Auditory Research publications

Objective: Age-related hearing loss (AHL), or presbycusis, is the most common sensory disorder among the elderly. We used C57BL/6J mice as an AHL model to determine a possible association between AHL and a high-fat diet (HFD). Methods: Forty C57BL/6J mice were randomly assigned to a control or HFD group. Each group was divided into the following subgroups: 1-, 3-, 5- and 12-month groups (HFD, n = 5/subgroup; control, n = 5/subgroup). Nine CBA/N-slc mice were also used as a 12-month control (n = 5) or 12-month HFD (n = 4) group. The mice were fed a HFD or normal (control) diet throughout this study. Hearing function was evaluated at 1, 3, 5 and 12 months using auditory evoked brainstem responses (ABRs). Spiral ganglion cells (SGCs) were also counted. Results: The elevation of ABR thresholds (at 4 and 32 kHz) at 3 and 5 months was significantly suppressed in the HFD group compared with the control groups for C57BL/6J mice. After 12 months, the elevation of ABR thresholds was significantly suppressed in the HFD group at all frequencies for C57BL/6J mice. In contrast, CBA/N-slc mice displayed opposite outcomes, as ABR thresholds at all frequencies at 12 months were significantly elevated in the HFD group compared with the control group. For the C57BL/6J mice at 12 months, SGC numbers significantly decreased in all parts of the cochleae in the control group compared with the HFD groups. In contrast, for the CBA/N-slc mice, SGC numbers significantly decreased, particularly in the upper parts of the cochleae in the HFD group compared with the control groups. Conclusions: The elevation in ABR thresholds and SGC loss associated with aging in the HFD-fed C57BL/6J mice were significantly suppressed compared with those in the normal diet-fed mice. These results suggest that HFD delays AHL progression in the C57B/6J mice.

Retrograde degeneration of spiral ganglion cells in the cochlea following hair cell loss is similar to dying back in pathology. The EFR3A gene has recently been discovered to be involved in the pathogenesis of dying back. The relationship of EFR3A and spiral ganglion degeneration, however, was rarely investigated. In this study, we destroyed the hair cells of the mouse cochlea by co-administration of kanamycin and furosemide and then investigated the EFR3A expression during the induced spiral ganglion cell degeneration. Our results revealed that co-administration of kanamycin and furosemide quickly induced hair cell loss in the C57BL/6J mice and then resulted in progressive degeneration of the spiral ganglion beginning at day 5 following drug administration. The number of the spiral ganglion cells began to decrease at day 15. The expression of EFR3A increased remarkably in the spiral ganglion at day 5 and then decreased to near normal level within the next 10 days. Our study suggested that the change of EFR3A expression in the spiral ganglion was coincident with the time of the spiral ganglion degeneration, which implied that high expression of EFR3A may be important to prompt initiation of spiral ganglion degeneration following hair cell loss.

Reactive oxygen species (ROS) accumulation are involved in noise- and ototoxic drug-induced hair cell loss, which is the major cause of hearing loss. Bmi1 is a member of the Polycomb protein family and has been reported to regulate mitochondrial function and ROS level in thymocytes and neurons. In this study, we reported the expression of Bmi1 in mouse cochlea and investigated the role of Bmi1 in hair cell survival. Bmi1 expressed in hair cells and supporting cells in mouse cochlea. Bmi1 −/− mice displayed severe hearing loss and patched outer hair cell loss from postnatal day 22. Ototoxic drug-induced hair cells loss dramatically increased in Bmi1 −/− mice compared with that in wild-type controls both in vivo and in vitro , indicating Bmi1 −/− hair cells were significantly more sensitive to ototoxic drug-induced damage. Cleaved caspase-3 and TUNEL staining demonstrated that apoptosis was involved in the increased hair cell loss of Bmi1 −/− mice. Aminophenyl fluorescein and MitoSOX Red staining showed the level of free radicals and mitochondrial ROS increased in Bmi1 −/− hair cells due to the aggravated disequilibrium of antioxidant–prooxidant balance. Furthermore, the antioxidant N -acetylcysteine rescued Bmi1 −/− hair cells from neomycin injury both in vitro and in vivo , suggesting that ROS accumulation was mainly responsible for the increased aminoglycosides sensitivity in Bmi1 −/− hair cells. Our findings demonstrate that Bmi1 has an important role in hair cell survival by controlling redox balance and ROS level, thus suggesting that Bmi1 may work as a new therapeutic target for the prevention of hair cell death.

