Auditory Research publications

Corticothalamic (CT) neurons comprise the largest component of the descending sensory corticofugal pathway, but their contributions to brain function and behavior remain an unsolved mystery. To address the hypothesis that layer 6 (L6) CTs may be activated by extra-sensory inputs prior to anticipated sounds, we performed optogenetically targeted single-unit recordings and two-photon imaging of Ntsr1-Cre+ L6 CT neurons in the primary auditory cortex (A1) while mice were engaged in an active listening task. We found that L6 CTs and other L6 units began spiking hundreds of milliseconds prior to orofacial movements linked to sound presentation and reward, but not to other movements such as locomotion, which were not linked to an explicit behavioral task. Rabies tracing of monosynaptic inputs to A1 L6 CT neurons revealed a narrow strip of cholinergic and non-cholinergic projection neurons in the external globus pallidus, suggesting a potential source of motor-related input. These findings identify new pathways and local circuits for motor modulation of sound processing and suggest a new role for CT neurons in active sensing.

Neurotransmission of acoustic signals from the hair cells to the auditory nerve relies on a tightly controlled communication between pre-synaptic ribbons and post-synaptic glutamatergic terminals. After noise overexposure, de-afferentation occurs as a consequence of excessive glutamate release. What maintains synaptic integrity in the cochlea is poorly understood. The objective of this study is to evaluate the role of GLAST in maintaining synaptic integrity in the cochlea in absence or presence of noise, and its impact on sound-evoked brain activity using manganese-enhanced MRI (MeMRI). The glutamate aspartate transporter GLAST is present in supporting cells near the afferent synapse and its genetic deletion leads to greater synaptic swelling after noise overexposure. At baseline, GLAST knockout (GLAST KO) mice displayed two-fold lower wave 1 amplitude of the auditory brainstem response (ABR) when compared to their wild-type littermates in spite of similar ABR and distortion product otoacoustic emissions (DPOAE) thresholds. While the abundance of ribbons was not affected by the loss of GLAST function, the number of paired synapses was halved in GLAST KO mice, suggestive of a pre-existing auditory synaptopathy. Immediately after the noise exposure ABR thresholds rose by 41-62dB to a similar degree in GLAST WT and KO mice and DPOAE remained unaffected. In the acute phase following noise exposure, GLAST KO mice showed near complete de-afferentation unlike WT mice which maintained four to seven paired synapses per IHC. Brain activity using MeMRI found noise exposure to cause greater activity in the inferior colliculus in GLAST KO but not in WT mice. No changes in brain activity was found in GLAST KO mice at baseline in spite of affected afferent synapses, suggesting that auditory synaptopathy may not be sufficient to alter brain activity in the absence of noise exposure.

Elucidating changes in sensory processing across attentional and arousal states is a major focus in neuroscience. The local/global deviant (LGD) stimulus paradigm engages auditory predictive coding over short (local deviance, LD) and long (global deviance, GD) time scales, and has been used to assay disruption of auditory predictive coding upon loss of consciousness. Our previous work (Nourski et al., 2018, J Neurosci 38:8441-52) examined effects of general anesthesia on short- and long-term novelty detection. GD effects were suppressed at subhypnotic doses of propofol, suggesting that they may be more related to task engagement than consciousness per se. The present study addressed this hypothesis by comparing cortical responses to auditory novelty during passive versus active listening conditions in awake listeners. Subjects were seven adult neurosurgical patients undergoing chronic invasive monitoring for medically intractable epilepsy. LGD stimuli were sequences of four identical vowels followed by a fifth identical or different vowel. In the passive condition, the stimuli were presented to subjects as they watched a silent TV program and were instructed to attend to its content. In the active condition, stimuli were presented in the absence of a TV program, and subjects were instructed to press a button in response to GD target stimuli. Intracranial recordings were made from multiple brain regions, including core and non-core auditory, auditory-related, prefrontal and sensorimotor cortex. Metrics of task performance included hit rate, sensitivity index, and reaction times. Cortical activity was measured as averaged auditory evoked potentials (AEPs) and event-related band power in high gamma (70-150 Hz) and alpha (8-14 Hz) frequency bands. The vowel stimuli and LD elicited robust AEPs in all studied brain areas in both passive and active conditions. High gamma responses to stimulus onset and LD were localized predominantly to the auditory cortex in the superior temporal plane and had a comparable prevalence and spatial extent between the two conditions. In contrast, GD effects (AEPs, high gamma and alpha suppression) were greatly enhanced during the active condition in all studied brain areas. The prevalence of high gamma GD effects was positively correlated with individual subjects' task performance. The data demonstrate distinct task engagement-related effects on responses to auditory novelty across the auditory cortical processing hierarchy. The results motivate a closer examination of effective connectivity underlying attentional modulation of cortical sensory responses, and serve as a foundation for examining changes in sensory processing associated with general anesthesia, sleep and disorders of consciousness.

