[Inner hair cells loss by carboplatin and the changes of cochlear compound action potential in chinchillas].

Objective: To measure the cochlear compound action potential (CAP) and the densities of hair cells (HCs) along the whole length of the basilar membrane (BM) in adult chinchillas. And to investigate the relationship between the severity of inner hair cells (IHCs) loss and the changes of CAP by using carboplatin-cochlear lesion model. Methods: Totally 18 chinchillas were recruited after ontological evaluation. They were randomly divided into three groups (with 6 subjects in each), A: control, B and C: legion groups treated with one or two shot(s) of carboplatin respectively (76 mg/kg in one shot, i.p., one-week interval between the two shots). Endpoint tests were performed 30 days after the carboplatin treatment in groups B and C, and matched time in group A. A sliver-ball electrode was placed into round window niche via hypotympanic approach in anesthetized chinchilla. CAP was measured in response to clicks and tone burst of 0.5, 1, 2, 4, 8, 16 kHz respectively under anesthesia. CAP amplitudes and thresholds were measured and compared across the groups. After the recording, the whole cochlea surface preparation was made and the HCs were stained in histochemistry against substrate of succinate dehydrogenase (SDH). Images were taken with high-resolution digital camera under light microscope and across the whole cochlea. The length of the basilar membrane (BM) and the number of both IHCs and OHCs were counted. The HC density was calculated as the number of HCs per 10% BM length. Results: The CAP thresholds were (7.1±2.6), (25.4±5.0), (24.6±5.4), (10.4±5.0), (0.4±1.4), (4.2±6.3) and (17.1±14.1) dB SPL (from 6 subjects in group A, n=12 ears) corresponding to stimuli of Click and 0.5, 1, 2, 4, 8, 16 kHz tone bursts respectively. The total number of cochlear HCs were measured as (8 936±643) (x±s) and the average length of the BMs was (17.73±1.012) mm from the six subjects in the group A (n=12 ears). The HC density was found to be varied slightly across the BM. There was no significant CAP threshold difference between the control (group A) and the group B, which received one shot of carboplatin. However, the maximal CAP amplitude was reduced by 40% in the group B and compared with group A. Correspondingly, approximately 40% loss of IHCs were seen. In contrast, a significant CAP threshold shift was seen in subjects receiving two shots of carboplatin (group C), which was accompanied by a loss of 90% IHCs. Conclusions: The CAP thresholds of adult chinchillas show typical open-V shape with the lowest values at 2, 4, and 8 kHz. IHC loss by carboplatin in certain degree is well correlated with CAP amplitude reduction, but does not change the threshold when inner hair cell loss reaches 40%, however, if inner hair cell loss exceeds 80%, the threshold shift of CAP will be inevitable.

HMGA1-mediated miR-671-5p targets APC to promote metastasis of clear cell renal cell carcinoma through Wnt signaling.

This study aimed to investigate the effect of miR-671-5p on metastasis of clear cell renal cell carcinoma (ccRCC) and underlying mechanism involved. The migration and invasion of ccRCC cells were determined by transwell and boyden assays in vitro and in vivo. Genes mRNA and protein expression were detected by quantitative polymerase chain reaction (qPCR) and western blot analysis, respectively. The target gene of miRNA was confirmed by luciferase reporter assays. Transcriptional regulation of miRNA by transcription factor was detected by chromatin immunoprecipitation assay (ChIP). The expression of miRNA in clinical specimens were detected by in situ hybridization (ISH). miR-671-5p promoted migration and invasion of ccRCC in vivo and in vitro. Moreover, miR-671-5p directly targeted APC to activate Wnt signaling, thus inducing the epithelial-mesenchymal transition (EMT) in ccRCC. Intriguingly, miR-671-5p expression was transcriptionally enhanced by HMGA1. Consistently, bioinformatics analysis suggested that HMGA1 was positively correlated with miR-671 expression, however, miR-671 was negatively correlated with APC. In situ hybridization analysis showed that miR-671-5p was upregulated in ccRCC compared with paracarcinoma and correlated with poor prognosis of ccRCC patients. In addition, univariate and multivariate analysis indicated that miR-671-5p expression was an independent prognostic factor for overall survival in ccRCC patients. Our data suggest that miR-671-5p is a tumor enhancer in regulating of ccRCC metastasis, and miR-671-5p may be utilized as a factor for the clinical diagnosis and prognosis of ccRCC.