During communication we combine auditory and visual information. Neurophysiological research in nonhuman primates has shown that single neurons in ventrolateral prefrontal cortex (VLPFC) exhibit multisensory responses to faces and vocalizations presented simultaneously. However, whether VLPFC is also involved in maintaining those communication stimuli in working memory or combining stored information across different modalities is unknown, although its human homolog, the inferior frontal gyrus, is known to be important in integrating verbal information from auditory and visual working memory. To address this question, we recorded from VLPFC while rhesus macaques ( Macaca mulatta ) performed an audiovisual working memory task. Unlike traditional match-to-sample/nonmatch-to-sample paradigms, which use unimodal memoranda, our nonmatch-to-sample task used dynamic movies consisting of both facial gestures and the accompanying vocalizations. For the nonmatch conditions, a change in the auditory component (vocalization), the visual component (face), or both components was detected. Our results show that VLPFC neurons are activated by stimulus and task factors: while some neurons simply responded to a particular face or a vocalization regardless of the task period, others exhibited activity patterns typically related to working memory such as sustained delay activity and match enhancement/suppression. In addition, we found neurons that detected the component change during the nonmatch period. Interestingly, some of these neurons were sensitive to the change of both components and therefore combined information from auditory and visual working memory. These results suggest that VLPFC is not only involved in the perceptual processing of faces and vocalizations but also in their mnemonic processing.

Electromotile activity in auditory outer hair cells (OHCs) is essential for sound amplification. It relies on the highly specialized membrane motor protein prestin, and its interactions with the cytoskeleton. It is believed that the expression of prestin and related molecules involved in OHC electromotility may be dynamically regulated by signals from the acoustic environment. However little is known about the nature of such signals and how they affect the expression of molecules involved in electromotility in OHCs. We show evidence that prestin oligomerization is regulated, both at short and relatively long term, by acoustic input and descending efferent activity originating in the cortex, likely acting in concert. Unilateral removal of the middle ear ossicular chain reduces levels of trimeric prestin, particularly in the cochlea from the side of the lesion, whereas monomeric and dimeric forms are maintained or even increased in particular in the contralateral side, as shown in Western blots. Unilateral removal of the auditory cortex (AC), which likely causes an imbalance in descending efferent activity on the cochlea, also reduces levels of trimeric and tetrameric forms of prestin in the side ipsilateral to the lesion, whereas in the contralateral side prestin remains unaffected, or even increased in the case of trimeric and tetrameric forms. As far as efferent inputs are concerned, unilateral ablation of the AC up-regulates the expression of α10 nicotinic Ach receptor (nAChR) transcripts in the cochlea, as shown by RT-Quantitative real-time PCR (qPCR). This suggests that homeostatic synaptic scaling mechanisms may be involved in dynamically regulating OHC electromotility by medial olivocochlear efferents. Limited, unbalanced efferent activity after unilateral AC removal, also affects prestin and β-actin mRNA levels. These findings support that the concerted action of acoustic and efferent inputs to the cochlea is needed to regulate the expression of major molecules involved in OHC electromotility, both at the transcriptional and posttranscriptional levels.

The acoustical cues and physiological processing mechanisms underlying the perception of the distance of sound sources are not well understood. To understand the relation between physiology and behavior, a first step is to use an animal model to study distance sensitivity. The goal of these experiments was to establish the capacity of the Dutch-belted rabbit to discriminate between sound sources at two distances. Trains of noise bursts were presented from speakers that were located either directly in front of the rabbit or at a 45 ° angle in azimuth. The reference speaker was positioned at distances of 20, 40, and 60 cm from the subject, and the more distant test speaker was systematically moved to determine the smallest difference in distance that could be reliably discriminated by the subject. Noise stimuli had one of three bandwidths: wideband (0.1-10 kHz), low-pass (0.1-3 kHz), or high-pass (3-10 kHz). The mean stimulus level was 60 dB sound pressure level (SPL) at the location of the rabbit's head, and the level was roved over a 12-dB range from trial to trial to reduce the availability of level cues. An operant one-interval two-alternative non-forced choice task was used, with a blocked two-down-one-up tracking procedure to determine the distance discriminability. Rabbits were consistently able to discriminate two distances when they were sufficiently separated. Sensitivity was better when the reference distance was 60 cm at either azimuth (distance ratio = 1.5) and was worse when the reference distance was 20 cm (distance ratio = 2.4 at 0 ° and 1.75 at 45 °).

