Auditory Research publications

Introduction The leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) is a tissue resident stem cell marker, which it is expressed in supporting cells (SCs) in the organ of Corti in the mammalian inner ear. These LGR5+ SCs can be used as an endogenous source of progenitor cells for regeneration of hair cells (HCs) to treat hearing loss and deafness. We have recently reported that LGR5+ SCs survive 1 week after ototoxic trauma. Here, we evaluated Lgr5 expression in the adult cochlea and long-term survival of LGR5+ SCs following severe hearing loss. Methods Lgr5GFP transgenic mice and wild type mice aged postnatal day 30 (P30) and P200 were used. P30 animals were deafened with a single dose of furosemide and kanamycin. Seven and 28 days after deafening, auditory brainstem responses (ABRs) were recorded. Cochleas were harvested to characterize mature HCs and LGR5+ SCs by immunofluorescence microscopy and quantitative reverse transcription PCR (q-RT-PCR). Results There were no significant age-related changes in Lgr5 expression when comparing normal-hearing (NH) mice aged P200 with P30. Seven and 28 days after ototoxic trauma, there was severe outer HC loss and LGR5 was expressed in the third row of Deiters’ cells and in inner pillar cells. Seven days after induction of ototoxic trauma there was an up-regulation of the mRNA expression of Lgr5 compared to the NH condition; 28 days after ototoxic trauma Lgr5 expression was similar to NH levels. Discussion The presence of LGR5+ SCs in the adult mouse cochlea, which persists after severe HC loss, suggests potential regenerative capacity of endogenous cochlear progenitor cells in adulthood. To our knowledge, this is the first study showing not only long-term survival of LGR5+ SCs in the normal and ototoxically damaged cochlea, but also increased Lgr5 expression in the adult mouse cochlea after deafening, suggesting long-term availability of potential target cells for future regenerative therapies.

Objectives This study investigated the effect of synchronized activation of automatic gain control (AGC) on sound-localization and speech-recognition performance in cochlear implant users who use a contralateral hearing aid (bimodal listeners). Bimodal listeners often have poor spatial-hearing abilities, which could be partly due to perturbed interaural spatial acoustic cues from the two devices, as these act independently and provide incongruent or mismatched information. Synchronized AGC activation may remove this perturbation and improve spatial hearing. Design Ten bimodal listeners were fitted with a bimodal prototype allowing real-time communication between hearing aid and CI. They were tested for their horizontal localization ability of brief (150 ms) noise bursts presented in the frontal hemisphere. To test for frequency- and level-specific effects, sounds were band-passed (broadband 0.25-6 kHz, high-pass 1.5-6 kHz, and low-pass 0.25-0.85 kHz) and presented at levels of 50 and 80 dBA (i.e., below and above AGC activation threshold). Speech-in-noise recognition was assessed for short sentences presented at 75 dBA with a noise-adaptive algorithm. Sentences were presented from the front, with the noise presented either from the front or at a horizontal angle of ±70 deg. The sound-localization and speech-recognition tests were performed both with independently acting and synchronized AGC settings. Results Localization bias (mean error [95% confidence interval lower, upper range]) varied with sound type: -46 [-53, -38], -31 [-37, -23] and -2 [-16, 10] deg for high-pass, broadband and low-pass sounds, respectively. AGC synchronization did not systematically affect bias (paired difference in mean error with independent and synchronized AGCs: 6 [-3, 20] deg). However, AGC synchronization did reduce sound-localization error variability for 80-dB broadband sounds by 15 [6, 26] deg from an error standard deviation of 67 [63, 77] to 52 [45, 59] deg for independent and synchronized AGCs, respectively (no systematic difference was found for 50-dB and the high-pass and low-pass sounds). Speech-in-noise thresholds differed for noise presented from the front (0.3 [-1.3, 1.1] dB), implanted side (0.6 [-1.3, 2.3] dB), and non-implanted side (-2.4 [-4.6, 0.1] dB), but synchronization did not have an effect in these conditions. However, spatial release from masking thresholds did improve with synchronization when the noise was presented at the hearing-aid side: -2.7 [-4.5, -0.6] dB. Conclusions AGC synchronization improved the localization of broadband sounds presented above the AGC activation threshold in bimodal listeners. This is in line with the hypothesis that bimodal interaural level differences can be preserved for loud broadband sounds through AGC synchronization. Synchronization did not compromise the listener’s speech perception abilities, despite the reduction of the level of speech when AGC kicks in. Moreover, spatial release from masking was enhanced, suggesting that improved spatial hearing benefits speech recognition in noise