[Clinical characteristics and microsurgical strategy of intracranial posterior circulation aneurysms].

Objective: To explore the clinical characteristics and microsurgical strategies of intracranial posterior circulation aneurysms. Methods: The clinical manifestations, imaging data, surgical approaches and follow-up results of 35 patients with circulating aneurysms (37 aneurysms) treated by microsurgery in the First Affiliated Hospital of Zhengzhou University from January 2013 to January 2018 were analyzed retrospectively. Results: A total of 22 aneurysms were clipped, 13 were clipped and resected, 1 case was clipped and together with AVM resection and 1 case was isolated. Of 37 aneurysms in 35 patients, 11 aneurysms were at the basilar artery apexes, 10 at the posterior cerebral arteries, 6 at the posterior inferior cerebellar arteries, 3 at the basilar arteries, 3 at the vertebral arteries (including 1 case of vertebral arterial dissecting aneurysm), 2 at the anterior inferior cerebellar arteries and 2 at the superior cerebellar arteries. The surgical approaches included pterional approach, extensive pterional approach, infratemporal fossa approach, retrosigmoid approach and far-lateral approach. The Glasgow Outcome Scale (GOS) scores showed good recovery in 24 cases, moderate neurological dysfunction in 6 cases, severe neurological dysfunction in 2 cases, persistent vegetative state in 1 case and 2 cases of death 6 months after their discharge from hospital. Conclusions: Posterior circulation aneurysms are adjacent to important structures. They are deep in position, with small operation space and difficult to operate. Full preoperative evaluation of the condition, selection of appropriate surgical methods are the key factors to benefit the patients.

Reversible and irreversible damage to cochlear afferent neurons by kainic acid excitotoxicity.

Kainic acid (KA) selectively damages afferent synapses that innervate, in chickens, mainly tall hair cells. To better understand the nature of KA-induced excitotoxic damage to the cochlear afferent neurons, KA, at two different concentrations (0.3 or 5 mM), was injected directly into the inner ear of adult chickens. Pathologic changes in the afferent nerve ending and cell body were evaluated with light and transmission electron microscopy at various time points after KA application. The compound action potential (CAP) and cochlear microphonic (CM) potential were recorded to monitor the physiologic status of the afferent neurons and hair cells, respectively. Hair cell morphology and function were essentially normal after KA treatment. However, afferent synapses beneath tall hair cells were swollen within 30 minutes after KA at both low (KA-L) and high (KA-H) doses. In the KA-L group, the swelling disappeared within 1 day and the morphology of the postsynaptic region returned to near normal condition. In the KA-H group, by contrast, the vacant region beneath tall hair cells remained evident even 20 weeks after KA. The number of cochlear ganglion neurons in the KA-H group decreased progressively from 1 to 8-20 weeks, whereas hair cells in the basilar papilla remained morphologically intact out to 20 weeks after KA. There was no significant change in neuron number in the KA-L group. Temporal changes in the CAP amplitude paralleled the anatomic changes, although the CAP only partially recovered. These results suggest that KA induces partially reversible damage to cochlear afferent neurons with low KA concentration; above this level, KA triggers irreversible, progressive neurodegeneration.

Effects of perineural application of glycerol on the facial nerve: an experimental study.

Current procedures for treating hemifacial spasm control its symptoms but the condition is often complicated by facial weakness. We undertook this study using a rat facial nerve model to determine whether peripheral glycerol injection could be recommended as a feasible and safe technique in the management of hemifacial spasm. The animals were given a perineural application of glycerol on the facial nerve and killed at 3 days or 2 or 4 weeks after operation. The facial nerves were then examined with light and electron microscopy. Our results show that myelin disintegration and axolysis occurred after glycerol application and both the myelinated and unmyelinated fibers were affected at random, although the most striking histological changes were seen in the myelinated fibers. No evidence of persistent facial weakness in the animals was associated with this method.

Reduction of noise-induced hearing loss using L-NAC and salicylate in the chinchilla.

