Auditory Research publications

Frequency analysis by the cochlea forms a key foundation for all subsequent auditory processing. Stimulus-frequency otoacoustic emissions (SFOAEs) are a potentially powerful alternative to traditional behavioral experiments for estimating cochlear tuning without invasive testing, as is necessary in humans. Which methods accurately predict cochlear tuning remains controversial due to only a single animal study comparing SFOAE-based, behavioral, and cochlear frequency tuning in the same species. The budgerigar ( Melopsittacus undulatus ) is a parakeet species with human-like behavioral sensitivity to many sounds and the capacity to mimic speech. Intriguingly, previous studies of critical bands, psychophysical tuning curves, and critical ratios in budgerigars show that behavioral tuning sharpness increases dramatically with increasing frequency from 1 to 3.5 kHz, doubling once per octave with peak tuning sharpness from 3.5 to 4 kHz. The pattern contrasts with slower monotonic growth of behavioral tuning sharpness with increasing frequency in other animals, including most avian species, suggesting a possible auditory specialization in budgerigars. We measured SFOAE-based and cochlear-afferent tuning in budgerigars, for comparison to previously reported behavioral results. SFOAE-based and cochlear-afferent tuning sharpness both increased monotonically and relatively slowly for higher frequencies, in contrast to the behavioral pattern. SFOAE-based tuning in budgerigars accurately predicted cochlear frequency tuning, and both measures aligned with typical patterns of cochlear tuning in other species. Divergent behavioral tuning in budgerigars is unlikely attributable to the periphery and could reflect specializations for central processing of masked signals. Our findings highlight the value of SFOAEs for estimating cochlear tuning and caution against direct inference of peripheral tuning from behavioral critical bands, psychophysical tuning curves, and critical ratios.

A crucial aspect of auditory perception is the ability to use sound cues to predict future events and to time actions accordingly. For example, the sound of an approaching vehicle signals when it is safe to cross the street; distinct smartphone notification sounds reflect a call that needs to be answered within a few seconds, or a text that can be read later. Other animals similarly use sounds to plan, time and execute behaviors such as hunting, evading predation and tending to offspring. However, the neural mechanisms that underlie sound-guided prediction of upcoming salient event timing are not well understood. To address this gap, we employed an appetitive sound-triggered reward time prediction behavior in head-fixed mice. We find that mice trained on this task reliably estimate the time from a sound cue to upcoming reward on the scale of a few seconds, as demonstrated by learning-dependent well-timed increases in predictive licking for reward. Moreover, mice showed a dramatic impairment in their ability to use sound to predict delayed reward when the auditory cortex was inactivated, demonstrating its causal involvement. To identify the neurophysiological signatures of auditory cortical reward-timing prediction, we recorded local field potentials during learning and performance of this behavior and found that the magnitude of auditory cortical responses to the sound prospectively encoded the duration of the anticipated sound-reward time interval. Next, we explored how and where these sound-triggered time interval prediction signals propagate from the auditory cortex to time and initiate consequent action. We targeted the monosynaptic projections from the auditory cortex to the posterior striatum and found that chemogenetic inactivation of these projections impaired animals’ ability to predict sound-triggered delayed reward. Simultaneous neural recordings in the auditory cortex and posterior striatum during task performance revealed coordination of neural activity across these regions during the sound cue predicting the time interval to reward. Collectively, our findings identify an auditory cortical-striatal circuit supporting sound-triggered timing-prediction behaviors.

The preservation of synaptic integrity and physiological activity is pivotal for post-traumatic auditory rehabilitation following acoustic overexposure. Neuritin, a neurotrophic factor that facilitates synapse formation, maturation, and enhanced synaptic transmission, is essential for synapse development. In this study, we established a noise-induced cochlear synaptopathy model in CBA/CaJ mice, revealing a temporal association between endogenous Neuritin expression and synaptic density. Furthermore, administration of recombinant Human Neuritin (rhNeuritin) effectively preserves synaptic density in the cochlear basal turn at 7 days and 14 days following noise exposure. Importantly, it preserves the density of functional synapses (represented by overlapping CtBP2 and GluA2 puncta) and synapse function (indicated by ABR I wave amplitudes), thus diminishing the impairment of auditory function. In addition, rhNeuritin reverses the decrease in phosphorylated extracellular signal-regulated protein kinase 1/2 (p-ERK1/2) levels resulting from noise exposure. By primarily preserving both the number and functionality of synapses in the basal turn, potentially via the induction of ERK1/2 phosphorylation, rhNeuritin mitigated hearing loss. These findings underscore the protective efficacy of rhNeuritin against noise-induced synaptic injury.

