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Intracellular studies of hair cells in the mammalian cochlea.

Russell, I J; Sellick, P M
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /11/1978 EN
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1. Intracellular recordings were made from inner hair cells in the first turn of the guinea-pig cochlea, the recording sites being confirmed by the injection of Procion yellow dye and subsequent histology. 2. The receptor potential, in response to a pure tone burst, consisted of an AC response which followed the wave form of the stimulus and was analogous to the extracellularly recorded cochlear microphonic and a depolarizating DC response which followed the envelope of the tone burst and was analogous to the extracellularly recorded summating potential. 3. The DC response was broadly tuned at high sound pressure having a maximal amplitude of 27 mV at a sound pressure level of ca. 100 db; however the bandwidth of the response was reduced at lower sound pressure level. Isoamplitude curves for the DC response were indistinguishable from the threshold curves for auditory nerve fibres. 4. The AC response was tuned in a similar fashion to the DC response except that it was attenuated at 6-9 db/octave with respect to the DC response. It is suggested that this difference was due to the effect of membrane capacitance and resistance on the AC response. In contrast the extracellularly recorded AC component was not subject to this attenuation. 5. The total resistance and capacitance in three cells were found to be 46-61 Momega and 7.8-15.8 muF respectively. 6. Intracellular resistance changes were measured during sound stimulation...

Exogenous BDNF rescues rat spiral ganglion neurons in vivo

McGuinness, Sarah L.; Shepherd, Robert K.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /09/2005 EN
Relevância na Pesquisa
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The loss of hair cells resulting in a sensorineural hearing loss (SNHL) also leads to the secondary degeneration of spiral ganglion neurons (SGNs). The effectiveness of cochlear implantation in patients with a profound SNHL relies, in part, upon the survival of SGNs; therefore any therapy that can prevent or halt the loss of these neurons would be of potential clinical benefit. Previous research has shown that intracochlear infusion with neurotrophins can provide trophic support to SGNs in deafened guinea pigs. It remains to be determined whether this effect is seen in other species. After documenting the rate of SGN degeneration following ototoxic deafening, we investigated the trophic effects of exogenous brain-derived neurotrophic factor (BDNF) on rat SGNs. The left cochleae of profoundly deafened rats were implanted with a drug delivery system connected to a mini-osmotic pump. BDNF or artificial perilymph (AP) was infused for 28 days and the cochleae were then prepared for histology. Treatment with BDNF led to a statistically significant increase in SGN density and a highly significant increase in SGN soma area compared to AP-treated and untreated deafened cochleae. This work has demonstrated the trophic advantage of exogenous BDNF in the mature rat cochlea and provides confidence that SGN rescue following SNHL with exogenous BDNF may have clinical application.

Visualization of spiral ganglion neurites within the scala tympani with a cochlear implant in situ

Chikar, Jennifer A.; Batts, Shelley A.; Pfingst, Bryan E.; Raphael, Yehoash
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
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Current cochlear histology methods do not allow in situ processing of cochlear implants. The metal components of the implant preclude standard embedding and mid-modiolar sectioning, and whole mounts do not have the spatial resolution needed to view the implant within the scala tympani. One focus of recent auditory research is the regeneration of structures within the cochlea, particularly the ganglion cells and their processes, and there are multiple potential benefits to cochlear implant users from this work. To facilitate experimental investigations of auditory nerve regeneration performed in conjunction with cochlear implantation, it is critical to visualize the cochlear tissue and the implant together to determine if the nerve has made contact with the implant. This paper presents a novel histological technique that enables simultaneous visualization of the in situ cochlear implant and neurofilament – labeled nerve processes within the scala tympani, and the spatial relationship between them.

Mice lacking ganglioside GM3 synthase exhibit complete hearing loss due to selective degeneration of the organ of Corti

