Auditory Research publications

Cisplatin is used to treat a variety of solid tumors in both children and adults. However, cisplatin has serious side-effects, some of which may permanently affect patients' quality of life following treatment, such as ototoxicity. There is currently no FDA-approved therapy for the prevention or treatment of cisplatin-induced hearing loss. Herein we examine the potential for statins to prevent cisplatin-induced ototoxicity. Statins, a class of drugs commonly used to prevent or manage hypercholesterolemia, have been of clinical utility for decades with dependable outcomes and reliable safety profiles in humans. Statins are known to be protective in animal models of noise-induced and age-related hearing loss. Moreover, studies have demonstrated an additive benefit of statins in cancer treatment. In the current study, lovastatin reduces cisplatin-induced hearing loss in adult mice. Lovastatin-mediated protection was significantly greater among female than male mice, and the dose of lovastatin required for protection was different between the sexes. Taken together our data indicate that lovastatin reduces cisplatin-induced hearing loss in mice and suggest that concurrent statin and cisplatin therapy may represent a feasible clinical strategy for reducing cisplatin-induced ototoxicity that should be explored for future clinical use.

It is commonly assumed that difficulty in listening to speech in noise is at least partly due to deficits in neural temporal processing. Given that noise reduces the temporal fidelity of the auditory brainstem response (ABR) to speech, it has been suggested that the speech ABR may serve as an index of such neural deficits. However, the temporal fidelity of ABRs, to both speech and non-speech sounds, is also known to be influenced by the cochlear origin of the response, as responses from higher-frequency cochlear regions are faster and more synchronous than responses from lower-frequency regions. Thus, if noise caused a reweighting of response contributions from higher- to lower-frequency cochlear regions, the temporal fidelity of the aggregate response should be reduced even in the absence of any changes in neural processing. This ‘place mechanism’ has been demonstrated for non-speech ABRs. The aim of this study was to test whether it also applies to speech ABRs. We used the so-called ‘derived-band’ method to isolate response contributions from frequency-limited cochlear regions. Broadband and derived-band speech ABRs were measured both in quiet and in noise. Whilst the noise caused significant changes to the temporal properties of the broadband response, its effects on the derived-band responses were mostly restricted to the response amplitudes. Importantly, the amplitudes of the higher-frequency derived-band responses were much more strongly affected than those of the lower-frequency responses, suggesting that the noise indeed caused a reweighting effect. Our results indicate that, as for non-speech ABRs, the cochlear place mechanism can represent a potentially substantial confound to speech-ABR-in-noise measurements.

We investigated whether contrast gain control is mediated by shunting inhibition from parvalbumin-positive interneurons in auditory cortex. We performed extracellular and intracellular recordings in mouse auditory cortex while presenting sensory stimuli with varying contrasts and manipulated parvalbumin-positive interneuron activity using optogenetics. We show that while parvalbumin-positive interneuron activity modulates the gain of cortical responses, this activity is not the primary mechanism for contrast gain control in auditory cortex.

Sensory systems integrate multiple stimulus features to generate coherent percepts. Spectral surround suppression, the phenomenon by which sound-evoked responses of auditory neurons are suppressed by stimuli outside their receptive field, is an example of this integration taking place in the auditory system. While this form of global integration is commonly observed in auditory cortical neurons, and potentially used by the nervous system to separate signals from noise, the mechanisms that underlie this suppression of activity are not well understood. We evaluated the contributions to spectral surround suppression of the two most common inhibitory cell types in the cortex, parvalbumin-expressing (PV+) and somatostatin-expressing (SOM + ) interneurons, in mice of both sexes. We found that inactivating SOM + cells, but not PV+ cells, significantly reduces sustained spectral surround suppression in excitatory cells, indicating a dominant causal role for SOM + cells in the integration of information across multiple frequencies. The similarity of these results to those from other sensory cortices provides evidence of common mechanisms across the cerebral cortex for generating global percepts from separate features. SIGNIFICANCE STATEMENT To generate coherent percepts, sensory systems integrate simultaneously occurring features of a stimulus, yet the mechanisms by which this integration occurs are not fully understood. Our results show that neurochemically distinct neuronal subtypes in the primary auditory cortex have different contributions to the integration of different frequency components of an acoustic stimulus. Together with findings from other sensory cortices, our results provide evidence of a common mechanism for cortical computations used for global integration of stimulus features.