The effects of a combination of two antioxidant compounds were studied in a chinchilla model of noise-induced hearing loss. After obtaining baseline hearing thresholds using inferior colliculus evoked potentials, chinchillas were exposed for 6 h to octave band noise centered at 4 kHz (105 dB SPL). Post-noise thresholds were obtained 1 h after the noise exposure, and then animals received either saline or salicylate and N-L-acetylcysteine combination. Another group received antioxidant treatment 1 h prior to noise. Hearing was tested at 1, 2 and 3 weeks post-noise. Subsequently, the cochleae were harvested, and cytocochleograms were prepared. There was a 20-40 dB SPL threshold shift at 3 weeks for tested controls. Permanent threshold shifts (PTS) were significantly reduced (P<0.05) to approximately 10 dB for the pre-treatment group at week 3. The PTS for the post-treatment group at week 3 was similar to the pre-treatment group at 1 and 2 kHz (0-10 dB) but was intermediate between the control and pre-treatment groups at 4 and 8 kHz (23 dB). Animals pre-treated with antioxidant had a significant reduction in hair cell loss but those post-treated with antioxidant had no protection from hair cell loss. These findings demonstrate the feasibility of reduction of noise-induced hearing loss using clinically available antioxidant compounds.

D-Methionine attenuates inner hair cell loss in carboplatin-treated chinchillas.

Carboplatin, a second-generation platinum-based antineoplastic drug, preferentially destroys inner hair cells (IHCs) in the chinchilla while sparing outer hair cells (OHCs). D-Methionine (D-Met), a sulfur-containing amino acid, has been shown to protect hair cells from cisplatin damage in rats, but its ability to protect IHCs from carboplatin damage has not yet been evaluated in the chinchilla. We tested whether D-Met would protect the hair cells in the chinchilla from carboplatin. Animals were divided into two groups: a control group that only received carboplatin (100 mg/kg, i.p.) and an experimental group that received 300 mg/kg D-Met (i.p.) 30 min before carboplatin treatment. Ototoxicity was assessed by measuring the amount of IHC and OHC loss. Average IHC loss in the group treated with D-Met was 62% compared with 84% in the untreated control group. Thus, D-Met causes a statistically significant reduction in IHC loss induced by carboplatin.

Cochlear de-efferentation and impulse noise-induced acoustic trauma in the chinchilla.

The olivocochlear bundle (OCB) has been shown to protect the ear from acoustic trauma induced by continuous noise or tones. The present study examines the OCB's role in the ear's response to impulse noise (150 dB pSPL, 100 impulses, 50 s total exposure duration). Successful section of the OCB was achieved through a posterior parafloccular fossa approach for the right ears of six out of 15 adult chinchillas. The left ears from the same animals served as efferent-innervated controls. Measurements of inferior colliculus evoked potentials (ICPs) showed that the de-efferented ears incurred similar temporary and permanent threshold shifts as the control ears. Twenty days after noise exposure, depressed ICP amplitudes had virtually recovered to pre-values in the control ears whereas those in the de-efferented ears remained significantly depressed. Greater loss of inner hair cells was seen in the de-efferented ears than in the control ears. Both control and de-efferented ears incurred large loss of outer hair cells, with no statistically significant differences between groups. The current data are intriguing, yielding tentative evidence to suggest that inner hair cells of de-efferented ears are more susceptible to impulse noise than those in efferented control ears. In contrast, outer hair cell vulnerability to impulse noise appears to be unaffected by de-efferentation.

Excitotoxic effect of kainic acid on chicken otoacoustic emissions and cochlear potentials.

Kainic acid (KA) is a potent glutamate analog that can temporarily or permanently damage glutamatergic neurons. The purpose of the present study was to determine the short- and long-term effects of KA on chicken otoacoustic emissions and cochlear potentials. A chronic electrode was used to record the compound action potential (CAP), cochlear microphonic (CM), and the slow, positive neural potential (SPNP), a predominantly dc response. The CM, CAP, SPNP, and distortion product otoacoustic emissions (DPOAEs) were recorded before and after infusing 10 microl of a low dose (KA-L, 0.3 mM) or high dose (KA-H, 5 mM) of KA into scala tympani. KA caused a rapid and large reduction in CAP and SPNP amplitude in both the KA-H and KA-L groups; however, the CM and DPOAEs were largely unchanged. The amplitude of the CAP and SPNP in the KA-L group began to recover around 1 week post-KA, but was approximately 50% below normal at 4 weeks post-KA. In contrast, the CAP and SPNP showed no signs of recovery in the KA-H group. The results suggest that KA has no effect on the CM and DPOAEs generated by the hair cells, but selectively damages the CAP generated by the cochlear ganglion neurons. The reduction in the avian SPNP suggests that the response originates in the cochlear afferent neurons, unlike the summating potential (SP) in mammals that is generated in hair cells.