Current models of hierarchical processing in auditory cortex have been based principally on anatomical connectivity while functional interactions between individual regions have remained largely unexplored. Previous cortical deactivation studies in the cat have addressed functional reciprocal connectivity between primary auditory cortex (A1) and other hierarchically lower level fields. The present study sought to assess the functional contribution of inputs along multiple stages of the current hierarchical model to a higher order area, the dorsal zone (DZ) of auditory cortex, in the anaesthetized cat. Cryoloops were placed over A1 and posterior auditory field (PAF). Multiunit neuronal responses to noise burst and tonal stimuli were recorded in DZ during cortical deactivation of each field individually and in concert. Deactivation of A1 suppressed peak neuronal responses in DZ regardless of stimulus and resulted in increased minimum thresholds and reduced absolute bandwidths for tone frequency receptive fields in DZ. PAF deactivation had less robust effects on DZ firing rates and receptive fields compared with A1 deactivation, and combined A1/PAF cooling was largely driven by the effects of A1 deactivation at the population level. These results provide physiological support for the current anatomically based model of both serial and parallel processing schemes in auditory cortical hierarchical organization.

Hearing loss with increasing age adversely affects the ability to understand speech, an effect that results partly from reduced audibility. The aims of this study were to establish whether aging reduces speech intelligibility for listeners with normal audiograms, and, if so, to assess the relative contributions of auditory temporal and cognitive processing. Twenty-one older normal-hearing (ONH; 60-79 years) participants with bilateral audiometric thresholds ≤ 20 dB HL at 0.125-6 kHz were matched to nine young (YNH; 18-27 years) participants in terms of mean audiograms, years of education, and performance IQ. Measures included: (1) identification of consonants in quiet and in noise that was unmodulated or modulated at 5 or 80 Hz; (2) identification of sentences in quiet and in co-located or spatially separated two-talker babble; (3) detection of modulation of the temporal envelope (TE) at frequencies 5-180 Hz; (4) monaural and binaural sensitivity to temporal fine structure (TFS); (5) various cognitive tests. Speech identification was worse for ONH than YNH participants in all types of background. This deficit was not reflected in self-ratings of hearing ability. Modulation masking release (the improvement in speech identification obtained by amplitude modulating a noise background) and spatial masking release (the benefit obtained from spatially separating masker and target speech) were not affected by age. Sensitivity to TE and TFS was lower for ONH than YNH participants, and was correlated positively with speech-in-noise (SiN) identification. Many cognitive abilities were lower for ONH than YNH participants, and generally were correlated positively with SiN identification scores. The best predictors of the intelligibility of SiN were composite measures of cognition and TFS sensitivity. These results suggest that declines in speech perception in older persons are partly caused by cognitive and perceptual changes separate from age-related changes in audiometric sensitivity.

Spatial hearing evolved independently in mammals and birds and is thought to adapt to altered developmental input in different ways. We found, however, that ferrets possess multiple forms of plasticity that are expressed according to which spatial cues are available, suggesting that the basis for adaptation may be similar across species. Our results also provide insight into the way sound source location is represented by populations of cortical neurons.

