Auditory Research publications

Plastic change in neuronal connectivity is the foundation of memory encoding. It is not clear whether the changes during anesthesia can alter subsequent behavior. Here, we demonstrated that in male rodents under anesthesia, a visual stimulus (VS) was associated with electrical stimulation of the auditory cortex or natural auditory stimulus in the presence of cholecystokinin (CCK), which guided the animals' behavior in a two-choice auditory task. Auditory neurons became responsive to the VS after the pairings. Moreover, high-frequency stimulation of axon terminals of entorhinal CCK neurons in the auditory cortex enabled LTP of the visual response in the auditory cortex. Such pairing during anesthesia also generated VS-induced freezing in an auditory fear conditioning task. Finally, we verified that direct inputs from the entorhinal CCK neurons and the visual cortex enabled the above neural plasticity in the auditory cortex. Our findings suggest that CCK-enabled visuoauditory association during anesthesia can be translated to the subsequent behavior action. SIGNIFICANCE STATEMENT Our study provides strong evidence for the hypothesis that cholecystokinin plays an essential role in the formation of cross-modal associative memory. Moreover, we demonstrated that an entorhinal–neocortical circuit underlies such neural plasticity, which will be helpful to understand the mechanisms of memory formation and retrieval in the brain.

Lateral olivocochlear (LOC) efferent neurons modulate auditory nerve fiber (ANF) activity using a large repertoire of neurotransmitters, including dopamine (DA) and acetylcholine (ACh). Little is known about how individual neurotransmitter systems are differentially utilized in response to the ever-changing acoustic environment. Here we present quantitative evidence in rodents that the dopaminergic LOC input to ANFs is dynamically regulated according to the animal’s recent acoustic experience. Sound exposure upregulates tyrosine hydroxylase, an enzyme responsible for dopamine synthesis, in cholinergic LOC intrinsic neurons, suggesting that individual LOC neurons might at times co-release ACh and DA. We further demonstrate that dopamine down-regulates ANF firing rates by reducing both the hair cell release rate and the size of synaptic events. Collectively, our results suggest that LOC intrinsic neurons can undergo on-demand neurotransmitter re-specification to re-calibrate ANF activity, adjust the gain at hair cell/ANF synapses, and possibly to protect these synapses from noise damage.

Platinum-based agents, such as cisplatin, form the mainstay of currently used chemotherapeutic regimens for several malignancies; however, the main limitations are chemoresistance and ototoxic side effects. In this study we used two different polyphenols, curcumin and ferulic acid as adjuvant chemotherapeutics evaluating (1) in vivo their antioxidant effects in protecting against cisplatin ototoxicity and (2) in vitro the transcription factors involved in tumor progression and cisplatin resistance. We reported that both polyphenols show antioxidant and oto-protective activity in the cochlea by up-regulating Nrf-2/HO-1 pathway and downregulating p53 phosphorylation. However, only curcumin is able to influence inflammatory pathways counteracting NF-κB activation. In human cancer cells, curcumin converts the anti-oxidant effect into a pro-oxidant and anti-inflammatory one. Curcumin exerts permissive and chemosensitive properties by targeting the cisplatin chemoresistant factors Nrf-2, NF-κB and STAT-3 phosphorylation. Ferulic acid shows a biphasic response: it is pro-oxidant at lower concentrations and anti-oxidant at higher concentrations promoting chemoresistance. Thus, polyphenols, mainly curcumin, targeting ROS-modulated pathways may be a promising tool for cancer therapy. Thanks to their biphasic activity of antioxidant in normal cells undergoing stressful conditions and pro-oxidant in cancer cells, these polyphenols probably engage an interplay among the key factors Nrf-2, NF-κB, STAT-3 and p53.

It has been demonstrated that isolated auditory sensory cells, outer hair cells, can generate distortion products at low frequencies. It remains unknown, however, whether or not motile outer hair cells are able to generate two-tone distortion at high frequencies in living cochleae under the mechanical loads caused by surounding tissues and fluids. By measuring sub-nanometer vibration directly from the apical ends of outer hair cells using a custom-built heterodyne low-coherence interferometer, here we show outer hair cell-generated two-tone distortion in reticular lamina motion in the living cochlea. Reticular-lamina distortion is significantly greater and occurs at a broader frequency range than that of the basilar membrane. Contrary to expectations, our results indicate that motile outer hair cells are capable of generating two-tone distortion in vivo not only at the locations tuned to primary tones but also at a broad region basal to these locations.