Rett syndrome (RTT) is a neurodevelopmental disorder primarily caused by loss-of-function mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene. Genetic restoration of MECP2 in mice can reverse phenotypes, providing hope for disease-modifying therapies in the disease. Studies in people with and mouse models of RTT have identified neurophysiological features, such as auditory event-related potentials (AEPs), that correlate with disease severity, suggesting potential as translatable biomarkers. We have identified reductions in the expression and function of the group III metabotropic glutamate receptor 7 (mGlu7), a G protein-coupled receptor regulating presynaptic neurotransmitter release, in both human and mouse RTT brains. Additionally, treatment of RTT mice with a positive allosteric modulator (PAM) of the group III mGlu receptors (VU0422288) improves behavioral phenotypes, most likely via mGlu7 potentiation. To evaluate whether VU0422288 treatment modulates neurophysiological biomarkers, we acutely treated RTT mice with VU0422288 at 3,10, and 30 mg/kg and assessed neurophysiological features. VU0422288 treatment caused increases in AEP peak amplitudes in RTT mice but not in wild-type controls, with no effect on basal electroencephalogram power. Treatment with a different compound, ADX88178, a PAM that activates the mGlu4, 6and 8 receptors, did not affect neurophysiological assessments, suggesting that the target of VU0422288 is likely mGlu7. These findings suggest that neurophysiological features, like AEP, have potential as sensitive and quantitative biomarkers that may be useful in evaluating mGlu7 PAMs and other pharmacological interventions as novel RTT treatment strategies. SIGNIFICANCE STATEMENT: Correlations between neurophysiological features and disease severity in Rett syndrome suggest their potential as translatable biomarkers sensitive to pharmacological modulation. This study demonstrates that potentiation of group III metabotropic glutamate receptors improves neurophysiological features in Rett syndrome mice.

Aging is associated with deficits in auditory functioning. Characterization of auditory deficits that originate in middle-age is crucial for understanding the initial age-related functional impairments and the spatio-temporal progression of age-related auditory pathophysiology. Early age-related deficits in auditory processing are evident in difficult listening conditions, such as background noise, before becoming evident in quiet. To investigate the effect of noise on age-related auditory dysfunction, we collected suprathreshold auditory brainstem responses (ABRs) from young, middle-aged, and aged CBA/CaJ mice in quiet and broad-band background noise. We utilized multiple ABR metrics, including phase locking value (PLV), a measure of neural synchrony correlated to speech-in-noise understanding in humans. Despite no differences in auditory processing in quiet between young and middle-aged mice, middle-aged mice exhibited a distinct auditory phenotype from both young and aged mice in background noise conditions. We found that noise significantly decreased amplitude in middle-aged mice more than in young and aged mice. Noise significantly increased latencies for wave I and V in young mice, but only affected wave V in middle-aged mice and did not affect aged latencies. Noise significantly decreased PLV in middle-aged mice to a greater extent than in young mice, but to a lesser extent in aged mice. These results show that middle-aged mice have a distinct, auditory dysfunction phenotype evident in background noise. Our data show that suprathreshold auditory function in noise can identify early age-related hearing loss and can be used as a sensitive tool for detecting auditory dysfunction in normal hearing animal models.