Conditioning-induced protection from impulse noise in female and male chinchillas.

Sound conditioning (pre-exposure to a moderate-level acoustic stimulus) can induce resistance to hearing loss from a subsequent traumatic exposure. Most sound conditioning experiments have utilized long-duration tones and noise at levels below 110 dB SPL as traumatic stimuli. It is important to know if sound conditioning can also provide protection from brief, high-level stimuli such as impulses produced by gunfire, and whether there are differences between females and males in the response of the ear to noise. In the present study, chinchillas were exposed to 95 dB SPL octave band noise centered at 0.5 kHz for 6 h/day for 5 days. After 5 days of recovery, they were exposed to simulated M16 rifle fire at a level of 150 dB peak SPL. Animals that were sound conditioned showed less hearing loss and smaller hair cell lesions than controls. Females showed significantly less hearing loss than males at low frequencies, but more hearing loss at 16 kHz. Cochleograms showed slightly less hair cell loss in females than in males. The results show that significant protection from impulse noise can be achieved with a 5-day conditioning regimen, and that there are consistent differences between female and male chinchillas in the response of the cochlea to impulse noise.

Cochlear microphonics and otoacoustic emissions in chronically de-efferented chinchilla.

The effects of eliminating the olivocochlear bundle (OCB) on cochlear electromechanical properties were examined by measuring cochlear microphonics (CM) and distortion product otoacoustic emissions (DPOAEs) in chronically de-efferented chinchillas. The OCB fibers to the right ears were successfully sectioned in six out of 15 adult chinchillas via a posterior paraflocular fossa approach. At the end of the experiment, these ears were histologically verified as being deprived of both lateral and medial OCB fibers. The opposite (left) ears from the animals served as controls. Following de-efferentation, changes of the inter-modulation distortion components (2f(1)-f(2), f(2)-f(1), 3f(1)-2f(2), 3f(2)-2f(1)) varied, depending on the frequencies and levels of the stimuli. DPOAE amplitudes to low-level stimuli were within the 95% confidence intervals around mean DPOAE amplitudes of the control ears at all the frequencies (1-8 kHz). At high stimulus levels, DPOAE amplitudes increased by 5-20 dB at 1 and 2 kHz while remaining in the normal range at 4 and 8 kHz. In contrast, the CM input/output functions to stimuli from 1 to 8 kHz were significantly reduced by approximately 40-50% at all input levels. The results suggest that the OCB may play a role in modulating electrical properties of the outer hair cells and in reducing the magnitude of cochlear distortion to high-level stimuli.

Targeted mutation of the gene for cellular glutathione peroxidase (Gpx1) increases noise-induced hearing loss in mice.

Reactive oxygen species (ROS) and oxidative stress have been implicated in cochlear injury following loud noise and ototoxins. Genetic mutations that impair antioxidant defenses would be expected to increase cochlear injury following acute insults and to contribute to cumulative injury that presents as age-related hearing loss. We examined whether genetically based deficiency of cellular glutathione peroxidase, a major antioxidant enzyme, increases noise-induced hearing loss in mice. Two-month-old "knockout" mice with a targeted inactivating mutation of the gene coding for glutathione peroxidase (Gpx1) and wild type controls were exposed to broadband noise for one hour at 110 dB SPL. Auditory brainstem response (ABR) thresholds at test frequencies ranging from 5 to 40 kHz were obtained two and four weeks after exposure to determine the stable permanent component of the hearing loss. Depending on test frequency, (compared with controls) Gpx1 knockout mice showed up to 16 dB higher ABR thresholds prior to noise exposure, and up to 15 dB greater noise-induced hearing loss, compared with normal control. Within the cochlear base, there was also a significant contribution of the knockout to inner and outer hair cell loss, as well as nerve fiber loss. Our results support a link between genetic impairment of antioxidant defenses, vulnerability of the cochlea injury, and cochlear degeneration. Such impairment produces characteristics expected of some mutations associated with age-related hearing loss and offers one possible mechanism for their action.

