Auditory Research publications

The auditory system relies on extraordinarily precise timing cues for the accurate perception of speech, music, and object identification. Epidemiological research has documented the age-related progressive decline in hearing sensitivity that is known to be a major health concern for the elderly. Although smaller investigations indicate that auditory temporal processing also declines with age, such measures have not been included in larger studies. Temporal gap detection thresholds (TGDTs; an index of auditory temporal resolution) measured in 1071 listeners (aged 18-98 years) were shown to decline at a minimum rate of 1.05 ms (15%) per decade. Age was a significant predictor of TGDT when controlling for audibility (partial correlation) and when restricting analyses to persons with normal-hearing sensitivity (n = 434). The TGDTs were significantly better for males (3.5 ms; 51%) than females when averaged across the life span. These results highlight the need for indices of temporal processing in diagnostics, as treatment targets, and as factors in models of aging.

The C57BL/6J (B6) mouse strain carries a cadherin 23 mutation (Cdh23(753A), also known as Ahl), which affects inner ear structures and results in age-related hearing loss. The B6.CAST strain harbors the wild type Cdh23 gene, and hence, the influence of Ahl is absent. The purpose of the present study was to characterize the effect of age and gender on gravity receptor function in B6 and B6.CAST strains and to compare functional aging between auditory and vestibular modalities. Auditory sensitivity declined at significantly faster rates than gravity receptor sensitivity for both strains. Indeed, vestibular functional aging was minimal for both strains. The comparatively smaller loss of macular versus cochlear sensitivity in both the B6 and B6.CAST strains suggests that the contribution of Ahl to the aging of the vestibular system is minimal, and thus very different than its influence on aging of the auditory system. Alternatively, there exist unidentified genes or gene modifiers that serve to slow the degeneration of gravity receptor structures and maintain gravity receptor sensitivity into advanced age.

In adult animals, the neuropeptide calcitonin gene‐related peptide ( CGRP ) is contained in cochlear efferent fibers projecting out to the cochlea, and contributes to increased suprathreshold sound‐evoked activity in the adult auditory nerve. Similarly, CGRP applied to the lateral‐line organ (hair cell organ) increases afferent nerve activity in adult frogs (post‐metamorphic day 30), yet this increase is developmentally delayed from post‐metamorphic day 4–30. In this study, we discovered that there was also a developmental delay in increased suprathreshold sound‐evoked activity auditory nerve between juvenile and adult mice similar to what had been observed previously in frog. Moreover, juvenile mice with a targeted deletion of the α CGRP gene [ CGRP null (−/−)] did not show a similar developmental increase in nerve activity, suggesting CGRP signaling is involved. This developmental delay is not due to a delay in CGRP expression, but instead is due to a delay in receptor formation. We observed that the increase in sound‐evoked nerve activity is correlated with increased formation of cochlear CGRP receptors, which require three complexed proteins ( CLR , RAMP 1, RCP ) to be functional. CGRP receptor formation in the cochlea was incomplete at 1 month of age (juvenile), but complete by 3 months (adult), which corresponded to the onset of suprathreshold enhancement of sound‐evoked activity in wild‐type animals. Taken together, these data support a model for cochlear function that is enhanced by maturation of CGRP receptor complexes.

Cochlear implants (CIs) provide children with access to speech information from a young age. Despite bilateral cochlear implantation becoming common, use of spatial cues in free field is smaller than in normal-hearing children. Clinically fit CIs are not synchronized across the ears; thus binaural experiments must utilize research processors that can control binaural cues with precision. Research to date has used single pairs of electrodes, which is insufficient for representing speech. Little is known about how children with bilateral CIs process binaural information with multi-electrode stimulation. Toward the goal of improving binaural unmasking of speech, this study evaluated binaural unmasking with multi- and single-electrode stimulation. Results showed that performance with multi-electrode stimulation was similar to the best performance with single-electrode stimulation. This was similar to the pattern of performance shown by normal-hearing adults when presented an acoustic CI simulation. Diotic and dichotic signal detection thresholds of the children with CIs were similar to those of normal-hearing children listening to a CI simulation. The magnitude of binaural unmasking was not related to whether the children with CIs had good interaural time difference sensitivity. Results support the potential for benefits from binaural hearing and speech unmasking in children with bilateral CIs.