Noise-induced hearing loss (NIHL) poses an emerging global health problem with only ear protection or sound avoidance as preventive strategies. The cochlea receives some protection from medial olivocochlear efferent neurons, providing a potential target for therapeutic enhancement. Cholinergic efferents release acetylcholine (ACh) to hyperpolarize and shunt the outer hair cells (OHCs), reducing sound-evoked activation. The (α9)2(α10)3 nicotinic ACh receptor (nAChR) on the OHCs mediates this effect. Transgenic knockin mice with a gain-of-function nAChR (α9L9'T) suffer less NIHL. α9 knockout mice are more vulnerable to NIHL but can be rescued by viral transduction of the α9L9'T subunit. In this study, an HA-tagged gain-of-function α9 isoform was expressed in wild-type mice to reduce NIHL. Synaptic integration of the virally expressed nAChR subunit was confirmed by HA immunopuncta localized to the postsynaptic membrane of OHCs. After noise exposure, AAV2.7m8-CAG-α9L9'T-HA (α9L9'T-HA)-injected mice had less hearing loss (auditory brainstem response [ABR] thresholds and threshold shifts) than did control mice. ABRs of α9L9'T-HA-injected mice also had larger wave-1 amplitudes and better recovery of wave-1 amplitudes post noise exposure. Thus, virally expressed α9L9'T combines effectively with native α9 and α10 subunits to mitigate NIHL in wild-type cochleas.

Socially effective vocal communication requires brain regions that encode expressive and receptive aspects of vocal communication in a social context-dependent manner. Here, we combined a novel behavioral assay with microendoscopic calcium imaging to interrogate neuronal activity (regions of interest [ROIs]) in the posterior insula (pIns) in socially interacting mice as they switched rapidly between states of vocal expression and reception. We found that largely distinct subsets of pIns ROIs were active during vocal expression and reception. Notably, pIns activity during vocal expression increased prior to vocal onset and was also detected in congenitally deaf mice, pointing to a motor signal. Furthermore, receptive pIns activity was modulated strongly by social context. Lastly, tracing experiments reveal that deep-layer neurons in the pIns directly bridge the auditory thalamus to a midbrain vocal gating region. Therefore, the pIns is a site that encodes vocal expression and reception in a manner that depends on social context.

Aminoglycoside antibiotics remain indispensable despite their ototoxicity. Like other sensorineural forms, aminoglycoside-induced hearing loss (AGIHL) has no effective pharmacotherapy. Oxidative stress, apoptosis, excitotoxicity and inflammation are key pathological factors of the disease. We hypothesised that selegiline, an irreversible monoamine oxidase-B (MAO-B) inhibitor used in Parkinson’s disease, could be repurposed as an otoprotective agent against AGIHL and its effect on dopamine (DA) release from lateral olivocochlear (LOC) fibres, the efferent division of a protective feedback loop plays a major role in the protection against excitotoxicity. Selegiline mitigated AGIHL in BALB/c mice in a dose-dependent manner at different auditory brainstem response frequencies, including 16 kHz, the hearing sensitivity optimum of the animals. It also enhanced the action potential-evoked DA release from LOC efferents in mouse cochlear preparation dose-dependently. Inhibition of DA reuptake contributed to its basic effect of saving DA from metabolism. Among four selegiline analogues tested, the one that increased LOC DA release also provided otoprotection. In contrast, neither safinamide (a reversible MAO-B inhibitor) nor LJP-1207 (a selective semicarbazide-sensitive amine oxidase/vascular-adhesion protein 1 (SSAO/VAP1) inhibitor) prevented AGIHL, despite their antioxidant and anti-inflammatory properties. The reversibility or lack of MAO-B inhibition in safinamide and LJP-1207, respectively, as well as the absence of the propargylamine moiety with known intrinsic neuroprotective activity in both molecules, may explain their ineffectiveness. Selegiline, or certain propargylamine analogues of it, offer a promising therapy against AGIHL by addressing its multifactorial pathology through antioxidant, antiapoptotic, neuroprotective, and anti-inflammatory actions, while enhancing endogenous DAergic protective mechanisms.