Background Ototoxicity is one of the major side effects of platinum-based chemotherapy, especially cisplatin therapy. To date, no FDA approved agents to alleviate or prevent this ototoxicity are available. However, ototoxicity is generally believed to be produced by excessive generation of reactive oxygen species (ROS) in the inner ear, thus leading to the development of various antioxidants, which act as otoprotective agents. Astaxanthin (ATX) is an interesting candidate in the development of new therapies for preventing and treating oxidative stress-related pathologies, owing to its unique antioxidant capacity. Methods and results In this study, we aimed to evaluate the potential antioxidant properties of ATX in the inner ear by using the HEI-OC1 cell line, zebrafish, and guinea pigs. Because ATX has poor solubility and cannot pass through round window membranes (RWM), we established lipid-polymer hybrid nanoparticles (LPN) for loading ATX. The LPN enabled ATX to penetrate RWM and maintain concentrations in the perilymph in the inner ear for 24 h after a single injection. ATX-LPN were found to have favorable biocompatibility and to strongly affect cisplatin-induced generation of ROS, on the basis of DCFHDA staining in HEI-OC1 cells. JC-1 and MitoTracker Green staining suggested that ATX-LPN successfully reversed the decrease in mitochondrial membrane potential induced by cisplatin in vitro and rescued cells from early stages of apoptosis, as demonstrated by FACS stained with Annexin V-FITC/PI. Moreover, ATX-LPN successfully attenuated OHC losses in cultured organ of Corti and animal models (zebrafish and guinea pigs) in vivo. In investigating the protective mechanism of ATX-LPN, we found that ATX-LPN decreased the expression of pro-apoptotic proteins (caspase 3/9 and cytochrome-c) and increased expression of the anti-apoptotic protein Bcl-2. In addition, the activation of JNK induced by CDDP was up-regulated and then decreased after the administration of ATX-LPN, while P38 stayed unchanged. Conclusions To best of our knowledge, this is first study concluded that ATX-LPN as a new therapeutic agent for the prevention of cisplatin-induced ototoxicity.

The cochlea's wave-based signal processing allows it to efficiently decompose a complex acoustic waveform into frequency components. Because cochlear responses are nonlinear, the waves arising from one frequency component of a complex sound can be altered by the presence of others that overlap with it in time and space (e.g., two-tone suppression). Here, we investigate the suppression of basilar-membrane (BM) velocity responses to a transient signal (a test click) by another click or tone. We show that the BM response to the click can be reduced when the stimulus is shortly preceded or followed by another (suppressor) click. More surprisingly, the data reveal two curious dependencies on the interclick interval, Δt. First, the temporal suppression curve (amount of suppression vs. Δt) manifests a pronounced and nearly periodic microstructure. Second, temporal suppression is generally strongest not when the two clicks are presented simultaneously (Δt = 0), but when the suppressor click precedes the test click by a time interval corresponding to one to two periods of the best frequency (BF) at the measurement location. By systematically varying the phase of the suppressor click, we demonstrate that the suppression microstructure arises from alternating constructive and destructive interference between the BM responses to the two clicks. And by comparing temporal and tonal suppression in the same animals, we test the hypothesis that the asymmetry of the temporal-suppression curve around Δt = 0 stems from cochlear dispersion and the well-known asymmetry of tonal suppression around the BF. Just as for two-tone suppression, BM responses to clicks are most suppressed by tones at frequencies just above the BF of the measurement location. On average, the frequency place of maximal suppressibility of the click response predicted from temporal-suppression data agrees with the frequency at which tonal suppression peaks, consistent with our hypothesis.