Neural adaptation enables sensory information to be represented optimally in the brain despite large fluctuations over time in the statistics of the environment. Auditory contrast gain control represents an important example, which is thought to arise primarily from cortical processing. Here we show that neurons in the auditory thalamus and midbrain of mice show robust contrast gain control, and that this is implemented independently of cortical activity. Although neurons at each level exhibit contrast gain control to similar degrees, adaptation time constants become longer at later stages of the processing hierarchy, resulting in progressively more stable representations. We also show that auditory discrimination thresholds in human listeners compensate for changes in contrast, and that the strength of this perceptual adaptation can be predicted from physiological measurements. Contrast adaptation is therefore a robust property of both the subcortical and cortical auditory system and accounts for the short-term adaptability of perceptual judgments.

Etimicin (ETM), a fourth-generation aminoglycosides (AGs), is now widely clinically used in China due to its high efficacy and low toxicity. However, the mechanisms underlying its low nephrotoxicity and ototoxicity remain unclear. In the present study we compared the antibacterial and toxicity profiles of etimicin, gentamicin (GM, a second-generation AG), and amikacin (AMK, a third-generation AG), and investigated their pharmacokinetic properties in the toxicity target organs (kidney and inner ear) and subcellular compartments. We first demonstrated that ETM exhibited superior antibacterial activities against clinical isolates to GM and AMK, and it exerted minimal nephrotoxicity and ototoxicity in rats following multi-dose administration. Then, we conducted pharmacokinetic studies in rats, showed that the three AGs accumulated in the kidney and inner ear with ETM being distributed to a lesser degree in the two toxicity target organs as compared with GM and AMK high-dose groups. Furthermore, we conducted in vitro experiments in NRK-52E rat renal tubular epithelial cells and HEI-OC1 cochlear hair cells, and revealed that all the three AGs were distributed predominantly in the mitochondria with ETM showing minimal accumulation; they not only directly inhibited the activity of mitochondrial complexes IV and V but also inhibited mitochondrial function and its related PGC-1α-NRF1-TFAM pathway; ETM caused minimal damage to the mitochondrial complex and mitochondrial biogenesis. Our results demonstrate that the minimal otonephrotoxicity of ETM results from its lesser accumulation in mitochondria of target cells and subsequently lesser inhibition of mitochondrial function. These results provide a new strategy for discovering novel AGs with high efficacy and low toxicity.

Parvalbumin-positive (PV+) interneurons are major regulators of adult experience-dependent plasticity. Acute manipulation of PV+ cell activity before learning alters the rate of acquisition of new skills, whereas transient inactivation of PV+ cells interferes with retrieval of previously learned information. However, the effects of sustained PV+ cell manipulation throughout training remain largely unknown. Using chemogenetics in rat auditory cortex during an adaptive sound disrimination task, here we show that PV+ cells exert bidirectional control over the rate of perceptual learning. Down-regulation of PV+ cell activity accelerated learning, but increasing their activity resulted in slower learning. However, both interventions led to reduced gains in perceptual acuity by the end of training relative to controls. Furthermore, longitudinal training performance was functionally correlated with measures of neural synchrony and stimulus-specific adaptation. These findings suggest that, whereas restricting PV+ cell activity may initially facilitate training-induced plasticity, a subsequent increase in PV+ cell activity is necessary to prevent further plastic changes and consolidate learning.