Background Age-related hearing loss, known as presbycusis, is the result of auditory system degeneration. Numerous studies have suggested that reactive oxygen species (ROS) and mitochondrial oxidative damage play important roles in the occurrence and progression of aging. The D-galactose (D-gal)-induced aging model is well known and widely utilized in aging research. Our previous studies demonstrate that administration of D-gal causes mitochondrial oxidative damage and causes subsequent dysfunction in the cochlear ribbon synapses, which in turn leads to hearing changes and early stage presbycusis. Stria vascularis (SV) cells are vital for hearing function. However, it is unclear to what extent D-gal induces oxidative damage and apoptosis in the cochlear SV of mice. In addition, the source of the causative ROS in the cochlear SV has not been fully investigated. Methods In this study, we investigated ROS generation in the cochlear SV of mice treated with D-gal. Hearing function was measured using the auditory brainstem response (ABR). Immunofluorescence was used to examine apoptosis and oxidative damage. Transmission electron microscopy was also used to investigate the mitochondrial ultrastructure. DNA fragmentation was determined using the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) assay. Mitochondrial membrane potential (MMP) and ATP were also measured. Results We found that D-gal-treated mice exhibited a significant shift in the mean amplitude and latency of the ABR; a remarkable increase in the levels of NADPH oxidase (NOX-2), Uncoupling protein 2 (UCP2) and cleaved caspase-3 (c-Cas3) was observed, as well as an increase in the number of TUNEL-positive cells were observed in the SV of mice. Both the expression of the DNA oxidative damage biomarker 8-hydroxy-2-deoxyguanosine (8-OHdG) and a commonly occurring mitochondrial DNA deletion were markedly elevated in the SV of mice that had been treated with D-gal to induce aging. Conversely, the ATP level and MMP were significantly reduced in D-gal-induced aging mice. We also found alterations in the mitochondrial ultrastructure in the SV of aging mice, which include swollen and distorted mitochondrial shape, shortened and thickened microvilli, and the accumulation of lysosomes in the SV. Conclusion Our findings suggest that the impairment of cochlear SV during presbycusis may be caused by mitochondrial oxidative damage and subsequent apoptosis.

Receivers of acoustic communication signals evaluate signal features to identify conspecifics. Changes in the ambient temperature can alter these features, rendering species recognition a challenge. To maintain effective communication, temperature coupling—changes in receiver signal preferences that parallel temperature-induced changes in signal parameters—occurs among genetically coupled signallers and receivers. Whether eavesdroppers of communication signals exhibit temperature coupling is unknown. Here, we investigate if the parasitoid fly Ormia ochracea , an eavesdropper of cricket calling songs, exhibits song pulse rate preferences that are temperature coupled. We use a high-speed treadmill system to record walking phonotaxis at three ambient temperatures (21, 25, and 30°C) in response to songs that varied in pulse rates (20 to 90 pulses per second). Total walking distance, peak steering velocity, angular heading, and the phonotaxis performance index varied with song pulse rates and ambient temperature. The peak of phonotaxis performance index preference functions became broader and shifted to higher pulse rate values at higher temperatures. Temperature-related changes in cricket songs between 21 and 30°C did not drastically affect the ability of flies to recognize cricket calling songs. These results confirm that temperature coupling can occur in eavesdroppers that are not genetically coupled with signallers.

