Detection and differentiation of sensorineural hearing loss in mice using auditory steady-state responses and transient auditory brainstem responses

Sensorineural hearing loss (SNHL) comprises hearing disorders with diverse pathologies of the inner ear and the auditory nerve. To date, an unambiguous phenotypical characterization of the specific pathologies in an affected individual remains impossible. Here, we evaluated the use of scalp-recorded auditory steady-state responses (ASSR) and transient auditory brainstem responses (ABR) for differentiating the disease mechanisms underlying sensorineural hearing loss in well-characterized mouse models. We first characterized the ASSR evoked by sinusoidally amplitude-modulated tones in wild-type mice. ASSR were robustly elicited within three ranges of modulation frequencies below 200 Hz, from 200 to 600 Hz and beyond 600 Hz in most recordings. Using phase information we estimated the apparent ASSR latency to be about 3 ms, suggesting generation in the auditory brainstem. Auditory thresholds obtained by automated and visual analysis of ASSR recordings were comparable to those found with tone-burst evoked ABR in the same mice. We then recorded ASSR and ABR from mouse mutants bearing defects of either outer hair cell amplification (KCNQ4-knockout) or inner hair cell synaptic transmission (Bassoon-mutant). Both mutants showed an increase of ASSR and ABR thresholds of approximately 40 dB versus wild-type when investigated at 8 weeks of age. Mice with defective amplification displayed a steep rise of ASSR and ABR amplitudes with increasing sound intensity, presumably reflecting a strong recruitment of synchronously activated neural elements beyond threshold. In contrast, the amplitudes of ASSR and ABR responses of mice with impaired synaptic transmission grew very little with sound intensity. In summary, ASSR allow for a rapid, objective and frequency-specific hearing assessment and together with ABR and otoacoustic emissions can contribute to the differential diagnosis of SNHL.     

氨基糖甙类药物毒性对耳蜗内毛细胞传入神经突触后谷氨酸受体的影响

目的 探讨氨基糖甙类耳毒性药物暴露下小鼠内毛细胞传入神经突触后谷氨酸受体表达水平的变化,以及这种变化和小鼠听功能改变之间的关系。方法 选择5周大小的C57BL/6J小鼠,每天腹腔注射庆大霉素1次,药物浓度为100mg/kg,连续给药14d,分别在第7天、第14天时检测受试小鼠的ABR(Click&Tone burst),并以未进行腹腔注射给药的小鼠(0d)作为对照组。使用抗GluR2/3抗体对小鼠基底膜铺片标本进行染色标记,以观察耳蜗内毛细胞传入神经突触后谷氨酸受体(GluR2/3)的表达情况。结果 注射庆大霉素小鼠在第7天、10天、14天时听力损失明显,听力阈值显著高于对照组(p<0.05)。应用庆大霉素后第7天和14天,耳蜗内毛细胞传入神经突触后谷氨酸受体(GluR2/3)的表达水平和对照组相比显著增高,听力损失最为严重,提示GluR2/3在突触后的过高表达和耳聋程度存在相关性。结论 氨基糖甙类耳毒性药物持续暴露可以造成耳蜗内毛细胞传入神经突触间隙内谷氨酸递质过表达,与耳聋程度呈正相关。     

Plectin regulates the organization of glial fibrillary acidic protein in Alexander disease

Alexander disease (AxD) is a rare but fatal neurological disorder caused by mutations in the astrocyte-specific intermediate filament protein glial fibrillary acidic protein (GFAP). Histologically, AxD is characterized by cytoplasmic inclusion bodies called Rosenthal fibers (RFs), which contain GFAP, small heat shock proteins, and other undefined components. Here, we describe the expression of the cytoskeletal linker protein plectin in the AxD brain. RFs displayed positive immunostaining for plectin and GFAP, both of which were increased in the AxD brain. Co-localization, co-immunoprecipitation, and in vitro overlay analyses demonstrated direct interaction of plectin and GFAP. GFAP with the most common AxD mutation, R239C (RC GFAP), mainly formed abnormal aggregates in human primary astrocytes and murine plectin-deficient fibroblasts. Transient transfection of full-length plectin cDNA converted these aggregates to thin filaments, which exhibited diffuse cytoplasmic distribution. Compared to wild-type GFAP expression, RC GFAP expression lowered plectin levels in astrocytoma-derived stable transfectants and plectin-positive fibroblasts. A much higher proportion of total GFAP was found in the Triton X-insoluble fraction of plectin-deficient fibroblasts than in wild-type fibroblasts. Taken together, our results suggest that insufficient amounts of plectin, due to RC GFAP expression, promote GFAP aggregation and RF formation in AxD.     

