Auditory Research publications

Noise-exposed rat pups provide a model of early deprivation of sensory input to the central auditory system, allowing the study of developmental neuroplasticity. Our previous results have demonstrated that a brief exposure of rats to broadband noise (125 dB SPL 8 min, 14th postnatal day) at the onset of hearing resulted in an altered intensity perception and frequency discrimination in adulthood despite normal hearing thresholds. In this study, we assessed the gap-detection ability and possible presence of tinnitus- and hyperacusis-like behavior in adult rats after the same neonatal acoustic trauma, using measurements of the acoustic startle response (ASR) in quiet and noisy environments and its prepulse inhibition by gaps in noise (gap-PPI). A significant deficit in the ability to detect gap was observed in the exposed rats when 55 dB SPL broadband noise was used as background. An increase of noise intensity to 65-75 dB SPL led to strengthening of the gap-PPI in exposed animals, which approached the gap-PPI values of control animals at these levels. Behavioral signs of tinnitus (gap detection deficits in 10 kHz narrow band noise) were found in 25% of exposed rats. An increased sensitivity to continuous noise was manifested in all exposed rats by suppression of the ASR at significantly lower background noise levels than in the controls. This effect was particularly pronounced in rats with tinnitus-like behavior. Our results indicate that neonatal acoustic trauma, producing only a transient threshold shift, may produce permanent abnormalities in suprathreshold auditory functions and the development of tinnitus and hyperacusis-like behavior.

Sensory responses of the neocortex are strongly influenced by brain state changes. However, it remains unclear whether and how the sensory responses of the midbrain are affected. Here we addressed this issue by using in vivo two-photon calcium imaging to monitor the spontaneous and sound-evoked activities in the mouse inferior colliculus (IC). We developed a method enabling us to image the first layer of non-lemniscal IC (IC shell L1) in awake behaving mice. Compared with the awake state, spectral tuning selectivity of excitatory neurons was decreased during isoflurane anesthesia. Calcium imaging in behaving animals revealed that activities of inhibitory neurons were highly correlated with locomotion. Compared with stationary periods, spectral tuning selectivity of excitatory neurons was increased during locomotion. Taken together, our studies reveal that neuronal activities in the IC shell L1 are brain state dependent, whereas the brain state modulates the excitatory and inhibitory neurons differentially.

Human p.V37I mutation of GJB2 gene was strongly correlated with late-onset progressive hearing loss, especially among East Asia populations. We generated a knock-in mouse model based on human p.V37I variant (c.109G>A) that recapitulated the human phenotype. Cochlear pathology revealed no significant hair cell loss, stria vascularis atrophy or spiral ganglion neuron loss, but a significant change in the length of gap junction plaques, which may have contributed to the observed mild endocochlear potential (EP) drop in homozygous mice lasting lifetime. The cochlear amplification in homozygous mice was compromised, but outer hair cells' function remained unchanged, indicating that the reduced amplification was EP- rather than prestin-generated. In addition to ABR threshold elevation, ABR wave I latencies were also prolonged in aged homozygous animals. We found in homozygous IHCs a significant increase in ICa but no change in Ca2+ efficiency in triggering exocytosis. Environmental insults such as noise exposure, middle ear injection of KCl solution and systemic application of furosemide all exacerbated the pathological phenotype in homozygous mice. We conclude that this Gjb2 mutation-induced hearing loss results from 1) reduced cochlear amplifier caused by lowered EP, 2) IHCs excitotoxicity associated with potassium accumulation around hair cells, and 3) progression induced by environmental insults.

Although information theoretic approaches have been used extensively in the analysis of the neural code, they have yet to be used to describe how information is accumulated in time while sensory systems are categorizing dynamic sensory stimuli such as speech sounds or visual objects. Here, we present a novel method to estimate the cumulative information for stimuli or categories. We further define a time-varying categorical information index that, by comparing the information obtained for stimuli versus categories of these same stimuli, quantifies invariant neural representations. We use these methods to investigate the dynamic properties of avian cortical auditory neurons recorded in zebra finches that were listening to a large set of call stimuli sampled from the complete vocal repertoire of this species. We found that the time-varying rates carry 5 times more information than the mean firing rates even in the first 100 ms. We also found that cumulative information has slow time constants (100-600 ms) relative to the typical integration time of single neurons, reflecting the fact that the behaviorally informative features of auditory objects are time-varying sound patterns. When we correlated firing rates and information values, we found that average information correlates with average firing rate but that higher-rates found at the onset response yielded similar information values as the lower-rates found in the sustained response: the onset and sustained response of avian cortical auditory neurons provide similar levels of independent information about call identity and call-type. Finally, our information measures allowed us to rigorously define categorical neurons; these categorical neurons show a high degree of invariance for vocalizations within a call-type. Peak invariance is found around 150 ms after stimulus onset. Surprisingly, call-type invariant neurons were found in both primary and secondary avian auditory areas.