Predictive coding is an influential theory of neural processing underlying perceptual inference. However, it is unknown to what extent prediction violations of different sensory features are mediated in different regions in auditory cortex, with different dynamics, and by different mechanisms. This study investigates the neural responses to synthesized acoustic syllables, which could be expected or unexpected, along several features. By using electrocorticography (ECoG) in rat auditory cortex (subjects: adult female Wistar rats with normal hearing), we aimed at mapping regional differences in mismatch responses to different stimulus features. Continuous streams of morphed syllables formed roving oddball sequences in which each stimulus was repeated several times (thereby forming a standard) and subsequently replaced with a deviant stimulus which differed from the standard along one of several acoustic features: duration, pitch, interaural level differences (ILD), or consonant identity. Each of these features could assume one of several different levels, and the resulting change from standard to deviant could be larger or smaller. The deviant stimuli were then repeated to form new standards. We analyzed responses to the first repetition of a new stimulus (deviant) and its last repetition in a stimulus train (standard). For the ECoG recording, we implanted urethane-anaesthetized rats with 8 × 8 surface electrode arrays covering a 3 × 3 mm cortical patch encompassing primary and higher-order auditory cortex. We identified the response topographies and latencies of population activity evoked by acoustic stimuli in the rat auditory regions, and mapped their sensitivity to expectation violations along different acoustic features. For all features, the responses to deviant stimuli increased in amplitude relative to responses to standard stimuli. Deviance magnitude did not further modulate these mismatch responses. Mismatch responses to different feature violations showed a heterogeneous distribution across cortical areas, with no evidence for systematic topographic gradients for any of the tested features. However, within rats, the spatial distribution of mismatch responses varied more between features than the spatial distribution of tone-evoked responses. This result supports the notion that prediction error signaling along different stimulus features is subserved by different cortical populations, albeit with substantial heterogeneity across individuals.

Purpose: to investigate the auditory recognition of intermittent speech in relation to different modulation rates and ages. Methods: 20 young people, 20 middle-aged adults, and 16 older adults, all of them with auditory thresholds equal to or lower than 25 dB HL up to the frequency of 4000 Hz. The participants were submitted to intermittent speech recognition tests presented in three modulation conditions: 4 Hz, 10 Hz, and 64 Hz. The percentages of correct answers were compared between age groups and modulation rates. ANOVA and post hoc tests were conducted to investigate the modulation rate effect, and the mixed linear regression model (p < 0.001). Results: regarding the age effect, the data showed a significant difference between young people and older adults, and between middle-aged and older adults. As for the modulation rate effect, the indexes of correct answers were significantly lower at the slower rate (4 Hz) in the three age groups. Conclusion: an age effect was verified on intermittent speech recognition: older adults have greater difficulty. A modulation rate effect was also noticed in the three age groups: the higher the rate, the better the performance.

