ABR/DPOAE publications

The neurodevelopmental disorder Angelman syndrome (AS) is characterized by intellectual disability, motor dysfunction, distinct behavioral aspects, and epilepsy. AS is caused by a loss of the maternally expressed UBE3A gene, and many of the symptoms are recapitulated in a Ube3a mouse model of this syndrome. At the cellular level, changes in the axon initial segment (AIS) have been reported, and changes in vesicle cycling have indicated the presence of presynaptic deficits. Here we studied the role of UBE3A in the auditory system by recording synaptic transmission at the calyx of Held synapse in the medial nucleus of the trapezoid body (MNTB) through in vivo whole cell and juxtacellular recordings. We show that MNTB principal neurons in Ube3a mice exhibit a hyperpolarized resting membrane potential, an increased action potential (AP) amplitude and a decreased AP half width. Moreover, both the pre- and postsynaptic AP in the calyx of Held synapse of Ube3a mice showed significantly faster recovery from spike depression. An increase in AIS length was observed in the principal MNTB neurons of Ube3a mice, providing a possible substrate for these gain-of-function changes. Apart from the effect on APs, we also observed that EPSPs showed decreased short-term synaptic depression (STD) during long sound stimulations in AS mice, and faster recovery from STD following these tones, which is suggestive of a presynaptic gain-of-function. Our findings thus provide in vivo evidence that UBE3A plays a critical role in controlling synaptic transmission and excitability at excitatory synapses.

The prevalence and importance of hearing damage caused by noise levels not previously thought to cause permanent hearing impairment has become apparent in recent years. The damage to, and loss of, afferent terminals of auditory nerve fibres at the cochlear inner hair cell has been well established, but the effects of noise exposure and terminal loss on the inner hair cell are less known. Using three-dimensional structural studies in mice we have examined the consequences of afferent terminal damage on inner hair cell morphology and intracellular structure. We identified a structural phenotype in the pre-synaptic regions of these damaged hair cells that persists for four weeks after noise exposure, and demonstrates a specific dysregulation of the synaptic vesicle recycling pathway. We show evidence of a failure in regeneration of vesicles from small membrane cisterns in damaged terminals, resulting from a failure of separation of small vesicle buds from the larger cisternal membranes.

Acoustic trauma is being reported to damage the auditory periphery and central system, and the compromised cortical inhibition is involved in auditory disorders, such as hyperacusis and tinnitus. Parvalbumin-containing neurons (PV neurons), a subset of GABAergic neurons, greatly shape and synchronize neural network activities. However, the change of PV neurons following acoustic trauma remains to be elucidated. The present study investigated how auditory cortical PV neurons change following unilateral 1 hour noise exposure (left ear, one octave band noise centered at 16 kHz, 116 dB SPL). Noise exposure elevated the auditory brainstem response threshold of the exposed ear when examined 7 days later. More detectable PV neurons were observed in both sides of the auditory cortex of noise-exposed rats when compared to control. The detectable PV neurons of the left auditory cortex (ipsilateral to the exposed ear) to noise exposure outnumbered those of the right auditory cortex (contralateral to the exposed ear). Quantification of Western blotted bands revealed higher expression level of PV protein in the left cortex. These findings of more active PV neurons in noise-exposed rats suggested that a compensatory mechanism might be initiated to maintain a stable state of the brain.

The prevalence of tinnitus is known to increase with age. The age-dependent mechanisms of tinnitus may have important implications for the development of new therapeutic treatments. High doses of salicylate can be used experimentally to induce transient tinnitus and hearing loss. Although accumulating evidence indicates that salicylate induces tinnitus by directly targeting neurons in the peripheral and central auditory systems, the precise effect of salicylate on neural networks in the auditory cortex (AC) is unknown. Here, we examined salicylate-induced changes in stimulus-driven laminar responses of AC slices with salicylate superfusion in young and aged senescence-accelerated-prone (SAMP) and -resistant (SAMR) mice. Of the two strains, SAMP1 is known to be a more suitable model of presbycusis. We recorded stimulus-driven laminar local field potential (LFP) responses at multi sites in AC slice preparations. We found that for all AC slices in the two strains, salicylate always reduced stimulus-driven LFP responses in all layers. However, for the amplitudes of the LFP responses, the two senescence-accelerated mice (SAM) strains showed different laminar properties between the pre- and post-salicylate conditions, reflecting strain-related differences in local circuits. As for the relationships between auditory brainstem response (ABR) thresholds and the LFP amplitude ratios in the pre- vs. post-salicylate condition, we found negative correlations in layers 2/3 and 4 for both older strains, and in layer 5 (L5) in older SAMR1. In contrast, the GABAergic agonist muscimol (MSC) led to positive correlations between ABR thresholds and LFP amplitude ratios in the pre- vs. post-MSC condition in younger SAM mice from both strains. Further, in younger mice, salicylate decreased the firing rate in AC L4 pyramidal neurons. Thus, salicylate can directly reduce neural excitability of L4 pyramidal neurons and thereby influence AC neural circuit activity. That we observed age-dependent effects of salicylate and varied GABAergic sensitivity in the AC among mouse strains with hearing loss implies that potential therapeutic mechanisms for tinnitus may operate differently in young vs. aged subjects. Therefore, scientists developing new therapeutic modalities for tinnitus treatment should consider using both aged and young animals.