Difference limens for fundamental frequency (F0), F0DLs, are usually small for complex tones containing low harmonics that are resolved in the auditory periphery, but worsen when the rank of the lowest harmonic increases above about 6–8 and harmonics become less resolved. The traditional explanation for this, in terms of resolvability, has been challenged and an alternative explanation in terms of harmonic rank was suggested. Here, to disentangle the effects of resolvability and harmonic rank the complex tones were presented either diotically (all harmonics to both ears) or dichotically (even and odd harmonics to opposite ears); the latter increases resolvability but does not affect harmonic rank. F0DLs were measured for 14 listeners for complex tones containing harmonics 6–10 with F0s of 280 and 1400 Hz, presented diotically or dichotically. For the low F0, F0DLs were significantly lower for the dichotic than for the diotic condition. This is consistent with a benefit of increased resolvability of harmonics for F0 discrimination and extends previous results to harmonics as low as the sixth. In contrast, for the high F0, F0DLs were similar for the two presentation modes, adding to evidence for differences in pitch perception between tones with low-to-medium and very-high frequency content.

Mutations in Atp2b2 , an outer hair cell gene, cause dominant hearing loss in humans. Using a mouse model Atp2b2 Obl /+ , with a dominant hearing loss mutation (Oblivion), we show that liposome-mediated in vivo delivery of CRISPR-Cas9 ribonucleoprotein complexes leads to specific editing of the Obl allele. Large deletions encompassing the Obl locus and indels were identified as the result of editing. In vivo genome editing promotes outer hair cell survival and restores their function, leading to hearing recovery. We further show that in a double-dominant mutant mouse model, in which the Tmc1 Beethoven mutation and the Atp2b2 Oblivion mutation cause digenic genetic hearing loss, Cas9/sgRNA delivery targeting both mutations leads to partial hearing recovery. These findings suggest that liposome-RNP delivery can be used as a strategy to recover hearing with dominant mutations in OHC genes and with digenic mutations in the auditory hair cells, potentially expanding therapeutics of gene editing to treat hearing loss.

Background Behavior consists of the interaction between an organism and its environment, and is controlled by the brain. Brain activity varies at sub-second time scales, but behavioral measures are usually coarse (often consisting of only binary trial outcomes). Results To overcome this mismatch, we developed the Rat Interactive Foraging Facility (RIFF): a programmable interactive arena for freely moving rats with multiple feeding areas, multiple sound sources, high-resolution behavioral tracking, and simultaneous electrophysiological recordings. The paper provides detailed information about the construction of the RIFF and the software used to control it. To illustrate the flexibility of the RIFF, we describe two complex tasks implemented in the RIFF, a foraging task and a sound localization task. Rats quickly learned to obtain rewards in both tasks. Neurons in the auditory cortex as well as neurons in the auditory field in the posterior insula had sound-driven activity during behavior. Remarkably, neurons in both structures also showed sensitivity to non-auditory parameters such as location in the arena and head-to-body angle. Conclusions The RIFF provides insights into the cognitive capabilities and learning mechanisms of rats and opens the way to a better understanding of how brains control behavior. The ability to do so depends crucially on the combination of wireless electrophysiology and detailed behavioral documentation available in the RIFF.

Lots of adrenergic receptors (ARs) are widely present across the auditory pathways and are positioned to affect auditory and vestibular functions. However, noradrenergic regulation in the cochlea has not been well characterized. In this study, a rat model of noise-induced hearing loss was developed to investigate the expression of α2A-adrenergic receptor (AR) after acoustic trauma, then, we investigated the expression of α2A-AR in the developing rat cochlea using immunofluorescence, qRT-PCR, and Western blotting. We found that the expression of α2A-AR significantly increased in rats exposed to noise compared with controls. Immunofluorescence analysis demonstrated that α2A-AR is localized on hair cells (HCs), spiral ganglion neurons (SGNs), and the stria vascularis (SV) in the postnatal developing cochlea from post-natal day (P) 0 to P28. Furthermore, we observed α2A-AR mRNA reached a maximum level at P14 and P28 when compared with P0, while no significant differences in α2A-AR protein levels at the various stages when compared with P0. This study provides direct evidence for the expression of α2A-AR in HCs, SGNs, and the SV of the cochlea, indicating that norepinephrine might play a vital role in hearing function within the cochlea through α2A-AR.

