Auditory Research publications

The mechanisms that govern thalamocortical transmission are poorly understood. Recent data have shown that sensory stimuli elicit activity in ensembles of cortical neurons that recapitulate stereotyped spontaneous activity patterns. Here, we elucidate a possible mechanism by which gating of patterned population cortical activity occurs. In this study, sensory-evoked all-or-none cortical population responses were observed in the mouse auditory cortex in vivo and similar stochastic cortical responses were observed in a colliculo-thalamocortical brain slice preparation. Cortical responses were associated with decreases in auditory thalamic synaptic inhibition and increases in thalamic synchrony. Silencing of corticothalamic neurons in layer 6 (but not layer 5) or the thalamic reticular nucleus linearized the cortical responses, suggesting that layer 6 corticothalamic feedback via the thalamic reticular nucleus was responsible for gating stochastic cortical population responses. These data implicate a corticothalamic-thalamic reticular nucleus circuit that modifies thalamic neuronal synchronization to recruit populations of cortical neurons for sensory representations.

The LIM homeodomain transcription factor ISL1 is essential for the different aspects of neuronal development and maintenance. In order to study the role of ISL1 in the auditory system, we generated a transgenic mouse (Tg) expressing Isl1 under the Pax2 promoter control. We previously reported a progressive age-related decline in hearing and abnormalities in the inner ear, medial olivocochlear system, and auditory midbrain of these Tg mice. In this study, we investigated how Isl1 overexpression affects sound processing by the neurons of the inferior colliculus (IC). We recorded extracellular neuronal activity and analyzed the responses of IC neurons to broadband noise, clicks, pure tones, two-tone stimulation and frequency-modulated sounds. We found that Tg animals showed a higher inhibition as displayed by two-tone stimulation; they exhibited a wider dynamic range, lower spontaneous firing rate, longer first spike latency and, in the processing of frequency modulated sounds, showed a prevalence of high-frequency inhibition. Functional changes were accompanied by a decreased number of calretinin and parvalbumin positive neurons, and an increased expression of vesicular GABA/glycine transporter and calbindin in the IC of Tg mice, compared to wild type animals. The results further characterize abnormal sound processing in the IC of Tg mice and demonstrate that major changes occur on the side of inhibition.

Although moving sound-sources abound in natural auditory scenes, it is not clear how the human brain processes auditory motion. Previous studies have indicated that, although ocular localization responses to stationary sounds are quite accurate, ocular smooth pursuit of moving sounds is very poor. We here demonstrate that human subjects faithfully track a sound’s unpredictable movements in the horizontal plane with smooth-pursuit responses of the head. Our analysis revealed that the stimulus–response relation was well described by an under-damped passive, second-order low-pass filter in series with an idiosyncratic, fixed, pure delay. The model contained only two free parameters: the system’s damping coefficient, and its central (resonance) frequency. We found that the latter remained constant at ∼0.6 Hz throughout the experiment for all subjects. Interestingly, the damping coefficient systematically increased with trial number, suggesting the presence of an adaptive mechanism in the auditory pursuit system (APS). This mechanism functions even for unpredictable sound-motion trajectories endowed with fixed, but covert, frequency characteristics in open-loop tracking conditions. We conjecture that the APS optimizes a trade-off between response speed and effort. Taken together, our data support the existence of a pursuit system for auditory head-tracking, which would suggest the presence of a neural representation of a spatial auditory fovea (AF).

Purpose. Slc26a4-/- mice exhibit severer defects in the development of the cochlea and develop deafness, while the underlying mechanisms responsible for these effects remain unclear. Our study was to investigate the potential mechanism linking SLC26A4 deficiency to hearing loss. Materials and Methods. RNA sequencing was applied to analyze the differential gene expression of the stria vascularis (SV) from wildtype and Slc26a4-/- mice. GO and KEGG pathway analysis were performed. Quantitative RT-PCR was applied to validate the expression of candidate genes affected by Slc26a4. ELISA and immunofluorescence technique were used to detect the homocysteine (Hcy) level in serum, brain, and SV, respectively. Results. 183 upregulated genes and 63 downregulated genes were identified in the SV associated with Slc26a4 depletion. Transcriptomic profiling revealed that Slc26a4 deficiency significantly affected the expression of genes associated with cell adhesion, transmembrane transport, and the biogenesis of multicellular organisms. The SV from Slc26a4-/- mice exhibited a higher expression of Bhmt mRNAs, as well as altered homocysteine (Hcy) metabolism. Conclusions. The altered expression of Bhmt results in a dramatic change in multiple biochemical reactions and a disruption of nutrient homeostasis in the endolymph which may contribute to hearing loss of Slc26a4 knockout mouse.