Synemin is expressed in reactive astrocytes and Rosenthal fibers in Alexander disease

Alexander disease (AxD) is a neurodegenerative disorder with prominent white matter degeneration and the presence of Rosenthal fibers containing aggregates of glial fibrillary acidic protein (GFAP), and small stress proteins HSP27 and αB‐crystallin, and widespread reactive gliosis. AxD is caused by mutations in GFAP, the main astrocyte intermediate filament protein. We previously showed that intermediate filament protein synemin is upregulated in reactive astrocytes after neurotrauma. Here, we examined immunohistochemically the presence of synemin in reactive astrocytes and Rosenthal fibers in two patients with AxD. There was an abundance of GFAP‐positive Rosenthal fibers and widespread reactive gliosis in the white matter and subpial regions. Many of the GFAP‐positive reactive astrocytes were positive for synemin, and synemin was also present in Rosenthal fibers. We show that synemin is expressed in reactive astrocytes in AxD, and is also present in Rosenthal fibers. The potential role of synemin in AxD pathogenesis remains to be investigated.     

Cochlear outer hair cells in a dominant-negative connexin26 mutant mouse preserve non-linear capacitance in spite of impaired distortion product otoacoustic emission

Mutations in the connexin26 gene (GJB2) are the most common genetic cause of congenital bilateral non-syndromic sensorineural hearing loss. Transgenic mice were established carrying human Cx26 with the R75W mutation that was identified in a deaf family with autosomal dominant negative inheritance [Kudo T et al. (2003) Hum Mol Genet 12:995–1004]. A dominant-negative Gjb2 R75W transgenic mouse model shows incomplete development of the cochlear supporting cells, resulting in profound deafness from birth [Inoshita A et al. (2008) Neuroscience 156:1039–1047]. The Cx26 defect in the Gjb2 R75W transgenic mouse is restricted to the supporting cells; it is unclear why the auditory response is severely disturbed in spite of the presence of outer hair cells (OHCs). The present study was designed to evaluate developmental changes in the in vivo and in vitro function of the OHC, and the fine structure of the OHC and adjacent supporting cells in the R75W transgenic mouse. No detectable distortion product otoacoustic emissions were observed at any frequencies in R75W transgenic mice throughout development. A characteristic phenotype observed in these mice was the absence of the tunnel of Corti, Nuel's space, and spaces surrounding the OHC; the OHC were compressed and squeezed by the surrounding supporting cells. On the other hand, the OHC developed normally. Structural features of the lateral wall, such as the membrane-bound subsurface cisterna beneath the plasma membrane, were intact. Prestin, the voltage-dependent motor protein, was observed by immunohistochemistry in the OHC basolateral membranes of both transgenic and non-transgenic mice. No significant differences in electromotility of isolated OHCs during development was observed between transgenic and control mice. The present study indicates that normal development of the supporting cells is indispensable for proper cellular function of the OHC.     