Mouse ultrasonic vocalizations (USVs) contain predictable sequential structures like bird songs and speech. Neural representation of USVs in the mouse primary auditory cortex (Au1) and its plasticity with experience has been largely studied with single-syllables or dyads, without using the predictability in USV sequences. Studies using playback of USV sequences have used randomly selected sequences from numerous possibilities. The current study uses mutual information to obtain context-specific natural sequences (NSeqs) of USV syllables capturing the observed predictability in male USVs in different contexts of social interaction with females. Behavioral and physiological significance of NSeqs over random sequences (RSeqs) lacking predictability were examined. Female mice, never having the social experience of being exposed to males, showed higher selectivity for NSeqs behaviorally and at cellular levels probed by expression of immediate early gene c- fos in Au1. The Au1 supragranular single units also showed higher selectivity to NSeqs over RSeqs. Social-experience-driven plasticity in encoding NSeqs and RSeqs in adult females was probed by examining neural selectivities to the same sequences before and after the above social experience. Single units showed enhanced selectivity for NSeqs over RSeqs after the social experience. Further, using two-photon Ca 2+ imaging, we observed social experience-dependent changes in the selectivity of sequences of excitatory and somatostatin-positive inhibitory neurons but not parvalbumin-positive inhibitory neurons of Au1. Using optogenetics, somatostatin-positive neurons were identified as a possible mediator of the observed social-experience-driven plasticity. Our study uncovers the importance of predictive sequences and introduces mouse USVs as a promising model to study context-dependent speech like communications. SIGNIFICANCE STATEMENT Humans need to detect patterns in the sensory world. For instance, speech is meaningful sequences of acoustic tokens easily differentiated from random ordered tokens. The structure derives from the predictability of the tokens. Similarly, mouse vocalization sequences have predictability and undergo context-dependent modulation. Our work investigated whether mice differentiate such informative predictable sequences (NSeqs) of communicative significance from RSeqs at the behavioral, molecular, and neuronal levels. Following a social experience in which NSeqs occur as a crucial component, mouse auditory cortical neurons become more sensitive to differences between NSeqs and RSeqs, although preference for individual tokens is unchanged. Thus, speech-like communication and its dysfunction may be studied in circuit, cellular, and molecular levels in mice.

Cochlear implants (CIs) have restored enough of a sense of hearing to around one million severely hearing impaired patients to enable speech understanding in quiet. However, several aspects of hearing with CIs remain very poor. This includes a severely limited ability of CI patients to make use of interaural time difference (ITD) cues for spatial hearing and noise reduction. A major cause for this poor ITD sensitivity could be that current clinical devices fail to deliver ITD information in a manner that is accessible to the auditory pathway. CI processors measure the envelopes of incoming sounds and then stimulate the auditory nerve with electrical pulse trains which are amplitude modulated to reflect incoming sound envelopes. The timing of the pulses generated by the devices is largely or entirely independent of the incoming sounds. Consequently, bilateral CIs (biCIs) provide veridical envelope (ENV) ITDs but largely or entirely replace the “fine structure” ITDs that naturally occur in sounds with completely arbitrary electrical pulse timing (PT) ITDs. To assess the extent to which this matters, we devised experiments that measured the sensitivity of deafened rats to precisely and independently controlled PT and ENV ITDs for a variety of different CI pulse rates and envelope shapes. We observed that PT ITDs completely dominate ITD perception, while the sensitivity to ENV ITDs was almost negligible in comparison. This strongly suggests that the confusing yet powerful PT ITDs that contemporary clinical devices deliver to biCI patients may be a major cause of poor binaural hearing outcomes with biCIs. Significance Statement CIs deliver spectro-temporal envelopes, including speech formants, to severely deaf patients, but they do little to cater to the brain’s ability to process temporal sound features with sub-millisecond precision. CIs “sample” sound envelope signals rapidly and accurately, and thus provide information which should make it possible in principle for CI listeners to detect envelope ITDs in a similar way to normal listeners. However, here we demonstrate through behavioral experiments on CI implanted rats trained to detect sub-millisecond ITDs that pulse timing ITDs completely dominate binaural hearing. This provides the strongest confirmation to date that the arbitrary pulse timing widely used in current clinical CIs is a critical obstacle to good binaural hearing through prosthetic devices.

