ABR/DPOAE publications

Gap junction Beta 2 Protein (GJB2, Connexin26, Cx26), the primary genetic cause of hereditary hearing loss (25%–50% of cases), has been exclusively regarded as forming an intercellular channel that mediates rapid communication. Here, we redefine its biological role by discovering its nuclear localization and direct transcriptional regulatory function in cochlear structure development. We demonstrate that Cx26 could aggregate in the nucleus of cochlear support cell and cell lines. Cx26 can bind to the promoter transcription start point of genomic DNA and directly regulate gene transcription, thus controlling the structural development of the tunnel of Corti during cochlear development. Further, we provide strategies based on mechanisms to promote the TC development and hearing rescue in Cx26 deficient cochlea, which has important implications for the discovery and development of treatment strategies for hearing loss caused by Cx26 deficiency.

Hearing loss is the most common sensory organ disorder, with genetic factors contributing substantially to the disease. Among the 87 genes responsible for autosomal recessive nonsyndromic hearing loss, mutations in MPZL2 have been frequently linked to mild-to-moderate autosomal recessive hearing loss (DFNB111). Here, we present multiple families whose hearing loss arose from biallelic mutations in the MPZL2 gene and found that the MPZL2 p.Q74∗ mutation may be a founder allele among East Asians. Furthermore, we generated an Mpzl2 p.Q74∗ knockin mouse model that exhibited autosomal recessive, progressive, ski-sloping hearing loss with Deiter's cell degeneration. Gene supplementation using AAV-DJ or AAV-PHP.eB to deliver human MPZL2 (hMPZL2) under control of the CAG promoter induced ototoxicity, whereas employing an alternative EF1α promoter with AAV-DJ (DJ-EF1α-hMPZL2) circumvented this issue, restoring long-term auditory function and Deiter's cell survival in Mpzl2Q74∗/Q74∗ mice for up to 24 weeks. Overall, this study provides the foundational steps for developing a safe and effective biological treatment for DFNB111 and underscores the importance of precise regulation of target cells and transgene expression in AAV-based treatments.

Objective: The purpose of this paper is to present a chronic, preclinical, pilot study of a multi-electrode auditory nerve implant. To date, the most successful auditory neuroprosthesis is the cochlear implant, but these devices have known limitations. Intraneural stimulation of the auditory nerve is a promising alternative, but preclinical investigations of multi-electrode devices have been limited to acute or semi-chronic studies. Methods: Six cats were chronically implanted in the right auditory nerve with a 15-channel Utah Slant ArrayTM. The array's position in the internal auditory canal was confirmed using computed tomography. Electrode impedance and evoked responses were recorded regularly during the indwelling period to evaluate performance. Results: Two of the six implants met endpoint criteria at 6 months, with stable electrode impedances and robust evoked responses on at least 50% of their channels. Another two implants exhibited stable electrode impedances, but activation thresholds increased over three months. Two implants failed within the first two weeks due to device migration caused by connector-related issues. Conclusion: This study reports the first successful chronic deployment of an multi-electrode auditory nerve implant in a preclinical model. Two implanted cats exhibited stable chronic performance, marked by a consistent set of electrodes capable of eliciting evoked responses. The failure modes of the remaining four cats are discussed and recommendations are made to stabilize implant placement. The study lays a solid foundation for future chronic safety and efficacy investigations as part of an effort to translate this new neuroprosthetic technology into the clinic.

In adults with acquired hearing loss, cortical reorganization and cross‐modal plasticity critically influence the timing and outcomes of cochlear implantation. This study examined the effects of 2 weeks of bilateral auditory deprivation—induced by intense broadband noise—on the structure and gene expression in the primary auditory (A1) and visual (V1) cortices of adult rats. The results revealed that the total neuronal counts in both the A1 and V1 remained unchanged compared to controls. Morphological analysis showed no significant change in mature dendritic spine density in either region, but immature spine density was significantly reduced in the V1 cortex. Ultrastructural examination demonstrated notable synaptic alterations in the A1 cortex, including significant reductions in postsynaptic density (PSD) length, thickness, area, and synaptic vesicle number—changes that were not observed in the V1 cortex. Transcriptomic profiling indicated a region‐specific response, with 197 differentially expressed genes (DEGs) in the A1 cortex, compared to a broader alteration of 545 DEGs in the V1 cortex, which were significantly involved in neuronal signaling and synaptic transmission. These findings demonstrate that auditory deprivation induces distinct molecular and synaptic remodeling in the A1 and V1 cortices, identifying neuronal plasticity and synaptic regulation as central mechanisms for cross‐modal reorganization in the adult brain.