Targeted deletion of the cytosolic Cu/Zn-superoxide dismutase gene (Sod1) increases susceptibility to noise-induced hearing loss.

Reactive oxygen species (ROS) such as superoxide, peroxide and hydroxyl radicals are generated during normal cellular metabolism and are increased in acute injury and in many chronic disease states. When their production is inadequately regulated, ROS accumulate and irreversibly damage cell components, causing impaired cellular function and death. Antioxidant enzymes such as superoxide dismutase (SOD) play a vital role in minimizing ROS levels and ROS-mediated damage. The cytosolic form of Cu/Zn-SOD appears specialized to remove superoxide produced as a result of injury. 'Knockout' mice with targeted deletion of Sod1, the gene that codes for Cu/Zn-SOD, develop normally but show enhanced susceptibility to central nervous system injury. Since loud noise is injurious to the cochlea and is associated with elevated cochlear ROS, we hypothesized that Sod1 knockout mice would be more susceptible to noise-induced permanent threshold shifts (PTS) than wild-type and heterozygous control mice. Fifty-nine mice (15 knockout, 29 heterozygous and 15 wild type for Sod1) were exposed to broad-band noise (4.0-45.0 kHz) at 110 dB SPL for 1 h. Hearing sensitivity was evaluated at 5, 10, 20 and 40 kHz using auditory brainstem responses before exposure and 1, 14 and 28 days afterward. Cu/Zn-SOD deficiency led to minor (0-7 dB) threshold elevations prior to noise exposure, and about 10 dB of additional noise-induced PTS at all test frequencies, compared to controls. The distribution of thresholds at 10 and 20 kHz at 28 days following exposure contained three modes, each showing an effect of Cu/Zn-SOD deficiency. Thus another factor, possibly an additional unlinked gene, may account for the majority of the observed PTS. Our results indicate that genes involved in ROS regulation can impact the vulnerability of the cochlea to noise-induced hearing loss.

Auditory nerve fiber responses following chronic cochlear de-efferentation.

The aim of the present study was to examine the role of the olivocochlear system in auditory processing by examining the long-term effects of cochlear de-efferentation on auditory nerve response properties in adult chinchillas. Spontaneous rates, response thresholds, tuning curves, discharge rate-level functions, and adaptation of single auditory nerve fibers were measured in chinchillas with complete cochlear de-efferentation produced by sectioning the olivocochlear bundle in the internal auditory meatus. De-efferentation was verified as successful on the basis of acetylcholinesterase staining of surface preparations of the organ of Corti. Following chronic de-efferentation, there was a striking decrease in spontaneous rate, consistent with earlier observations in cats. In addition, the present study shows that complete de-efferentation results in: (1) increased driven discharge rates and decreased dynamic range of discharge rate-level functions, (2) larger onset-to-steady state ratio of discharge rate at moderate intensities, and (3) a hypersensitive tail of the tuning curve. These effects, largely confined to neurons that were most sensitive to frequencies between 2-8 kHz, indicate that the cochlear efferent system is important in maintaining normal function (e.g., frequency and intensity selectivity) of the auditory periphery by modulating auditory nerve fiber response properties.

Age- and strain-related differences in dehydrogenase activity and glycogen levels in CBA and C57 mouse cochleas.