Objectives: In the absence of binaural hearing, individuals with single-sided deafness can adapt to use monaural level and spectral cues to improve their spatial hearing abilities. Contralateral routing of signal is the most common form of rehabilitation for individuals with single-sided deafness. However, little is known about how these devices affect monaural localization cues, which single-sided deafness listeners may become reliant on. This study aimed to investigate the effects of contralateral routing of signal hearing aids on localization performance in azimuth and elevation under monaural listening conditions. Design: Localization was assessed in 10 normal hearing adults under three listening conditions: (1) normal hearing (NH), (2) unilateral plug (NH-plug), and (3) unilateral plug and CROS aided (NH-plug + CROS). Monaural hearing simulation was achieved by plugging the ear with E-A-Rsoft™ FX™ foam earplugs. Stimuli consisted of 150 ms high-pass noise bursts (3–20 kHz), presented in a random order from fifty locations spanning ±70° in the horizontal and ±30° in the vertical plane at 45, 55, and 65 dBA. Results: In the unilateral plugged listening condition, participants demonstrated good localization in elevation and a response bias in azimuth for signals directed at the open ear. A significant decrease in performance in elevation occurs with the contralateral routing of signal hearing device on, evidenced by significant reductions in response gain and low r2 value. Additionally, performance in azimuth is further reduced for contralateral routing of signal aided localization compared to the simulated unilateral hearing loss condition. Use of the contralateral routing of signal device also results in a reduction in promptness of the listener response and an increase in response variability. Conclusions: Results suggest contralateral routing of signal hearing aids disrupt monaural spectral and level cues, which leads to detriments in localization performance in both the horizontal and vertical dimensions. Increased reaction time and increasing variability in responses suggests localization is more effortful when wearing the contralateral rerouting of signal device.

Synaptic zinc signaling modulates synaptic activity and is present in specific populations of cortical neurons, suggesting that synaptic zinc contributes to the diversity of intracortical synaptic microcircuits and their functional specificity. To understand the role of zinc signaling in the cortex, we performed whole-cell patch-clamp recordings from intratelencephalic (IT)-type neurons and pyramidal tract (PT)-type neurons in layer 5 of the mouse auditory cortex during optogenetic stimulation of specific classes of presynaptic neurons. Our results show that synaptic zinc potentiates AMPA receptor (AMPAR) function in a synapse-specific manner. We performed in vivo 2-photon calcium imaging of the same classes of neurons in awake mice and found that changes in synaptic zinc can widen or sharpen the sound-frequency tuning bandwidth of IT-type neurons but only widen the tuning bandwidth of PT-type neurons. These results provide evidence for synapse- and cell-type-specific actions of synaptic zinc in the cortex.