The perception of a sound can be influenced by another sound in a space-dependent manner. An understanding of this perceptual phenomenon depends on knowledge about how the spatial relationship between two sounds affects neural responses to the sounds. We used the rat as a model system and equal-probability two-tone sequences as stimuli to evaluate how spatial separation between two asynchronously recurring sounds affected responses to the sounds in midbrain auditory neurons. We found that responses elicited by two tone bursts when they were colocalized at the ear contralateral to the neuron were different from the responses elicited by the same sounds when they were separated with one at the contralateral ear while the other at another location. For neurons with transient sound-driven firing and not responsive to stimulation presented at the ipsilateral ear, the response to a sound with a fixed location at the contralateral ear was enhanced when the second sound was separated. These neurons were likely important for detecting a sound in the presence of a spatially separated competing sound. Our results suggest that mechanisms underlying effects of spatial separation on neural responses to sounds may include adaptation and long-lasting binaural excitatory/inhibitory interaction.

Methylmercury (MeHg) is well known to induce auditory disorders such as dysarthria. When we performed a global analysis on the brains of mice exposed to MeHg by magnetic resonance imaging, an increase in the T1 signal in the inferior colliculus (IC), which is localized in the auditory pathway, was observed. Therefore, the purpose of this study is to examine the pathophysiology and auditory dysfunction induced by MeHg, focusing on the IC. Measurement of the auditory brainstem response revealed increases in latency and decreases in threshold in the IC of mice exposed to MeHg for 4 weeks compared with vehicle mice. Incoordination in MeHg-exposed mice was noted after 6 weeks of exposure, indicating that IC dysfunction occurs earlier than incoordination. There was no change in the number of neurons or microglial activity, while the expression of glial fibrillary acidic protein, a marker for astrocytic activity, was elevated in the IC of MeHg-exposed mice after 4 weeks of exposure, indicating that astrogliosis occurs in the IC. Suppression of astrogliosis by treatment with fluorocitrate exacerbated the latency and threshold in the IC evaluated by the auditory brainstem response. Therefore, astrocytes in the IC are considered to play a protective role in the auditory pathway. Astrocytes exposed to MeHg increased the expression of brain-derived neurotrophic factor in the IC, suggesting that astrocytic brain-derived neurotrophic factor is a potent protectant in the IC. This study showed that astrogliosis in the IC could be an adaptive response to MeHg toxicity. The overall toxicity of MeHg might be determined on the basis of the balance between MeHg-mediated injury to neurons and protective responses from astrocytes.

Significance Cochlear hair cells transduce sound into electrical signals by activation of mechanically sensitive ion channels thought to be formed by TMC1. We generated a single aspartate/asparagine substitution in mouse TMC1 which is homologous to a human genetic deafness mutation. The main consequence was reduction in the Ca 2+ permeability of the mechanically sensitive channel with little change in its unitary conductance. Nevertheless, there was a much reduced expression of the ion channel, which led within 4 wk to death of the outer hair cells culminating in deafness. The mouse mutant accounts for the human deafness and implies that TMC1, in addition to forming the mechanically sensitive ion channel, regulates its own expression.