Background DFNB16, the second most common genetic cause of hearing loss, is caused by mutations of the STRC gene encoding stereocilin, a protein essential for the effective functioning of outer hair cells (OHCs) as cochlear amplifiers. Strc −/− mice, which lack stereocilin, display severe to profound deafness and constitute a relevant preclinical model for DFNB16. Methods Using Strc − / − mice, we developed a gene therapy strategy based on the use of dual AAV9‐PHP.eB vectors to deliver the full‐length Strc cDNA. Therapeutic efficacy was assessed by evaluating stereocilin expression, OHC bundle architecture, and their attachment to the tectorial membrane, together with functional recovery using distortion product otoacoustic emissions (DPOAEs), auditory brainstem responses (ABR) measurements and Go/No‐Go behavioral testing with psychometric analysis. Results Dual‐AAV–mediated Strc gene delivery restored stereocilin expression, OHC bundle architecture and their attachment to the tectorial membrane, leading to the recovery of cochlear amplification and hearing to near normal thresholds, as confirmed by distortion product otoacoustic emission (DPOAE) and auditory brainstem response measurements. Behavioural assessment showed that treated Strc −/− mice regained normal frequency discrimination, indicating a restoration of higher‐order auditory processing, up to 100 days post‐treatment. Conclusion These findings provide the first proof‐of‐principle that peripheral gene therapy can restore OHC function, cochlear amplification and central auditory perception in a DFNB16 model. Key points Dual AAV‐mediated gene delivery restored peripheral hearing in a DFNB16 preclinical mouse model. The same treatment also restored central auditory processing. AAV‐mediated gene therapy represents a promising curative strategy for DFNB16. These results reinforce the translational potential for treating human genetic deafness.

Sensorineural hearing loss (SNHL) is significantly more prevalent in individuals with chronic kidney disease (CKD) than in the general population. Although a strong independent association has been observed between kidney dysfunction and the risk of hearing loss, the underlying mechanisms linking these conditions remain poorly understood. This study investigated the pathophysiology of hearing impairment using adriamycin nephropathy (AN), a well-established animal model of CKD. AN was induced in male BALB/c mice using 10 or 12 mg/kg of adriamycin (ADR), resulting in severe kidney injury and concurrent hearing loss. ADR-treated mice exhibited significant glomerular injury, podocyte damage, and elevated renal neutrophil gelatinase-associated lipocalin (NGAL), along with increased serum creatinine and blood urea nitrogen levels. Hearing impairment was evident after 4-8 weeks of ADR treatment, as assessed by auditory brainstem response and distortion-product otoacoustic emissions, and was accompanied by cochlear hair cell loss and ribbon synapse degeneration. AN affected cochlear function by altering ion channel expression in the stria vascularis and inducing blood-labyrinth barrier (BLB) hyperpermeability, along with changes in endothelial cells, pericytes, and perivascular-resident macrophage-like melanocytes. AN significantly increased cochlear NGAL and NLRP3 levels at 4 and 8 weeks following ADR administration. NGAL was highly expressed in the tectorial membrane, cochlear neurons, and organ of Corti, while its receptor, 24p3R, was co-localized with NGAL. These findings demonstrated the role of NGAL and BLB disruption in ADR-induced SNHL, providing novel insights into the mechanistic link between CKD and hearing loss.

Although age-related hearing loss (ARHL) is the most common sensory loss in older adults, underlying mechanisms remain unclear. Recent genome-wide association studies (GWAS) linked variation in several genes with ARHL risk, including KLHDC7B , a gene of unknown function not previously linked to hearing. We demonstrate Klhdc7b is expressed exclusively in sensory hair cells in mouse cochlea. Utilizing two independent mouse knockout models ( Klhdc7b IMPC-/- and Klhdc7b Regn Δ/Δ ) we find that absence of Klhdc7b leads to severe early-onset, progressive hearing loss. Hair cells appear to develop normally, but outer hair cells are progressively lost from base-to-apex of the cochlea, a common pathology in ARHL. These results suggest KLHDC7B is required for maintenance rather than development, of auditory function. The validation in mouse of a human ARHL GWAS association suggests other novel candidates should be investigated. Our work provides two mouse models to study KLHDC7B function, and for development of therapeutic tools for ARHL.