Background Niemann–Pick disease type C (NPC) is a fatal neurodegenerative disorder caused by abnormal intracellular cholesterol trafficking. Cyclodextrins (CDs), the most promising therapeutic candidates for NPC, but with concerns about ototoxicity, are cyclic oligosaccharides with dual functions of unesterified cholesterol (UC) shuttle and sink that catalytically enhance the bidirectional flux and net efflux of UC, respectively, between the cell membrane and the extracellular acceptors. However, the properties of CDs that regulate these functions and how they could be used to improve treatments for NPC are unclear. Methods We estimated CD–UC complexation for nine CD derivatives derived from native α‐, β‐, and γ‐CD with different cavity sizes, using solubility and molecular docking analyses. The stoichiometry and complexation ability of the resulting complexes were investigated in relation to the therapeutic effectiveness and toxicity of each CD derivative in NPC experimental models. Findings We found that shuttle and sink activities of CDs are dependent on cavity size‐dependent stoichiometry and substituent‐associated stability of CD–UC complexation. The ability of CD derivatives to form 1:1 and 2:1 complexes with UC were correlated with their ability to normalize intracellular cholesterol trafficking serving as shuttle and with their cytotoxicity associated with cellular UC efflux acting as sink, respectively, in NPC model cells. Notably, the ability of CD derivatives to form an inclusion complex with UC was responsible for not only efficacy but ototoxicity, while a representative derivative without this ability negligibly affected auditory function, underscoring its preventability. Conclusions Our findings highlight the importance of strategies for optimizing the molecular structure of CDs to overcome this functional dilemma in the treatment of NPC.

Usher syndrome type 1F (USH1F), characterized by congenital lack of hearing and balance and progressive loss of vision, is caused by mutations in the PCDH15 gene. In the Ashkenazi population, a recessive truncation mutation accounts for a large proportion of USH1F cases. The truncation is caused by a single C→T mutation, which converts an arginine codon to a stop (R245X). To test the potential for base editors to revert this mutation, we developed a humanized Pcdh15R245X mouse model for USH1F. Mice homozygous for the R245X mutation were deaf and exhibited profound balance deficits, while heterozygous mice were unaffected. Here we show that an adenine base editor (ABE) is capable of reversing the R245X mutation to restore the PCDH15 sequence and function. We packaged a split-intein ABE into dual adeno-associated virus (AAV) vectors and delivered them into cochleas of neonatal USH1F mice. Hearing was not restored in a Pcdh15 constitutive null mouse despite base editing, perhaps because of early disorganization of cochlear hair cells. However, injection of vectors encoding the split ABE into a late-deletion conditional Pcdh15 knockout rescued hearing. This study demonstrates the ability of an ABE to correct the PCDH15 R245X mutation in the cochlea and restore hearing.

Schroeder-phase harmonic tone complexes can have a flat temporal envelope and rising or falling instantaneous-frequency sweeps within F0 periods, depending on the phase-scaling parameter C. Human tone-detection thresholds in a concurrent Schroeder masker are 10-15 dB lower for positive C values (rising frequency sweeps) compared to negative (falling sweeps), potentially due to cochlear mechanics, though this hypothesis remains controversial. Birds provide an interesting model for studies of Schroeder masking because many species produce vocalizations containing frequency sweeps. Prior behavioral studies in birds suggest less behavioral threshold difference between maskers with opposite C values than in humans, but focused on low masker F0s and did not explore neural mechanisms. We performed behavioral Schroeder-masking experiments in budgerigars (Melopsittacus undulatus) using a wide range of masker F0 and C values. Signal frequency was 2800 Hz. Neural recordings from the midbrain characterized encoding of behavioral stimuli in awake animals. Behavioral thresholds increased with increasing masker F0 and showed minimal difference between opposite C values, consistent with prior budgerigar studies. Midbrain recordings showed prominent temporal and rate-based encoding of Schroeder F0, and in many cases, marked asymmetry in Schroeder responses between C polarities. Neural thresholds for Schroeder-masked tone detection were often based on a response decrement compared to the masker alone, consistent with prominent modulation tuning in midbrain neurons, and were generally similar between opposite C values. The results highlight the likely importance of envelope cues in Schroeder masking and show that differences in supra-threshold Schroeder responses do not necessarily result in neural threshold differences.