Precise temporal coding is necessary for proper acoustic analysis. However, at cortical level, forward suppression appears to limit the ability of neurons to extract temporal information from natural sound sequences. Here we studied how temporal processing can be maintained in the bats’ cortex in the presence of suppression evoked by natural echolocation streams that are relevant to the bats’ behavior. We show that cortical neurons tuned to target-distance actually profit from forward suppression induced by natural echolocation sequences. These neurons can more precisely extract target distance information when they are stimulated with natural echolocation sequences than during stimulation with isolated call-echo pairs. We conclude that forward suppression does for time domain tuning what lateral inhibition does for selectivity forms such as auditory frequency tuning and visual orientation tuning. When talking about cortical processing, suppression should be seen as a mechanistic tool rather than a limiting element.

Many postnatal onset neurological disorders such as autism spectrum disorders (ASDs) and intellectual disability are thought to arise largely from disruption of excitatory/inhibitory homeostasis. Although mouse models of Rett syndrome (RTT), a postnatal neurological disorder caused by loss-of-function mutations in MECP2, display impaired excitatory neurotransmission, the RTT phenotype can be largely reproduced in mice simply by removing MeCP2 from inhibitory GABAergic neurons. To determine what role excitatory signaling impairment might play in RTT pathogenesis, we generated conditional mouse models with Mecp2 either removed from or expressed solely in glutamatergic neurons. MeCP2 deficiency in glutamatergic neurons leads to early lethality, obesity, tremor, altered anxiety-like behaviors, and impaired acoustic startle response, which is distinct from the phenotype of mice lacking MeCP2 only in inhibitory neurons. These findings reveal a role for excitatory signaling impairment in specific neurobehavioral abnormalities shared by RTT and other postnatal neurological disorders.

The degree of order versus randomness in mammalian cortical circuits has been the subject of much discussion. Previous reports showed that at a large scale there is smooth tonotopy in mouse auditory cortex, while at the single neuron level the representation is the traditional “salt and pepper” configuration attributed to rodent cortex. Here we show that at the micro columnar scale we find a large variety of response profiles, but neurons tend to share similar preference in terms of frequency, bandwidth and latency. However, this smooth representation was fractured and large differences were possible between neighbouring neurons. Despite the tendency of most groups of neurons to operate redundantly, high information gains were achieved between cells that had a high signal correlation. Connectivity between neurons was highly non-random, in agreement with a previous in-vitro report from layer five. Our results suggest the existence of functional clusters, connecting neighbouring mini-columns. This supports the idea of a “salt and pepper” configuration at the level of functional clusters of neurons rather than single units.

Sound-source localization in the horizontal plane relies on detecting small differences in the timing and level of the sound at the two ears, including differences in the timing of the modulated envelopes of high-frequency sounds (envelope interaural time differences (ITDs)). We investigated responses of single neurons in the inferior colliculus (IC) to a wide range of envelope ITDs and stimulus envelope shapes. By a novel means of visualizing neural activity relative to different portions of the periodic stimulus envelope at each ear, we demonstrate the role of neuron-specific excitatory and inhibitory inputs in creating ITD sensitivity (or the lack of it) depending on the specific shape of the stimulus envelope. The underlying binaural brain circuitry and synaptic parameters were modeled individually for each neuron to account for neuron-specific activity patterns. The model explains the effects of envelope shapes on sensitivity to envelope ITDs observed in both normal-hearing listeners and in neural data, and has consequences for understanding how ITD information in stimulus envelopes might be maximized in users of bilateral cochlear implants-for whom ITDs conveyed in the stimulus envelope are the only ITD cues available.