Congenital hearing loss affects 1 in every 1000 births, with genetic mutations contributing to more than 50% of all cases. X-linked nonsyndromic hereditary hearing loss is associated with six loci (DFNX1-6) and five genes. Recently, the missense mutation (c.1771G>A, p.Gly591Ser) in COL4A6 , encoding the basement membrane (BM) collagen α6(IV) chain, was shown to be associated with X-linked congenital nonsyndromic hearing loss with cochlear malformation. However, the mechanism by which the COL4A6 mutation impacts hereditary hearing loss has not yet been elucidated. Herein, we investigated Col4a6 knockout (KO) effects on hearing function and cochlear formation in mice. Immunohistochemistry showed that the collagen α6(IV) chain was distributed throughout the mouse cochlea within subepithelial BMs underlying the interdental cells, inner sulcus cells, basilar membrane, outer sulcus cells, root cells, Reissner’s membrane, and perivascular BMs in the spiral limbus, spiral ligament, and stria vascularis. However, the click-evoked auditory brainstem response analysis did not show significant changes in the hearing threshold of Col4a6 KO mice compared with wild-type (WT) mice with the same genetic background. In addition, the cochlear structures of Col4a6 KO mice did not exhibit morphological alterations, according to the results of high-resolution micro-computed tomography and histology. Hence, loss of Col4a6 gene expression in mice showed normal click ABR thresholds and normal cochlear formation, which differs from humans with the COL4A6 missense mutation c.1771G>A, p.Gly591Ser. Therefore, the deleterious effects in the auditory system caused by the missense mutation in COL4A6 are likely due to the dominant-negative effects of the α6(IV) chain and/or α5α6α5(IV) heterotrimer with an aberrant structure that would not occur in cases with loss of gene expression.

Numerous studies indicate that deficits in the proper integration or migration of specific GABAergic precursor cells from the subpallium to the cortex can lead to severe cognitive dysfunctions and neurodevelopmental pathogenesis linked to intellectual disabilities. A different set of GABAergic precursors cells that express Pax2 migrate to hindbrain regions, targeting, for example auditory or somatosensory brainstem regions. We demonstrate that the absence of BDNF in Pax2-lineage descendants of Bdnf Pax 2 KOs causes severe cognitive disabilities. In Bdnf Pax 2 KOs, a normal number of parvalbumin-positive interneurons ( PV-IN s) was found in the auditory cortex ( AC ) and hippocampal regions, which went hand in hand with reduced PV-labeling in neuropil domains and elevated activity-regulated cytoskeleton-associated protein ( Arc/Arg3.1 ; here: Arc ) levels in pyramidal neurons in these same regions. This immaturity in the inhibitory/excitatory balance of the AC and hippocampus was accompanied by elevated LTP, reduced (sound-induced) LTP/LTD adjustment, impaired learning, elevated anxiety, and deficits in social behavior, overall representing an autistic-like phenotype. Reduced tonic inhibitory strength and elevated spontaneous firing rates in dorsal cochlear nucleus ( DCN ) brainstem neurons in otherwise nearly normal hearing Bdnf Pax 2 KOs suggests that diminished fine-grained auditory-specific brainstem activity has hampered activity-driven integration of inhibitory networks of the AC in functional (hippocampal) circuits. This leads to an inability to scale hippocampal post-synapses during LTP/LTD plasticity. BDNF in Pax2-lineage descendants in lower brain regions should thus be considered as a novel candidate for contributing to the development of brain disorders, including autism.

DBA/2 mice are a well-known animal model for hearing loss developed due to intrinsic properties of these animals. However, results on the phenotype of hearing loss in DBA/2 mice have been mainly reported at an early stage in mice aged ≤7 weeks. Instead, the present study evaluated the hearing ability at 5, 13, and 34 weeks of age using DBA/2korl mice. Auditory brainstem response test was performed at 8–32 KHz at 5, 13, and 34 weeks of age, and hearing loss was confirmed to be induced in a time-dependent manner. In addition, histopathological evaluation at the same age confirmed the morphological damage of the cochlea. The findings presented herein are the results of the long-term observation of the phenotype of hearing loss in DBA/2 mice and can be useful in studies related to aging-dependent hearing loss.