The auditory brainstem response to a dolphin's own emitted biosonar click can be measured by averaging epochs of the instantaneous electroencephalogram (EEG) that are time-locked to the emitted click. In this study, averaged EEGs were measured using surface electrodes placed on the head in six different configurations while dolphins performed an echolocation task. Simultaneously, biosonar click emissions were measured using contact hydrophones on the melon and a hydrophone in the farfield. The averaged EEGs revealed an electrophysiological potential (the pre-auditory wave, PAW) that preceded the production of each biosonar click. The largest PAW amplitudes occurred with the non-inverting electrode just right of the midline-the apparent side of biosonar click generation-and posterior of the blowhole. Although the source of the PAW is unknown, the temporal and spatial properties rule out an auditory source. The PAW may be a neural or myogenic potential associated with click production; however, it is not known if muscles within the dolphin nasal system can be actuated at the high rates reported for dolphin click production, or if sufficiently coordinated and fast motor endplates of nasal muscles exist to produce a PAW detectable with surface electrodes.

Approximately 15% of American adults report some degree of difficulty hearing in a noisy environment or have auditory filtering difficulties. There are objective clinical tests of auditory filtering, yet few tests exist for mouse models that do not rely on extensive training. We have used reflex modification audiometry (RMA) and developed exclusion criteria for the mouse model. This RMA based test makes use of the acoustic startle response (ASR) and the ability of prepulses to inhibit the ASR [i.e., prepulse inhibition (PPI)] to assess the mouse's ability to detect prepulse signals presented in quiet or embedded in masking noise. We have studied PPI behavior across four inbred mouse strains with normal cochlear function and developed pre-testing exclusion criteria and test/retest reliability measures. Moreover, because both the medial (MOC) and the lateral (LOC) olivocochlear efferent feedback systems have been proposed to improve auditory behavior performance, especially in noisy backgrounds, we have examined PPI abilities in mice (with their littermate controls) either lacking the MOC receptor subunit α9 nicotinic acetylcholine receptor [α9 nAChR (-/-)] or expressing an overactive receptor [Ld'T mutation in α9 nAChR KI], or lacking an LOC efferent neuropeptide, alpha calcitonin gene-related peptide [αCGRP (-/-)] only in the CNS. Because CGRP receptor formation has been shown to mature from juvenile to adult ages, we also studied if this maturation would be reflected in PPI behavioral responses in juvenile and adult (+/+) controls and in adult αCGRP (-/-) animals. We show that 50% PPI response thresholds (sound level with 50% correct responses) in quiet are decreased in the (-/-) α9 nAChR animals, and 50% PPI responses are increased for mice with an overactive receptor (α9 nAChR KI) and are increased in adult mice lacking αCGRP (-/-). However, in background noise, only mice lacking αCGRP exhibited increased 50% PPI response thresholds, as there were no significant differences between α9 nAChR adult mouse lines and their littermate controls. These findings suggest that MOC and LOC olivocochlear neurotransmission work in tandem to improve behavioral responses to sound. These experiments further pave the way for rapid behavioral hearing assessments in other mouse models.

Extracellular field potentials (EFPs) are an important source of information in neuroscience, but their physiological basis is in many cases still a matter of debate. Axonal sources are typically discounted in modeling and data analysis because their contributions are assumed to be negligible. Here, we established experimentally and theoretically that contributions of axons to EFPs can be significant. Modeling action potentials propagating along axons, we showed that EFPs were prominent in the presence of terminal zones where axons branch and terminate in close succession, as found in many brain regions. Our models predicted a dipolar far field and a polarity reversal at the center of the terminal zone. We confirmed these predictions using EFPs from the barn owl auditory brainstem where we recorded in nucleus laminaris using a multielectrode array. These results demonstrate that axonal terminal zones can produce EFPs with considerable amplitude and spatial reach.