Key points Lateral superior olive (LSO) principal neurons receive AMPA receptor (AMPAR) ‐ and NMDA receptor (NMDAR)‐mediated EPSCs and glycinergic IPSCs. Both EPSCs and IPSCs have slow kinetics in prehearing animals, which during developmental maturation accelerate to sub‐millisecond decay time‐constants. This correlates with a change in glutamate and glycine receptor subunit composition quantified via mRNA levels. The NMDAR‐EPSCs accelerate over development to achieve decay time‐constants of 2.5 ms. This is the fastest NMDAR‐mediated EPSC reported. Acoustic trauma (AT, loud sounds) slow AMPAR‐EPSC decay times, increasing GluA1 and decreasing GluA4 mRNA. Modelling of interaural intensity difference suggests that the increased EPSC duration after AT shifts interaural level difference to the right and compensates for hearing loss. Two months after AT the EPSC decay times recovered to control values. Synaptic transmission in the LSO matures by postnatal day 20, with EPSCs and IPSCs having fast kinetics. AT changes the AMPAR subunits expressed and slows the EPSC time‐course at synapses in the central auditory system. Abstract Damaging levels of sound (acoustic trauma, AT) diminish peripheral synapses, but what is the impact on the central auditory pathway? Developmental maturation of synaptic function and hearing were characterized in the mouse lateral superior olive (LSO) from postnatal day 7 (P7) to P96 using voltage‐clamp and auditory brainstem responses. IPSCs and EPSCs show rapid acceleration during development, so that decay kinetics converge to similar sub‐millisecond time‐constants (τ, 0.87 ± 0.11 and 0.77 ± 0.08 ms, respectively) in adult mice. This correlated with LSO mRNA levels for glycinergic and glutamatergic ionotropic receptor subunits, confirming a switch from Glyα2 to Glyα1 for IPSCs and increased expression of GluA3 and GluA4 subunits for EPSCs. The NMDA receptor (NMDAR)‐EPSC decay τ accelerated from >40 ms in prehearing animals to 2.6 ± 0.4 ms in adults, as GluN2C expression increased. In vivo induction of AT at around P20 disrupted IPSC and EPSC integration in the LSO, so that 1 week later the AMPA receptor (AMPAR)‐EPSC decay was slowed and mRNA for GluA1 increased while GluA4 decreased. In contrast, GlyR IPSC and NMDAR‐EPSC decay times were unchanged. Computational modelling confirmed that matched IPSC and EPSC kinetics are required to generate mature interaural level difference functions, and that longer‐lasting EPSCs compensate to maintain binaural function with raised auditory thresholds after AT. We conclude that LSO excitatory and inhibitory synaptic drive matures to identical time‐courses, that AT changes synaptic AMPARs by expression of subunits with slow kinetics (which recover over 2 months) and that loud sounds reversibly modify excitatory synapses in the brain, changing synaptic function for several weeks after exposure.

Hair cells (HCs) are mechanosensors that play crucial roles in perceiving sound, acceleration, and fluid motion. The precise architecture of the auditory epithelium and its repair after HC loss is indispensable to the function of organ of Corti (OC). In this study, we showed that Brg1 was highly expressed in auditory HCs. Specific deletion of Brg1 in postnatal HCs resulted in rapid HC degeneration and profound deafness in mice. Further experiments showed that cell-intrinsic polarity of HCs was abolished, docking of outer hair cells (OHCs) by Deiter’s cells (DCs) failed, and scar formation in the reticular lamina was deficient. We demonstrated that Brg1 ablation disrupted the Gαi/Insc/LGN and aPKC asymmetric distributions, without overt effects on the core planer cell polarity (PCP) pathway. We also demonstrated that Brg1-deficient HCs underwent apoptosis, and that leakage in the reticular lamina caused by deficient scar formation shifted the mode of OHC death from apoptosis to necrosis. Together, these data demonstrated a requirement for Brg1 activity in HC development and suggested a role for Brg1 in the proper cellular structure formation of HCs.

Acoustic overstimulation traumatizes the cochlea, resulting in auditory dysfunction. As a consequence of acoustic injury, the immune system in the cochlea is activated, leading to the production of inflammatory mediators and the infiltration of immune cells. However, the molecular mechanisms responsible for initiating these immune responses remain unclear. Here, we investigate the functional role of Toll-like receptor 4 (Tlr4), a cellular receptor that activates the innate immune system, in the regulation of cochlear responses to acoustic overstimulation. Using a Tlr4 knockout mouse model, we examined how Tlr4 deficiency affects sensory cell pathogenesis, auditory dysfunction and cochlear immune activity. We demonstrate that Tlr4 knockout does not affect sensory cell viability under physiological conditions, but reduces the level of sensory cell damage and cochlear dysfunction after acoustic injury. Together, these findings suggest that Tlr4 promotes sensory cell degeneration and cochlear dysfunction after acoustic injury. Acoustic injury provokes a site-dependent inflammatory response in both the organ of Corti and the tissues of the lateral wall and basilar membrane. Tlr4 deficiency affects these inflammatory responses in a site-dependent manner. In the organ of Corti, loss of Tlr4 function suppresses the production of interleukin 6 (Il6), a pro-inflammatory molecule, after acoustic injury. By contrast, the production of inflammatory mediators, including Il6, persists in the lateral wall and basilar membrane. In addition to immune molecules, Tlr4 knockout inhibits the expression of major histocompatibility complex class II, an antigen-presenting molecule, in macrophages, suggesting that Tlr4 participates in the antigen-presenting function of macrophages after acoustic trauma. Together, these results suggest that Tlr4 regulates multiple aspects of the immune response in the cochlea and contributes to cochlear pathogenesis after acoustic injury.

