Hiromichi Kuriyama

Direct inner ear infusion of dexamethasone attenuates noise-induced trauma in guinea pig

The protective effect of dexamethasone (DEX) against noise-induced trauma, as reflected in hair cell destruction and elevation in auditory brainstem response (ABR) sensitivity, was assessed in guinea pigs. The animals were administered DEX (1, 10, 100, and 1000 ng/ml) or artificial perilymph (AP) via a mini-osmotic pump directly into scala tympani and, on the fourth day after pump implantation, exposed to 120 dB SPL octave band noise, centered at 4 kHz, for 24 h. Animals receiving DEX demonstrated a dose-dependent reduction in noise-induced outer hair cell loss (significant at 1, 10 and 100 ng/ml DEX animals compared to AP control animals) and a similar attenuation of the noise-induced ABR threshold shifts, observed 7 days following exposure (significant at 100 ng/ml DEX animals compared to AP control animals). These physiological and morphological results indicate that direct infusion of DEX into the perilymphatic space has protective effects against noise-induced trauma in the guinea pig cochlea.

Intra-cochlear administration of dexamethasone attenuates aminoglycoside ototoxicity in the guinea pig

This study demonstrates the attenuation of aminoglycoside ototoxicity by cochlear infusion of dexamethasone (Dex) using a microcannulation-osmotic pump delivery system. The results indicate that treating the cochlea with Dex both before and after kanamycin administration was more effective in preventing ototoxicity than Dex treatment only after kanamycin administration. A concentration of 1 ng/ml Dex showed the greatest protective effect on both kanamycin-induced threshold shift of the auditory brainstem response and outer hair cell survival. These results show that the Dex treatment attenuates both functional and structural damage of the inner ear from aminoglycoside toxicity.

Gene transfer into guinea pig cochlea using adeno-associated virus vectors

Several genes are candidates for treating inner ear diseases. For clinical applications, minimally invasive approaches to the inner ear are desirable along with minimal side‐effects.

Roles of the glutamate receptor ε2 and δ2 subunits in the potentiation and prepulse inhibition of the acoustic startle reflex

We examined the regulation of the acoustic startle response in mutant mice of the N‐methyl‐d‐aspartate (NMDA)‐ and δ‐subtypes of the glutamate receptor (GluR) channel, which play important roles in neural plasticity in the forebrain and the cerebellum, respectively. Heterozygous mutant mice with reduced GluRε2 subunits of the NMDA receptor showed strongly enhanced startle responses to acoustic stimuli. On the other hand, heterozygous and homozygous mutation of the other NMDA receptor GluRε subunits exerted no, or only small effects on acoustic startle responses. The threshold of the auditory brainstem response of the GluRε2‐mutant mice was comparable to that of the wild‐type littermates. The primary circuit of the acoustic startle response is a relatively simple oligosynaptic pathway located in the lower brainstem, whilst the expression of GluRε2 is restricted to the forebrain. We thus suggest that the NMDA receptor GluRε2 subunit plays a role in the regulation of the startle reflex. Ablation of the cerebellar Purkinje cell‐specific δ2 subunit of the GluR channel exerted little effect on the acoustic startle response but resulted in the enhancement of prepulse inhibition of the reflex. Because inhibition of the acoustic startle response by a weak prepulse is a measure of sensorimotor gating, the process by which an organism filters sensory information, these observations indicate the involvement of the cerebellum in the modulation of sensorimotor gating.

Coexistence of calcitonin gene-related peptide and enkephalin in single neurons of the lateral superior olivary nucleus of the guinea pig that project to the cochlea as lateral olivocochlear system

Abstract Immunocytochemical double staining analysis revealed that some of the calcitonin gene-related peptide-containing neurons in the lateral olivary nucleus contained enkephalin in the guinea pig.

The N-methyl-d-aspartate (NMDA)-type glutamate receptor GluRε2 is important for delay and trace eyeblink conditioning in mice

It has been proposed that the N-methyl-d-aspartate (NMDA)-type glutamate receptor (GluR) plays an important role in synaptic plasticity, learning, and memory. The four GluRepsilon (NR2) subunits, which constitute NMDA receptors with a GluRzeta (NR1) subunit, differ both in their expression patterns in the brain and in their functional properties. In order to specify the distinct participation of each of these subunits, we focused on the GluRepsilon2 subunits, which are expressed mainly in the forebrain. We investigated delay and trace eyeblink conditioning in GluRepsilon2 heterozygous mutant mice whose content of GluRepsilon2 protein was decreased to about half of that in wild-type mice. GluRepsilon2 mutant mice exhibited severe impairment of the attained level of conditioned response (CR) in the delay paradigm, for which the cerebellum is essential and modulation by the forebrain has been suggested. Moreover, GluRepsilon2 mutant mice showed no trend toward CR acquisition in the trace paradigm with a trace interval of 500 ms, in which the forebrain is critically involved in successful learning. On the other hand, the reduction of GluRepsilon2 proteins did not disturb any basic sensory and motor functions which might have explained the observed impairment. These results are different from those obtained with GluRepsilon1 null mutant mice, which attain a normal level of the CR but at a slower rate in the delay paradigm, and showed a severe impairment in the trace paradigm. Therefore, the NMDA receptor GluRepsilon2 plays a more critical role than the GluRepsilon1 subunit in classical eyeblink conditioning.