The functional organization of human auditory cortex can be probed by characterizing responses to various classes of sound at different anatomical locations. Along with histological studies this approach has revealed a primary field in posteromedial Heschl's gyrus (HG) with pronounced induced high-frequency (70–150 Hz) activity and short-latency responses that phase-lock to rapid transient sounds. Low-frequency neural oscillations are also relevant to stimulus processing and information flow, however, their distribution within auditory cortex has not been established. Alpha activity (7–14 Hz) in particular has been associated with processes that may differentially engage earlier versus later levels of the cortical hierarchy, including functional inhibition and the communication of sensory predictions. These theories derive largely from the study of occipitoparietal sources readily detectable in scalp electroencephalography. To characterize the anatomical basis and functional significance of less accessible temporal-lobe alpha activity we analyzed responses to sentences in seven human adults (4 female) with epilepsy who had been implanted with electrodes in superior temporal cortex. In contrast to primary cortex in posteromedial HG, a non-primary field in anterolateral HG was characterized by high spontaneous alpha activity that was strongly suppressed during auditory stimulation. Alpha-power suppression decreased with distance from anterolateral HG throughout superior temporal cortex, and was more pronounced for clear compared to degraded speech. This suppression could not be accounted for solely by a change in the slope of the power spectrum. The differential manifestation and stimulus-sensitivity of alpha oscillations across auditory fields should be accounted for in theories of their generation and function. SIGNIFICANCE STATEMENT To understand how auditory cortex is organized in support of perception, we recorded from patients implanted with electrodes for clinical reasons. This allowed measurement of activity in brain regions at different levels of sensory processing. Oscillations in the alpha range (7–14 Hz) have been associated with functions including sensory prediction and inhibition of regions handling irrelevant information, but their distribution within auditory cortex is not known. A key finding was that these oscillations dominated in one particular non-primary field, anterolateral Heschl's gyrus, and were suppressed when subjects listened to sentences. These results build on our knowledge of the functional organization of auditory cortex and provide anatomical constraints on theories of the generation and function of alpha oscillations.

Noise is one of the most common causes of hearing loss in industrial countries. There are many studies about chemical agents to prevent noise-induced hearing loss (NIHL). However, there is no commercially available drug yet. Retinoic acid is an active metabolite of Vitamin A; it has an anti-apoptic role in NIHL. This study aims to verify the differences among selective agonists of retinoic acid receptors (RARs) in NIHL. All-trans retinoic acid (ATRA), AM80 (selective retinoic acid receptor α agonist), AC261066 (Selective retinoic acid receptor β1 agonist), and CD1530 (Selective retinoic acid λ agonist) were injected to 6–7 weeks old CJ5BL/6 mice before noise (110 dB for 3 h) exposure. In the auditory brainstem response test pre-, post 1, 3, and 7 days after noise exposure, not only ATRA but all kinds of selective RAR agonists showed protective effects in hearing threshold and wave I amplitude. Though there was no significant difference in the level of protective effects between agonists, α agonist showed the most prominent effect in preserving hearing function as well as outer hair cells after noise exposure. In conclusion, selective agonists of RAR demonstrate comparable protective effects against NIHL to retinoic acid. Given that these selective RAR agonists have less side effects than retinoic acid, they may be promising potential drugs against NIHL.

Cleavage of amyloid precursor protein (APP) by β-secretase BACE1 initiates the production and accumulation of neurotoxic amyloid-β peptides, which is widely considered an essential pathogenic mechanism in Alzheimer's disease (AD). Here, we report that BACE1 is essential for normal auditory function. Compared with wild-type littermates, BACE1 −/− mice of either sex exhibit significant hearing deficits, as indicated by increased thresholds and reduced amplitudes in auditory brainstem responses (ABRs) and decreased distortion product otoacoustic emissions (DPOAEs). Immunohistochemistry revealed aberrant synaptic organization in the cochlea and hypomyelination of auditory nerve fibers as predominant neuropathological substrates of hearing loss in BACE1 −/− mice. In particular, we found that fibers of spiral ganglion neurons (SGN) close to the organ of Corti are disorganized and abnormally swollen. BACE1 deficiency also engenders organization defects in the postsynaptic compartment of SGN fibers with ectopic overexpression of PSD95 far outside the synaptic region. During postnatal development, auditory fiber myelination in BACE1 −/− mice lags behind dramatically and remains incomplete into adulthood. We relate the marked hypomyelination to the impaired processing of Neuregulin-1 when BACE1 is absent. To determine whether the cochlea of adult wild-type mice is susceptible to AD treatment-like suppression of BACE1, we administered the established BACE1 inhibitor NB-360 for 6 weeks. The drug suppressed BACE1 activity in the brain, but did not impair hearing performance and, upon neuropathological examination, did not produce the characteristic cochlear abnormalities of BACE1 −/− mice. Together, these data strongly suggest that the hearing loss of BACE1 knock-out mice represents a developmental phenotype. SIGNIFICANCE STATEMENT Given its crucial role in the pathogenesis of Alzheimer's disease (AD), BACE1 is a prime pharmacological target for AD prevention and therapy. However, the safe and long-term administration of BACE1-inhibitors as envisioned in AD requires a comprehensive understanding of the various physiological functions of BACE1. Here, we report that BACE1 is essential for the processing of auditory signals in the inner ear, as BACE1-deficient mice exhibit significant hearing loss. We relate this deficit to impaired myelination and aberrant synapse formation in the cochlea, which manifest during postnatal development. By contrast, prolonged pharmacological suppression of BACE1 activity in adult wild-type mice did not reproduce the hearing deficit or the cochlear abnormalities of BACE1 null mice.