Loss of alpha CGRP reduces sound-evoked activity in the cochlear nerve

alpha-Calcitonin gene-related peptide (alphaCGRP) is one of several neurotransmitters immunolocalized in the unmyelinated component of the cochlear efferent innervation, the lateral olivocochlear (OC) system, which makes axo-dendritic synapses with cochlear sensory neurons. In rodents, CGRP is also immunocolocalized in the myelinated medial OC system, which contacts cochlear outer hair cells (OHCs). To understand the role(s) of this neuropeptide in the OC system, we characterized the auditory phenotype of alphaCGRP-null mice. Cochlear threshold sensitivity was normal in mutant mice, both via a neural metric, the auditory brain stem response (ABR), and an OHC-based metric, distortion product otoacoustic emissions (DPOAEs). Medial OC function and resistance to acoustic injury were also unaffected by alphaCGRP deletion: the former was assessed by measuring cochlear response suppression with electrical stimulation of the OC bundle, the latter by measuring temporary threshold shifts after exposure to high level sound. However, significant abnormality in alphaCGRP-null mice was seen in the growth of cochlear neural responses with increasing stimulus level. This observation, contrasted with normal amplitude-versus-level functions for DPOAEs, is consistent with a selective, postsynaptic effect on cochlear neurons via alphaCGRP release from lateral OC terminals. This constitutes the most direct evidence to date for a functional role of the lateral OC system in the auditory periphery.     

Noise-induced cell death in the mouse medial geniculate body and primary auditory cortex

Noise-induced effects within the inner ear have been well investigated for several years. However, this peripheral damage cannot fully explain the audiological symptoms in noise-induced hearing loss (NIHL), e.g. tinnitus, recruitment, reduced speech intelligibility, hyperacusis. There are few reports on central noise effects. Noise can induce an apoptosis of neuronal tissue within the lower auditory pathway. Higher auditory structures (e.g. medial geniculate body, auditory cortex) are characterized by metabolic changes after noise exposure. However, little is known about the microstructural changes of the higher auditory pathway after noise exposure. The present paper was therefore aimed at investigating the cell density in the medial geniculate body (MGB) and the primary auditory cortex (AI) after noise exposure. Normal hearing mice were exposed to noise (10 kHz center frequency at 115 dB SPL for 3 h) at the age of 21 days under anesthesia (Ketamin/Rompun, 10:1). After 1 week, auditory brainstem response recordings (ABR) were performed in noise exposed and normal hearing animals. After fixation, the brain was microdissected and stained (Kluever-Barrera). The cell density in the MGB subdivisions and the AI were determined by counting the cells within a grid. Noise-exposed animals showed a significant ABR threshold shift over the whole frequency range. Cell density was significantly reduced in all subdivisions of the MGB and in layers IV-VI of AI. The present findings demonstrate a significant noise-induced change of the neuronal cytoarchitecture in central key areas of auditory processing. These changes could contribute to the complex psychoacoustic symptoms after NIHL.     

Effect of baicalein from Scutellaria baicalensis on prevention of noise-induced hearing loss

Noise-induced hearing loss (NIHL) has been thought to primarily involve damage to the sensory hair cells of the cochlea via mechanical and metabolic mechanisms. This study examined the effects of baicalin, baicalein, and Scutellaria baicalensis (SB) extract against NIHL in a mouse model. Mice received oral treatment with SB, baicalin, baicalein beginning 30 min prior to noise exposure and continuing once daily throughout the study. Hearing threshold shift was assessed by auditory brain stem responses for 35 days following noise exposure. Central auditory function was evaluated by auditory middle latency responses. Cochlear function was determined based on transient evoked otoacoustic emissions. SB significantly reduced threshold shift, central auditory function damage, and cochlear function deficits, suggesting that SB may protect auditory function in NIHL and that the active constituent may be a flavonoid, baicalein.     