Hepatocyte growth factor (HGF) is a multifunctional protein that signals through the MET receptor. HGF stimulates cell proliferation, cell dispersion, neuronal survival, and wound healing. In the inner ear, levels of HGF must be fine-tuned for normal hearing. In mice, a deficiency of HGF expression limited to the auditory system, or an overexpression of HGF, causes neurosensory deafness. In humans, noncoding variants in HGF are associated with nonsyndromic deafness DFNB39 . However, the mechanism by which these noncoding variants causes deafness was unknown. Here, we reveal the cause of this deafness using a mouse model engineered with a noncoding intronic 10 bp deletion (del10) in Hgf . Male and female mice homozygous for del10 exhibit moderate-to-profound hearing loss at 4 weeks of age as measured by tone burst auditory brainstem responses. The wild type (WT) 80 mV endocochlear potential was significantly reduced in homozygous del10 mice compared with WT littermates. In normal cochlea, endocochlear potentials are dependent on ion homeostasis mediated by the stria vascularis (SV). Previous studies showed that developmental incorporation of neural crest cells into the SV depends on signaling from HGF/MET. We show by immunohistochemistry that, in del10 homozygotes, neural crest cells fail to infiltrate the developing SV intermediate layer. Phenotyping and RNAseq analyses reveal no other significant abnormalities in other tissues. We conclude that, in the inner ear, the noncoding del10 mutation in Hgf leads to developmental defects of the SV and consequently dysfunctional ion homeostasis and a reduction in the EP, recapitulating human DFNB39 nonsyndromic deafness. SIGNIFICANCE STATEMENT Hereditary deafness is a common, clinically and genetically heterogeneous neurosensory disorder. Previously, we reported that human deafness DFNB39 is associated with noncoding variants in the 3′UTR of a short isoform of HGF encoding hepatocyte growth factor. For normal hearing, HGF levels must be fine-tuned as an excess or deficiency of HGF cause deafness in mouse. Using a Hgf mutant mouse with a small 10 bp deletion recapitulating a human DFNB39 noncoding variant, we demonstrate that neural crest cells fail to migrate into the stria vascularis intermediate layer, resulting in a significantly reduced endocochlear potential, the driving force for sound transduction by inner ear hair cells. HGF-associated deafness is a neurocristopathy but, unlike many other neurocristopathies, it is not syndromic.

The ability to detect short gaps in noise is an important tool for assessing the temporal resolution in the auditory cortex. However, the mere existence of responses to temporal gaps bounded by two short broadband markers is surprising, because of the expected short-term suppression that is prevalent in auditory cortex. Here, we used in-vivo intracellular recordings in anesthetized rats to dissect the synaptic mechanisms that underlie gap-related responses. When a gap is bounded by two short markers, a gap termination response was evoked by the onset of the second marker with minimal contribution from the offset of the first marker. Importantly, we show that the gap termination response was driven by a different (potentially partially overlapping) synaptic population than that underlying the onset response to the first marker. This recruitment of additional synaptic resources is a novel mechanism contributing to the important perceptual task of gap detection.

Lateral posterior nucleus (LP) of thalamus, the rodent homologue of primate pulvinar, projects extensively to sensory cortices. However, its functional role in sensory cortical processing remains largely unclear. Here, bidirectional activity modulations of LP or its projection to the primary auditory cortex (A1) in awake mice reveal that LP improves auditory processing in A1 supragranular-layer neurons by sharpening their receptive fields and frequency tuning, as well as increasing the signal-to-noise ratio (SNR). This is achieved through a subtractive-suppression mechanism, mediated largely by LP-to-A1 axons preferentially innervating specific inhibitory neurons in layer 1 and superficial layers. LP is strongly activated by specific sensory signals relayed from the superior colliculus (SC), contributing to the maintenance and enhancement of A1 processing in the presence of auditory background noise and threatening visual looming stimuli respectively. Thus, a multisensory bottom-up SC-pulvinar-A1 pathway plays a role in contextual and cross-modality modulation of auditory cortical processing.

In macaques, the middle lateral auditory cortex (ML) is a belt region adjacent to primary auditory cortex (A1) and believed to be at a hierarchically higher level. Although ML single-unit responses have been studied for several auditory stimuli, the ability of ML cells to encode amplitude modulation (AM) – an ability which has been widely studied in A1 – has not yet been characterized. Here we compare the responses of A1 and ML neurons to amplitude modulated (AM) noise in awake macaques. While several of the basic properties of A1 and ML responses to AM noise are similar, we found several key differences. ML neurons do not phase lock as strongly, are less likely to phase lock, and are more likely to respond in a non-synchronized fashion than A1 cells, consistent with a temporal-to-rate transformation as information ascends the auditory hierarchy. ML neurons tend to have lower temporally (phase-locking) based best modulation frequencies than A1. At the level of ML, neurons that decrease firing rate with increasing modulation depth become more common than in A1. In both A1 and ML we find a prevalent class of neurons with excitatory rate responses at lower modulation frequencies and suppressed rate responses relative to the unmodulated carrier at middle modulation frequencies.