The binaural masking level difference (BMLD) is a phenomenon whereby a signal that is identical at each ear (S0), masked by a noise that is identical at each ear (N0), can be made 12–15 dB more detectable by inverting the waveform of either the tone or noise at one ear (Sπ, Nπ). Single-cell responses to BMLD stimuli were measured in the primary auditory cortex of urethane-anesthetized guinea pigs. Firing rate was measured as a function of signal level of a 500 Hz pure tone masked by low-passed white noise. Responses were similar to those reported in the inferior colliculus. At low signal levels, the response was dominated by the masker. At higher signal levels, firing rate either increased or decreased. Detection thresholds for each neuron were determined using signal detection theory. Few neurons yielded measurable detection thresholds for all stimulus conditions, with a wide range in thresholds. However, across the entire population, the lowest thresholds were consistent with human psychophysical BMLDs. As in the inferior colliculus, the shape of the firing-rate versus signal-level functions depended on the neurons' selectivity for interaural time difference. Our results suggest that, in cortex, BMLD signals are detected from increases or decreases in the firing rate, consistent with predictions of cross-correlation models of binaural processing and that the psychophysical detection threshold is based on the lowest neural thresholds across the population.

Background: The auditory steady-state response, which measures the ability of neural ensembles to entrain to rhythmic auditory stimuli, has been used in human electroencephalogram studies to assess sensory processing and electrical oscillatory deficits. Patients with schizophrenia show a deficit in auditory steady-state response at 40 Hz, and therefore this may be a useful biomarker to study this disorder. Methods: We used auditory steady-state response recordings from the primary auditory cortex, hippocampus, and vertex electroencephalogram sites in awake behaving rats to determine whether pharmacological impairment of excitatory or inhibitory neurotransmission mimics auditory steady-state response abnormalities in schizophrenia. Results: We found the most robust response to auditory stimuli in the primary auditory cortex, in line with previous studies suggesting this region is the primary generator of the auditory steady-state response in humans. Acute MK-801 (0.1mg/kg i.p.) increased primary auditory cortex intertrial coherence during auditory steady-state response at 20 and 40 Hz. Chronic MK-801 (21-day exposure at this daily dose) had no significant effect on 40-Hz auditory steady-state response. Furthermore, we found no effect of acute or chronic picrotoxin (a GABA-A antagonist) on intertrial coherence. Conclusions: Our data indicate that acute N-methyl-d-aspartate receptor antagonism increases synchronous activity in the primary auditory cortex in a frequency-specific manner, supporting the widely held view that acute N-methyl-d-aspartate antagonism augments gamma oscillations. Thus, rodent auditory steady-state response could be a valuable method to study the cortical ability to support synchronous activity at specific frequencies.

Objectives: To determine the influence of hearing loss on perception of vowel slices. Methods: Fourteen listeners aged 20-27 participated; ten (6 males) had hearing within normal limits and four (3 males) had moderate-severe sensorineural hearing loss (SNHL). Stimuli were six naturally-produced words consisting of the vowels /i a u æ ɛ ʌ/ in a /b V b/ context. Each word was presented as a whole and in eight slices: the initial transition, one half and one fourth of initial transition, full central vowel, one-half central vowel, ending transition, one half and one fourth of ending transition. Each of the 54 stimuli was presented 10 times at 70 dB SPL (sound press level); listeners were asked to identify the word. Stimuli were shaped using signal processing software for the listeners with SNHL to mimic gain provided by an appropriately-fitting hearing aid. Results: Listeners with SNHL had a steeper rate of decreasing vowel identification with decreasing slice duration as compared to listeners with normal hearing, and the listeners with SNHL showed different patterns of vowel identification across vowels when compared to listeners with normal hearing. Conclusion: Abnormal temporal integration is likely affecting vowel identification for listeners with SNHL, which in turn affects vowel internal representation at different levels of the auditory system.

Sensory systems function most efficiently when processing natural stimuli, such as vocalizations, and it is thought that this reflects evolutionary adaptation. Among the best-described examples of evolutionary adaptation in the auditory system are the frequent matches between spectral tuning in both the peripheral and central auditory systems of anurans (frogs and toads) and the frequency spectra of conspecific calls. Tuning to the temporal properties of conspecific calls is less well established, and in anurans has so far been documented only in the central auditory system. Using auditory evoked potentials, we asked whether there are species-specific or sex-specific adaptations of the auditory systems of gray treefrogs (Hyla chrysoscelis) and green treefrogs (H. cinerea) to the temporal modulations present in conspecific calls. Modulation rate transfer functions (MRTFs) constructed from auditory stead-state responses (ASSRs) revealed that each species was more sensitive than the other to the modulation rates typical of conspecific advertisement calls. In addition, auditory brainstem responses (ABRs) to paired-clicks indicated relatively better temporal resolution in green treefrogs, which could represent an adaptation to the faster modulation rates present in this species' calls. MRTFs and recovery of ABRs to paired-clicks were generally similar between the sexes, and we found no evidence that males were more sensitive than females to the temporal modulation patterns characteristic of the aggressive calls used in male-male competition. Together, our results suggest that efficient processing of the temporal properties of behaviorally relevant sounds begins at potentially very early stages of the anuran auditory system that include the periphery.