Yoshikawa, Misato; Go, Shinji; Takasaki, Kotaro; Kakazu, Yasuhiro; Ohashi, Mitsuru; Nagafuku, Masakazu; Kabayama, Kazuya; Sekimoto, Junji; Suzuki, Shun-ichi; Takaiwa, Kazutaka; Kimitsuki, Takashi; Matsumoto, Nozomu; Komune, Shizuo; Kamei, Daisuke; Saito,
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
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The ganglioside GM3 synthase (SAT-I), encoded by a single-copy gene, is a primary glycosyltransferase for the synthesis of complex gangliosides. In SAT-I null mice, hearing ability, assessed by brainstem auditory-evoked potentials (BAEP), was impaired at the onset of hearing and had been completely lost by 17 days after birth (P17), showing a deformity in hair cells in the organ of Corti. By 2 months of age, the organ of Corti had selectively and completely disappeared without effect on balance or motor function or in the histology of vestibule. Interestingly, spatiotemporal changes in localization of individual gangliosides, including GM3 and GT1b, were observed during the postnatal development and maturation of the normal inner ear. GM3 expressed in almost all regions of cochlea at P3, but at the onset of hearing it distinctly localized in stria vascularis, spiral ganglion, and the organ of Corti. In addition, SAT-I null mice maintain the function of stria vascularis, because normal potassium concentration and endocochlear potential of endolymph were observed even when they lost the BAEP completely. Thus, the defect of hearing ability of SAT-I null mice could be attributed to the functional disorganization of the organ of Corti, and the expression of gangliosides...

Selective Vulnerability of the Cochlear Basal Turn to Acrylonitrile and Noise

Pouyatos, B.; Gearhart, C. A.; Nelson-Miller, A.; Fulton, S.; Fechter, L. D.
Fonte: Hindawi Publishing Corporation Publicador: Hindawi Publishing Corporation
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
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Exposure to acrylonitrile, a high-production industrial chemical, can promote noise-induced hearing loss (NIHL) in the rat even though this agent does not itself produce permanent hearing loss. The mechanism by which acrylonitrile promotes NIHL includes oxidative stress as antioxidant drugs can partially protect the cochlea from acrylonitrile + noise. Acrylonitrile depletes glutathione levels while noise can increase the formation of reactive oxygen species. It was previously noted that the high-frequency or basal turn of the cochlea was particularly vulnerable to the combined effects of acrylonitrile and noise when the octave band noise (OBN) was centered at 8 kHz. Normally, such a noise would be expected to yield damage at a more apical region of the cochlea. The present study was designed to determine whether the basal cochlea is selectively sensitive to acrylonitrile or whether, by adjusting the frequency of the noise band, it would be possible to control the region of the auditory impairment. Rats were exposed to one of three different OBNs centered at different frequencies (4 kHz, 110 dB and 8 or 16 kHz at 97 dB) for 5 days, with and without administration of acrylonitrile (50 mg/kg/day). The noise was set to cause limited NIHL by itself. Auditory function was monitored by recording distortion products...

Adenosine amine congener mitigates noise-induced cochlear injury

Vlajkovic, Srdjan M.; Lee, Kyu-Hyun; Wong, Ann Chi Yan; Guo, Cindy X.; Gupta, Rita; Housley, Gary D.; Thorne, Peter R.
Fonte: Springer Netherlands Publicador: Springer Netherlands
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
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Hearing loss from noise exposure is a leading occupational disease, with up to 5% of the population at risk world-wide. Here, we present a novel purine-based pharmacological intervention that can ameliorate noise-induced cochlear injury. Wistar rats were exposed to narrow-band noise (8–12 kHz, 110 dB SPL, 2–24 h) to induce cochlear damage and permanent hearing loss. The selective adenosine A1 receptor agonist, adenosine amine congener (ADAC), was administered intraperitoneally (100 µg/kg/day) at time intervals after noise exposure. Hearing thresholds were assessed using auditory brainstem responses and the hair cell loss was evaluated by quantitative histology. Free radical damage in the organ of Corti was assessed using nitrotyrosine immunohistochemistry. The treatment with ADAC after noise exposure led to a significantly greater recovery of hearing thresholds compared with controls. These results were upheld by increased survival of sensory hair cells and reduced nitrotyrosine immunoreactivity in ADAC-treated cochlea. We propose that ADAC could be a valuable treatment for noise-induced cochlear injury in instances of both acute and extended noise exposures.

Conditional Deletion of N-Myc Disrupts Neurosensory and Non-sensory Development of the Ear

Kopecky, Benjamin; Santi, Peter; Johnson, Shane; Schmitz, Heather; Fritzsch, Bernd
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
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Ear development requires interactions of transcription factors for proliferation and differentiation. The proto-oncogene N-Myc is a member of the Myc family that regulate proliferation. To investigate the function of N-Myc, we conditionally knocked out N-Myc in the ear using Tg(Pax2-Cre) and Foxg 1KiCre. N-Myc CKOs had reduced growth of the ear, abnormal morphology including fused sensory epithelia, disrupted histology, and disorganized neuronal innervation. Using Thin-Sheet Laser Imaging Microscopy (TSLIM), 3D reconstruction and quantification of the cochlea revealed a greater than fifty percent size reduction. Immunochemistry and in situ hybridization showed a gravistatic organ-cochlear fusion and a “circularized” apex with no clear inner and outer hair cells. Furthermore, the abnormally developed cochlea had cross innervation from the vestibular ganglion near the basal tip. These findings are put in the context of the possible functional relationship of N-Myc with a number of other cell proliferative and fate determining genes during ear development.