Human perception requires the many-to-one mapping between continuous sensory elements and discrete categorical representations. This grouping operation underlies the phenomenon of categorical perception (CP)-the experience of perceiving discrete categories rather than gradual variations in signal input. Speech perception requires CP because acoustic cues do not share constant relations with perceptual-phonetic representations. Beyond facilitating perception of unmasked speech, we reasoned CP might also aid the extraction of target speech percepts from interfering sound sources (i.e., noise) by generating additional perceptual constancy and reducing listening effort. Specifically, we investigated how noise interference impacts cognitive load and perceptual identification of unambiguous (i.e., categorical) vs. ambiguous stimuli. Listeners classified a speech vowel continuum (/u/-/a/) at various signal-to-noise ratios (SNRs [unmasked, 0 and -5 dB]). Continuous recordings of pupil dilation measured processing effort, with larger, later dilations reflecting increased listening demand. Critical comparisons were between time-locked changes in eye data in response to unambiguous (i.e., continuum endpoints) tokens vs. ambiguous tokens (i.e., continuum midpoint). Unmasked speech elicited faster responses and sharper psychometric functions, which steadily declined in noise. Noise increased pupil dilation across stimulus conditions, but not straightforwardly. Noise-masked speech modulated peak pupil size (i.e., [0 and -5 dB] > unmasked). In contrast, peak dilation latency varied with both token and SNR. Interestingly, categorical tokens elicited earlier pupil dilation relative to ambiguous tokens. Our pupillary data suggest CP reconstructs auditory percepts under challenging listening conditions through interactions between stimulus salience and listeners' internalized effort and/or arousal.

Age-related hearing loss (ARHL) is one of the most common disorders affecting elderly individuals. There is an urgent need for effective preventive measures for ARHL because none are currently available. Cockayne syndrome (CS) is a premature aging disease that presents with progressive hearing loss at a young age, but is otherwise similar to ARHL. There are two human genetic complementation groups of CS, A and B. While the clinical phenotypes in patients are similar, the proteins have very diverse functions, and insight into their convergence is of great interest. Here, we use mouse models for CS ( CSA − /− and CSB m/m ) that recapitulate the hearing loss in human CS patients. We previously showed that NAD + , a key metabolite with various essential functions, is reduced in CS and associated with multiple CS phenotypes. In this study, we report that NAD + levels are reduced in the cochlea of CSB m/m mice and that short-term treatment (10 days) with the NAD + precursor nicotinamide riboside (NR), prevents hearing loss, restores outer hair cell loss, and improves cochlear health in CSB m/m mice. Similar, but more modest effects were observed in CSA − /− mice. Remarkably, we observed a reduction in synaptic ribbon counts in the presynaptic zones of inner hair cells in both CSA −/− and CSB m/m mice, pointing to a converging mechanism for cochlear defects in CS. Ribbon synapses facilitate rapid and sustained synaptic transmission over long periods of time. Ribeye, a core protein of synaptic ribbons, possesses an NAD(H) binding pocket which regulates its activity. Intriguingly, NAD + supplementation rescues reduced synaptic ribbon formation in both CSA −/− and CSB m/m mutant cochleae. These findings provide valuable insight into the mechanism of CS- and ARHL-associated hearing loss, and suggest a possible intervention.

Anurans (frogs and toads) are the most vocal amphibians. In most species, only males produce advertisement calls for defending territories and attracting mates. Female vocalizations are the exceptions among frogs, however in the African clawed frog (Xenopus laevis) both males and females produce distinct vocalizations. The matched filter hypothesis predicts a correspondence between peripheral auditory tuning of receivers and properties of species-specific acoustic signals, but few studies have assessed this relationship between the sexes. Measuring hearing sensitivity with a binaural recording of distortion product otoacoustic emissions, we have found that the ears of the males of this species are tuned to the dominant frequency of the female's calls, whereas the ears of the females are tuned close to the dominant frequency of the male's calls. Our findings provide support for the matched filter hypothesis extended to include male-female calling. This unique example of reciprocal matched filtering ensures that males and females communicate effectively in high levels of background noise, each sex being most sensitive to the frequencies of the other sex's calls.

