are strongly influenced by aging and the presence of a competing sound that likely reduces or shifts the pool of responsive neurons.

Stereocilia are mechanosensitive protrusions on the surfaces of sensory hair cells in the inner ear that detect sound, gravity, and head movement. Their cores are composed of parallel actin filaments that are cross-linked and stabilized by several actin-binding proteins, including fascin-2, plastin-1, espin, and XIRP2. The actin filaments are the most stable known, with actin turnover primarily occurring at the stereocilia tips. While stereocilia actin dynamics has been well studied, little is known about the behavior of the actin cross-linking proteins, which are the most abundant type of protein in stereocilia after actin and are critical for stereocilia morphogenesis and maintenance. Here, we developed a novel transgenic mouse to monitor EGFP-fascin-2 incorporation . In contrast to actin, EGFP-fascin-2 readily enters the stereocilia core. We also compared the effect of EGFP-fascin-2 expression on developing and mature stereocilia. When it was induced during hair cell development, we observed increases in both stereocilia length and width. Interestingly, stereocilia size was not affected when EGFP-fascin-2 was induced in adult stereocilia. Regardless of the time of induction, EGFP-fascin-2 displaced both espin and plastin-1 from stereocilia. Altering the actin cross-linker composition, even as the actin filaments exhibit little to no turnover, provides a mechanism for ongoing remodeling and repair important for stereocilia homeostasis.

Introduction: Injuries to the peripheral auditory system are among the most common results of high intensity impulsive acoustic exposure. Prior studies of high intensity sound transmission by the ossicular chain have relied upon measurements in animal models, measurements at more moderate sound levels (i.e. < 130 dB SPL), and/or measured responses to steady-state noise. Here, we directly measure intracochlear pressure in human cadaveric temporal bones, with fiber optic pressure sensors placed in scala vestibuli (SV) and tympani (ST), during exposure to shock waves with peak positive pressures between ∼7 and 83 kPa. Methods: Eight full-cephalic human cadaver heads were exposed, face-on, to acoustic shock waves in a 45 cm diameter shock tube. Specimens were exposed to impulses with nominal peak overpressures of 7, 28, 55, & 83 kPa (171, 183, 189, & 192 dB pSPL), measured in the free field adjacent to the forehead. Specimens were prepared bilaterally by mastoidectomy and extended facial recess to expose the ossicular chain. Ear canal (EAC), middle ear, and intracochlear sound pressure levels were measured with fiber-optic pressure sensors. Surface-mounted sensors measured SPL and skull strain near the opening of each EAC and at the forehead. Results: Measurements on the forehead showed incident peak pressures approximately twice that measured by adjacent free-field and EAC entrance sensors, as expected based on the sensor orientation (normal vs tangential to the shock wave propagation). At 7 kPa, EAC pressure showed gain, calculated from the frequency spectra, consistent with the ear canal resonance, and gain in the intracochlear pressures (normalized to the EAC pressure) were consistent with (though somewhat lower than) previously reported middle ear transfer functions. Responses to higher intensity impulses tended to show lower intracochlear gain relative to EAC, suggesting sound transmission efficiency along the ossicular chain is reduced at high intensities. Tympanic membrane (TM) rupture was observed following nearly every exposure 55 kPa or higher. Conclusions: Intracochlear pressures reveal lower middle-ear transfer function magnitudes (i.e. reduced gain relative to the ear canal) for high sound pressure levels, thus revealing lower than expected cochlear exposure based on extrapolation from cochlear pressures measured at more moderate sound levels. These results are consistent with lowered transmissivity of the ossicular chain at high intensities, and are consistent with our prior report measuring middle ear transfer functions in human cadaveric temporal bones with high intensity tone pips.