Throughout life, sensory systems adapt to the sensory environment to provide optimal responses to relevant tasks. In the case of a developing system, sensory inputs induce changes that are permanent and detectable up to adulthood. Previously, we have shown that rearing rat pups in a complex acoustic environment (spectrally and temporally modulated sound) from postnatal day 14 (P14) to P28 permanently improves the response characteristics of neurons in the inferior colliculus and auditory cortex, influencing tonotopical arrangement, response thresholds and strength, and frequency selectivity, along with stochasticity and the reproducibility of neuronal spiking patterns. In this study, we used a set of behavioral tests based on a recording of the acoustic startle response (ASR) and its prepulse inhibition (PPI), with the aim to extend the evidence of the persistent beneficial effects of the developmental acoustical enrichment. The enriched animals were generally not more sensitive to startling sounds, and also, their PPI of ASR, induced by noise or pure tone pulses, was comparable to the controls. They did, however, exhibit a more pronounced PPI when the prepulse stimulus was represented either by a change in the frequency of a background tone or by a silent gap in background noise. The differences in the PPI of ASR between the enriched and control animals were significant at lower (55 dB SPL), but not at higher (65-75 dB SPL), intensities of background sound. Thus, rearing pups in the acoustically enriched environment led to an improvement of the frequency resolution and gap detection ability under more difficult testing conditions, i.e., with a worsened stimulus clarity. We confirmed, using behavioral tests, that an acoustically enriched environment during the critical period of development influences the frequency and temporal processing in the auditory system, and these changes persist until adulthood.

The ability to use temporal relationships between cross-modal cues facilitates perception and behavior. Previously we observed that temporally correlated changes in the size of a visual stimulus and the intensity in an auditory stimulus influenced the ability of listeners to perform an auditory selective attention task (Maddox, Atilgan, Bizley, & Lee, 2015). Participants detected timbral changes in a target sound while ignoring those in a simultaneously presented masker. When the visual stimulus was temporally coherent with the target sound, performance was significantly better than when the visual stimulus was temporally coherent with the masker, despite the visual stimulus conveying no task-relevant information. Here, we trained observers to detect audiovisual temporal coherence and asked whether this changed the way in which they were able to exploit visual information in the auditory selective attention task. We observed that after training, participants were able to benefit from temporal coherence between the visual stimulus and both the target and masker streams, relative to the condition in which the visual stimulus was coherent with neither sound. However, we did not observe such changes in a second group that were trained to discriminate modulation rate differences between temporally coherent audiovisual streams, although they did show an improvement in their overall performance. A control group did not change their performance between pretest and post-test and did not change how they exploited visual information. These results provide insights into how crossmodal experience may optimize multisensory integration.

Budgerigars ( Melopsittacus undulatus ) are small Australian parrots with a well-documented, learned vocal repertoire and a high degree of vocal production learning. These birds live in large, social flocks and they vocally interact with each other in a dynamic, reciprocal manner. We assume that budgerigars must process and integrate a wide variety of sensory stimuli when selecting appropriate vocal responses to conspecifics during vocal interactions, but the relative contributions of these different stimuli to that process are next to impossible to tease apart in a natural context. Here we show that budgerigars, under operant control, can learn to respond to specific stimuli with a specific vocal response. Budgerigars were trained to produce contact calls to a combination of auditory and visual cues. Birds learned to produce specific contact calls to stimuli that differed either in location (visual or auditory) or quality (visual). Interestingly, the birds could not learn to associate different vocal responses with different auditory stimuli coming from the same location. Surprisingly, this was so even when the auditory stimuli and the responses were the same (i.e., the bird’s own contact call). These results show that even in a highly controlled operant context, acoustic cues alone were not sufficient to support vocal production learning in budgerigars. From a different perspective, these results highlight the significant role that social interaction likely plays in vocal production learning so elegantly shown by Irene Pepperberg’s work in parrots.