Collision with wind turbines is a conservation concern for eagles with population abundance implications. The development of acoustic alerting technologies to deter eagles from entering hazardous air spaces is a potentially significant mitigation strategy to diminish associated morbidity and mortality risks. As a prelude to the engineering of deterrence technologies, auditory function was assessed in bald eagles (Haliaeetus leucocephalus), as well as in red-tailed hawks (Buteo jamaicensis). Auditory brainstem responses (ABRs) to a comprehensive battery of clicks and tone bursts varying in level and frequency were acquired to evaluate response thresholds, as well as suprathreshold response characteristics of wave I of the ABR, which represents the compound potential of the VIII cranial nerve. Sensitivity curves exhibited an asymmetric convex shape similar to those of other avian species, response latencies decreased exponentially with increasing stimulus level and response amplitudes grew with level in an orderly manner. Both species were responsive to a frequency band at least four octaves wide, with a most sensitive frequency of 2 kHz, and a high-frequency limit of approximately 5.7 kHz in bald eagles and 8 kHz in red-tailed hawks. Findings reported here provide a framework within which acoustic alerting signals might be developed.

Cisplatin is one of the most widely used chemotherapeutic drugs for the treatment of cancer. Unfortunately, one of its major side effects is permanent hearing loss. Here, we show that glutathione transferase α4 (GSTA4), a member of the Phase II detoxifying enzyme superfamily, mediates reduction of cisplatin ototoxicity by removing 4-hydroxynonenal (4-HNE) in the inner ears of female mice. Under cisplatin treatment, loss of Gsta4 results in more profound hearing loss in female mice compared to male mice. Cisplatin stimulates GSTA4 activity in the inner ear of female wild-type, but not male wild-type mice. In female Gsta4 −/− mice, cisplatin treatment results in increased levels of 4-HNE in cochlear neurons compared to male Gsta4 −/− mice. In CBA/CaJ mice, ovariectomy decreases mRNA expression of Gsta4 , and the levels of GSTA4 protein in the inner ears. Thus, our findings suggest that GSTA4-dependent detoxification may play a role in estrogen-mediated neuroprotection.

In order to survive and function in the world, we must understand the content of our environment. This requires us to gather and parse complex, sometimes conflicting, information. Yet, the brain is capable of translating sensory stimuli from disparate modalities into a cohesive and accurate percept with little conscious effort. Previous studies of multisensory integration have suggested that the brain's integration of cues is well-approximated by an ideal observer implementing Bayesian causal inference. However, behavioral data from tasks that include only one stimulus in each modality fail to capture what is in nature a complex process. Here we employed an auditory spatial discrimination task in which listeners were asked to determine on which side they heard one of two concurrently presented sounds. We compared two visual conditions in which task-uninformative shapes were presented in the center of the screen, or spatially aligned with the auditory stimuli. We found that performance on the auditory task improved when the visual stimuli were spatially aligned with the auditory stimuli-even though the shapes provided no information about which side the auditory target was on. We also demonstrate that a model of a Bayesian ideal observer performing causal inference cannot explain this improvement, demonstrating that humans deviate systematically from the ideal observer model.