Auditory hypersensitivity is a prominent symptom in Fragile X syndrome (FXS), the most prevalent monogenic cause of autism and intellectual disability. FXS arises through the loss of the protein encoded by the FMR1 (Fragile X Messenger Ribonucleoprotein 1) gene, FMRP, required for normal neural circuit excitability. In the brainstem, FMRP is necessary for normal development of acoustic reactivity, and its loss has been implicated in audiogenic seizures (AGS) in Fmr1 knockout (KO) mice, modeling auditory hypersensitivity and seizures in FXS patients. The present study investigated the correlation between auditory brainstem function and behavioral expression of AGS at the early (postnatal day P20, infancy) and late (P32, juvenile) stages of auditory development in Fmr1 KO mice compared with wildtype (WT) mice, and in both females and males. We tested responsiveness to pure tones of select auditory pathway elements through auditory brainstem responses, and neural synchronization to amplitude envelopes of modulated acoustic stimuli through auditory steady‐state responses. AGS behavior was categorized for severity during 5‐min exposure to loud sound. Expression of the immediate early gene cFos was quantified as a marker for neuronal activity in the inferior colliculus. During infancy, more severe AGS expression in Fmr1 KO mice compared with WT mice was accompanied by increased responsiveness to acoustic stimuli at the level of the superior olivary complex and inferior colliculus, and stronger neural synchronicity in subcortical auditory neurons. Fmr1 KO mice also had higher cFos positive cell counts in the inferior colliculus after exposure to loud sound. With age, both AGS susceptibility and exaggerated acoustic stimulus‐evoked activity in the Fmr1 KO mice subsided. Intriguingly, Fmr1 KO mice displayed an altered developmental profile in both the threshold and amplitude of auditory brainstem response. Our findings support evidence that AGS activity relies upon hyperexcitability in the auditory system, including in the lower brainstem, possibly due to disturbed auditory maturation. Hyper‐synchronization to modulated sounds in subcortical auditory neurons seemed to predict AGS severity. The developmental trajectory of the auditory hyperresponsiveness and hypersynchrony suggests a transient processing alteration underlying heightened AGS susceptibility in Fmr1 KO mice. A better understanding of FXS‐related circuit and behavioral symptoms of auditory processing across development provides the potential to identify therapeutic strategies to achieve auditory function recovery in FXS.

The cochlear implant is a widely available hearing restoration technology that can provide speech understanding in quiet environments. This technology struggles however, in noisy settings or situations involving multiple speakers. The primary cause of these performance limitations is a poor neural interface, in which the bony wall of the cochlea separates the electrode surface from the auditory nerve fibers, thus causing unwanted current spread and non-specific frequency activation. This study utilizes an alternative auditory prosthetic technology (auditory nerve implant, ANI) that enables direct auditory nerve stimulation, which provides a potentially superior neural interface and enables more precise targeting of auditory nerve fibers than traditional cochlear implants. As auditory nerve implants progress towards clinical translation, new implant designs and stimulation strategies will be created. Animal models to efficiently test and iterate through these new designs will be useful for the continued development of ANI technology. We present a viable surgical approach in the non-human primate (rhesus macaque) along with electrophysiological results that demonstrate robust activation of the auditory system at low current levels via intraneural stimulation. Our findings indicate that the rhesus macaque, which possesses an inner ear anatomy more similar to the human compared to other animal models used in the hearing field (e.g., rodents, felines and ferrets), has strong potential as a useful preclinical testbed involving an upright head model for future ANI prototypes and stimulation strategy development.