The harmonic structure of sounds is an important grouping cue in auditory scene analysis. The ability of ferrets to detect mistuned harmonics was measured using a go/no-go task paradigm. Psychometric functions plotting sensitivity as a function of degree of mistuning were used to evaluate behavioral performance using signal detection theory. The mean (± standard error of the mean) threshold for mistuning detection was 0.8 ± 0.1 Hz, with sensitivity indices and reaction times depending on the degree of mistuning. These data provide a basis for investigation of the neural basis for the perception of complex sounds in ferrets, an increasingly used animal model in auditory research.

Purpose Natural speech comes with variation in pitch, which serves as an important cue for speech recognition. The present study investigated older listeners' dynamic pitch perception with a focus on interindividual variability. In particular, we asked whether some of the older listeners' inability to perceive dynamic pitch stems from the higher susceptibility to the interference from formant changes. Method A total of 22 older listeners and 21 younger controls with at least near-typical hearing were tested on dynamic pitch identification and discrimination tasks using synthetic monophthong and diphthong vowels. Results The older listeners' ability to detect changes in pitch varied substantially, even when musical and linguistic experiences were controlled. The influence of formant patterns on dynamic pitch perception was evident in both groups of listeners. Overall, strong pitch contours (i.e., more dynamic) were perceived better than weak pitch contours (i.e., more monotonic), particularly with rising pitch patterns. Conclusions The findings are in accordance with the literature demonstrating some older individuals' difficulty perceiving dynamic pitch cues in speech. Moreover, they suggest that this problem may be prominent when the dynamic pitch is carried by natural speech and when the pitch contour is not strong.

In this study of visual (V-only) and audiovisual (AV) speech recognition in adults aged 22-92 years, the rate of age-related decrease in V-only performance was more than twice that in AV performance. Both auditory-only (A-only) and V-only performance were significant predictors of AV speech recognition, but age did not account for additional (unique) variance. Blurring the visual speech signal decreased speech recognition, and in AV conditions involving stimuli associated with equivalent unimodal performance for each participant, speech recognition remained constant from 22 to 92 years of age. Finally, principal components analysis revealed separate visual and auditory factors, but no evidence of an AV integration factor. Taken together, these results suggest that the benefit that comes from being able to see as well as hear a talker remains constant throughout adulthood and that changes in this AV advantage are entirely driven by age-related changes in unimodal visual and auditory speech recognition. (PsycINFO Database Record

Hearing impairment is the most common sensory deficit. It is frequently caused by the expression of an allele carrying a single dominant missense mutation. Herein, we show that a single intracochlear injection of an artificial microRNA carried in a viral vector can slow progression of hearing loss for up to 35 weeks in the Beethoven mouse, a murine model of non-syndromic human deafness caused by a dominant gain-of-function mutation in Tmc1 (transmembrane channel-like 1). This outcome is noteworthy because it demonstrates the feasibility of RNA-interference-mediated suppression of an endogenous deafness-causing allele to slow progression of hearing loss. Given that most autosomal-dominant non-syndromic hearing loss in humans is caused by this mechanism of action, microRNA-based therapeutics might be broadly applicable as a therapy for this type of deafness.

Age-related hearing loss (ARHL), clinically referred to as presbycusis, is one of the three most prevalent chronic medical conditions of our elderly, with the majority of persons over the age of 60 suffering from some degree of ARHL. The progressive loss of auditory sensitivity and perceptual capability results in significant declines in workplace productivity, quality of life, cognition and abilities to communicate effectively. Aldosterone is a mineralocorticoid hormone produced in the adrenal glands and plays a role in the maintenance of key ion pumps, including the Na-K(+)-Cl co-transporter 1 or NKCC1, which is involved in homeostatic maintenance of the endocochlear potential. Previously we reported that aldosterone (1 μM) increases NKCC1 protein expression in vitro and that this up-regulation of NKCC1 was not dose-dependent (dosing range from 1 nM to 100 μM). In the current study we measured behavioral and electrophysiological hearing function in middle-aged mice following long-term systemic treatment with aldosterone. We also confirmed that blood pressure remained stable during treatment and that NKCC1 protein expression was upregulated. Pre-pulse inhibition of the acoustic startle response was used as a functional measure of hearing, and the auditory brainstem response was used as an objective measure of peripheral sensitivity. Long-term treatment with aldosterone improved both behavioral and physiological measures of hearing (ABR thresholds). These results are the first to demonstrate a protective effect of aldosterone on age-related hearing loss and pave the way for translational drug development, using aldosterone as a key component to prevent or slow down the progression of ARHL.