The genus Peromyscus has been extensively used as a model for ecological, behavioral, and evolutionary studies. This study used auditory brainstem responses (ABRs), craniofacial morphology, and pinna measurements to compare two wild-caught species, Peromyscus leucopus and Peromyscus maniculatus. It was observed that P. leucopus exhibited larger features and bigger overall size compared to P. maniculatus. ABR recordings showed similar hearing thresholds with peak sensitivity between 8 and 46 kHz for both species. There were no significant differences between species for absolute amplitudes of waves IV and I, with significantly higher amplitude ratio of wave IV to wave I in P. leucopus across intensities. There were also species differences (faster wave I in P. maniculatus) and sex differences (faster wave I in female P. leucopus) for absolute latency, which were no longer significant when considering inter-peak latency between waves I and IV. Finally, faster normalized latencies of the binaural interaction component (BIC) were observed in P. maniculatus, while no differences were observed across relative BIC amplitude between species. These results provide additional ABR related data that expand the use of both Peromyscus species as future models for auditory research.

The neural processes that change when falling asleep are only partially understood. At the cortical level, features of both spontaneous neural activity and sensory responses change between wakefulness and sleep. For example, in the early auditory cortex, sleep increases the occurrence of postonset silent (OFF) periods and elevates population synchrony. However, it remains unknown whether such changes occur abruptly or gradually around sleep onset and awakening. Here, we recorded spontaneous and sound-evoked neuronal spiking activity in the early auditory cortex along with polysomnography during thousands of episodes when male rats fell asleep or woke up. We found that when falling asleep, stimulus-induced neuronal silent periods (OFF periods), characteristic of nonrapid eye movement sleep, increased within a few seconds around sleep onset. In contrast, a gradual increase in neuronal population synchrony built up over tens of seconds until reaching maximal levels. EEG auditory-evoked potentials likely representing stimulus-triggered “K-complexes” changed along with postonset neuronal firing, whereas ongoing EEG slow-wave activity was associated with neuronal population synchrony. Similar effects, but with opposite direction, were observed around awakenings. The results highlight late stimulus-induced neuronal silence as a key feature changing abruptly around transitions between vigilance states, likely reflecting neuronal bistability and manifesting also in EEG-evoked potentials. More generally, these findings emphasize the added value of going beyond monitoring ongoing activity and perturbing the nervous system to reveal its state—an insight that could also help guide the development of more sensitive noninvasive monitors of falling asleep in humans.

Background/Objectives: Obesity is a risk factor for several diseases; however, less has been researched about how diet-induced obesity may affect the auditory system. In this sense, the purpose of this study was to evaluate the effect of diet-induced obesity on the functionality and integrity of the outer hair cells, a key component of the organ of Corti, inside the cochlea. Furthermore, we hypothesized that adipose tissue (AT) status is associated with impaired outer hair cell auditory amplification in young C57BL/6 mice, contributing to increased vulnerability to hearing damage. Methods: Weaning male C57BL/6J mice (7 weeks old) weighing 22–23 g were divided into two diet groups: (i) a control diet or (ii) a high-fat diet (HFD) for 12 or 16 weeks. Metabolic parameters (body and AT weight, glucose tolerance test), AT dysfunction markers (AT remodeling, adipocyte size, crown-like structures), and outer hair cell function (distortion products otoacoustic emissions (DPOAEs) threshold and amplitudes) and integrity (hair cells cell count) were evaluated. Results: We observed that mice fed an HFD for 16 weeks showed a higher DPOAE threshold against stimuli at 16 KHz and a lower count of outer hair cells in the medial section of the cochlea. These results demonstrate a correlation between body and AT weight specifically at 16 weeks of treatment, the time point at which we observed a marked AT dysfunction. Conclusions: Taken together, our results suggest that obese mice with AT dysfunction have an altered auditory efferent system, characterized by a higher DPOAE threshold and a lower outer hair cell count in the medial section, which may impact signal transduction.