No pharmacological interventions exist that can restore or preserve auditory function in the mammalian cochlea. Auditory hair cells (HCs) do not spontaneously regenerate, leading to permanent hearing loss. In non-mammalian vertebrates, HC regeneration happens through proliferation and differentiation of their clonally related supporting cells (SCs). The present study supports the potential of quinoxaline (Qx), a nonsteroidal anti-inflammatory compound, to stimulate SC proliferation in the auditory sensory epithelium, a process that may prime the tissue for future HC regeneration. We synthesized a series of Qx derivatives by introducing various substitutions, ranging from hydrophilic to lipophilic. Seventy analogs were generated and tested in vitro and in vivo. Among those, only one (Qx-100) exhibited the best medicinal chemistry profile and was further modified to expand the structure–activity relationship of the chemotype, develop additional analogs, and optimize potency, bioavailability, and in vivo efficacy. Ten new lead variants were generated. Of those, Qx-294 and Qx-301 demonstrated promising in vitro Absorption, Distribution, Metabolism, and Excretion (ADME) profiles and were selected for further testing. Overall, both compounds were rapidly absorbed in zebrafish and mice and promoted cell proliferation in vitro and in vivo without signs of apoptosis, supporting their potential for sensory HC regeneration.

Hearing loss is the most common sensory disorder, with a substantial proportion caused by genetic mutations. KCNQ4, a voltage-gated potassium channel highly expressed in cochlear outer hair cells, is a common genetic etiology implicated in autosomal dominant progressive hearing loss (DFNA2). The dominant-negative KCNQ4 p.W276S (c.827G>C) mutation represents a mutational hotspot in DFNA2, yet no effective treatments exist. Here, we developed allele-preferential antisense oligonucleotides (ASOs) targeting this dominant-negative KCNQ4 mutation. In a systemic in vitro screen, ASO-123 demonstrated a knockdown of mutant Kcnq4 while preserving wild-type transcripts. In a Kcnq4 p.W277S knockin mouse model mimicking DFNA2, ASO-123 preferentially suppressed mutant transcripts, attenuated progressive hearing loss, and improved outer hair cell survival while enhancing their electrophysiologic function. Comprehensive transcriptomic analyses further validated the efficacy of ASO-123. Thus, our findings establish ASO-based therapy as a promising strategy for treating hereditary hearing loss caused by dominant-negative KCNQ4 mutations.

Outer hair cells (OHCs) in the cochlea contain specialized stereociliary structures essential for auditory function. These include horizontal top connectors (HTCs), linking adjacent stereocilia and tectorial membrane (TM)-attachment crowns (ACs), anchoring the tallest stereocilia to the TM. The known molecular components of these structures, such as stereocilin, otogelin, otogelin-like, and tubby, lack transmembrane domains, suggesting the existence of anchoring proteins. This study identifies TMEM145, a transmembrane protein with a Golgi dynamics domain, as a crucial OHC stereocilia component. TMEM145 is expressed in both OHCs and spiral ganglion neurons, with specific localization to TM-ACs and HTCs in OHCs. Tmem145 knockout (KO) mice exhibit profound hearing impairment at 3 weeks of age, with complete loss of distortion product otoacoustic emissions, indicating OHC dysfunction. Immunostaining and scanning electron microscopy reveal the absence of TM-ACs and HTCs in Tmem145 KO mice. In heterologous cell systems, TMEM145 interacts with stereocilin and tubby, facilitating their extracellular secretion. TMEM145 is undetectable in Stereocilin KO and tubby mutant mice, indicating interdependence among these proteins. These findings establish TMEM145 as an essential membrane protein for the structural integrity of OHC stereocilia, providing insights into the molecular architecture of cochlear hair cells and their role in auditory function.

Noise-induced hearing loss (NIHL) is a primary contributor to tinnitus, involving mechanisms such as inflammatory damage, central sensitization, and auditory cortex remodeling. However, not all cases of tinnitus are accompanied by NIHL, and the precise relationship between the two remains incompletely understood. Phosphorylation/dephosphorylation, as a core mechanism for fine cellular regulation, influences neuronal excitability, immune responses, and disease development by modulating protein activity, signal transduction, and gene expression. We hypothesized that aberrant phosphorylation levels may alter auditory cortex neuron function, leading to pathological changes at the protein level. Leveraging auditory cortex tissue from a noise-induced tinnitus model, we systematically investigated the pathogenesis of tinnitus and its distinction from NIHL through integrated proteomic and phosphoproteomic analyses. Compared to animals with NIHL alone, the tinnitus model exhibited enhanced neuronal excitability, synaptic dysfunction, hyperactive energy metabolism, and weakened neuroprotection, with disordered membrane receptor function playing a critical role. Multi-omics analysis further revealed that tinnitus development primarily depends on phosphorylation-mediated post-translational modifications reshaping cellular function, rather than changes in protein abundance caused by alterations in gene transcription levels. Collectively, this study elucidates the physiological and cellular structural alterations in noise-induced tinnitus from the dimensions of protein expression and phosphorylation modification. It confirms that tinnitus leads to neural dysfunction through abnormal membrane receptor activity, and the characteristic proteins and phosphorylation sites identified offer novel therapeutic targets for modulating central hyperexcitability in tinnitus.