This study measured listener sensitivity to increments of a target inter-onset interval (IOI) embedded within tone sequences that featured different rhythmic patterns. The sequences consisted of six 50-ms 1000-Hz tone bursts separated by silent intervals that were adjusted to create different timing patterns. Control sequences were isochronous, with all tonal IOIs fixed at either 200 or 400 ms, while other patterns featured combinations of the two IOIs arranged to create different sequential tonal groupings. Duration difference limens in milliseconds for increments of a single sequence IOI were measured adaptively by adjusting the duration of an inter-tone silent interval. Specific target IOIs within sequences differed across discrimination conditions. Listeners included younger normal-hearing adults and groups of older adults with and without hearing loss. Discrimination performance measured for each of the older groups of listeners was observed to be equivalent, with each group exhibiting significantly poorer discrimination performance than the younger listeners in each sequence condition. Additionally, the specific influence of variable rhythmic grouping on temporal sensitivity was found to be greatest among older listeners.

Connexin26 (Cx26, GJB2) mutations account for >50% of nonsyndromic hearing loss. The deafness is not always congenital. A large group of these patients (∼30%) demonstrate a late-onset hearing loss, starting in childhood. They have normal hearing early in life and are therefore good candidates for applying protective and therapeutic interventions. However, the underlying deafness mechanism is unclear. In this study, we used a time-controlled, inducible gene knockout technique to knockout Cx26 expression in the cochlea after birth. We found that deletion of Cx26 after postnatal day 5 (P5) in mice could lead to late-onset hearing loss. Similar to clinical observations, the mice demonstrated progressive, mild to moderate hearing loss. The hearing loss initiated at high frequencies and then extended to the middle- and low-frequency range. The cochlea showed normal development and had no apparent hair cell loss. However, distortion product otoacoustic emission (DPOAE) was reduced. The reduction was also progressive and large at high-frequencies. Consistent with DPOAE reduction, we found that outer hair cell electromotility-associated nonlinear capacitance was shifted to the right and the slope of voltage dependence was reduced. The endocochlear potential was reduced in Cx26 conditional knockout (cKO) mice but the reduction was not associated with progressive hearing loss. These data suggest that Cx26 deficiency may impair active cochlear amplification leading to late-onset hearing loss. Our study also helps develop newer protective and therapeutic interventions to this common nonsyndromic hearing loss.

Field potentials (FPs) recorded within the brain, often called “local field potentials” (LFPs), are useful measures of net synaptic activity in a neuronal ensemble. However, due to volume conduction, FPs spread beyond regions of underlying synaptic activity, and thus an “LFP” signal may not accurately reflect the temporal patterns of synaptic activity in the immediately surrounding neuron population. To better understand the physiological processes reflected in FPs, we explored the relationship between the FP and its membrane current generators using current source density (CSD) analysis in conjunction with a volume conductor model. The model provides a quantitative description of the spatiotemporal summation of immediate local and more distant membrane currents to produce the FP. By applying the model to FPs in the macaque auditory cortex, we have investigated a critical issue that has broad implications for FP research. We have shown that FP responses in particular cortical layers are differentially susceptible to activity in other layers. Activity in the supragranular layers has the strongest contribution to FPs in other cortical layers, and infragranular FPs are most susceptible to contributions from other layers. To define the physiological processes generating FPs recorded in loci of relatively weak synaptic activity, strong effects produced by synaptic events in the vicinity have to be taken into account. While outlining limitations and caveats inherent to FP measurements, our results also suggest specific peak and frequency band components of FPs can be related to activity in specific cortical layers. These results may help improving the interpretability of FPs.