Tsukushi (TSK)—a small, secreted, leucine-rich-repeat proteoglycan—interacts with and regulates essential cellular signaling cascades. However, its functions in the mouse inner ear are unknown. In this study, measurement of auditory brainstem responses, fluorescence microscopy, and scanning electron microscopy revealed that TSK deficiency in mice resulted in the formation of abnormal stereocilia in the inner hair cells and hearing loss but not in the loss of these cells. TSK accumulated in nonprosensory regions during early embryonic stages and in both nonprosensory and prosensory regions in late embryonic stages. In adult mice, TSK was localized in the organ of Corti, spiral ganglion cells, and the stria vascularis. Moreover, loss of TSK caused dynamic changes in the expression of key genes that drive the differentiation of the inner hair cells in prosensory regions. Finally, our results revealed that TSK interacted with Sox2 and BMP4 to control stereocilia formation in the inner hair cells. Hence, TSK appears to be an essential component of the molecular pathways that regulate inner ear development.

Humans engagement in music rests on underlying elements such as the listeners’ cultural background and interest in music. These factors modulate how listeners anticipate musical events, a process inducing instantaneous neural responses as the music confronts these expectations. Measuring such neural correlates would represent a direct window into high-level brain processing. Here we recorded cortical signals as participants listened to Bach melodies. We assessed the relative contributions of acoustic versus melodic components of the music to the neural signal. Melodic features included information on pitch progressions and their tempo, which were extracted from a predictive model of musical structure based on Markov chains. We related the music to brain activity with temporal response functions demonstrating, for the first time, distinct cortical encoding of pitch and note-onset expectations during naturalistic music listening. This encoding was most pronounced at response latencies up to 350 ms, and in both planum temporale and Heschl’s gyrus.

Nowadays, the majority of the progress in the development of implantable neuroprostheses has been achieved by improving the knowledge of brain functions so as to restore sensorial impairments. Intracortical microstimulation (ICMS) is a widely used technique to investigate site-specific cortical responses to electrical stimuli. Herein, we investigated the neural modulation induced in the primary auditory cortex (A1) by an acousto-electric transduction of ultrasonic signals using a bio-inspired intracortical microstimulator. The developed electronic system emulates the transduction of ultrasound signals in the cochlea, providing bio-inspired electrical stimuli. Firstly, we identified the receptive fields in the primary auditory cortex devoted to encoding ultrasonic waves at different frequencies, mapping each area with neurophysiological patterns. Subsequently, the activity elicited by bio-inspired ICMS in the previously identified areas, bypassing the sense organ, was investigated. The observed evoked response by microstimulation resulted as highly specific to the stimuli, and the spatiotemporal dynamics of neural oscillatory activity in the alpha, beta, and gamma waves were related to the stimuli preferred by the neurons at the stimulated site. The alpha waves modulated cortical excitability only during the activation of the specific tonotopic neuronal populations, inhibiting neural responses in unrelated areas. Greater neuronal activity in the posterior area of A1 was observed in the beta band, whereas a gamma rhythm was induced in the anterior A1. The results evidence that the proposed bio-inspired acousto-electric ICMS triggers high-frequency oscillations, encoding information about the stimulation sites and involving a large-scale integration in the brain.

Previous research has shown that musical beat perception is a surprisingly complex phenomenon involving widespread neural coordination across higher-order sensory, motor and cognitive areas. However, the question of how low-level auditory processing must necessarily shape these dynamics, and therefore perception, is not well understood. Here, we present evidence that the auditory cortical representation of music, even in the absence of motor or top-down activations, already favours the beat that will be perceived. Extracellular firing rates in the rat auditory cortex were recorded in response to 20 musical excerpts diverse in tempo and genre, for which musical beat perception had been characterized by the tapping behaviour of 40 human listeners. We found that firing rates in the rat auditory cortex were on average higher on the beat than off the beat. This ‘neural emphasis’ distinguished the beat that was perceived from other possible interpretations of the beat, was predictive of the degree of tapping consensus across human listeners, and was accounted for by a spectrotemporal receptive field model. These findings strongly suggest that the ‘bottom-up’ processing of music performed by the auditory system predisposes the timing and clarity of the perceived musical beat.