Although human cytomegalovirus (HCMV) is a known cause of sensorineural hearing loss in infants with congenital HCMV (cCMV) infections, mechanisms that contribute to sensorineural hearing loss (SNHL) in infants with cCMV infection are not well defined. Using a murine model of CMV infection during auditory development, we have shown that peripheral infection of newborn mice with murine CMV (MCMV) results in focal infection of the cochlea and virus-induced cochlear inflammation. Approximately 50%–60% of infected mice exhibited increased auditory brainstem response (ABR) thresholds across a range of sound frequencies. Histological analyses of the cochlea in MCMV-infected mice with elevated ABR thresholds revealed preservation of hair cell (HC) number and morphology in the organ of Corti. In contrast, the number of spiral ganglion neurons (SGN), synapses, and neurites connecting the cochlear HC and SGN nerve terminals were decreased. Decreasing cochlear inflammation by corticosteroid treatment of MCMV-infected mice resulted in preservation of SGN and improved auditory function. These findings show that virus-induced cochlear inflammation during early auditory development, rather than direct virus-mediated damage, could contribute to histopathology in the cochlea and altered auditory function without significant loss of HCs in the sensory epithelium.

Foxg1 is one of the forkhead box genes that are involved in morphogenesis, cell fate determination, and proliferation, and Foxg1 was previously reported to be required for morphogenesis of the mammalian inner ear. However, Foxg1 knock-out mice die at birth, and thus the role of Foxg1 in regulating hair cell (HC) regeneration after birth remains unclear. Here we used Sox2 CreER/+ Foxg1 loxp/loxp mice and Lgr5-EGFP CreER/+ Foxg1 loxp/loxp mice to conditionally knock down Foxg1 specifically in Sox2+ SCs and Lgr5+ progenitors, respectively, in neonatal mice. We found that Foxg1 conditional knockdown (cKD) in Sox2+ SCs and Lgr5+ progenitors at postnatal day (P)1 both led to large numbers of extra HCs, especially extra inner HCs (IHCs) at P7, and these extra IHCs with normal hair bundles and synapses could survive at least to P30. The EdU assay failed to detect any EdU+ SCs, while the SC number was significantly decreased in Foxg1 cKD mice, and lineage tracing data showed that much more tdTomato+ HCs originated from Sox2+ SCs in Foxg1 cKD mice compared to the control mice. Moreover, the sphere-forming assay showed that Foxg1 cKD in Lgr5+ progenitors did not significantly change their sphere-forming ability. All these results suggest that Foxg1 cKD promotes HC regeneration and leads to large numbers of extra HCs probably by inducing direct trans-differentiation of SCs and progenitors to HCs. Real-time qPCR showed that cell cycle and Notch signaling pathways were significantly down-regulated in Foxg1 cKD mice cochlear SCs. Together, this study provides new evidence for the role of Foxg1 in regulating HC regeneration from SCs and progenitors in the neonatal mouse cochlea.

Glucocorticoid (GC) is a steroid hormone secreted from the adrenal cortex in response to stress, which acts by binding to cytoplasmic glucocorticoid receptors (GRs). Dexamethasone (DEX) is a synthetic GC exhibiting immunosuppressive effects in both human and rodent models of hearing loss. While clinical evidence has shown the effectiveness of DEX for treatment of various inner ear diseases, its mechanisms of action and the optimal timing of treatment are not well understood. In the present study, intergroup comparisons were conducted based on the time point of treatment with DEX: (1) pretreatment; (2) posttreatment; and (3) pre&post-noise. The pre&post DEX treatment group showed a significant improvement in threshold shift at 1 day post-noise exposure as compared to the TTS (transient threshold shift)-only group at 8 and 16 kHz. Both TTS and PTS (permanent threshold shift) significantly reduced cochlear GR mRNA expression and increased serum corticosterone and cochlear inflammatory cytokines. The pre&post DEX treatment group showed a significant decrease in serum corticosterone level as compared to other DEX treatment groups and TTS-treated group at 3 days after acoustic trauma. Our results suggest that the timing of DEX administration differentially modulates systemic steroid levels, GR expression and cochlear cytokine expression.