Noise and the young mouse: genotype modifies the sensitive period for effects on cochlear physiology and audiogenic seizures

A sharply defined "critical period" has been described for the young C57BL/6 mouse, during which acoustic trauma will profoundly alter subsequent auditory behavior (audiogenic seizures, acoustic startle reflex). In several genotypes and species, a broader "sensitive period" exists, during which acoustic trauma is most damaging to cochlear functions in the young ear. In order to examine the correspondence of these two events, C57BL/6 and CBA inbred mice, at eight ages ranging from 12 to 54 days, were exposed to 2 min of a 124-dB (SPL) octave band noise (8-16 kHz). A noninvasive electrocochleographic technique was used to assess cochlear microphonic (CM) and action potential (AP) thresholds in exposed mice and their nonexposed littermate controls. This allowed cochlear functional measures and behavioral tests (susceptibility to audiogenic seizures) to be made in the same animals. Noise has no observable effect on the 12-day-old CBA mouse, produced a maximal threshold elevation (47 dB for AP, 28 dB for CM) at 30-36 days, with the effect declining to nearly half of this value in 54-day-old subjects. Susceptibility to audiogenic seizures in the exposed CBA mice was greatest at the peak of this sensitive period for cochlear damage (r = .95). C57BL/6 mice also appeared unaffected when noise exposure occurred at 12 days of age; they had maximal AP (23 dB) and CM (17 dB) threshold elevations at 36 days, and 54-day-old mice had an 18-dB elevation of the AP and their CM was no longer affected. Susceptibility to audiogenic seizures was greatest in C57BL/6 mice exposed to noise at 18 days, and it did not correspond with the sensitive period for cochlear damage (r = .21). Therefore, both genotypes have a sensitive period for the effects of noise trauma on the CM and AP, the CBA has a sensitive period for acoustic priming for audiogenic seizures, and the C57BL/6 has a critical period for acoustic priming. Genetic differences in age-related losses of central nervous system auditory functions are postulated as being responsible for these behavioral differences. These data are compared with known auditory functions of the SJL and BALB/c mouse strains in order to explain genetically determined differences of the sensitive (or critical) period of acoustic priming, and for the length of time the mice subsequently remain susceptible to audiogenic seizures.     

Post-exposure treatment with ginsenoside compound K ameliorates auditory functional injury associated with noise-induced hearing loss in mice

Noise-induced hearing loss (NIHL) is thought to primarily involve damage to the sensory hair cells of the cochlea via mechanical and metabolic mechanisms. Unfortunately, initial studies assessing the effectiveness of post-exposure treatment after hearing loss have yielded largely disappointing results. This study explored the effects of oral treatment with Korean red ginseng (RG) and with two bioavailable ginsenoside metabolites, ginsenoside Rh1 and ginsenoside compound K (GCK), in response to NIHL in a murine model. Pharmacological treatments began 24h after noise exposure and were continued once daily for 7 days. Central auditory function was evaluated using auditory middle latency responses, and cochlear function was determined based on transient evoked otoacoustic emissions. Additionally, cochlear hair cell morphology was investigated after noise exposure. Both Korean red ginseng and compound K reduced threshold shifts, central auditory function damage, and cochlear functional and morphological deficits. In contrast, treatment with ginsenoside Rh1 did not result in recovery of NIHL in mice. These results suggest that consumption of Korean red ginseng may facilitate recovery from noise-induced hearing loss. Furthermore, one of the active constituents in ginseng is likely ginsenoside compound K.     

Inner hair cell ribbon synapse plasticity might be molecular basis of temporary hearing threshold shifts in mice

Recent studies have reported that noise exposure at relatively low intensities can cause temporary threshold shifts (TTS) in hearing. However, the mechanism underlying the TTS is still on debate. Here, we report that an acoustic stimulation (100 dB SPL, white noise) induced TTS in mice, with the maximal ABR threshold elevations seen on the 4^th day after noise exposure. On the other hand, there were no significant morphological changes in the cochlea. Further, there were paralleled changes of pre-synaptic ribbons in both the number and postsynaptic density (PSDs) during this noise exposure. The numbers of presynaptic ribbon, postsynaptic density (PSDs), and colocalized puncta correlated with the shifts of ABR thresholds. Moreover, a complete recovery of ABR thresholds and synaptic puncta was seen on the 14^th day after the noise stimulations. Thus, our study may indicate that noise exposure can cause a decline in cochlear ribbon synapses and result in consequent hearing loss. The reduction of synaptic puncta appears reversible and may contribute to hearing restoration in mice after noise exposure.     