Acquired hearing loss is caused by complex interactions of multiple environmental risk factors, such as elevated levels of lead and noise, which are prevalent in urban communities. This study delineates the mechanism underlying lead-induced auditory dysfunction and its potential interaction with noise exposure. Young-adult C57BL/6 mice were exposed to: 1) control conditions; 2) 2 mM lead acetate in drinking water for 28 days; 3) 90 dB broadband noise 2 h/day for two weeks; and 4) both lead and noise. Blood lead levels were measured by inductively coupled plasma mass spectrometry analysis (ICP-MS) lead-induced cochlear oxidative stress signaling was assessed using targeted gene arrays, and the hearing thresholds were assessed by recording auditory brainstem responses. Chronic lead exposure downregulated cochlear Sod1, Gpx1, and Gstk1, which encode critical antioxidant enzymes, and upregulated ApoE, Hspa1a, Ercc2, Prnp, Ccl5, and Sqstm1, which are indicative of cellular apoptosis. Isolated exposure to lead or noise induced 8-12 dB and 11-25 dB shifts in hearing thresholds, respectively. Combined exposure induced 18-30 dB shifts, which was significantly higher than that observed with isolated exposures. This study suggests that chronic exposure to lead induces cochlear oxidative stress and potentiates noise-induced hearing impairment, possibly through parallel pathways.

Despite the common use of guinea pigs in investigations of the neural mechanisms of binaural and spatial hearing, their behavioral capabilities in spatial hearing tasks have surprisingly not been thoroughly investigated. To begin to fill this void, we tested the spatial hearing of adult male guinea pigs in several experiments using a paradigm based on the prepulse inhibition (PPI) of the acoustic startle response. In the first experiment, we presented continuous broadband noise from one speaker location and switched to a second speaker location (the "prepulse") along the azimuth prior to presenting a brief, ∼110 dB SPL startle-eliciting stimulus. We found that the startle response amplitude was systematically reduced for larger changes in speaker swap angle (i.e., greater PPI), indicating that using the speaker "swap" paradigm is sufficient to assess stimulus detection of spatially separated sounds. In a second set of experiments, we swapped low- and high-pass noise across the midline to estimate their ability to utilize interaural time- and level-difference cues, respectively. The results reveal that guinea pigs can utilize both binaural cues to discriminate azimuthal sound sources. A third set of experiments examined spatial release from masking using a continuous broadband noise masker and a broadband chirp signal, both presented concurrently at various speaker locations. In general, animals displayed an increase in startle amplitude (i.e., lower PPI) when the masker was presented at speaker locations near that of the chirp signal, and reduced startle amplitudes (increased PPI) indicating lower detection thresholds when the noise was presented from more distant speaker locations. In summary, these results indicate that guinea pigs can: 1) discriminate changes in source location within a hemifield as well as across the midline, 2) discriminate sources of low- and high-pass sounds, demonstrating that they can effectively utilize both low-frequency interaural time and high-frequency level difference sound localization cues, and 3) utilize spatial release from masking to discriminate sound sources. This report confirms the guinea pig as a suitable spatial hearing model and reinforces prior estimates of guinea pig hearing ability from acoustical and physiological measurements.

Neurons in the developing auditory system exhibit spontaneous bursts of activity before hearing onset. How this intrinsically generated activity influences development remains uncertain, because few mechanistic studies have been performed in vivo. We show using macroscopic calcium imaging in unanesthetized mice that neurons responsible for processing similar frequencies of sound exhibit highly synchronized activity throughout the auditory system during this critical phase of development. Spontaneous activity normally requires synaptic excitation of spiral ganglion neurons (SGNs). Unexpectedly, tonotopic spontaneous activity was preserved in a mouse model of deafness in which glutamate release from hair cells is abolished. SGNs in these mice exhibited enhanced excitability, enabling direct neuronal excitation by supporting cell-induced potassium transients. These results indicate that homeostatic mechanisms maintain spontaneous activity in the pre-hearing period, with significant implications for both circuit development and therapeutic approaches aimed at treating congenital forms of deafness arising through mutations in key sensory transduction components.