Sleep entails a disconnection from the external environment. By and large, sensory stimuli do not trigger behavioral responses and are not consciously perceived as they usually are in wakefulness. Traditionally, sleep disconnection was ascribed to a thalamic "gate," which would prevent signal propagation along ascending sensory pathways to primary cortical areas. Here, we compared single-unit and LFP responses in core auditory cortex as freely moving rats spontaneously switched between wakefulness and sleep states. Despite robust differences in baseline neuronal activity, both the selectivity and the magnitude of auditory-evoked responses were comparable across wakefulness, Nonrapid eye movement (NREM) and rapid eye movement (REM) sleep (pairwise differences <8% between states). The processing of deviant tones was also compared in sleep and wakefulness using an oddball paradigm. Robust stimulus-specific adaptation (SSA) was observed following the onset of repetitive tones, and the strength of SSA effects (13-20%) was comparable across vigilance states. Thus, responses in core auditory cortex are preserved across sleep states, suggesting that evoked activity in primary sensory cortices is driven by external physical stimuli with little modulation by vigilance state. We suggest that sensory disconnection during sleep occurs at a stage later than primary sensory areas.

We have previously hypothesized that the reason why physical activity increases precursor cell proliferation in adult neurogenesis is that movement serves as non-specific signal to evoke the alertness required to meet cognitive demands. Thereby a pool of immature neurons is generated that are potentially recruitable by subsequent cognitive stimuli. Along these lines, we here tested whether auditory stimuli might exert a similar non-specific effect on adult neurogenesis in mice. We used the standard noise level in the animal facility as baseline and compared this condition to white noise, pup calls, and silence. In addition, as patterned auditory stimulus without ethological relevance to mice we used piano music by Mozart (KV 448). All stimuli were transposed to the frequency range of C57BL/6 and hearing was objectified with acoustic evoked potentials. We found that except for white noise all stimuli, including silence, increased precursor cell proliferation (assessed 24 h after labeling with bromodeoxyuridine, BrdU). This could be explained by significant increases in BrdU-labeled Sox2-positive cells (type-1/2a). But after 7 days, only silence remained associated with increased numbers of BrdU-labeled cells. Compared to controls at this stage, exposure to silence had generated significantly increased numbers of BrdU/NeuN-labeled neurons. Our results indicate that the unnatural absence of auditory input as well as spectrotemporally rich albeit ethological irrelevant stimuli activate precursor cells-in the case of silence also leading to greater numbers of newborn immature neurons-whereas ambient and unstructured background auditory stimuli do not.

Neurobiological theories of memory posit that the neocortex is a storage site of declarative memories, a hallmark of which is the association of two arbitrary neutral stimuli. Early sensory cortices, once assumed uninvolved in memory storage, recently have been implicated in associations between neutral stimuli and reward or punishment. We asked whether links between neutral stimuli also could be formed in early visual or auditory cortices. Rats were presented with a tone paired with a light using a sensory preconditioning paradigm that enabled later evaluation of successful association. Subjects that acquired this association developed enhanced sound evoked potentials in their primary and secondary visual cortices. Laminar recordings localized this potential to cortical Layers 5 and 6. A similar pattern of activation was elicited by microstimulation of primary auditory cortex in the same subjects, consistent with a cortico-cortical substrate of association. Thus, early sensory cortex has the capability to form neutral stimulus associations. This plasticity may constitute a declarative memory trace between sensory cortices.

Behavioral improvement within the first hour of training is commonly explained as procedural learning (i.e., strategy changes resulting from task familiarization). However, it may additionally reflect a rapid adjustment of the perceptual and/or attentional system in a goal-directed task. In support of this latter hypothesis, we show feature-specific gains in performance for groups of participants briefly trained to use either a spectral or spatial difference between 2 vowels presented simultaneously during a vowel identification task. In both groups, the neuromagnetic activity measured during the vowel identification task following training revealed source activity in auditory cortices, prefrontal, inferior parietal, and motor areas. More importantly, the contrast between the 2 groups revealed a striking double dissociation in which listeners trained on spectral or spatial cues showed higher source activity in ventral ("what") and dorsal ("where") brain areas, respectively. These feature-specific effects indicate that brief training can implicitly bias top-down processing to a trained acoustic cue and induce a rapid recalibration of the ventral and dorsal auditory streams during speech segregation and identification.