Background: Digital noise reduction (DNR) processing is used in hearing aids to enhance perception in noise by classifying and suppressing the noise acoustics. However, the efficacy of DNR processing is not known under reverberant conditions where the speech-in-noise acoustics are further degraded by reverberation. Purpose: The purpose of this study was to investigate acoustic and perceptual effects of DNR processing across a range of reverberant conditions for individuals with hearing impairment. Research Design: This study used an experimental design to investigate the effects of varying reverberation on speech-in-noise processed with DNR. Study Sample: Twenty-six listeners with mild-to-moderate sensorineural hearing impairment participated in the study. Data Collection and Analysis: Speech stimuli were combined with unmodulated broadband noise at several signal-to-noise ratios (SNRs). A range of reverberant conditions with realistic parameters were simulated, as well as an anechoic control condition without reverberation. Reverberant speech-in-noise signals were processed using a spectral subtraction DNR simulation. Signals were acoustically analyzed using a phase inversion technique to quantify improvement in SNR as a result of DNR processing. Sentence intelligibility and subjective ratings of listening effort, speech naturalness, and background noise comfort were examined with and without DNR processing across the conditions. Results: Improvement in SNR was greatest in the anechoic control condition and decreased as the ratio of direct to reverberant energy decreased. There was no significant effect of DNR processing on speech intelligibility in the anechoic control condition, but there was a significant decrease in speech intelligibility with DNR processing in all of the reverberant conditions. Subjectively, listeners reported greater listening effort and lower speech naturalness with DNR processing in some of the reverberant conditions. Listeners reported higher background noise comfort with DNR processing only in the anechoic control condition. Conclusions: Results suggest that reverberation affects DNR processing using a spectral subtraction algorithm in such a way that decreases the ability of DNR to reduce noise without distorting the speech acoustics. Overall, DNR processing may be most beneficial in environments with little reverberation and that the use of DNR processing in highly reverberant environments may actually produce adverse perceptual effects. Further research is warranted using commercial hearing aids in realistic reverberant environments.

Diving birds spend up to several minutes underwater during pursuit-dive foraging. To find and capture prey, like fish and squid, they probably need several senses in addition to vision. Cormorants, very efficient predators of fishes, have unexpectedly low visual acuity underwater. So, underwater hearing may be an important sense, as for other diving animals. We measured auditory thresholds and eardrum vibrations in air and underwater of the great cormorant (Phalacrocorax carbo sinensis). Wild-caught cormorant fledglings were anesthetized, and their auditory brainstem response (ABR) and eardrum vibrations to clicks and tone bursts were measured, first in an anechoic box in air and then in a large water-filled tank, with their head and ears submerged 10 cm below the surface. Both the ABR-response waveshape and latency, as well as the ABR-thresholds, measured in units of sound pressure, were similar in air and water. The best average sound pressure sensitivity was found at 1 kHz, both in air (53 dB re. 20 µPa) and underwater (58 dB re. 20 µPa). When thresholds were compared in units of intensity, however, the sensitivity underwater was higher than in air. Eardrum vibration amplitudes in both media reflected the ABR-threshold curves. These results suggest that cormorants have in-air hearing abilities comparable to similar-sized diving birds, and that their underwater hearing sensitivity is at least as good as their aerial sensitivity. This together with the morphology of the outer ear (collapsible meatus) and middle ear (thickened eardrum), suggest that cormorants may have anatomical and physiological adaptations for amphibious hearing.

Hypothesis: Local administration of the calcium-channel blocker (CCB), diltiazem, via intratympanic (IT) chitosan-glycerophosphate (CGP) hydrogel will protect against cisplatin-induced ototoxicity. Background: Cisplatin induces calcium-mediated apoptosis of cochlear outer hair cells (OHCs). Previous work demonstrated otoprotection and reduced auditory brainstem response (ABR) threshold shifts in a cisplatin-induced ototoxicity mouse model treated with multiple doses of IT diltiazem given in solution. Here, we evaluated the role of a single dose of IT CGP-diltiazem as a novel otoprotectant against cisplatin-induced ototoxicity. Methods: Baseline pure-tone and click-evoked ABRs were performed in control (IT CGP-saline, n = 13) and treatment (IT CGP-diltiazem 2 mg/kg, n = 9) groups of female CBA/J mice. A single dose of IT CGP hydrogel was administered just before intraperitoneal injection of cisplatin (14 mg/kg). On Day 7 posttreatment, ABRs were performed and cochleae were harvested. Hair cells were quantified using anti-myosin VIIa immunostaining and inner hair cell ribbon synapses were quantified using Ctbp2 immunostaining. Results: There was a statistically significant effect of treatment on click- and tone-evoked ABRs between groups. The mean threshold shifts were significantly reduced in both click- and tone-evoked ABRs on Day 7 in IT CGP-diltiazem treated mice compared with CGP-saline control mice. There were no significant differences in OHC counting between groups, but there appears to be an otoprotection against loss of synapses in the apical turn from IT CGP-diltiazem treated mice ( p < 0.05). Conclusions: This preliminary work suggests that IT CGP-diltiazem reduces ABR threshold shifts with possible mechanisms of protecting ribbon synapses in the setting of cisplatin-induced ototoxicity. More work is necessary to determine the mechanism underlying this otoprotection.