The ability to selectively attend to speech in the presence of other competing talkers is critical for everyday communication; yet the neural mechanisms facilitating this process are poorly understood. Here, we use electroencephalography (EEG) to study how a mixture of two speech streams is represented in the brain as subjects attend to one stream or the other. To characterize the speech-EEG relationships and how they are modulated by attention, we estimate the statistical association between each canonical EEG frequency band (delta, theta, alpha, beta, low-gamma, and high-gamma) and the envelope of each of ten different frequency bands in the input speech. Consistent with previous literature, we find that low-frequency (delta and theta) bands show greater speech-EEG coherence when the speech stream is attended compared to when it is ignored. We also find that the envelope of the low-gamma band shows a similar attention effect, a result not previously reported with EEG. This is consistent with the prevailing theory that neural dynamics in the gamma range are important for attention-dependent routing of information in cortical circuits. In addition, we also find that the greatest attention-dependent increases in speech-EEG coherence are seen in the mid-frequency acoustic bands (0.5–3 kHz) of input speech and the temporal-parietal EEG sensors. Finally, we find individual differences in the following: (1) the specific set of speech-EEG associations that are the strongest, (2) the EEG and speech features that are the most informative about attentional focus, and (3) the overall magnitude of attentional enhancement of speech-EEG coherence.

It is currently unclear whether mice use their ultrasonic vocalizations (USVs) for communication purposes. It is also unknown whether mice require previous experience with USVs to understand conspecifics. There is some evidence that experience changes the perception of juvenile USVs; however, it is unclear whether similar plasticity also occurs for adult USVs. To examine whether social exposure or deprivation throughout development leads to changes in USV perception, eleven female CBA/CaJ mice were trained to discriminate between 18 USVs of three different categories using operant conditioning procedures. Mice were group housed with four females or housed individually from weaning for the duration of the experiment. Socially housed and isolated mice differed in initial training times on pure tones, suggesting isolated mice had a more difficult time learning the task. Both groups completed USV discrimination conditions quicker at the end of the testing phases relative to the beginning. The overall discrimination of USVs did not differ between the two housing conditions, but a multidimensional scaling analysis revealed that socially experienced and isolated mice perceive some USVs differently, illustrated by differences in locations of USVs on the scaling maps from the two groups. Finally, a negative correlation was found between spectrotemporal similarity and percent discrimination, and analyses support the idea that mice may show categorical perception of at least two of the three USV categories. Thus, experience with USVs changes USV perception.

Animals learn to fear conditioned sound stimuli (CSs) that accompany aversive unconditioned stimuli (USs). Auditory cortex (ACx) circuits reorganize to support auditory fear learning when CS-evoked activity temporally overlaps with US-evoked acetylcholine release from the basal forebrain. Here we describe robust fear learning and acetylcholine-dependent ACx plasticity even when the US is delayed by several seconds following CS offset. A 5-s CS-US gap was not bridged by persistent CS-evoked spiking throughout the trace period. Instead, within minutes following the start of conditioning, optogenetically identified basal forebrain neurons that encode the aversive US scaled up responses to the CS and increased functional coupling with the ACx. Over several days of conditioning, bulk imaging of cholinergic basal forebrain neurons revealed sustained sound-evoked activity that filled in the 5-s silent gap preceding the US. These findings identify a plasticity in the basal forebrain that supports learned associations between sensory stimuli and delayed reinforcement.

A mutation in the Cdh23 gene is implicated in both syndromic and nonsyndromic hearing loss in humans and age-related hearing loss in C57BL/6 mice. It is generally assumed that human patients (as well as mouse models) only have a hearing loss phenotype if the mutation is homozygous. However, a major complaint for patients with a hearing disability is a reduced speech intelligibility that may be related to temporal processing deficits rather than just elevated thresholds. In this study, we used the amplitude modulation following response (AMFR) to test whether mice heterozygous for Cdh23735A > G have an auditory phenotype that includes temporal processing deficits. The hearing of mice heterozygous for the Cdh23735A > G mutation was compared with age-matched mice homozygous for either the mutation or the wild type in 3 cohorts of mice of both sexes at 2-3, 6, and 12 months of age. The AMFR technique was used to generate objective hearing thresholds for all mice across their range of hearing and to test their temporal processing. We found a genotype-dependent hearing loss in mice homozygous for the mutation starting at 5-11 weeks of age, an age when mice on the C57BL/6 background are often presumed to have normal hearing. The heterozygous animals retained normal hearing thresholds up to one year of age. Nevertheless, the heterozygous animals showed a decline in temporal processing abilities at one year of age that was independent of their hearing thresholds. These results suggest that mice heterozygous for the Cdh23 mutation do not have truly normal hearing.