The Cochlear Spiral Ganglion Neurons: The Auditory Portion of the VIII Nerve

The VIII nerve is formed by sensory neurons that innervate the inner ear, i.e., the vestibular and the auditory receptors. Neurons of the auditory portion, the cochlear afferent fibers that innervate the sensory hair cells of the organ of Corti, have their somas in the cochlear spiral ganglion where two types of neurons can be distinguished. Afferent Type-I neurons are the 95% of the total population. Bipolar and myelinated fibers, each one innervates only one cochlear inner hair cell (IHC). In contrast, afferent Type-II neurons are only the 5% of the spiral ganglion population. They are pseudounipolar and unmyelinated fibers and innervate the cochlear outer hair cells (OHC) so that one afferent Type-II fiber contacts with multiple OHCs, but each OHC only receives one contact from one Type-II neuron. Both types of VIII nerve fibers are glutamatergic, but these asymmetric innervations of the cochlear sensory cells could suggest that the IHC codifies the truly auditory message but the OHC only informs about mechanical aspects of the state of the organ of Corti. In fact, the central nervous system (CNS) has control over the information transmitted by the Type-I neuron by means of axons from the superior olivary complex that innervate them to modulate, filter and/or inhibit the entry of auditory message to CNS. The aim of this paper is to review the current knowledge about the anatomy and physiology of the auditory portion of the VIII nerve. Anat Rec, 302:463–471, 2019. © 2018 Wiley Periodicals, Inc.     

Selective removal of lateral olivocochlear efferents increases vulnerability to acute acoustic injury

Cochlear sensory cells and neurons receive efferent feedback from the olivocochlear (OC) system. The myelinated medial component of the OC system and its effects on outer hair cells (OHCs) have been implicated in protection from acoustic injury. The unmyelinated lateral (L)OC fibers target ipsilateral cochlear nerve dendrites and pharmacological studies suggest the LOC's dopaminergic component may protect these dendrites from excitotoxic effects of acoustic overexposure. Here, we explore LOC function in vivo by selective stereotaxic destruction of LOC cell bodies in mouse. Lesion success in removing the LOC, and sparing the medial (M)OC, was assessed by histological analysis of brain stem sections and cochlear whole mounts. Auditory brain stem responses (ABRs), a neural-based metric, and distortion product otoacoustic emissions (DPOAEs), an OHC-based metric, were measured in control and surgical mice. In cases where the LOC was at least partially destroyed, there were increases in suprathreshold neural responses that were frequency- and level-independent and not attributable to OHC-based effects. These interaural response asymmetries were not found in controls or in cases where the lesion missed the LOC. In LOC-lesion cases, after exposure to a traumatic stimulus, temporary threshold shifts were greater in the ipsilateral ear, but only when measured in the neural response; OHC-based measurements were always bilaterally symmetric, suggesting OHC vulnerability was unaffected. Interaural asymmetries in threshold shift were not found in either unlesioned controls or in cases that missed the LOC. These findings suggest that the LOC modulates cochlear nerve excitability and protects the cochlea from neural damage in acute acoustic injury.     

Noise-induced time-dependent changes in oxidative stress in the mouse cochlea and attenuation by D-methionine

Oxidative stress in the cochlea is considered to play an important role in noise-induced hearing loss. This study determined changes in superoxide dismutase (SOD), catalase, lipid peroxidation (LPO) and the auditory brainstem response (ABR) in the cochlea of C57BL/6 mice prior to and immediately, 1, 3, 7, 10, 14 and 21 days after noise exposure (4 kHz octave band at the intensity of 110 dB SPL for 4 h). A significant increase in SOD activity immediately and on 1st day after noise exposure, without a concomitant increase in catalase activity suggested a difference in the time dependent changes in the scavenging enzymes, which facilitates the increase in LPO observed on day 7. The ABR indicated significant noise-induced functional deficits which stabilized in 2 weeks with a permanent threshold shift (PTS) of 15 dB at both 4 kHz and 8 kHz. The antioxidant D-methionine (D-Met) reversed the noise-induced changes in LPO levels and enzyme activities. It also significantly reduced the PTS observed on the 14th day from 15 dB to 5 dB for 4 kHz. In summary, the findings indicate that time-dependent alterations in scavenging enzymes facilitate the production of reactive oxygen species and that D-met effectively attenuates noise-induced oxidative stress and the associated functional loss in the mouse cochlea.     