Cisplatin‐induced ototoxicity remains a clinical dilemma with limited mechanistic understanding and no food and drug administration (FDA)‐approved therapies. Despite emerging roles of small extracellular vesicles (sEV) in drug ototoxicity, their molecular cargo profiles and causal roles to cisplatin‐induced ototoxicity are unexplored. This study systematically investigates sEV derived from cochlear explants treated with cisplatin (Cis‐sEV) and controls (Ctrl‐sEV) using multi‐omics profiling. Through small RNA sequencing, 83 differentially expressed microRNAs (miRNAs) are identified in Cis‐sEV compared to Ctrl‐sEV. Notably, mmu‐miR‐34a‐5p, mmu‐miR‐140‐5p, mmu‐miR‐15b‐5p, mmu‐miR‐25‐3p, and mmu‐miR‐339‐5p are significantly upregulation in Cis‐sEVs. Predicted target pathways of these differentially expressed miRNAs are enriched in apoptosis, inflammation, and cellular damage, indicating their potential involvement in cisplatin‐induced cochlear damage. LC‐MS/MS analysis reveals 90 upregulated and 150 downregulated proteins in Cis‐sEV, with many involved in damage response. Specifically, CLTC, CCT2, ANXA6, and HSPA8 are uniquely upregulated proteins in Cis‐sEV, and CLTC and ANXA6 are exclusively co‐localized in hair cells (HCs) post‐cisplatin exposure, suggesting that Cis‐sEV originate primarily from damaged HCs. Moreover, CLTC in sEV may serve as a potential biomarker for cisplatin‐induced ototoxicity as verified in both in vitro and in vivo models. This study provides novel insights into the molecular mechanisms of cisplatin‐induced ototoxicity and identifies potential biomarker and therapeutic targets.

The entire auditory system downstream of the cochlea features pronounced offset responses, which follow the termination of sounds. Because of their ubiquity, it is still an unsolved question whether offset responses are generated early in the auditory system and then propagated or recomputed at each processing stage. Here, we analysed large-scale sound responses datasets acquired in the cochlear nucleus, inferior colliculus, medial geniculate nucleus and auditory cortex of awake mice. All brain regions showed a significant proportion of offset responses often combined with onset and sustained responses in the same neuron. However, using population activity decoders, we observed that neural representations after the sound offset show a three-fold increase in sound encoding accuracy in the cortex relative to subcortical areas. This result indicates that cortical offsets encode a more precise short-term memory of the elapsed sound than subcortical offsets and that they likely result from specific computational steps. Key points summary Offset responses are found throughout the central auditory system Offset responses are often combined to sustained and onset responses at all central auditory system stages Offset responses provide richer information about elapsed sounds in the auditory cortex

Purpose Present-day cochlear-implant (CI) users can achieve high levels of speech reception in quiet surroundings. Nevertheless, sensitivity to the temporal pitch of sounds is limited, which contributes to deficits in speech reception amid multiple talkers and in appreciation of musical melodies. Short-term, invasive neurophysiological studies in animals have demonstrated limitations in neural phase locking in the tonotopic range of the auditory pathway that is activated by CIs. It remains an open question, however, whether those neural limitations can account for perceptual deficits in those animal species, let alone in human CI users. For that reason, we have evaluated non-invasive recordings of phase locking from cats chronically implanted with a CI. Methods Ten deafened cats (eight female) were implanted with an animal version of a clinical CI array. The electrically evoked frequency following response (eFFRs) was recorded from the scalps of sedated animals at ≥ 10 weeks post-implantation. Stimuli consisted of constant-amplitude electrical pulse trains at rates from ~ 40 to 640 pulses per second. Results Recordings of the eFFR demonstrated robust responses synchronized to electrical pulse trains across all stimulus rates. Analyses of eFFR amplitude and phase transfer functions confirmed that the eFFR, as with its normal-hearing counterpart, originates from multiple subcortical and cortical generators. The slopes of segments of eFFR phase transfer functions revealed stimulus-to-response latencies of generators that dominated the eFFR across restricted ranges of pulse rates. Those rate ranges must coincide with the limits of phase locking by putative generators at successive levels of the auditory neuroaxis and could inform our understanding of the limits to perceptual temporal acuity. Conclusion The eFFR demonstrated here in an animal model provides a valuable non-invasive measure of temporal processing in electric cochlear stimulation that can be related to ongoing perceptual measures in the same animals and is well-suited to evaluate novel modes of auditory prosthesis for enhancing temporal acuity.