Accurate sound source localization of low-frequency sounds in the horizontal plane depends critically on the comparison of arrival times at both ears. A specialized brainstem circuit containing the principal neurons of the medial superior olive (MSO) is dedicated to this comparison. MSO neurons are innervated by segregated inputs from both ears. The coincident arrival of excitatory inputs from both ears is thought to trigger action potentials, with differences in internal delays creating a unique sensitivity to interaural time differences (ITDs) for each cell. How the inputs from both ears are integrated by the MSO neurons is still debated. Using juxtacellular recordings, we tested to what extent MSO neurons from anesthetized Mongolian gerbils function as simple cross-correlators of their bilateral inputs. From the measured subthreshold responses to monaural wideband stimuli we predicted the rate-ITD functions obtained from the same MSO neuron, which have a damped oscillatory shape. The rate of the oscillations and the position of the peaks and troughs were accurately predicted. The amplitude ratio between dominant and secondary peaks of the rate-ITD function, captured in the width of its envelope, was not always exactly reproduced. This minor imperfection pointed to the methodological limitation of using a linear representation of the monaural inputs, which disregards any temporal sharpening occurring in the cochlear nucleus. The successful prediction of the major aspects of rate-ITD curves supports a simple scheme in which the ITD sensitivity of MSO neurons is realized by the coincidence detection of excitatory monaural inputs.

Temporal envelope processing is critical for speech comprehension, which is known to be affected by normal aging. Whereas the macaque is an excellent animal model for human cerebral cortical function, few studies have investigated neural processing in the auditory cortex of aged, nonhuman primates. Therefore, we investigated age-related changes in the spiking activity of neurons in primary auditory cortex (A1) of two aged macaque monkeys using amplitude-modulated (AM) noise and compared these responses with data from a similar study in young monkeys (Yin P, Johnson JS, O'Connor KN, Sutter ML. J Neurophysiol 105: 582–600, 2011). For each neuron, we calculated firing rate (rate code) and phase-locking using phase-projected vector strength (temporal code). We made several key findings where neurons in old monkeys differed from those in young monkeys. Old monkeys had higher spontaneous and driven firing rates, fewer neurons that synchronized with the AM stimulus, and fewer neurons that had differential responses to AM stimuli with both a rate and temporal code. Finally, whereas rate and temporal tuning functions were positively correlated in young monkeys, this relationship was lost in older monkeys at both the population and single neuron levels. These results are consistent with considerable evidence from rodents and primates of an age-related decrease in inhibition throughout the auditory pathway. Furthermore, this dual coding in A1 is thought to underlie the capacity to encode multiple features of an acoustic stimulus. The apparent loss of ability to encode AM with both rate and temporal codes may have consequences for stream segregation and effective speech comprehension in complex listening environments.

The aim of this work was to measure subjective speech intelligibility in an enclosure with a long reverberation time and comparison of these results with objective parameters. Impulse Responses (IRs) were first determined with a dummy head in different measurement points of the enclosure. The following objective parameters were calculated with Dirac 4.1 software: Reverberation Time (RT), Early Decay Time (EDT), weighted Clarity (C 50 ) and Speech Transmission Index (STI). For the chosen measurement points, a convolution of the IRs with the Polish Sentence Test (PST) and logatome tests was made. PST was presented at a background of a babble noise and speech reception threshold - SRT (i.e. SNR yielding 50% speech intelligibility) for those points were evaluated. A relationship of the sentence and logatome recognition vs. STI was determined. It was found that the final SRT data are well correlated with speech transmission index (STI), and can be expressed by a psychometric function. The difference between SRT determined in condition without reverberation and in reverberation conditions appeared to be a good measure of the effect of reverberation on speech intelligibility in a room. In addition, speech intelligibility, with and without use of the sound amplification system installed in the enclosure, was compared.

Recent evidence has shown that noise-induced damage to the synapse between inner hair cells (IHCs) and type I afferent auditory nerve fibers (ANFs) may occur in the absence of permanent threshold shift (PTS), and that synapses connecting IHCs with low spontaneous rate (SR) ANFs are disproportionately affected. Due to the functional importance of low-SR ANF units for temporal processing and signal coding in noisy backgrounds, deficits in cochlear coding associated with noise-induced damage may result in significant difficulties with temporal processing and hearing in noise (i.e., "hidden hearing loss"). However, significant noise-induced coding deficits have not been reported at the single unit level following the loss of low-SR units. We have found evidence to suggest that some aspects of neural coding are not significantly changed with the initial loss of low-SR ANFs, and that further coding deficits arise in association with the subsequent reestablishment of the synapses. This suggests that synaptopathy in hidden hearing loss may be the result of insufficient repair of disrupted synapses, and not simply due to the loss of low-SR units. These coding deficits include decreases in driven spike rate for intensity coding as well as several aspects of temporal coding: spike latency, peak-to-sustained spike ratio and the recovery of spike rate as a function of click-interval.