Electron microscopic observation of calcitonin gene-related peptide-like immunoreactivity in the organ of Corti of the rat

Calcitonin gene-related peptide (CGRP)-like immunoreactive (CGRP-IR) nerve terminals in the organ of Corti of rats were studied by light and electron microscopy. Surface preparation of the organ of Corti were immunostained using anti-CGRP antiserum for avidin-biotin immunohistochemistry. Dense CGRP-IR fiber bundles were observed by light microscopy in the inner spiral bundles, tunnel spiral bundles and outer spiral bundles. Electron microscopic analysis indicated that CGRP-IR fibers belong to efferent nerves. In the inner spiral bundles, the CGRP-IR fibers showed a direct contact mainly with non-immunoreactive afferent fibers. Some CGRP-IR nerve endings in the inner spiral bundles formed contacts directly with inner hair cells. In the outer spiral bundles, CGRP-IR fibers formed synaptic contacts exclusively with the outer hair cells. It should be noted that the number of synapses of CGRP nerve endings with outer hair cells varied depending upon the sub-row: a falling gradient in number occurred along the inner-outer axis. Our results suggest that CGRP acts as an efferent neuromodulator in the organ of Corti.

Administration of amitriptyline attenuates noise-induced hearing loss via glial cell line-derived neurotrophic factor (GDNF) induction

Antidepressant treatments have been described to induce neurotrophic factors (NTFs) and reverse the cell loss observed in rodent stress models. Amitriptyline (AT), a tricyclic antidepressant agent, has been reported in recent studies to induce glial cell line-derived neurotrophic factor (GDNF) synthesis and release in rat C6 glioblastoma cells. GDNF has shown protection against acoustic trauma in previous studies. Therefore, we investigated whether AT could induce GDNF synthesis in the cochlea and attenuate cochlea damage against acoustic trauma. We used Hartley guinea pigs and injected AT (30 mg/kg) or saline into the peritoneum. Subjects were exposed to 117 dB SPL octave band noise centered at 4 kHz for 24 h. Noise-induced hearing loss (NIHL) was assessed with auditory brain stem response (ABR) at 4, 8 and 16 kHz measured prior to the injection, 3 days and 7 days after noise exposure. For histological assessment, we observed the sensory epithelium using a surface preparation technique and assessed the quantitative hair cell (HC) damage. We evaluated GDNF synthesis with or without intense noise exposure at 3, 12 and 24 h after the administration of AT in the cochlea using Western blot analysis. GDNF expression was shown 3 h and 12 h after the injection without noise, whereas with noise the GDNF expression lasted for 24 h. The AT-administrated group showed significantly reduced ABR threshold shift and less HC damage than the saline-administrated group. These findings suggest that the administration of AT-induced GDNF levels in the cochlea and attenuated cochlea damage from NIHL.

Hearing results for ossicular reconstruction using a cartilage-connecting hydroxyapatite prosthesis with a spearhead.

Objective: Assessment of the efficacy of ossicular reconstruction using a cartilage-connecting hydroxyapatite prosthesis designed with a spearhead to reduce extrusion and dislocation of the implant. Patients: All patients undergoing ossicular reconstruction after chronic ear surgery, connecting the cartilage to the prosthesis, with a minimum of 1 year of postoperative follow-up. Main Outcome Measures: Postoperative change in pure-tone averages. Air-bone gap closures, and implant extrusion rates. Results: Overall mean pure-tone averages improved by 12.2 dB (ranged between −40 and 60 dB). In total, 68.4% of the patients achieved an air-bone gap less than 20 dB. Gains in the mean air conduction thresholds were 9.5 dB in cases of partial ossicular reconstruction and 14.9 dB in cases with total ossicular reconstruction (p < 0.05). The overall extrusion rate was 4.21%. Conclusion: The cartilage-connecting hydroxyapatite prosthesis with a spearhead was found to restore hearing to a satisfactory level. The extrusion rate was relatively low. The cartilage-connecting hydroxyapatite prosthesis with a spearhead is an effective ossicular implant and offers an attractive alternative for ossicular reconstruction, particularly for total ossicular reconstructions.

Auditory pathway and auditory brainstem response in mice lacking NMDA receptor ϵ1 and ϵ4 subunits

Abstract There is considerable evidence that the N -methyl- d -aspartate receptor ((NMDAR) is a component of excitatory amino acid synapses in the ascending auditory pathway. The availability of mice that are defective in NMDAR ϵ 1 or NMDAR ϵ 4 subunit paves the way for investigations on the role of this receptor in auditory function. Non-radioactive in situ hybridization was used in the parent C57/6J wild strain to determine if these subunits are normally expressed in cochlear nucleus (CN) and superior olivary complex (SOC) and to confirm their absence in the respective mutant mice. Evoked auditory brainstem response (ABR) to normal acoustic stimulation was investigated to assess function. In situ hybridization revealed the expression of NMDAR ϵ 1 and ϵ 4 subunits mRNAs in major neuronal types in the CN and SOC of the wild type mice while ϵ 1 and ϵ 4 expression were absent in their respective mutant mice. The ABR threshold for the ϵ 1 mutant mice was similar to that of wild type mice however the threshold for the ϵ 4 mutant mice was significantly elevated. These results suggest a role for the NMDAR ϵ 4 in normal auditory functions while the NMDAR ϵ 1 may have a less critical function under normal conditions.