Congenital cytomegalovirus (CMV) infection is the most common non-hereditary cause of sensorineural hearing loss (SNHL) yet the mechanisms of hearing loss remain obscure. Natural Killer (NK) cells play a critical role in regulating murine CMV infection via NK cell recognition of the Ly49H cell surface receptor of the viral-encoded m157 ligand expressed at the infected cell surface. This Ly49H NK receptor/m157 ligand interaction has been found to mediate host resistance to CMV in the spleen, and lung, but is much less effective in the liver, so it is not known if this interaction is important in the context of SNHL. Using a murine model for CMV-induced labyrinthitis, we have demonstrated that the Ly49H/m157 interaction mediates host resistance in the temporal bone. BALB/c mice, which lack functional Ly49H, inoculated with mCMV at post-natal day 3 developed profound hearing loss and significant outer hair cell loss by 28 days of life. In contrast, C57BL/6 mice, competent for the Ly49H/m157 interaction, had minimal hearing loss and attenuated outer hair cell loss with the same mCMV dose. Administration of Ly49H blocking antibody or inoculation with a mCMV viral strain deleted for the m157 gene rendered the previously resistant C57BL/6 mouse strain susceptible to hearing loss to a similar extent as the BALB/c mouse strain indicating a direct role of the Ly49H/m157 interaction in mCMV-dependent hearing loss. Additionally, NK cell recruitment to sites of infection was evident in the temporal bone of inoculated susceptible mouse strains. These results demonstrate participation of NK cells in protection from CMV-induced labyrinthitis and SNHL in mice.

Development of electrophysiological means to assess the medial olivocochlear (MOC) system in humans is important to further our understanding of the function of that system and for the refinement and validation of psychoacoustical and otoacoustic emission methods which are thought to probe the MOC. Based on measurements in anesthetized animals it has been hypothesized that the MOC-reflex (MOCR) can enhance the response to signals in noise, and several lines of evidence support such a role in humans. A difficulty in these studies is the isolation of efferent effects. Efferent activation can be triggered by acoustic stimulation of the contralateral or ipsilateral ear, but ipsilateral stimulation is thought to be more effective. However, ipsilateral stimulation complicates interpretation of effects since these sounds can affect the perception of other ipsilateral sounds by mechanisms not involving olivocochlear efferents. We assessed the ipsilaterally evoked MOCR in human using a transtympanic procedure to record mass-potentials from the cochlear promontory or the niche of the round window. Averaged compound action potential (CAP) responses to masked probe tones of 4 kHz with and without a precursor (designed to activate the MOCR but not the stapedius reflex) were extracted with a polarity alternating paradigm. The masker was either a simultaneous narrow band noise masker or a short (20-ms) tonal ON- or OFF-frequency forward masker. The subjects were screened for normal hearing (audiogram, tympanogram, threshold stapedius reflex) and psychoacoustically tested for the presence of a precursor effect. We observed a clear reduction of CAP amplitude by the precursor, for different masking conditions. Even without an MOCR, this is expected because the precursor will affect the response to subsequent stimuli via neural adaptation. To determine whether the precursor also activated the efferent system, we measured the CAP over a range of masker levels, with or without precursor, and for different types of masker. The results show CAP reduction consistent with the type of gain reduction caused by the MOCR. These results generally support psychoacoustical paradigms designed to probe the efferent system as indeed activating the MOCR system, but not all observations are consistent with this mechanism.

Xeroderma pigmentosum (XP) is a rare recessive heredity disease caused by DNA repair impairment characterized by photosensitivity and neurologic symptoms in half of the cases. There are eight subtypes of XP: XP-A-XP-G and XP variant. Among eight subtypes, XP complementation group A (XP-A) display the lowest DNA repair ability and the severest cutaneous and neurologic symptoms. While its pathogenesis of skin symptoms have been well-studied, that of neurological symptoms, including sensorineural hearing loss (SNHL) remains unknown. Basic studies have suggested that SNHL may be caused by inner ear damage, including damage to the spiral ganglion neurons and organ of Corti, and that the XP-A is associated with most severe form of SNHL in humans. Here, we report the occurrence of SNHL in Xpa-deficient mice. Xpa-deficient mice and wild-type mice underwent measurements for auditory brainstem response, and the results revealed that Xpa-deficient mice exhibited significantly greater (p < 0.01) ABR thresholds at 4, 8, and 16 kHz than the wild-type mice. Furthermore, the number of spiral ganglion neurons was reduced in Xpa-deficient mice compared with that in wild-type mice, indicating that hearing loss may be related to spiral ganglion neuron deficiency, consistent with the few reports published in human patients with XP. These results provide important insights into the pathogenesis of SNHL in patients with XP-A.