Although hippocampal changes due to noise‐induced hearing loss have been suggested, little is known about the miRNA levels due to these hippocampal changes. Three‐week‐old Sprague‐Dawley rats were divided into noise and control groups ( n = 20 per group). The noise group rats were exposed to white Gaussian noise (115 dB SPL, 4 hours per day) for three days. One day after noise exposure, the hippocampi of rats were harvested and miRNA expressions were analyzed using the Affymetrix miRNA 4.0 microarray ( n = 6 per group). The predicted target genes of each miRNA were retrieved, and the pathways related to the predicted target genes were analyzed. miR‐758‐5p, miR‐210‐5p, miR‐370‐5p, miR‐652‐5p, miR‐3544, miR‐128‐1‐5p, miR‐665, miR‐188‐5p, and miR‐874‐5p expression increased in the hippocampal tissue of the noise group compared to that in the control group. The overlapping predicted target genes included Bend4 , Creb1 , Adcy6 , Creb5 , Kcnj9 , and Pten . The pathways related to these genes were the estrogen signaling pathway, vasopressin‐regulated water reabsorption, thyroid hormone synthesis, aldosterone synthesis and secretion, insulin secretion, circadian entrainment, insulin resistance, cholinergic synapse, dopaminergic synapse, cGMP‐PKG signaling pathway, cAMP signaling pathway, PI3K‐Akt signaling pathway, TNF signaling pathway, and AMPK signaling pathway. miR‐448‐3p, miR204‐5p, and miR‐204‐3p expression decreased in the hippocampal tissue of the noise group compared to that in the control group. The overlapping predicted target genes of these three miRNAs were Rps6kas , Nfactc3 , Rictor , Spred1 , Cdh4 , Cdh6 , Dvl3 , and Rcyt1b . Pathway analysis suggested that the Wnt signaling pathway is related to Dvl3 and Nfactc3 . Noise‐induced hearing loss dysregulates miR‐758‐5p, miR210‐5p, miR370‐5p, miR‐652‐5p, miR‐3544, miR‐128‐1‐5p, miR‐665, miR‐188‐5p, miR‐874‐5p, miR‐448‐3p, miR‐204‐5p, miR‐204‐3p, and miR‐140‐5p expression in the hippocampus. These miRNAs have been predicted to be associated with hormonal, inflammatory, and synaptic pathways.

The mixture of ketamine and xylazine is widely used for the auditory brainstem response (ABR) measurement. Esketamine is twice as potent as ketamine. Our objective was to assess the influence of esketamine in mice undergoing cochlear function measurement including ABR and distortion product otoacoustic emission (DPOAE) measurement. C57Bl/6J mice were treated with an equivalent dose of analgesia and received either a single intraperitoneal (ip) injection of 100 mg/kg ketamine and 25 mg/kg xylazine or 50 mg/kg esketamine and 25 mg/kg xylazine. Hearing thresholds, peak latencies of waves I and V, and DPOAE thresholds were recorded. Time to loss of righting and time to regain righting were also assessed. We found that hearing thresholds, the peak latencies of waves I and V, and DPOAE thresholds were similar between the two groups (all P>0.05). Time to regain righting was significantly shorter in the esketamine group (P<0.001) than in the ketamine group. We concluded that when using equivalent doses of analgesia, esketamine may be an ideal substitute for ketamine during cochlear function test.

Continuous acoustic streams, such as speech signals, can be chunked into segments containing reoccurring patterns (e.g., words). Noninvasive recordings of neural activity in humans suggest that chunking is underpinned by low-frequency cortical entrainment to the segment presentation rate, and modulated by prior segment experience (e.g., words belonging to a familiar language). Interestingly, previous studies suggest that also primates and rodents may be able to chunk acoustic streams. Here, we test whether neural activity in the rat auditory cortex is modulated by previous segment experience. We recorded subdural responses using electrocorticography (ECoG) from the auditory cortex of 11 anesthetized rats. Prior to recording, four rats were trained to detect familiar triplets of acoustic stimuli (artificial syllables), three were passively exposed to the triplets, while another four rats had no training experience. While low-frequency neural activity peaks were observed at the syllable level, no triplet-rate peaks were observed. Notably, in trained rats (but not in passively exposed and naïve rats), familiar triplets could be decoded more accurately than unfamiliar triplets based on neural activity in the auditory cortex. These results suggest that rats process acoustic sequences, and that their cortical activity is modulated by the training experience even under subsequent anesthesia.