Observer-based procedures are used to assess auditory behavior in infants, often incorporating adaptive tracking algorithms. These procedures are reliable, but effects of modifications made to accommodate infant testing are not fully understood. One modification is that observation intervals are undefined for the listener, introducing signal-temporal uncertainty and increasing the likelihood that listener response bias will influence estimates of performance. The effect of these factors was evaluated by comparing threshold estimates obtained from adults using two tasks: (1) single-interval, yes/no and (2) two-interval, forced-choice. Detection thresholds were estimated adaptively for a 1000-Hz FM tone in quiet and for a word presented in two-talker speech masking. Trials were initiated and judged by the observer (observer-based) or the listener (listener-based). Thus, listening intervals were temporally uncertain in observer-based procedures and temporally defined in listener-based procedures. Thresholds were higher for observer-based relative to corresponding listener-based procedures. The magnitude of this difference was similar across the yes/no and two-interval tasks, and was larger for masked word detection than tone detection in quiet. Listeners adopted a conservative criterion when tested using the observer-based, yes/no procedure, but modeling results suggest that signal-temporal uncertainty accounts for the largest portion of the threshold difference between observer-based and listener-based procedures.

During critical periods, neural circuits develop to form receptive fields that adapt to the sensory environment and enable optimal performance of relevant tasks. We hypothesized that early exposure to background noise can improve signal-in-noise processing, and the resulting receptive field plasticity in the primary auditory cortex can reveal functional principles guiding that important task. We raised rat pups in different spectro-temporal noise statistics during their auditory critical period. As adults, they showed enhanced behavioral performance in detecting vocalizations in noise. Concomitantly, encoding of vocalizations in noise in the primary auditory cortex improves with noise-rearing. Significantly, spectro-temporal modulation plasticity shifts cortical preferences away from the exposed noise statistics, thus reducing noise interference with the foreground sound representation. Auditory cortical plasticity shapes receptive field preferences to optimally extract foreground information in noisy environments during noise-rearing. Early noise exposure induces cortical circuits to implement efficient coding in the joint spectral and temporal modulation domain.

In the auditory system, the spectrotemporal structure of acoustic signals determines the temporal pattern of spikes. Here, we investigated this effect in neurons of the barn owl’s auditory midbrain ( Tyto furcata ) that are selective for auditory space and whether it can influence the coding of sound direction. We found that in the nucleus where neurons first become selective to combinations of sound localization cues, reproducibility of spike trains across repeated trials of identical sounds, a metric of across-trial temporal fidelity of spiking patterns evoked by a stimulus, was maximal at the sound direction that elicited the highest firing rate. We then tested the hypothesis that this stimulus-dependent patterning resulted in rate co-modulation of cells with similar frequency and spatial selectivity, driving stimulus-dependent synchrony of population responses. Tetrodes were used to simultaneously record multiple nearby units in the optic tectum (OT), where auditory space is topographically represented. While spiking of neurons in OT showed lower reproducibility across trials compared with upstream nuclei, spike-time synchrony between nearby OT neurons was highest for sounds at their preferred direction. A model of the midbrain circuit explained the relationship between stimulus-dependent reproducibility and synchrony, and demonstrated that this effect can improve the decoding of sound location from the OT output. Thus, stimulus-dependent spiking patterns in the auditory midbrain can have an effect on spatial coding. This study reports a functional connection between spike patterning elicited by spectrotemporal features of a sound and the coding of its location.