Focused attention on expected voice features, such as fundamental frequency (F0) and spectral envelope, may facilitate segregation and selection of a target talker in competing talker backgrounds. Age-related declines in attention may limit these abilities in older adults, resulting in poorer speech understanding in complex environments. To test this hypothesis, younger and older adults with normal hearing listened to sentences with a single competing talker. For most trials, listener attention was directed to the target by a cue phrase that matched the target talker’s F0 and spectral envelope. For a small percentage of randomly occurring probe trials, the target’s voice unexpectedly differed from the cue phrase in terms of F0 and spectral envelope. Overall, keyword recognition for the target talker was poorer for older adults than younger adults. Keyword recognition was poorer on probe trials than standard trials for both groups, and incorrect responses on probe trials contained keywords from the single-talker masker. No interaction was observed between age-group and the decline in keyword recognition on probe trials. Thus, reduced performance by older adults overall could not be attributed to declines in attention to an expected voice. Rather, other cognitive abilities, such as speed of processing and linguistic closure, were predictive of keyword recognition for younger and older adults. Moreover, the effects of age interacted with the sex of the target talker, such that older adults had greater difficulty understanding target keywords from female talkers than male talkers.

Background: Combined electrical-acoustical stimulation (EAS) has gained popularity as patients with residual hearing are increasingly undergoing cochlear implantation. Preservation of residual hearing correlates with hearing outcomes, but loss of hearing occurs in a subset of these patients. Several mechanisms have been proposed as causing this hearing loss; we have previously described high amplitude pressure transients, equivalent to high-level noise exposures, in the inner ear during electrode insertion. The source of these transients has not been identified. Methods: Cadaveric human heads were prepared with an extended facial recess. Fiber-optic pressure sensors were inserted into the scala vestibuli and scala tympani to measure intracochlear pressures. Two cochlear implant (CI) electrode styles (straight and perimodiolar) were inserted during time-synced intracochlear pressures and video fluoroscopy measurements. Results: CI electrode insertions produced pressure transients in the cochlea up to 160 to 170 dB pSPL equivalent for both styles, consistent with previous results. However, the position of the electrode within the cochlea when transients were generated differed (particularly contact with the medial or lateral walls). Conclusions: These results begin to elucidate the insertion pressure profiles of CI electrodes, which can be used to improve CI electrode designs and facilitate “silent-insertions” to improve chances of hearing preservation.

Introduction The vestibular system is essential for normal postural control and balance. Because of their proximity to the cochlea, the otolith organs are vulnerable to noise. We previously showed that head jerks that evoke vestibular nerve activity were no longer capable of inducing a response after noise overstimulation. The present study adds a greater range of jerk intensities to determine if the response was abolished or required more intense stimulation (threshold shift). Materials and Methods Vestibular short-latency evoked potential (VsEP) measurements were taken before noise exposure and compared to repeated measurements taken at specific time points for 28 days after noise exposure. Calretinin was used to identify changes in calyx-only afferents in the sacculus. Results Results showed that more intense jerk stimuli could generate a VsEP, although it was severely attenuated relative to prenoise values. When the VsEP was evaluated 4 weeks after noise exposure, partial recovery was observed. Conclusion These data suggest that noise overstimulation, such as can occur in the military, could introduce an increased risk of imbalance that should be evaluated before returning a subject to situations that require normal agility and motion. Moreover, although there is recovery with time, some dysfunction persists for extended periods.