Background CLN3 disease, also known as juvenile Batten disease, is a recessively inherited neurodevelopmental disorder caused by mutations in the CLN3 gene. It represents the most common form of Neuronal Ceroid Lipofuscinoses (NCLs), a group of lysosomal storage disorders that impair brain function. Clinical features include progressive vision loss, language impairment, and cognitive decline. The early onset of visual deficits complicates the neurological assessment of cognitive dysfunction, while the rarity of CLN3 cases limits the study of sex-specific disease trajectories in humans. Therefore, there is a critical need for objective, translational biomarkers to monitor disease progression and support therapeutic development in preclinical animal models. Methods Building on our recent studies in individuals with CLN3 disease, we developed a parallel experimental paradigm using high-density electroencephalography (EEG) in Cln3 knockout ( Cln3-/-) mice to longitudinally assess auditory neurophysiological changes. We applied a duration-based mismatch negativity (MMN) paradigm, similar to that used in our human studies, to evaluate automatic detection of auditory pattern changes in male and female mice between 3 and 9 months of age. Results Wild-type (WT) mice of both sexes showed robust and stable duration MMN responses across this age range. In contrast, Cln3-/- mice showed marked sex- and age-dependent deficits: female mutants displayed persistent MMN deficits, whereas male mutants exhibited early MMN abnormalities that unexpectedly improved with age. Auditory brainstem responses confirmed intact peripheral hearing in Cln3-/- mice, indicating a central origin for the observed abnormalities. Further analyses revealed that MMN impairments were driven by age- and sex-specific alterations in auditory evoked potentials to both standard and deviant stimuli. Conclusions These findings demonstrate sex- and age-dependent disruptions in central auditory processing in Cln3-/- mice and support auditory duration MMN as a sensitive, translational biomarker of brain dysfunction in CLN3 disease. This approach offers a functional, cross-species measure for tracking disease progression and evaluating therapeutic interventions in Batten disease.

Background: Millions of older adults have age-related hearing loss (ARHL), a disorder where potassium-secreting cells in the cochlea's lateral wall often degenerate. The degeneration reduces the force that drives ions into the sensory cells during sound stimulation, which is traditionally thought to explain the loss of hearing. Here we describe previously unknown mechanisms underlying this metabolic form of ARHL. Methods: Fluorescence spectroscopy and live-cell imaging was used in Dunkin-Hartley guinea pigs of either sex to investigate the effects of lateral wall dysfunction on the hearing organ and its accessory structures. Critical findings were confirmed by studying samples of human temporal bones. Findings: Lateral wall dysfunction caused calcium levels in the inner ear to decline, a change that was most pronounced in the tectorial membrane, an accessory structure crucial for transmitting acoustic stimuli to sensory cell stereocilia. This calcium depletion deprived the sensory cells of an essential ion. Additionally, the tectorial membrane detached from stereocilia, significantly impairing their ability to respond to sound. Sound-evoked responses were further decreased by sustained contraction of the entire hearing organ. Interpretation: These findings establish the tectorial membrane as a key factor in metabolic ARHL, which needs to be considered when developing better diagnostic tools or treatments. Funding: Swedish Research Council grants 2017-06092 and 2022-00548, Swedish Brain foundation grant FO2023-0171 and US National Institutes of Health grant R01DC000141-44.