The human auditory cortex simultaneously processes speech and determines the location of a speaker in space. Neuroimaging studies in humans have implicated core auditory areas in processing the spectrotemporal and the spatial content of sound; however, how these features are represented together is unclear. We recorded directly from human subjects implanted bilaterally with depth electrodes in core auditory areas as they listened to speech from different directions. We found local and joint selectivity to spatial and spectrotemporal speech features, where the spatial and spectrotemporal features are organized independently of each other. This representation enables successful decoding of both spatial and phonetic information. Furthermore, we found that the location of the speaker does not change the spectrotemporal tuning of the electrodes but, rather, modulates their mean response level. Our findings contribute to defining the functional organization of responses in the human auditory cortex, with implications for more accurate neurophysiological models of speech processing.

Round window membrane (RWM) application of ouabain is known to selectively destroy type I spiral ganglion cells (SGCs) in cochleas of several rodent species, while leaving hair cells intact. This protocol has been used in rats and Mongolian gerbils, but observations in the guinea pig are conflicting. This is why we reinvestigated the effect of ouabain on the guinea pig cochlea. Ouabain solutions of different concentrations were placed, in a piece of gelfoam, upon the RWM of the right cochleas. Auditory function was assessed using acoustically evoked auditory brainstem responses (aABR). Finally, cochleas were fixed and processed for histological examination. Due to variability within treatment groups, histological data was pooled and three categories based upon general histological observations were defined: cochleas without outer hair cell (OHC) and SGC loss (Category 1), cochleas with OHC loss only (Category 2), and cochleas with OHC and SGC loss (Category 3). Animals treated with 1 mM or 10 mM ouabain showed shifts in hearing thresholds, corresponding with varying histological changes in their cochleas. Most cochleas exhibited complete outer hair cell loss in the basal and middle turns, while some had no changes, together with either moderate or near-complete loss of SGCs. Neither loss of inner hair cells nor histological changes of the stria vascularis were observed in any of the animals. Cochleas in Category 1 had normal aABRs and morphology. On average, in Category 2 OHC loss was 46.0±5.7%, SGC loss was below threshold, ABR threshold shift was 44.9±2.7 dB, and ABR wave II amplitude was decreased by 17.1±3.8 dB. In Category 3 OHC loss was 68.3±6.9%, SGC loss was 49.4±4.3%, ABR threshold shift was 39.0±2.4 dB, and ABR amplitude was decreased by 15.8±1.6 dB. Our results show that ouabain does not solely destroy type I SGCs in the guinea pig cochlea.

The increasing rate of age-related hearing loss (ARHL), with its subsequent reduction in quality of life and increase in health care costs, requires new therapeutic strategies to reduce and delay its impact. The goal of this study was to determine if ARHL could be reduced in a rat model by administering a combination of antioxidant vitamins A, C, and E acting as free radical scavengers along with Mg++, a known powerful cochlear vasodilator (ACEMg). Toward this goal, young adult, 3 month-old Wistar rats were divided into two groups: one was fed with a diet composed of regular chow ("normal diet," ND); the other received a diet based on chow enriched in ACEMg ("enhanced diet," ED). The ED feeding began 10 days before the noise stimulation. Auditory brainstem recordings (ABR) were performed at 0.5, 1, 2, 4, 8, 16, and 32 kHz at 3, 6-8, and 12-14 months of age. No differences were observed at 3 months of age, in both ND and ED animals. At 6-8 and 12-14 months of age there were significant increases in auditory thresholds and a reduction in the wave amplitudes at all frequencies tested, compatible with progressive development of ARHL. However, at 6-8 months threshold shifts in ED rats were significantly lower in low and medium frequencies, and wave amplitudes were significantly larger at all frequencies when compared to ND rats. In the oldest animals, differences in the threshold shift persisted, as well as in the amplitude of the wave II, suggesting a protective effect of ACEMg on auditory function during aging. These findings indicate that oral ACEMg may provide an effective adjuvant therapeutic intervention for the treatment of ARHL, delaying the progression of hearing impairment associated with age.