Hearing loss is a sensory deprivation that can affect the quality of life. Currently, only rehabilitation devices such as hearing aids and cochlear implants are used, without a definitive cure. However, in chronic hearing‐deprived patients, in whom secondary auditory neural degeneration is expected, a relatively poor rehabilitation prognosis is projected. Stem cell therapy for cochlear neural structures would be an easier and feasible strategy compared with cochlear sensory cells. Considering the highly developed cochlear implantation technology, improving cochlear neural health has significant medical and social effects. Stem cell delivery to Rosenthal’s canal in an acutely damaged mouse model has been performed and showed cell survival and the possibility of differentiation. The results of stem cell transplantation in chronic auditory neural hearing loss should be evaluated because neural stem cell replacement therapy for chronic (long‐term) sensorineural hearing loss is a major target in clinics. In the present study, we established a mouse model that mimicked chronic auditory neural hearing loss (secondary degeneration of auditory neurons after loss of sensory input). Then, mouse embryonic stem cells (mESCs) were transplanted into the scala tympani and survival and distribution of transplanted cells were compared between the acute and chronic auditory neural hearing loss models induced by ouabain or kanamycin (KM), respectively. The mESC survival was similar to the acute model, and perilymphatic distribution of cell aggregates was more predominant in the chronic model. Lastly, the effects of mESC transplantation on neural signal transduction observed in the cochlear nucleus (CN) were compared and a statistical increase was observed in the chronic model compared with other models. These results indicated that after transplantation, mESCs survived in the cochlea and increased the neural signaling toward the central auditory pathway, even in the chronic (secondary) hearing loss mouse model.

Network analysis of large-scale neuroimaging data is a particularly challenging computational problem. Here, we adapt a novel analytical tool, the community dynamic inference method (CommDy), for brain imaging data from young and aged mice. CommDy, which was inspired by social network theory, has been successfully used in other domains in biology; this report represents its first use in neuroscience. We used CommDy to investigate aging-related changes in network metrics in the auditory and motor cortices by using flavoprotein autofluorescence imaging in brain slices and in vivo. We observed that auditory cortical networks in slices taken from aged brains were highly fragmented compared to networks observed in young animals. CommDy network metrics were then used to build a random-forests classifier based on NMDA receptor blockade data, which successfully reproduced the aging findings, suggesting that the excitatory cortical connections may be altered during aging. A similar aging-related decline in network connectivity was also observed in spontaneous activity in the awake motor cortex, suggesting that the findings in the auditory cortex reflect general mechanisms during aging. These data suggest that CommDy provides a new dynamic network analytical tool to study the brain and that aging is associated with fragmentation of intracortical networks.

A growing amount of evidence has confirmed the crucial role of the prolyl isomerase PIN1 in aging and age‐related diseases. However, the mechanism of PIN1 in age‐related hearing loss (ARHL) remains unclear. Pathologically, ARHL is primarily due to the loss and dysfunction of hair cells (HCs) and spiral ganglion cells (SGCs) in the cochlea. Therefore, in this study, we aimed to investigate the role of PIN1 in protecting hair cells and auditory HEI‐OC1 cells from senescence. Enzyme‐linked immunosorbent assays, immunohistochemistry, and immunofluorescence were used to detect the PIN1 protein level in the serum of ARHL patients and C57BL/6 mice in different groups, and in the SGCs and HCs of young and aged C57BL/6 mice. In addition, a model of HEI‐OC1 cell senescence induced by H 2 O 2 was used. Adult C57BL/6 mice were treated with juglone, or juglone and NAC, for 4 weeks. Interestingly, we found that the PIN1 protein expression decreased in the serum of patients with ARHL, in senescent HEI‐OC1 cells, and in the cochlea of aged mice. Moreover, under H 2 O 2 and juglone treatment, a large amount of ROS was produced, and phosphorylation of p53 was induced. Importantly, PIN1 expression was significantly increased by treatment with the p53 inhibitor pifithrin‐ α . Overexpression of PIN1 reversed the increased level of p‐p53 and rescued HEI‐OC1 cells from senescence. Furthermore, PIN1 mediated cellular senescence by the PI3K/Akt/mTOR signaling pathway. In vivo data from C57BL/6 mice showed that treatment with juglone led to hearing loss. Taken together, these findings demonstrated that PIN1 may act as a vital modulator in hair cell and HEI‐OC1 cell senescence.