Many animal training paradigms rely on head-fixation. Head-fixation training is typically laborious and can benefit from automation to relieve the workload and reduce the variability in the training outcome. Several groups have reported successful implementations of such systems, but throughput varied greatly across groups. In addition, most studies relied on brief periods of head-fixation sessions (≤ 1 minute) to reduce the potential stress on the animal. Here, we report the design of a new system that could achieve head-fixation sessions on the order of minutes with a high participation rate from the animal (100%). Throughout the training period, each mouse performed a total of close to 40 minutes of head-fixation training on average each day and learned common psychoacoustic tasks, i.e., tone detection and tone discrimination. Our system can achieve highly efficient training with minimum idling time, allowing combinations with high-end neural recording equipment to achieve maximum training and data collection efficiency.

For patients with severe and profound hearing loss, cochlear implant (CI), a common and effective modality for restoring hearing, directly stimulates spiral ganglion neurons (SGNs) to generate electrical activity and form auditory perception. However, the postoperative outcome of CI is significantly influenced by the number of surviving SGNs, ​​which is a key focus of preoperative evaluation​​. Existing audiologic function and radiographic tests cannot directly demonstrate the integrity of inner ear primary neurons. In this study, ​​we developed and validated​​ a radionuclide‐labeled anti‐vesicular glutamate transporter 1 (anti‐VGLUT1) antibody‐drug and achieved animal‐level in vivo imaging of cochlear SGNs using nuclear imaging. By screening the public single‐cell sequencing database, it is found that VGLUT1 can serve as a representative cell membrane marker for SGN in the cochlea. The potential of anti‐VGLUT1 conjugated to the long half‐life 177 Lu as a molecular probe to detect the relative number of SGNs in SGN‐injured mouse and pig models is explored. The study provides a novel method for assessing cochlear nerve integrity in vivo by visualizing target antigen expression levels through nuclear imaging. This approach is promising to help CI candidates with preoperative inner ear SGN integrity assessment, contributing to clinical decision‐making.

The role of P2X4, one of the most abundant ionotropic purinergic receptors in the central nervous system, is explored here in the context of auditory function. We observed, by using constitutive and conditional P2X4mCherryIN knock-in adult mouse models, a specific high expression of mCherry-tagged P2X4 in living cochlear outer hair cells (OHCs), from immature postnatal stages to adulthood. This P2X4-mCherry expression, confirmed by immuno-confocal fluorescence microscopy in wild-type mice, was mainly concentrated in the intracellular apical region of the OHCs, in the area of the Hensen’s body, a lysosomal rich region, specifically labeled with the fluorescent dye lysotracker. In addition, the basal cholinergic efferent synaptic region of the OHCs was found to express P2X4 at the cell membrane. Surprisingly, the assessment of the hearing function in constitutive P2X4 knock-out (P2X4KO) mice showed improved auditory brainstem responses with smaller latencies, larger amplitudes and smaller thresholds. These P2X4KO mice, as well as conditional P2X4KO-Myo15-Cre mice, displayed enhanced distortion product otoacoustic emissions (DPOAEs), suggesting an improved electromechanical ‘amplification’ activity by OHCs. These mutant animals showed reduced inhibition of DPOAEs by contralateral noise, consistent with a weaker inhibitory effect of the medial cholinergic olivocochlear efferent circuit (MOC) on OHCs. We concluded that the MOC negative feedback modulation of cochlear micromechanics, in addition to involve Ca 2+ permeable α9/α10 nicotinic receptors, also requires the activation of postsynaptic P2X4 receptors in OHCs. SIGNIFICANCE STATEMENT Our study reveals a specific strong expression of P2X4 in mouse cochlear outer hair cells (OHCs), these cells being essential for generating the distortion products otoacoustic emissions (DPOAES) and tuning the sensitivity and frequency selectivity of the cochlea. Mice lacking P2X4 showed a deficient inhibitory control of their cochlear DPOAEs when activating the medial olivocochlear efferent pathway innervating the OHCs. We propose P2X4 receptors as an important Ca 2+ regulatory component of the micromechanics of OHCs and that genetic defects in these purinergic receptors may potentially lead to hearing disorders such as tinnitus and hyperacusis.