We investigated fibroblast growth factor 12 (FGF12) as a transcript enriched in the inner ear by searching published cDNA library databases. FGF12 is a fibroblast growth factor homologous factor, a subset of the FGF superfamily. To date, its localisation and function in the inner ear have not been determined. Here, we show that FGF12 mRNA is localised in spiral ganglion neurons (SGNs) and the vestibular ganglion. We also show that FGF12 protein is localised in SGNs, the vestibular ganglion, and nerve fibres extending beneath hair cells. Moreover, we investigated FGF12 function in auditory and vestibular systems using Fgf12 -knockout (FGF12-KO) mice generated with CRISPR/Cas9 technology. Our results show that the inner ear morphology of FGF12-KO mice is not significantly different compared with wild-type mice. However, FGF12-KO mice exhibited an increased hearing threshold, as measured by the auditory brainstem response, as well as deficits in rotarod and balance beam performance tests. These results suggest that FGF12 is necessary for normal auditory and equilibrium function.

Cocktail parties pose a difficult yet solvable problem for the auditory system. Previous work has shown that the cocktail-party problem is considerably easier when all sounds in the target stream are spoken by the same talker (the voice-continuity benefit). The present study investigated the contributions of two of the most salient voice features — glottal-pulse rate (GPR) and vocal-tract length (VTL) — to the voice-continuity benefit. Twenty young, normal-hearing listeners participated in two experiments. On each trial, listeners heard concurrent sequences of spoken digits from three different spatial locations and reported the digits coming from a target location. Critically, across conditions, GPR and VTL either remained constant or varied across target digits. Additionally, across experiments, the target location either remained constant (Experiment 1) or varied (Experiment 2) within a trial. In Experiment 1, listeners benefited from continuity in either voice feature, but VTL continuity was more helpful than GPR continuity. In Experiment 2, spatial discontinuity greatly hindered listeners’ abilities to exploit continuity in GPR and VTL. The present results suggest that selective attention benefits from continuity in target voice features, and that VTL and GPR play different roles for perceptual grouping and stream segregation in the cocktail party.

Sensorineural hearing loss (SNHL) has been demonstrated in many clinical reports as a risk factor that promotes the development of cognitive impairment. However, the underlying neurological mechanisms are not clear. Noise exposure is one of the most common causes of SNHL. Although noise exposure causes relatively less damage to general health as compared with other methods for creating hearing loss (such as ototoxicity), it does impair cognitive function. Many studies have shown that the noise-induced cognitive impairment occur via the oxidative stress induced by the noise. In those studies, the effects of the noise-induced hearing loss induced (NIHL) were not addressed. Previously, we have demonstrated in the CBA/CaJ mouse model that oxidative stress was transient after a brief noise exposure, but the NIHL was permanent. In addition, NIHL was followed by a declined cognitive function and decreased hippocampal neurogenesis that were developed long after the oxidative stress disappeared. Therefore, NIHL can cause cognitive impairment independent of its stress effect and can serve as a model to investigate the relationship between hearing loss and the development of cognitive impairment. In the present study, we further demonstrated that the oxidative stress produced by the brief noise exposure did not damage the stem cell bank of hippocampus that was evaluated shortly after the noise exposure. In addition to the reduction in the rate of cell proliferation in hippocampus that was found previously, we found that the NIHL significantly reduced the promoting effect of learning activity on various stages of hippocampal neurogenesis, accompanied by the reduction in learning-induced expression of immediate early genes (IEGs) in hippocampus. Since the MWM-tested spatial function does not directly require auditory input, the results provide evidence for the maintenance role of auditory input on the cognitive function; the reduction of IEG expression that is required in memory-formation may be the initial step in blocking the effect of learning activity on neurogenesis in subjects with NIHL.