So-called duplex speech stimuli with perceptually ambiguous spectral cues to one ear and isolated low- versus high-frequency third formant “chirp” to the opposite ear yield a coherent percept supporting their phonetic categorization. Critically, such dichotic sounds are only perceived categorically upon binaural integration. Here, we used frequency-following responses (FFRs), scalp-recorded potentials reflecting phase-locked subcortical activity, to investigate brainstem responses to fused speech percepts and to determine whether FFRs reflect binaurally integrated category-level representations. We recorded FFRs to diotic and dichotic stop-consonants (/da/, /ga/) that either did or did not require binaural fusion to properly label along with perceptually ambiguous sounds without clear phonetic identity. Behaviorally, listeners showed clear categorization of dichotic speech tokens confirming they were heard with a fused, phonetic percept. Neurally, we found FFRs were stronger for categorically perceived speech relative to category-ambiguous tokens but also differentiated phonetic categories for both diotically and dichotically presented speech sounds. Correlations between neural and behavioral data further showed FFR latency predicted the degree to which listeners labeled tokens as “da” versus “ga.” The presence of binaurally integrated, category-level information in FFRs suggests human brainstem processing reflects a surprisingly abstract level of the speech code typically circumscribed to much later cortical processing.

Background Autism spectrum disorders (ASD) encompass a wide array of debilitating symptoms, including sensory dysfunction and delayed language development. Auditory temporal processing is crucial for speech perception and language development. Abnormal development of temporal processing may account for the language impairments associated with ASD. Very little is known about the development of temporal processing in any animal model of ASD. Methods In the current study, we quantify auditory temporal processing throughout development in the Fmr1 knock-out (KO) mouse model of Fragile X Syndrome (FXS), a leading genetic cause of intellectual disability and ASD-associated behaviors. Using epidural electrodes in awake and freely moving wildtype (WT) and KO mice, we recorded auditory event related potentials (ERP) and auditory temporal processing with a gap-in-noise auditory steady state response (gap-ASSR) paradigm. Mice were recorded at three different ages in a cross sectional design: postnatal (p)21, p30 and p60. Recordings were obtained from both auditory and frontal cortices. The gap-ASSR requires underlying neural generators to synchronize responses to gaps of different widths embedded in noise, providing an objective measure of temporal processing across genotypes and age groups. Results We present evidence that the frontal, but not auditory, cortex shows significant temporal processing deficits at p21 and p30, with poor ability to phase lock to rapid gaps in noise. Temporal processing was similar in both genotypes in adult mice. ERP amplitudes were larger in Fmr1 KO mice in both auditory and frontal cortex, consistent with ERP data in humans with FXS. Conclusions These data indicate cortical region-specific delays in temporal processing development in Fmr1 KO mice. Developmental delays in the ability of frontal cortex to follow rapid changes in sounds may shape language delays in FXS, and more broadly in ASD.

We have recently reported that the central nucleus of the inferior colliculus (the auditory midbrain) is innervated by glutamatergic pyramidal cells originating not only in auditory cortex (AC) but also in multiple ‘non-auditory’ regions of the cerebral cortex. Using optogenetics and electrical stimulation, we investigated the functional properties of these descending connections in vivo in anaesthetised rats. A retrograde virus encoding green fluorescent protein (GFP) and channelrhodopsin (ChR2) injected into the central nucleus of the inferior colliculus (ICC), labelled discrete groups of cells in multiple areas of the cerebral cortex. Light stimulation of AC and M1 caused local activation of cortical neurones and increased the firing rate of neurones in ICc indicating a direct excitatory input from AC and M1 to ICC. Electrical stimulation of M1, secondary motor, somatosensory and prefrontal cortical regions evoked short, fixed latency firing events in ICC as well as longer latency, longer duration increases in firing activity. The short latency events were singular spikes of consistent shape and size likely resulting from monosynaptic excitation of individual ICC units. The longer latency responses comprised multiple units and spikes occurred with significant temporal jitter suggesting polysynaptic activation of local circuits within the ICC. The probability of the monosynaptic event, the magnitude of the polysynaptic response, and the area of ICC affected were dependent on the stimulus current. Our data are consistent with cortical regions exerting an important excitatory direct and indirect regulation of ICc neurones. Significance statement We have recently described inputs from motor, somatosensory, and executive cortices to the inferior colliculus (IC, auditory midbrain). Here we provide functional evidence for such connections. Optogenetics, using a retrograde virus encoding channelrhodopsin injected into IC revealed a direct excitatory influence of neurones in auditory and motor cortices on firing in IC. Electrical stimulation of discrete cortical regions revealed that multiple non-auditory cortical regions have a direct monosynaptic excitatory influence on neurones in the IC which, in turn, activates local circuits increasing the firing probability of multiple neurones in the IC. This is the first evidence for circuitry by which auditory processing can be influenced at an early stage by activity in the sensory, motor and executive domains.