Hearing relies upon speedy synaptic transmission of sound information from inner hair cells (IHCs) to spiral ganglion neurons. To accomplish this, IHCs use a sophisticated presynaptic machinery including the multi-C 2 domain protein otoferlin that is affected by human deafness mutations. Otoferlin is essential for IHC exocytosis, but how it binds Ca 2+ and the target membrane to serve synaptic vesicle (SV) tethering, docking, and fusion remained unclear. Here, we obtained cryo–electron microscopy structures of otoferlin and employed molecular dynamics simulations of membrane binding. We show that membrane binding by otoferlin involves C 2 B-C 2 G domains and repositions C 2 F and C 2 G domains. Disruption of Ca 2+ -binding sites of the C 2 D domain in mice altered synaptic sound encoding and eliminated the Ca 2+ cooperativity of IHC exocytosis, indicating that it requires the binding of several Ca 2+ -ions by otoferlin. Together, our findings elucidate molecular mechanisms underlying otoferlin-mediated SV docking and support the role of otoferlin as Ca 2+ sensor of SV fusion in IHCs.

The pre‐hearing mouse cochlea undergoes critical periods of spontaneous Ca 2+ ‐dependent activity that spreads across non‐sensory supporting cells and inner hair cells (IHCs). These signals have been shown to regulate not only the refinement of neural circuits along the auditory pathway towards functional maturity, but also the maturation of the hair cells into sensory receptors. Although the origin and interplay of these Ca 2+ signals during cochlear development have recently been investigated in live mice, the impact of anaesthesia on in vivo functional measurements was not explored. Here, we investigate the effects of different anaesthetic regimes (ketamine and xylazine; 2.5% isoflurane; and 1.0%–1.5% isoflurane with the sedative acepromazine) that provided an effective unconsciousness to perform the surgery and Ca 2+ ‐imaging recordings from the intact cochlea of live mice. The IHCs, supporting cells and spiral ganglion neuron terminals onto the IHCs showed spontaneous Ca 2+ ‐dependent activity under all anaesthetic regimes, with a few significant differences observed between conditions. Calcium waves from supporting cells synchronized the activity of IHCs. Moreover, we found that the endocochlear potential, which is crucial for cochlear function, was unaffected by the different anaesthetics. However, low concentrations of isoflurane produced the most stable recordings of vital physiological signs in mice, including heart rate and breathing rate. Although all anaesthetic regimes tested appeared to be suitable for performing Ca 2+ imaging from the cochlea of pre‐hearing live mice, a low concentration of isoflurane (1.0%–1.5%), combined with the pre‐anaesthetic sedative acepromazine and oxygenation, represents the most suitable approach to maintain a stable and long‐lasting depth of anaesthesia.

Introduction The posterior tail of the striatum receives dense inputs from sensory regions of cortex and thalamus, as well as midbrain dopaminergic innervation, providing a neural substrate for associative sensory learning. Previously, we have demonstrated that developmental hearing loss is associated with aberrant physiological states in striatal medium spiny neurons (MSNs). Methods Here we directly investigated auditory associative learning impairments in the striatum of adult Mongolian gerbils that underwent transient developmental hearing loss or sham hearing loss during the critical period of auditory development. We used electrophysiology to reveal significant changes to neuronal population responses in vivo and intrinsic and synaptic properties to medium spiny neurons in vitro as animals learned an appetitive “Go/No-Go” auditory discrimination task. For in vivo experiments a 64-channel electrode was implanted in the auditory region of the posterior tail of the striatum and neuronal recordings were carried out as animals learned the task. For in vitro experiments, corticostriatal slice preparations were made from animals on each day of training. Results In naïve animals from both groups there was limited to no phase locking to either auditory stimulus in vivo , and long term depression resulted from theta burst stimulation in vitro . Furthermore, intrinsic and synaptic properties in normal hearing animals were unaffected; however, the hearing loss group continued to show lowered synaptic inhibition, synaptic hyperexcitation, and suppressed intrinsic excitability in the hearing loss group. Starting around day 3–4 in both groups, the emergence of striatal medium spiny neuron phase locking to the auditory conditioning stimuli was observed in vivo . This occurred contemporaneous to an increased probability of theta burst induced LTP during MSN whole cell recording in vitro , and acquisition of the task as the correct rejection response significantly increased in the behaving animals. During the acquisition phase MSNs in the normal hearing group showed a significant decrease in synaptic inhibition and increase in synaptic excitation with no change to intrinsic excitability, while the MSNs in the hearing loss group showed a significant increase in synaptic inhibition, reduction of synaptic hyper excitability, and compensatory changes to intrinsic excitability that supported normal action potential generation. In both groups, synaptic properties were resolved to similar level of E/I balance that could be part of a conserved learning state. Discussion These changes to the intrinsic and synaptic properties likely support LTP induction in vivo and the strengthening of synapses between auditory inputs and MSNs that facilitate neuronal phase locking. These findings have significant implications for our understanding of striatal resilience to sensory impairments in early life, in addition to establishing a granular understanding of the striatal circuit changes that support reward driven stimulus–response learning.