Inhibition plays a key role in shaping sensory processing in the central auditory system and has been implicated in sculpting receptive field properties such as sound intensity coding and also in shaping temporal patterns of neuronal firing such as onset- or offset-evoked responses. There is substantial evidence supporting a decrease in inhibition throughout the ascending auditory pathway in geriatric animals. We therefore examined intensity coding of onset (ON) and offset (OFF) responses in auditory cortex of aged and young monkeys. A large proportion of cells in the primary auditory cortex (A1) and the caudolateral field (CL) displayed nonmonotonic rate-level functions for OFF responses in addition to nonmonotonic coding of ON responses. Aging differentially affected ON and OFF responses; the magnitude of effects was generally greater for ON responses. In addition to higher firing rates, neurons in old monkeys exhibited a significant increase in the proportion of monotonic rate-level functions and had higher best intensities than those in young monkeys. OFF responses in young monkeys displayed a range of intensity coding relationships with ON responses of the same cells, ranging from highly similar to highly dissimilar. Dissimilarity in ON/OFF coding was greater in CL and was reduced with aging, which was largely explained by a preferential decrease in the percentage of cells with nonmonotonic coding of ON and OFF responses. The changes we observed are consistent with previously demonstrated alterations in inhibition in the ascending auditory pathway of primates and could be involved in age-related deficits in the temporal processing of sounds. NEW & NOTEWORTHY Aging has a major impact on intensity coding of neurons in auditory cortex of rhesus macaques. Neural responses to sound onset and offset were affected to different extents, and their rate-level functions became more mutually similar, which could be accounted for by the loss of nonmonotonic intensity coding in geriatric monkeys. These findings were consistent with weakened inhibition in the central auditory system and could contribute to auditory processing deficits in elderly subjects.

Oxidative stress is a major contributor to noise-induced hearing loss, the most common cause of hearing loss among military personnel and young adults. HK-2 is a potent, orally-active, multifunctional, redox-modulating drug that has been shown to protect against a wide range of neurological disorders with no observed side effects. HK-2 protected cochlear HEI-OC1 cells against various forms of experimentally-induced oxidative stressors similar to those observed during and after intense noise exposure. The mechanisms by which HK-2 protects cells is twofold, first by its ability to reduce oxidative stress generated by free radicals, and second, by its ability to complex biologically active transition metals such as Fe+2, thus reducing their availability to participate in the Fenton reaction where highly toxic hydroxyl radicals are generated. For the rat in vivo studies, HK-2 provided significant protection against noise-induced hearing loss and hair cell loss. Noise-induced hearing loss was induced by an 8-16 kHz octave band noises presented for 8 h/d for 21 days at an intensity of 95 dB SPL. In the Prevention study, HK-2 was administered orally beginning 5 days before the start of the noise and ending 10 days after the noise. Treatment with HK-2 dose-dependently reduced the amount of noise-induced hearing impairment, reflected in the cochlear compound action potential, and noise-induced hair cell loss. In a subsequent Rescue experiment in which HK-2 was administered for 10 days starting after the noise was turned off, HK-2 also significantly reduced the amount of hearing impairment, but the effect size was substantially less than in the Prevention studies. HK-2 alone did not adversely affect HEI-OC1 cell viability, nor did it cause any adverse changes in rat body weight, behavior, cochlear function or hair cell integrity. Thus, HK-2 is a novel, safe, orally-deliverable and highly effective otoprotective compound with considerable potential for preventing hearing loss from noise and other hearing disorders linked to excessive oxidative stress.

The underlying causes of age-related hearing loss (ARHL) are not well understood, but it is clear from heritability estimates that genetics plays a role in addition to environmental factors. Genome-wide association studies (GWAS) in human populations can point to candidate genes that may be involved in ARHL, but follow-up analysis is needed to assess the role of these genes in the disease process. Some genetic variants may contribute a small amount to a disease, while other variants may have a large effect size, but the genetic architecture of ARHL is not yet well-defined. In this study, we asked if a set of 17 candidate genes highlighted by early GWAS reports of ARHL have detectable effects on hearing by knocking down expression levels of each gene in the mouse and analysing auditory function. We found two of the genes have an impact on hearing. Mutation of Dclk1 led to late-onset progressive increase in ABR thresholds and the A430005L14Rik (C1orf174) mutants showed worse recovery from noise-induced damage than controls. We did not detect any abnormal responses in the remaining 15 mutant lines either in thresholds or from our battery of suprathreshold ABR tests, and we discuss the possible reasons for this.