Systemic nicotine enhances neural processing in primary auditory cortex (A1) as determined using tone-evoked, current-source density (CSD) measurements. For example, nicotine enhances the characteristic frequency (CF)-evoked current sink in layer 4 of A1, increasing amplitude and decreasing latency. However, since presenting auditory stimuli within a stream of stimuli increases the complexity of response dynamics, we sought to determine the effects of nicotine on CSD responses to trains of CF stimuli (one-second trains at 2–40 Hz; each train repeated 25 times). CSD recordings were obtained using a 16-channel multiprobe inserted in A1 of urethane/xylazine-anesthetized mice, and analysis focused on two current sinks in the middle (layer 4) and deep (layers 5/6) layers. CF trains produced adaptation of the layer 4 response that was weak at 2 Hz, stronger at 5–10 Hz and complete at 20–40 Hz. In contrast, the layer 5/6 current sink exhibited less adaptation at 2–10 Hz, and simultaneously recorded auditory brainstem responses (ABRs) showed no adaptation even at 40 Hz. Systemic nicotine (2.1 mg/kg) enhanced layer 4 responses throughout the one-second stimulus train at rates ≤10 Hz. Nicotine enhanced both response amplitude within each train and the consistency of response timing across 25 trials. Nicotine did not alter the degree of adaptation over one-second trials, but its effect to increase amplitudes revealed a novel, slower form of adaptation that developed over multiple trials. Nicotine did not affect responses that were fully adapted (20–40 Hz trains), nor did nicotine affect any aspect of the layer 5/6 current sink or ABRs. The overall effect of nicotine in layer 4 was to enhance all responses within each train, to emphasize earlier trials across multiple trials, and to improve the consistency of timing across all trials. These effects may improve processing of complex acoustic streams, including speech, that contain information in the 2–10 Hz range.

Signaling between neurons and glia is necessary for the formation of functional neural circuits. A role for microglia in the maturation of connections in the medial nucleus of the trapezoid body (MNTB) was previously demonstrated by postnatal microglial elimination using a colony stimulating factor 1 receptor (CSF1R). Defective pruning of calyces of Held and significant reduction of the mature astrocyte marker glial fibrillary acidic protein (GFAP) were observed after hearing onset. Here, we investigated the time course required for microglia to populate the mouse MNTB after cessation of CSF1R inhibitor treatment. We then examined whether defects seen after microglial depletion were rectified by microglial repopulation. We found that microglia returned to control levels at four weeks of age (18 d postcessation of treatment). Calyceal innervation of MNTB neurons was comparable to control levels at four weeks and GFAP expression recovered by seven weeks. We further investigated the effects of microglia elimination and repopulation on auditory function using auditory brainstem recordings (ABRs). Temporary microglial depletion significantly elevated auditory thresholds in response to 4. 8, and 12 kHz at four weeks. Treatment significantly affected latencies, interpeak latencies, and amplitudes of all the ABR peaks in response to many of the frequencies tested. These effects largely recovered by seven weeks. These findings highlight the functions of microglia in the formation of auditory neural circuits early in development. Further, the results suggest that microglia retain their developmental functions beyond the period of circuit refinement.

A sequential dual-task design was used to assess the impacts of spoken sentence context and cognitive load on listening effort. Young adults with normal hearing listened to sentences masked by multitalker babble in which sentence-final words were either predictable or unpredictable. Each trial began with visual presentation of a short (low-load) or long (high-load) sequence of to-be-remembered digits. Words were identified more quickly and accurately in predictable than unpredictable sentence contexts. In addition, digits were recalled more quickly and accurately on trials on which the sentence was predictable, indicating reduced listening effort for predictable compared to unpredictable sentences. For word and digit recall response time but not for digit recall accuracy, the effect of predictability remained significant after exclusion of trials with incorrect word responses and was thus independent of speech intelligibility. In addition, under high cognitive load, words were identified more slowly and digits were recalled more slowly and less accurately than under low load. Participants’ working memory and vocabulary were not correlated with the sentence context benefit in either word recognition or digit recall. Results indicate that listening effort is reduced when sentences are predictable and that cognitive load affects the processing of spoken words in sentence contexts.