With their essential role in inner ear function, stereocilia of sensory hair cells demonstrate the importance of cellular actin protrusions. Actin packing in stereocilia is mediated by cross-linkers of the plastin, fascin, and espin families. Although mice lacking espin (ESPN) have no vestibular or auditory function, we found that mice that either lacked plastin 1 (PLS1) or had nonfunctional fascin 2 (FSCN2) had reduced inner ear function, with double-mutant mice most strongly affected. Targeted mass spectrometry indicated that PLS1 was the most abundant cross-linker in vestibular stereocilia and the second most abundant protein overall; ESPN only accounted for ∼15% of the total cross-linkers in bundles. Mouse utricle stereocilia lacking PLS1 were shorter and thinner than wild-type stereocilia. Surprisingly, although wild-type stereocilia had random liquid packing of their actin filaments, stereocilia lacking PLS1 had orderly hexagonal packing. Although all three cross-linkers are required for stereocilia structure and function, PLS1 biases actin toward liquid packing, which allows stereocilia to grow to a greater diameter.

Age-related hearing loss (ARHL) -presbycusis - is the most prevalent neurodegenerative disease and number one communication disorder of our aged population; and affects hundreds of millions of people worldwide. Its prevalence is close to that of cardiovascular disease and arthritis, and can be a precursor to dementia. The auditory perceptual dysfunction is well understood, but knowledge of the biological bases of ARHL is still somewhat lacking. Surprisingly, there are no FDA-approved drugs for treatment. Based on our previous studies of human subjects, where we discovered relations between serum aldosterone levels and the severity of ARHL, we treated middle age mice with aldosterone, which normally declines with age in all mammals. We found that hearing thresholds and suprathreshold responses significantly improved in the aldosterone-treated mice compared to the non-treatment group. In terms of cellular and molecular mechanisms underlying this therapeutic effect, additional experiments revealed that spiral ganglion cell survival was significantly improved, mineralocorticoid receptors were upregulated via post-translational protein modifications, and age-related intrinsic and extrinsic apoptotic pathways were blocked by the aldosterone therapy. Taken together, these novel findings pave the way for translational drug development towards the first medication to prevent the progression of ARHL.

The occurrence of tinnitus can be linked to hearing loss in the majority of cases, but there is nevertheless a large degree of unexplained heterogeneity in the relation between hearing loss and tinnitus. Part of the problem might be that hearing loss is usually quantified in terms of increased hearing thresholds, which only provides limited information about the underlying cochlear damage. Moreover, noise exposure that does not cause hearing threshold loss can still lead to "hidden hearing loss" (HHL), i.e., functional deafferentation of auditory nerve fibers (ANFs) through loss of synaptic ribbons in inner hair cells. While it is known that increased hearing thresholds can trigger increases in spontaneous neural activity in the central auditory system, i.e., a putative neural correlate of tinnitus, the central effects of HHL have not yet been investigated. Here, we exposed mice to octave-band noise at 100 and 105 dB SPL to generate HHL and permanent increases of hearing thresholds, respectively. Deafferentation of ANFs was confirmed through measurement of auditory brainstem responses and cochlear immunohistochemistry. Acute extracellular recordings from the auditory midbrain (inferior colliculus) demonstrated increases in spontaneous neuronal activity (a putative neural correlate of tinnitus) in both groups. Surprisingly, the increase in spontaneous activity was most pronounced in the mice with HHL, suggesting that the relation between hearing loss and neuronal hyperactivity might be more complex than currently understood. Our computational model indicated that these differences in neuronal hyperactivity could arise from different degrees of deafferentation of low-threshold ANFs in the two exposure groups. Our results demonstrate that HHL is sufficient to induce changes in central auditory processing, and they also indicate a non-monotonic relationship between cochlear damage and neuronal hyperactivity, suggesting an explanation for why tinnitus might occur without obvious hearing loss and conversely why hearing loss does not always lead to tinnitus.