The perception of spectrotemporal changes is crucial for distinguishing between acoustic signals, including vocalizations. Temporal modulation transfer functions (TMTFs) have been measured in many species and reveal that the discrimination of amplitude modulation suffers at rapid modulation frequencies. TMTFs were measured in six CBA/CaJ mice in an operant conditioning procedure, where mice were trained to discriminate an 800 ms amplitude modulated white noise target from a continuous noise background. TMTFs of mice show a bandpass characteristic, with an upper limit cutoff frequency of around 567 Hz. Within the measured modulation frequencies ranging from 5 Hz to 1280 Hz, the mice show a best sensitivity for amplitude modulation at around 160 Hz. To look for a possible parallel evolution between sound perception and production in living organisms, we also analyzed the components of amplitude modulations embedded in natural ultrasonic vocalizations (USVs) emitted by this strain. We found that the cutoff frequency of amplitude modulation in most of the individual USVs is around their most sensitive range obtained from the psychoacoustic experiments. Further analyses of the duration and modulation frequency ranges of USVs indicated that the broader the frequency ranges of amplitude modulation in natural USVs, the shorter the durations of the USVs.

Speech audiometry in noise based on sentence tests is an important diagnostic tool to assess listeners’ speech recognition threshold (SRT), i.e., the signal-to-noise ratio corresponding to 50% intelligibility. The clinical standard measurement procedure requires a professional experimenter to record and evaluate the response (expert-conducted speech audiometry). The use of automatic speech recognition enables self-conducted measurements with an easy-to-use speech-based interface. This article compares self-conducted SRT measurements using smart speakers with expert-conducted laboratory measurements. With smart speakers, there is no control over the absolute presentation level, potential errors from the automated response logging, and room acoustics. We investigate the differences between highly controlled measurements in the laboratory and smart speaker-based tests for young normal-hearing (NH) listeners as well as for elderly NH, mildly and moderately hearing-impaired listeners in low, medium, and highly reverberant room acoustics. For the smart speaker setup, we observe an overall bias in the SRT result that depends on the hearing loss. The bias ranges from +0.7 dB for elderly moderately hearing-impaired listeners to +2.2 dB for young NH listeners. The intrasubject standard deviation is close to the clinical standard deviation (0.57/0.69 dB for the young/elderly NH compared with 0.5 dB observed for clinical tests and 0.93/1.09 dB for the mild/moderate hearing-impaired listeners compared with 0.9 dB). For detecting a clinically elevated SRT, the speech-based test achieves an area under the curve value of 0.95 and therefore seems promising for complementing clinical measurements.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by a progressive loss of memory and cognitive decline. Over the last decade, it has been found that defects in sensory systems could be highly associated with AD. Hearing is an important neural sense. However, little is known about hearing functional changes in AD. In this study, APP/PS1 AD mice (Jackson Lab: Stack No. 004462) were used. Hearing function was assessed by auditory brainstem response (ABR), distortion product otoacoustic emission (DPOAE), and cochlear microphonics (CM) recordings. Wild-type (WT) littermates served as control. We found that APP/PS1 AD mice measured as ABR threshold had hearing loss. The hearing loss appeared at high frequency as early as 2 months old, prior to the reported occurrence of spatial learning deficit at 6-7 months of age in this AD mouse model. The hearing loss was progressive and extended from high frequency to low frequency. At 3-4 months old, the hearing loss appeared in the whole-frequency range. Moreover, the wave IV and V in the super-threshold ABR were eliminated, indicating substantial impairment in inferior colliculus, nuclei of lateral lemniscus, and medial geniculate body in the upper brainstem. DPOAE in APP/PS1 AD mice was also reduced. However, there was no reduction in CM in APP/PS1 mice. These data demonstrate that unlike age-related hearing loss APP/PS1 AD mice have early onset of hearing loss. These data also suggest that hearing function testing could provide a simple, sensitive, non-invasive screen-tool for early detecting AD and localizing lesion.