There is considerable interest in understanding cortical processing and the function of top-down and bottom-up human neural circuits that control speech production. Research efforts to investigate these circuits are aided by analysis of spectro-temporal response characteristics of neural activity recorded by electrocorticography (ECoG). Further, cortical processing may be altered in the case of hearing-impaired cochlear implant (CI) users, as electric excitation of the auditory nerve creates a markedly different neural code for speech compared with that of the functionally intact hearing system. Studies of cortical activity in CI users typically record scalp potentials and are hampered by stimulus artifact contamination and by spatiotemporal filtering imposed by the skull. We present a unique case of a CI user who required direct recordings from the cortical surface using subdural electrodes implanted for epilepsy assessment. Using experimental conditions where the subject vocalized in the presence (CIs ON) or absence (CIs OFF) of auditory feedback, or listened to playback of self-vocalizations without production, we observed ECoG activity primarily in γ (32-70 Hz) and high γ (70-150 Hz) bands at focal regions on the lateral surface of the superior temporal gyrus (STG). High γ band responses differed in their amplitudes across conditions and cortical sites, possibly reflecting different rates of stimulus presentation and differing levels of neural adaptation. STG γ responses to playback and vocalization with auditory feedback were not different from responses to vocalization without feedback, indicating this activity reflects not only auditory, but also attentional, efference-copy, and sensorimotor processing during speech production.

Polychlorinated biphenyls (PCBs) are enduring environmental toxicants and exposure is associated with neurodevelopmental deficits. The auditory system appears particularly sensitive, as previous work has shown that developmental PCB exposure causes both hearing loss and gross disruptions in the organization of the rat auditory cortex. However, the mechanisms underlying PCB-induced changes are not known, nor is it known whether the central effects of PCBs are a consequence of peripheral hearing loss. Here, we study changes in both peripheral and central auditory function in rats with developmental PCB exposure using a combination of optical and electrophysiological approaches. Female rats were exposed to an environmental PCB mixture in utero and until weaning. At adulthood, auditory brainstem responses (ABRs) were measured, and synaptic currents were recorded in slices from auditory cortex layer 2/3 neurons. Spontaneous IPSCs (sIPSCs) and miniature IPSCs (mIPSCs) were more frequent in PCB-exposed rats compared with controls and the normal relationship between IPSC parameters and peripheral hearing was eliminated in PCB-exposed rats. No changes in spontaneous EPSCs were found. Conversely, when synaptic currents were evoked by laser photostimulation of caged-glutamate, PCB exposure did not affect evoked inhibitory transmission, but increased the total excitatory charge, the number and distance of sites that evoke a significant response. Together, these findings indicate that early developmental exposure to PCBs causes long-lasting changes in both inhibitory and excitatory neurotransmission in the auditory cortex that are independent of peripheral hearing changes, suggesting the effects are because of the direct impact of PCBs on the developing auditory cortex.

A vocoder is used to simulate cochlear-implant sound processing in normal-hearing listeners. Typically, there is rapid improvement in vocoded speech recognition, but it is unclear if the improvement rate differs across age groups and speech materials. Children (8–10 years) and young adults (18–26 years) were trained and tested over 2 days (4 hours) on recognition of eight-channel noise-vocoded words and sentences, in quiet and in the presence of multi-talker babble at signal-to-noise ratios of 0, +5, and +10 dB. Children achieved poorer performance than adults in all conditions, for both word and sentence recognition. With training, vocoded speech recognition improvement rates were not significantly different between children and adults, suggesting that improvement in learning how to process speech cues degraded via vocoding is absent of developmental differences across these age groups and types of speech materials. Furthermore, this result confirms that the acutely measured age difference in vocoded speech recognition persists after extended training.

Reduced tolerance to sound stimuli (hyperacusis) is commonly seen in tinnitus patients. Dysfunction of limbic systems, such as the nucleus accumbens (NAc), may be involved in emotional reactions to the sound stimuli in tinnitus patients. To study the functional changes in the NAc in hyperacusis, we have examined the neural activity changes of the NAc using c-Fos staining in an animal model of hyperacusis. The c-Fos staining was also examined in the medial geniculate nucleus (MGN), a central auditory pathway which has neural projections to the NAc. Postnatal rats (14 days) were exposed to loud noise (115 dB SPL, 4 hours for two consecutive days) to induce hyperacusis ( n = 4 ). Rats without noise exposure were used as the controls ( n = 4 ). After P35, rats in both groups were put in a behavioral training for sound detection. After they were trained to detect sound stimuli, their reaction time to noise bursts centered at 2 kHz (40-110 dB SPL) was measured. Rats in the noise group showed a significantly shorter reaction time than those in the control group to the noise bursts at high intensities, suggesting the noise exposure induced hyperacusis behavior. The c-Fos expressions in the NAc and the MGNs of the noise group were significantly higher than those of the control group. Our results suggested that early-age noise exposure caused hyperactivity in the NAc and the MGNs which may induce the loudness increase in these rats.