The ear is the organ that is most sensitive to blast overpressure and ear damage is most frequently seen after blast exposure. Blast overpressure to the ear results in sensorineural hearing loss, which is untreatable and is often associated with a decline in the quality of life. In this study, we used a rat model to demonstrate the pathophysiological and structural changes in the inner ear that replicate pure sensorineural hearing loss associated with blast injury using laser-induced shock wave (LISW) without any conductive hearing loss. Our results indicate that threshold elevation of the auditory brainstem response (ABR) after blast exposure was primarily caused by outer hair cell dysfunction induced by stereociliary bundle disruption. The bundle disruption pattern was unique; disturbed stereocilia were mostly observed in the outermost row, whereas those in the inner and middle rows stereocilia remained intact. In addition, the ABR examination showed a reduction in wave I amplitude without elevation of the threshold in the lower energy exposure group. This phenomenon was caused by loss of the synaptic ribbon. This type of hearing dysfunction has recently been described as hidden hearing loss caused by cochlear neuropathy, which is associated with tinnitus or hyperacusis.

In the cochlea of the mustached bat, cochlear resonance produces extremely sharp frequency tuning to the dominant frequency of the echolocation calls, around 61 kHz. Such high frequency resolution in the cochlea is accomplished at the expense of losing temporal resolution because of cochlear ringing, an effect that is observable not only in the cochlea but also in the cochlear nucleus. In the midbrain, the duration of sounds is thought to be analyzed by duration-tuned neurons, which are selective to both stimulus duration and frequency. We recorded from 57 DTNs in the auditory midbrain of the mustached bat to assess if a spectral-temporal trade-off is present. Such spectral-temporal trade-off is known to occur as sharp tuning in the frequency domain which results in poorer resolution in the time domain, and vice versa. We found that a specialized sub-population of midbrain DTNs tuned to the bat’s mechanical cochlear resonance frequency escape the cochlear spectral-temporal trade-off. We also show evidence that points towards an underlying neuronal inhibition that appears to be specific only at the resonance frequency.

Acoustic overstimulation traumatizes the cochlea, resulting in auditory dysfunction. As a consequence of acoustic injury, the immune system in the cochlea is activated, leading to the production of inflammatory mediators and the infiltration of immune cells. However, the molecular mechanisms responsible for initiating these immune responses remain unclear. Here, we investigate the functional role of Toll-like receptor 4 (Tlr4), a cellular receptor that activates the innate immune system, in the regulation of cochlear responses to acoustic overstimulation. Using a Tlr4 knockout mouse model, we examined how Tlr4 deficiency affects sensory cell pathogenesis, auditory dysfunction and cochlear immune activity. We demonstrate that Tlr4 knockout does not affect sensory cell viability under physiological conditions, but reduces the level of sensory cell damage and cochlear dysfunction after acoustic injury. Together, these findings suggest that Tlr4 promotes sensory cell degeneration and cochlear dysfunction after acoustic injury. Acoustic injury provokes a site-dependent inflammatory response in both the organ of Corti and the tissues of the lateral wall and basilar membrane. Tlr4 deficiency affects these inflammatory responses in a site-dependent manner. In the organ of Corti, loss of Tlr4 function suppresses the production of interleukin 6 (Il6), a pro-inflammatory molecule, after acoustic injury. By contrast, the production of inflammatory mediators, including Il6, persists in the lateral wall and basilar membrane. In addition to immune molecules, Tlr4 knockout inhibits the expression of major histocompatibility complex class II, an antigen-presenting molecule, in macrophages, suggesting that Tlr4 participates in the antigen-presenting function of macrophages after acoustic trauma. Together, these results suggest that Tlr4 regulates multiple aspects of the immune response in the cochlea and contributes to cochlear pathogenesis after acoustic injury.

Background and objective: The auditory efferent system is a complex network of descending pathways, which mainly originate in the primary auditory cortex and are directed to several auditory subcortical nuclei. These descending pathways are connected to olivocochlear neurons, which in turn make synapses with auditory nerve neurons and outer hair cells (OHC) of the cochlea. The olivocochlear function can be studied using contralateral acoustic stimulation, which suppresses auditory nerve and cochlear responses. In the present work, we tested the proposal that the corticofugal effects that modulate the strength of the olivocochlear reflex on auditory nerve responses are produced through cholinergic synapses between medial olivocochlear (MOC) neurons and OHCs via alpha-9/10 nicotinic receptors. Methods: We used wild type (WT) and alpha-9 nicotinic receptor knock-out (KO) mice, which lack cholinergic transmission between MOC neurons and OHC, to record auditory cortex evoked potentials and to evaluate the consequences of auditory cortex electrical microstimulation in the effects produced by contralateral acoustic stimulation on auditory brainstem responses (ABR). Results: Auditory cortex evoked potentials at 15 kHz were similar in WT and KO mice. We found that auditory cortex microstimulation produces an enhancement of contralateral noise suppression of ABR waves I and III in WT mice but not in KO mice. On the other hand, corticofugal modulations of wave V amplitudes were significant in both genotypes. Conclusion: These findings show that the corticofugal modulation of contralateral acoustic suppressions of auditory nerve (ABR wave I) and superior olivary complex (ABR wave III) responses are mediated through MOC synapses.