Examining the auditory nerve fiber response to high rate cochlear implant stimulation: chronic sensorineural hearing loss and facilitation

Neural prostheses, such as cochlear and retinal implants, induce perceptual responses by electrically stimulating sensory nerves. These devices restore sensory system function by using patterned electrical stimuli to evoke neural responses. An understanding of their function requires knowledge of the nerves responses to relevant electrical stimuli as well as the likely effects of pathology on nerve function. We describe how sensorineural hearing loss (SNHL) affects the response properties of single auditory nerve fibers (ANFs) to electrical stimuli relevant to cochlear implants. The response of 188 individual ANFs were recorded in response to trains of stimuli presented at 200, 1,000, 2,000, and 5,000 pulse/s in acutely and chronically deafened guinea pigs. The effects of stimulation rate and SNHL on ANF responses during the 0-2 ms period following stimulus onset were examined to minimize the influence of ANF adaptation. As stimulation rate increased to 5,000 pulse/s, threshold decreased, dynamic range increased and first spike latency decreased. Similar effects of stimulation rate were observed following chronic SNHL, although onset threshold and first spike latency were reduced and onset dynamic range increased compared with acutely deafened animals. Facilitation, defined as an increased nerve excitability caused by subthreshold stimulation, was observed in both acute and chronic SNHL groups, although the magnitude of its effect was diminished in the latter. These results indicate that facilitation, demonstrated here using stimuli similar to those used in cochlear implants, influences the ANF response to pulsatile electrical stimulation and may have important implications for cochlear implant signal processing strategies.     

Noise-induced changes of neuronal spontaneous activity in mice inferior colliculus brain slices

The inferior colliculus (IC) in vivo is reportedly subject to a noise-induced decrease of GABA-related inhibitory synaptic transmission accompanied by an amplitude increase of auditory evoked responses, a widening of tuning curves and a higher neuronal discharge rate at suprathreshold levels. However, other in vivo experiments which demonstrated constant neuronal auditory thresholds or unchanged spontaneous activity in the IC after noise exposure did not confirm those findings. Perhaps this can be the result of complex noise-induced interactions between different central auditory structures. It was, therefore, the aim of the present study to investigate the effects of noise exposure on the spontaneous electrical activity of single neurons in a slice preparation of the isolated mouse IC. Normal hearing mice were exposed to noise (10 kHz center frequency at 115 dB SPL for 3 h) at the age of 21 days under anesthesia (Ketamin/Rompun 10:1). After one week, auditory brainstem response (ABR) recordings and extracellular single-unit recordings from spontaneously active neurons within the IC slice were performed in noise-exposed and in normal hearing control mice. Noise-exposed animals showed a significant ABR threshold shift in the whole tested frequency range and a significant lower neuronal spontaneous activity in all investigated isofrequency laminae compared to controls. In both groups, the firing rate of 80% of IC neurons (approximately) increased significantly during the application of the GABA(A) receptor antagonist Bicucullin (10 microM). The present findings demonstrate a noise-related modulation of spontaneous activity in the IC, which possibly contribute to the generation of noise-induced tinnitus and hearing loss.     