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

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

Introduction Cruciferous vegetables are a rich source of sulforaphane (SFN), which acts as a natural HDAC inhibitor (HDACi). Our previous study found that HDACi could restore histone acetyltransferase/histone deacetylase (HAT/HDAC) balance in the cochlea and attenuate gentamicin-induced hearing loss in guinea pigs. Here, we investigated the protective effect of SFN on cisplatin-induced hearing loss (CIHL). Methods Thirty rats were randomly divided into 3 equal groups: the control group, cisplatin group, and SFN+cisplatin group. Rats were injected with SFN (30 mg/kg once a day) and cisplatin (7 mg/kg twice a day) for 7 days to investigate the protective role of SFN on CIHL. We observed auditory brainstem response (ABR) threshold shifts and immunostained cochlear basilar membranes of rats. For in vitro experiments, we treated HEI-OC1 cells and rat cochlear organotypic cultures with SFN (5, 10, and 15 μM) and cisplatin (10 μM). Immunofluorescence, cell viability, and protein analysis were performed to further analyze the protective mechanism of SFN on CIHL. Results SFN (30 mg/kg once a day) decreased cisplatin (7 mg/kg twice a day)-induced ABR threshold shifts and outer hair cell loss. CCK-8 assay showed that cisplatin (10 μM) reduced the viability of HEI-OC1 cells to 42%, and SFN had a dose-dependent protective effect. In cochlear organotypic cultures, we found that SFN (10 and 15 μM) increased cisplatin (10 μM)-induced myosin 7a + cell count and restored ciliary morphology. SFN (5, 10, and 15 μM) reversed the cisplatin (10 μM)-induced increase in HDAC2, -4, and -5 and SFN (15 μM) reversed the cisplatin (10 μM)-induced decrease in H3-Ack9 [acetyl-histone H3 (Lys9)] protein expression in HEI-OC1 cells. Neither cisplatin nor cisplatin combined with SFN affected the expression of HDAC7, or HDAC9. Conclusion SFN prevented disruption of the HAT/HDAC balance, protecting against CIHL in rats.

The sound-field auditory steady-state response (ASSR) is a promising measure for the objective validation of hearing-aid fitting in patients who are unable to respond to behavioral testing reliably. To record the sound-field ASSR, the stimulus is reproduced through a loudspeaker placed in front of the patient. However, the reverberation and background noise of the measurement room could reduce the stimulus modulation used for eliciting the ASSR. As the ASSR level is heavily dependent on the stimulus modulation, any reduction due to room acoustics could affect the clinical viability of sound-field ASSR testing. This study investigated the effect of room acoustics on the level and detection rate of sound-field ASSR. The study also analyzed whether early decay time and an auditory-inspired relative modulation power model could be used to predict the changes in the recorded ASSR in rooms. A monaural auralization approach was used to measure sound-field ASSR via insert earphones. ASSR was measured for 15 normal-hearing adult subjects using narrow-band CE-Chirps® centered at the octave bands of 500, 1000, 2000, and 4000 Hz. These stimuli were convolved with simulated impulse responses of three rooms inspired by audiological testing rooms. The results showed a significant reduction of the ASSR level for the room conditions compared with the reference anechoic condition. Despite this reduction, the detection rates for the first harmonics of the ASSR were unaffected when sufficiently long recordings (up to 6 min) were made. Furthermore, the early decay time and relative modulation power appear to be useful predictors of the ASSR level in the measurement rooms.

ABSTRACTSOur previous study first investigated feasibility of applying ultrasound (US) and microbubbles (MBs) via external auditory canal to facilitate drug delivery into inner ear. However, most drugs are in aqueous formulae and eliminated via Eustachian tubes after drug application. In this study, feasibility of sustained release of thermosensitive poloxamer 407 (P407)-based MB gel for US mediation-enhanced inner ear drug (dexamethasone, DEX) delivery was investigated. The sol-to-gel transition temperature showed that mixture of DEX and only 10% and 12.5% P407 in MBs can be used for in vitro and in vivo drug delivery experiments. In in vitro Franz diffusion experiments, the release rates of 12.5% P407-MBs + US groups in the model using DEX as the delivered reagent at 3 h resulted in values 1.52 times greater than those of 12.5% P407-MBs groups. In guinea pigs, by filling tympanic bulla with DEX in 12.5% P407-MBs (DEX-P407-MBs), USMB applied at post-treatment days 1 and 7 induced 109.13% and 66.67% increases in DEX delivery efficiencies, respectively, compared to the group without US. On the 28th day after US-mediated P407-MB treatment, the safety assessment showed no significant changes in the hearing thresholds and no damage to the integrity of cochlea or middle ear. These are the first results to demonstrate feasibility of US-modified liquid form DEX-P407-MB cavitation for enhancing permeability of round window membrane. Then, a gel form of DEX-P407-MBs was generated and thus prolonged the release of DEX in middle ear to maintain the therapeutic DEX level in inner ear for at least 7 days.