Combined electric and acoustic stimulation has proven to be an effective strategy to improve hearing in some cochlear implant users. We describe an acoustic microactuator to directly deliver stimuli to the perilymph in the scala tympani. The 800 µm by 800 µm actuator has a silicon diaphragm driven by a piezoelectric thin film (e.g., lead-zirconium-titanium oxide or PZT). This device could also be used as a component of a bimodal acoustic-electric electrode array. In the current study, we established a guinea pig model to test the actuator for its ability to deliver auditory signals to the cochlea in vivo. The actuator was placed through the round window of the cochlea. Auditory brainstem response (ABR) thresholds, peak latencies, and amplitude growth were calculated for an ear canal speaker versus the intracochlear actuator for tone burst stimuli at 4, 8, 16, and 24 kHz. An ABR was obtained after removal of the probe to assess loss of hearing related to the procedure. In some animals, the temporal bone was harvested for histologic analysis of cochlear damage. We show that the device is capable of stimulating ABRs in vivo with latencies and growth functions comparable to stimulation in the ear canal. Further experiments will be necessary to evaluate the efficiency and safety of this modality in long-term auditory stimulation and its ability to be integrated with conventional cochlear implant arrays.

Auditory information relayed by auditory nerve fibers and somatosensory information relayed by granule cell parallel fibers converge on the fusiform cells (FCs) of the dorsal cochlear nucleus, the first brain station of the auditory pathway. In vitro, parallel fiber synapses on FCs exhibit spike-timing-dependent plasticity with Hebbian learning rules, partially mediated by the NMDA receptor (NMDAr). Well-timed bimodal auditory-somatosensory stimulation, in vivo equivalent of spike-timing-dependent plasticity, can induce stimulus-timing-dependent plasticity (StTDP) of the FCs spontaneous and tone-evoked firing rates. In healthy guinea pigs, the resulting distribution of StTDP learning rules across a FC neural population is dominated by a Hebbian profile while anti-Hebbian, suppressive and enhancing LRs are less frequent. In this study, we investigate in vivo, the NMDAr contribution to FC baseline activity and long term plasticity. We find that blocking the NMDAr decreases the synchronization of FC- spontaneous activity and mediates differential modulation of FC rate-level functions such that low, and high threshold units are more likely to increase, and decrease, respectively, their maximum amplitudes. Three significant alterations in mean learning-rule profiles were identified: transitions from an initial Hebbian profile towards (1) an anti-Hebbian; (2) a suppressive profile; and (3) transitions from an anti-Hebbian to a Hebbian profile. FC units preserving their learning rules showed instead, NMDAr-dependent plasticity to unimodal acoustic stimulation, with persistent depression of tone-evoked responses changing to persistent enhancement following the NMDAr antagonist. These results reveal a crucial role of the NMDAr in mediating FC baseline activity and long-term plasticity which have important implications for signal processing and auditory pathologies related to maladaptive plasticity of dorsal cochlear nucleus circuitry.

Extracellular signal-regulated kinase (ERK) is a member of the family of mitogen-activated protein kinases (MAPKs) and coordinately regulates a multitude of cellular processes. In response to a variety of extracellular stimuli, phosphorylation of both threonine and tyrosine residues activates ERK. Recent evidence indicates that ERK is activated in response to cellular stress such as acoustic trauma. However, the specific role of ERK isoforms in auditory function is not fully understood. Here, we show that the isoform ERK2 plays an important role in regulating hair cell (HC) survival and noise-induced hearing loss (NIHL) in mice (C57BL/6J). We found that conditional knockout mice deficient for Erk2 in the inner ear HCs had hearing comparable to control mice and exhibited no HC loss under normal conditions. However, we found that these knockout mice were more vulnerable to noise and had blunted recovery from NIHL compared to control mice. Furthermore, we observed a significantly lower survival rate of inner hair cells in these mice compared to control mice. Our results indicate that ERK2 plays important roles in the survival of HC in NIHL.