Objectives: Speech perception training can be a highly effective intervention to improve perception and language abilities in children who are deaf or hard of hearing. Most studies of speech perception training, however, only measure gains immediately following training. Only a minority of cases include a follow-up assessment after a period without training. A critical unanswered question was whether training-related benefits are retained for a period of time after training has stopped. A primary goal of this investigation was to determine whether children retained training-related benefits 4 to 6 weeks after they completed 16 hours of formal speech perception training. Training was comprised of either auditory or speechreading training, or a combination of both. Also important is to determine if “booster” training can help increase gains made during the initial intensive training period. Another goal of the study was to investigate the benefits of providing home-based booster training during the 4- to 6-week interval after the formal training ceased. The original investigation (Tye-Murray et al. 2022) compared the effects of talker familiarity and the relative benefits of the different types of training. We predicted that the children who received no additional training would retain the gains after the completing the formal training. We also predicted that those children who completed the booster training would realize additional gains. Design: Children, 6 to 12 years old, with hearing loss who had previously participated in the original randomized control study returned 4 to 6 weeks after the conclusion to take a follow-up speech perception assessment. The first group (n = 44) returned after receiving no formal intervention from the research team before the follow-up assessment. A second group of 40 children completed an additional 16 hours of speech perception training at home during a 4- to 6-week interval before the follow-up speech perception assessment. The home-based speech perception training was a continuation of the same training that was received in the laboratory formatted to work on a PC tablet with a portable speaker. The follow-up speech perception assessment included measures of listening and speechreading, with test items spoken by both familiar (trained) and unfamiliar (untrained) talkers. Results: In the group that did not receive the booster training, follow-up testing showed retention for all gains that were obtained immediately following the laboratory-based training. The group that received booster training during the same interval also maintained the benefits from the formal training, with some indication of minor improvement. Conclusions: Clinically, the present findings are extremely encouraging; the group that did not receive home-based booster training retained the benefits obtained during the laboratory-based training regimen. Moreover, the results suggest that self-paced booster training maintained the relative training gains associated with talker familiarity and training type seen immediately following laboratory-based training. Future aural rehabilitation programs should include maintenance training at home to supplement the speech perception training conducted under more formal conditions at school or in the clinic.

Sensorineural hearing loss is associated with dysfunction of cochlear cells. Although immune cells play a critical role in maintaining the inner ear microenvironment, the precise immune-related molecular mechanisms underlying the pathophysiology of hearing loss remain unclear. The complement cascade contributes to the regulation of immune cell activity. Additionally, activation of the complement cascade can lead to the cellular opsonization of cells and pathogens, resulting in their engulfment and elimination by phagocytes. Complement factor B (fB) is an essential activator protein in the alternative complement pathway, and variations in the fB gene are associated with age-related macular degeneration. Here we show that mice of both sexes deficient in fB functional alleles (fB −/− ) demonstrate progressive hearing impairment. Transcriptomic analysis of auditory nerves from adult mice detected 706 genes that were significantly differentially expressed between fB −/− and wild-type control animals, including genes related to the extracellular matrix and neural development processes. Additionally, a subset of differentially expressed genes was related to myelin function and neural crest development. Histological and immunohistochemical investigations revealed pathological alterations in auditory nerve myelin sheathes of fB −/− mice. Pathological alterations were also seen in the stria vascularis of the cochlear lateral wall in these mice. Our results implicate fB as an integral regulator of myelin maintenance and stria vascularis integrity, underscoring the importance of understanding the involvement of immune signaling pathways in sensorineural hearing loss.