Animals have evolved complex auditory systems to extract acoustic information from natural environmental noise, yet they are challenged by rising levels of novel anthropogenic noise. Songbirds adjust their vocal production in response to increasing noise, but auditory processing of signals in noise remains understudied. Auditory processing characteristics, including auditory filter bandwidth, filter efficiency and critical ratios (level-independent signal-to-noise ratios at threshold), likely influence auditory and behavioral responses to noise. Here, we investigated the effects of noise on auditory processing in three songbird species (black-capped chickadees, tufted titmice and white-breasted nuthatches) that live in mixed-species flocks and rely on heterospecific communication to coordinate mobbing behaviors. We determined masked thresholds and critical ratios from 1 to 4 kHz using auditory evoked potentials. We predicted that nuthatches would have the lowest critical ratios given that they have narrowest filters, followed by titmice and then chickadees. We found that nuthatches had the greatest sensitivity in quiet conditions, but the highest critical ratios, suggesting their auditory sensitivity is highly susceptible to noise. Titmice had the lowest critical ratios, suggesting relatively minor impacts of noise on their auditory processing. This is not consistent with predictions based on auditory filter bandwidth, but is consistent with both recent behavioral findings and predictions made by auditory filter efficiency measures. Detrimental effects of noise were most prevalent in the 2–4 kHz range, frequencies produced in vocalizations. Our results using the critical ratio as a measure of processing in noise suggest that low levels of anthropogenic noise may influence these three species differently.

Purpose Whrn , encoding whirlin, is one of the genes highly relevant to Usher syndrome (USH) that has been known as an autosomal recessive genetic disorder that is characterized with sensorineural hearing loss with retinitis pigmentosa. Although recent studies on the other USH genes, PDZD7 and Ush1 g , showed a possibility of haploinsufficiency effect, the potential contribution of heterozygous Whrn loss to hearing loss remains unclear. Methods To investigate the effect of Whrn haploinsufficiency, we conducted a longitudinal study assessing auditory function in heterozygous Whrn mutant ( Whrn + /− ) mice in which long isoform of Whrn was deleted by replacing exon 1 with Neo cassette without disturbing short isoform. The threshold of auditory brainstem responses (ABRs) was measured on 135 Whrn +/ − mice and littermate 133 wild-type (WT) mice from 1 to 6 months of ages. From those data, the threshold from male and female were separately analyzed to investigate sex-dependent effect. To further investigate underlie mechanisms, hair cell death was investigated using immunohistostaining from 4 to 5 WT, 5 female Whrn + /− , and 7 male Whrn + /− mice at 4–5 months old. Results Hearing threshold was significantly increased with aging in Whrn + /– mice compared to WT controls. Both WT and Whrn + /– mice exhibited sex-dependent variations in hearing sensitivity. Notably, Whrn + /– males showed a progressive hearing loss with age, while Whrn + /– females exhibited elevated hearing thresholds as early as 1–2 month of age compared to WT females. Conclusion These results provide evidence for a haploinsufficiency effect of Whrn on auditory function and highlight its potential role in progressive sensorineural hearing loss.

The postnatal brain undergoes substantial plasticity in order to represent features and statistics of the sensory world. To date, for technical reasons it has been difficult to examine experience-dependent changes over the course of postnatal development. Here we perform longitudinal two-photon calcium imaging of hundreds of neurons in the auditory cortex of young mice, from postnatal day (P) 12 into adulthood. Auditory cortical neurons started responding to tonal stimuli by P13-14 with an initial tonotopic organization that expanded over the next few days. We documented the daily variation in tuning curves and best frequency, and while some neurons gradually changed their frequency representation across days, altogether our findings support the functional maturation of a largely stable auditory map at the population level. We then compared the representation of mouse pup ultrasonic vocalizations to pure tone responses. Ultrasonic pure tone tuning developed with a delay, coinciding with emerging responses to ultrasonic vocalizations. Vocalization responses initially were observed in neurons tuned to ultrasonic frequencies, but over later development the vocalization responses became independent from ultrasonic frequency tuning. Our results show how varied sensory representations at the single-cell and population levels in the postnatal auditory cortex emerge and change over the course of early-life development.