In the C57 mouse strain, loss of sensory hair cells (HCs) begins during early adulthood, starting in the base of the cochlea and progressing toward the apex as aging continues. In contrast, the CBA mouse strain exhibits no significant cochlear histopathology until relatively late in life. These strain and age differences may be related to differences in cochlear energy metabolism. To examine this possibility, we used dehydrogenase and glycogen histochemistry to evaluate the metabolic capacities of HCs and stria vascularis (SV) in cochleas of C57 and CBA mice. Reaction product density was quantified and compared as a function of strain (1.5-month-old C57 mice vs. CBA mice) and age (CBA mice, 1.5, 18 and 36 months). Young C57 mice had significantly less HC dehydrogenase activity than CBA mice of any age, lower HC glycogen levels than 18-month-old CBA mice and lower SV glycogen levels than 18- or 36-month-old CBA animals. Within the CBA strain, HC dehydrogenase activity decreased significantly between 1.5 and 18 months of age, while glycogen levels in both HCs and SV increased over the same time period. Between 18 and 36 months, HC dehydrogenase activity and SV glycogen levels remained stable. The results show that there are significant age-related changes in energy metabolism in the inner ear of CBA mice that are correlated with age-related hearing loss. Genetically determined deficits in cochlear metabolic capacity in C57 mice could be linked to the early onset of hearing loss in this strain.

Recovery of kainic acid excitotoxicity in chinchilla cochlea.

The present study examines the recovery of the inner hair cell (IHC)/auditory nerve synapse following cochlear excitotoxicity induced by kainic acid (KA). Three hours after KA treatment, there was massive swelling of type I afferent endings under the IHCs. Five to ten days later, the pattern of IHC innervation appeared to be normal. Distortion-product otoacoustic emissions were normal during the whole experiment. The amplitude of the auditory nerve compound action potential (CAP) was significantly reduced immediately after KA treatment and then recovered over a 30-day period. However, it only took five days for the evoked response from the inferior colliculus (IC) to recover from a substantial depression. In contrast to amplitudes, thresholds for the CAP and IC recovered at the same rate and returned to normal within 5 days after KA. Single auditory nerve fibers were also assessed at various times after the KA treatment. Ten days after KA, these fibers had almost normal thresholds, tuning, spontaneous, and driven discharge rates. The results indicate that (1) excitotoxically damaged cochlear afferent neurons can rapidly regenerate and establish viable synapses with the IHCs, and (2) the central auditory system recovers more rapidly than the periphery.

Selective loss of inner hair cells and type-I ganglion neurons in carboplatin-treated chinchillas. Mechanisms of damage and protection.

Carboplatin preferentially destroys inner hair cells (IHCs) and type-I spiral ganglion neurons while sparing outer hair cells (OHCs). Loss of IHCs and type-I ganglion cells is associated with a significant reduction of the compound action potential (CAP). However, the cochlear microphonic (CM) potential and distortion product otoacoustic emissions (DPOAEs) remain normal, indicating that the OHCs are functionally intact. In the vestibular system, carboplatin selectively destroys type-I hair cells and their afferent neurons. Damage of type-I vestibular hair cells and their afferent terminals is associated with significant depression of nystagmus induced by cold, caloric stimulation. Histochemical studies revealed a rapid decrease in succinate dehydrogenase (SDH) staining in IHCs soon after carboplatin treatment, and staining intensity remained depressed in surviving IHCs for at least 1 month after carboplatin treatment. These results suggest that carboplatin depresses the metabolic function in surviving IHCs. Several lines of evidence suggest that free radicals may contribute to carboplatin-induced sensory cell damage. Intracochlear infusion of L-buthionine-[S,R]-sulfoximine (BSO), which depletes intracellular glutathione (GSH), increases IHC and OHC loss. Previous in vitro studies have shown that neurotrophin 4/5 (NT-4/5) promotes the survival of spiral ganglion neurons from cisplatin ototoxicity. In vivo perfusion of NT-4/5 promoted the survival of spiral ganglion neurons, but did not protect the hair cells.

Are inner or outer hair cells the source of summating potentials recorded from the round window?