Erratum to "Noise-induced changes of neuronal spontaneous activity in mice inferior colliculus brain slices"

The inferior colliculus (IC) in vivo is reportedly subject to a noise-induced decrease of GABA-related inhibitory synaptic transmission accompanied by an amplitude increase of auditory evoked responses, a widening of tuning curves and a higher neuronal discharge rate at suprathreshold levels. However, other in vivo experiments which demonstrated constant neuronal auditory thresholds or unchanged spontaneous activity in the IC after noise exposure did not confirm those findings. Perhaps this can be the result of complex noise-induced interactions between different central auditory structures. It was, therefore, the aim of the present study to investigate the effects of noise exposure on the spontaneous electrical activity of single neurons in a slice preparation of the isolated mouse IC. Normal hearing mice were exposed to noise (10 kHz center frequency at 115 dB SPL for 3 h) at the age of 21 days under anesthesia (Ketamin/Rompun 10:1). After one week, auditory brainstem response (ABR) recordings and extracellular single-unit recordings from spontaneously active neurons within the IC slice were performed in noise-exposed and in normal hearing control mice. Noise-exposed animals showed a significant ABR threshold shift in the whole tested frequency range and a significant lower neuronal spontaneous activity in all investigated isofrequency laminae compared to controls. In both groups, the firing rate of 80% of IC neurons (approximately) increased significantly during the application of the GABA(A) receptor antagonist Bicucullin (10 microM). The present findings demonstrate a noise-related modulation of spontaneous activity in the IC, which possibly contribute to the generation of noise-induced tinnitus and hearing loss.     

铁缺乏大鼠耳蜗肌动蛋白的检测及其意义

目的 检测铁缺乏大鼠耳蜗肌动蛋白的变化。探讨铁缺乏引起耳蜗毛细胞损伤的发生机制。方法 应用免疫组织化学染色法，SDS-PAGE和Western blot，检测正常及以缺铁饮食饲养8wk大鼠的耳蜗肌动蛋白水平的变化并进行比较。结果 出现感音神经性耳聋的铁缺乏组大鼠耳蜗肌动蛋白的相对含量降低，免疫组化的反应性明显减弱；听力正常的铁缺乏大鼠组中两者无明显变化。结论 耳蜗肌动蛋白含量及免疫组化染色反应性的变化。可能是铁缺乏引起的耳蜗毛细胞损伤的重要病理基础。     

Up-regulation of cochlear Hes1 expression in response to noise exposure

Hes1, a hairy and enhancer of split homolog, negatively regulates inner ear hair cell differentiation. The main objective of this study was to investigate the status of the Hes1 gene in the noise-damaged cochlea in relation to the degree of noise-induced hearing loss (NIHL). Adult albino guinea pigs were exposed to white-band noise (115 dB sound pressure level). Noise exposure for either 1 or 3 hours induced significant elevations of threshold in auditory brainstem response (ABR) compared with unexposed controls. Succinate dehydrogenase staining showed that white-band noise exposure caused significant outer hair cell losses. In addition, we found significant up-regulations of cochlear Hes1 mRNA and protein expressions following acoustic trauma, and Hes1 mRNA expression was positively correlated with NIHL. These findings suggest that up-regulation of Hes1 expression in response to noise exposure may be one of the underlying mechanisms of NIHL.     

Hearing loss in the laminin-deficient dy mouse model of congenital muscular dystrophy

Sensorineural hearing loss is found in many inherited forms of muscular dystrophy. We investigated the dy mouse model, which has congenital muscular dystrophy due to a defect in laminin alpha 2, for evidence of cochlear dysfunction. Auditory brainstem response (ABR) audiometry to pure tones was used to evaluate 3-month-old homozygous dy/dy and age-matched C57 control mice. The average ABR thresholds to tone-burst stimuli for four frequencies (4, 8, 16, and 32 kHz) were determined and statistically compared by ANOVA. The dy/dy mice demonstrated elevated auditory thresholds ranging from 25 to 27 dB at each frequency tested (p<0.0001). Anatomic evaluations of the ears revealed pathology ranging from extensive connective tissue infiltration within the inner ear to possible minor defects in the cells of the organ of Corti. These anatomic and physiologic observations suggest that the extracellular matrix protein laminin plays a crucial role in normal cochlear function. Furthermore, the dy congenital muscular dystrophy mouse offers a novel model for evaluation of sensorineural hearing loss associated with muscular dystrophy.