Regeneration of auditory hair cells in adult mammals is challenging. It is also difficult to track the sources of regenerated hair cells, especially in vivo. Previous paper found newly generated hair cells in deafened mouse by injecting a DNA methyltransferase inhibitor 5-azacytidine into the inner ear. This paper aims to investigate the cell sources of new hair cells. Transgenic mice with enhanced green fluorescent protein (EGFP) expression controlled by the Sox2 gene were used in the study. A combination of kanamycin and furosemide was applied to deafen adult mice, which received 4 mM 5-azacytidine injection into the inner ear three days later. Mice were followed for 3, 5, 7 and 14 days after surgery to track hair cell regeneration. Immunostaining of Myosin VIIa and EGFP signals were used to track the fate of Sox2-expressing supporting cells. The results show that (i) expression of EGFP in the transgenic mice colocalized the supporting cells in the organ of Corti, and (ii) the cell source of regenerated hair cells following 5-azacytidine treatment may be supporting cells during 5–7 days post 5-azacytidine injection. In conclusion, 5-azacytidine may promote the conversion of supporting cells to hair cells in chemically deafened adult mice.

Background and objectives: Animal results have suggested that auditory brainstem responses (ABRs) to transient sounds presented at supra-threshold levels may be useful for measuring hearing damage that is hidden to current audiometric tests. Evaluating such ABRs requires extracting the latencies and amplitudes of relevant deflections, or "waves". Currently, this is mostly done by human observers manually picking the waves' peaks and troughs in each individual response - a process that is both time-consuming and requiring of expert experience. Here, we propose a highly automated procedure for extracting individual ABR wave latencies and amplitudes based on the well-established methodology of non-linear curve registration. Methods: First, the to-be-analysed individual ABRs are temporally aligned - either with one another or, if available, with a pre-existing template - by locally compressing or stretching their time axes with smooth and invertible time warping functions. Then, the individual latencies and amplitudes of relevant ABR waves are obtained by picking the latencies of the waves' peaks and troughs on the common (aligned) time axis and combining these with the individual aligned responses and inverse time warping functions. Results: Using an example ABR data set with a wide range of response latencies and signal-to-noise ratios (SNRs), we test different choices for fitting the time warping functions. We cross-validate the warping results using independent response replicates and compare automatically and manually extracted latencies and amplitudes for ABR waves I and V. Using a Bayesian approach, we show that, for the best registration condition, automatic and manual data were statistically similar. Conclusions: Non-linear curve registration can be used to temporally align individual ABRs and extract their wave latencies and amplitudes in a way that closely matches results from manual picking.

The neural mechanisms underlying forward suppression in the auditory cortex remain a puzzle. Little attention is paid to thalamic contribution despite the important fact that the thalamus gates upstreaming information to the auditory cortex. This study compared the time courses of forward suppression in the auditory thalamus, thalamocortical inputs and cortex using the two-tone stimulus paradigm. The preceding and succeeding tones were 20-ms long. Their frequency and amplitude were set at the characteristic frequency and 20 dB above the minimum threshold of given neurons, respectively. In the ventral division of the medial geniculate body of the thalamus, we found that the duration of complete forward suppression was about 75 ms and the duration of partial suppression was from 75 ms to about 300 ms after the onset of the preceding tone. We also found that during the partial suppression period, the responses to the succeeding tone were further suppressed in the primary auditory cortex. The forward suppression of thalamocortical field excitatory postsynaptic potentials was between those of thalamic and cortical neurons but much closer to that of thalamic ones. Our results indicate that early suppression in the cortex could result from complete suppression in the thalamus whereas later suppression may involve thalamocortical and intracortical circuitry. This suggests that the complete suppression that occurs in the thalamus provides the cortex with a "silence" window that could potentially benefit cortical processing and/or perception of the information carried by the preceding sound.