The relative contribution of inner hair cells (IHCs) and outer hair cells (OHCs) to the production of the summating potential (SP) is unresolved in the literature. Since OHCs in the base of the cochlea have been reported to produce little dc receptor potential except at very high sound pressure levels [I. J. Russell and P. M. Sellick, J. Physiol (London) 284, 261-290 (1983)], the IHCs appear to be the dominant source of the SP. However, results of intracochlear recordings are conflicting, although deriving from measurements in different turns of the cochlea [e.g., I. J. Russell and P. M. Sellick, J. Physiol. (London) 284, 261-290 (1983) versus P. Dallos and M. A. Cheatham, Sensory Transduction (1992)]. To determine which type of hair cells is the dominant source of the SP recorded at the round window, we used carboplatin to selectively destroy IHCs or a combination of IHCs and OHCs in the chinchilla. Related work, using measurements of distortion product otoacoustic emissions and cochlear potentials to assess the functional status of the OHCs served to validate this animal model [Trautwein et al., Hearing Res. 96(1-2), 71-82 (1996)]. The SP, cochlear microphonic (CM), and compound action potential (CAP) were recorded from the round window, and cochleograms were determined using well-established histological methods. The results were reasonably distinctive among three groups of ears--control (from untreated normal chinchillas), IHC-loss (extensive IHC loss with minor or no loss of OHCs), and IHC-OHC loss (total IHC loss plus extensive loss of OHCs over the basal half of the cochlea). Ears of chinchillas in the IHC loss group had a decrease of over 50% in SP output compared to control ears with the exact reduction depending somewhat upon the stimulus conditions. Ears in the IHC + OHC loss group, nevertheless, showed even further reduction in SP output which was clearly attributable to destruction of OHCs in the cochlear base. It was concluded that, although the IHCs are responsible for a greater contribution of dc-receptor potential to the SP recorded at the round window, a significant contribution is made by the OHCs, as well. The results suggest, specifically, that the round window "sees" SP output roughly in inverse proportion to the IHC:OHC. Lastly, the complexity of SP production, as recorded from the round window, precludes a completely straightforward interpretation of the SP:CAP in clinical ECochG.

Evidence that inner hair cells are the major source of cochlear summating potentials.

The role of the inner hair cells (IHCs) in generating the cochlear summating potentials (SP) was assessed by measuring SP, cochlear nerve action potentials (CAP), cochlear microphonics (CM) and 2f1-f2 distortion product otoacoustic emissions (DPOAEs) in 15 chinchillas with either acute chemical de-afferentation, accomplished by applying kainic acid to the round window, or surgical de-afferentation and basal IHC loss, which developed within two months after sectioning the auditory nerve. In the auditory nerve sectioned ears, type I ganglion cells disappeared whereas most, if not all, type II ganglion cells were still present. Histological analysis of surface preparations and sections through the modiolus verified the de-afferentation in both models and showed a large IHC loss at the base of the cochlea in the ears with the auditory nerve sectioned while other structures of the cochlea remained intact. Unoperated (left) ears of 9 animals served as controls. CM and DPOAEs were normal in all ears whereas the CAP was substantially depressed in de-afferented ears. Comparisons among the SP input-output functions suggest that (1) the IHCs are the major generator of SP recorded from the round window in chinchilla, in particular at low to moderate stimulus levels, (2) the SP recorded from the round window largely reflects the responses from hair cells at the base of the cochlea, and (3) kainic acid results in an increase of SP amplitude to high-level stimuli whereas the SP to low- to moderate-level stimuli remains in the normal range.

The influence of the cochlear efferent system on chronic acoustic trauma.

The role of the olivocochlear bundle (OCB) in modulating noise-induced permanent injury to the auditory periphery was studied by completely sectioning the OCB fibers in chinchillas and exposing the animals while awake to a broad-band noise at 105 dB SPL for 6 h. Outer hair cell (OHC) function was assessed by measuring 2f1-f2 distortion product otoacoustic emissions (DPOAE) at frequencies from 1.2 to 9.6 kHz and cochlear microphonics (CM) at frequencies from 1 to 8 kHz. As a result of de-efferentation, the CM was decreased but the DPOAEs were unchanged in de-efferented ears as compared with efferented control and sham-operated ears. Following noise exposure, the ears that were de-efferented showed significantly more depression of DPOAE input/output functions and greater decrement of CM amplitude. The differences between de-efferented and efferent-innervated ears were evident across all the frequencies. The cochlear lesions of the OHCs reflected by traditional cytocochleograms, however, were minimal in both efferented and de-efferented ears. The results indicate that cochlear de-efferentation decreases the CM in chinchilla and increases the ear's susceptibility to noise-induced permanent hearing damage. More importantly, de-efferentation increases susceptibility at low frequencies as well as high frequencies.