Mutations in MYO7A , the gene encoding the unconventional myosin 7a, cause hereditary deafness in mice and humans. In the cochlea, MYO7A is present in the sensory hair cells from embryonic stages of development, and plays a critical role in the development and maintenance of the mechanosensitive hair bundles composed of actin‐rich stereocilia. Shaker‐1 mutant mice ( Myo7a Sh1/Sh1 ), the murine model of Usher 1B syndrome, exhibit a progressive loss of the stereocilia, subsequent degeneration of the sensory epithelium and ultimately profound deafness. In addition to the hair bundle defects, we found that the shaker‐1 mutation prevented both inner hair cells (IHCs) and outer hair cells (OHCs) from acquiring their fully mature basolateral current profile. Delivering exogenous Myo7a to newborn Myo7a Sh1/Sh1 mice using dual‐adeno‐associated virus 8 (AAV8)‐ Myo7a or dual‐AAV9‐PhP.eB‐ Myo7a , which primarily target IHCs, led to a substantial rescue of their hair bundle structure. The rescued bundles regained their ability to generate mechanoelectrical transducer (MET) currents in response to fluid jet displacement. Although the average MET current was smaller than in control IHCs, the normal resting open probability of the MET channel was fully restored. The IHCs of the treated cochlea also regained a mature basolateral membrane current profile. Functionally, rescue of the IHC structure and function, but not that of OHCs, leads to an average improvement of 20–30 dB in hearing thresholds across most frequencies. These results support dual AAV‐induced gene replacement therapy as an effective strategy to recover hair‐cell function in Myo7a Sh1/Sh1 mice. image Key points Shaker‐1 mutant mice ( Myo7a Sh1/Sh1 ), which carry a mutation in the unconventional myosin MYO7A and are the murine model of Usher 1B syndrome, become profoundly deaf at 1 month of age or soon after. In the mammalian cochlea, MYO7A is expressed in the hair cells, including within their actin‐rich stereociliary bundles. We show that hair cells of Myo7a Sh1/Sh1 mice progressively lose their transducing stereocilia and mechanoelectrical transduction, and fail to acquire their fully mature basolateral current profile. Delivering exogenous Myo7a to newborn Myo7a Sh1/Sh1 mice using dual‐adeno‐associated virus (AAVs) led to a substantial rescue of the bundle structure and function of inner hair cells, including mechanoelectrical transduction. This functional rescue led to a 20–30 dB improvement in hearing thresholds across most frequencies. These results support dual AAV‐induced gene replacement therapy as an effective strategy to recover the hair‐cell function in Myo7a Sh1/Sh1 mice.

Noise‐induced hearing loss (NIHL), caused by irreversible cochlear hair cell (HC) damage, lacks effective therapies due to a limited understanding of endogenous protective mechanisms. The echolocating bats exhibit natural resistance to intense noise, and this suggested novel insights into methods to protect against NIHL. Here, through comparative transcriptomic analysis of noise‐exposed cochleae from the eastern bent‐winged bats ( Miniopterus fuliginosus ) and mice, the specific transcriptional dynamics in noise‐resistant Miniopterus fuliginosus are revealed, thus highlighting potential mechanisms for preventing cochlear damage that mouse models cannot replicate, with Hras emerging as the most significant hub upregulator. Functional validation in mice demonstrates that HC‐specific Hras overexpression significantly attenuates noise‐induced HC death, synaptic loss, and auditory threshold shifts. Mechanistically, Hras confers protection by activating the PI3K/Akt signaling pathway, a critical pro‐survival cascade. The findings further disentangle the mechanisms of cochlear resistance to intense noise in echolocating bats and suggest that targeting Hras expression may be a potential therapeutic intervention against NIHL.