Defective primary cilia cause a range of diseases known as ciliopathies, including hearing loss. The etiology of hearing loss in ciliopathies, however, remains unclear. We analyzed cochleae from three ciliopathy mouse models exhibiting different ciliogenesis defects: Intraflagellar transport 88 ( Ift88 ), Tbc1d32 (a.k.a. bromi ), and Cilk1 (a.k.a. Ick ) mutants. These mutants showed multiple developmental defects including shortened cochlear duct and abnormal apical patterning of the organ of Corti. Although ciliogenic defects in cochlear hair cells such as misalignment of the kinocilium are often associated with the planar cell polarity pathway, our results showed that inner ear defects in these mutants are primarily due to loss of sonic hedgehog signaling. Furthermore, an inner ear-specific deletion of Cilk1 elicits low-frequency hearing loss attributable to cellular changes in apical cochlear identity that is dedicated to low-frequency sound detection. This type of hearing loss may account for hearing deficits in some patients with ciliopathies.

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

Genetic variants account for approximately half the cases of congenital and early‐onset deafness. Methods and technologies for viral delivery of genes into the inner ear have evolved over the past decade to render gene therapy a viable and attractive approach for treatment. Variants in SYNE4 , encoding the protein nesprin‐4, a member of the linker of nucleoskeleton and cytoskeleton (LINC), lead to DFNB76 human deafness. Syne4 −/− mice have severe‐to‐profound progressive hearing loss and exhibit mislocalization of hair cell nuclei and hair cell degeneration. We used AAV9‐PHP.B, a recently developed synthetic adeno‐associated virus, to deliver the coding sequence of Syne4 into the inner ears of neonatal Syne4 −/− mice. Here we report rescue of hair cell morphology and survival, nearly complete recovery of auditory function, and restoration of auditory‐associated behaviors, without observed adverse effects. Uncertainties remain regarding the durability of the treatment and the time window for intervention in humans, but our results suggest that gene therapy has the potential to prevent hearing loss in humans with SYNE4 mutations.

We and others have previously identified signalling pathways associated with the adenosine A1 receptor (A1R) as important regulators of cellular responses to injury in the cochlea. We have shown that the “post-exposure” treatment with adenosine A1R agonists confers partial protection against acoustic trauma and other forms of sensorineural hearing loss (SNHL). The aim of this study was to determine if increasing A1R responsiveness to endogenous adenosine would have the same otoprotective effect. This was achieved by pharmacological targeting of the Regulator of G protein Signalling 4 (RGS4). RGS proteins inhibit signal transduction pathways initiated by G protein-coupled receptors (GPCR) by enhancing GPCR deactivation and receptor desensitisation. A molecular complex between RGS4 and neurabin, an intracellular scaffolding protein expressed in neural and cochlear tissues, is the key negative regulator of A1R activity in the brain. In this study, Wistar rats (6–8 weeks) were exposed to traumatic noise (110 dBSPL, 8–16 kHz) for 2 h and a small molecule RGS4 inhibitor CCG-4986 was delivered intratympanically in a Poloxamer-407 gel formulation for sustained drug release 24 or 48 h after noise exposure. Intratympanic administration of CCG-4986 48 h after noise exposure attenuated noise-induced permanent auditory threshold shifts by up to 19 dB, whilst the earlier drug administration (24 h) led to even better preservation of auditory thresholds (up to 32 dB). Significant improvement of auditory thresholds and suprathreshold responses was linked to improved survival of sensorineural tissues and afferent synapses in the cochlea. Our studies thus demonstrate that intratympanic administration of CCG-4986 can rescue cochlear injury and hearing loss induced by acoustic overexposure. This research represents a novel paradigm for the treatment of various forms of SNHL based on regulation of GPCR.