Hearing Loss and Hair Cell Death in Mice Given the Cholesterol-Chelating Agent Hydroxypropyl-β-Cyclodextrin

Crumling, Mark A.; Liu, Liqian; Thomas, Paul V.; Benson, Jennifer; Kanicki, Ariane; Kabara, Lisa; Hälsey, Karin; Dolan, David; Duncan, R. Keith
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 28/12/2012 EN
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Cyclodextrins are sugar compounds that are increasingly finding medicinal uses due to their ability to complex with hydrophobic molecules. One cyclodextrin in particular, 2-hydroxypropyl-β-cyclodextrin (HPβCD), is used as a carrier to solubilize lipophilic drugs and is itself being considered as a therapeutic agent for treatment of Niemann-Pick Type C disease, due to its ability to mobilize cholesterol. Results from toxicological studies suggest that HPβCD is generally safe, but a recent study has found that it causes hearing loss in cats. Whether the hearing loss occurred via death of cochlear hair cells, rendering it permanent, was unexplored. In the present study, we examined peripheral auditory function and cochlear histology in mice after subcutaneous injection of HPβCD to test for hearing loss and correlate any observed auditory deficits with histological findings. On average, auditory brainstem response thresholds were elevated at 4, 16, and 32 kHz in mice one week after treatment with 8,000 mg/kg. In severely affected mice all outer hair cells were missing in the basal half of the cochlea. In many cases, surviving hair cells in the cochlear apex exhibited abnormal punctate distribution of the motor protein prestin, suggesting long term changes to membrane composition and integrity. Mice given a lower dose of 4...

Connexin 26 null mice exhibit spiral ganglion degeneration that can be blocked by BDNF gene therapy

Takada, Yohei; Beyer, Lisa A.; Swiderski, Donald L.; O’Neal, Aubrey L.; Prieskorn, Diane M.; Shivatzki, Shaked; Avraham, Karen B.; Raphael, Yehoash
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
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Mutations in the connexin 26 gene (GJB2) are the most common genetic cause of deafness, leading to congenital bilateral non-syndromic sensorineural hearing loss. Here we report the generation of a mouse model for a connexin 26 (C×26) mutation, in which cre-Sox10 drives excision of the C×26 gene from non-sensory cells flanking the auditory epithelium. We determined that these conditional knockout mice, designated Gjb2-CKO, have a severe hearing loss. Immunocytochemistry of the auditory epithelium confirmed absence of C×26 in the non-sensory cells. Histology of the organ of Corti and the spiral ganglion neurons (SGNs) performed at ages 1, 3, or 6 months revealed that in Gjb2-CKO mice, the organ of Corti began to degenerate in the basal cochlear turn at an early stage, and the degeneration rapidly spread to the apex. In addition, the density of SGNs in Rosenthal’s canal decreased rapidly along a gradient from the base of the cochlea to the apex, where some SGNs survived until at least 6 months of age. Surviving neurons often clustered together and formed clumps of cells in the canal. We then assessed the influence of brain derived neurotrophic factor (BDNF) gene therapy on the SGNs of Gjb2-CKO mice by inoculating Adenovirus BDNF (Ad.BDNF) into the base of the cochlea via the scala tympani or scala media. We determined that over-expression of BDNF beginning around 1 month of age resulted in a significant rescue of neurons in Rosenthal’s canal of the cochlear basal turn but not in the middle or apical portions. This data may be used to design therapies for enhancing the SGN physiological status in all GJB2 patients and to a sub-group of GJB2 patients where the hearing loss progresses due to ongoing degeneration of the auditory nerve...

FGF23 Deficiency Leads to Mixed Hearing Loss and Middle Ear Malformation in Mice

Lysaght, Andrew C.; Yuan, Quan; Fan, Yi; Kalwani, Neil; Caruso, Paul; Cunnane, MaryBeth; Lanske, Beate; Stanković, Konstantina M.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 22/09/2014 EN
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Fibroblast growth factor 23 (FGF23) is a circulating hormone important in phosphate homeostasis. Abnormal serum levels of FGF23 result in systemic pathologies in humans and mice, including renal phosphate wasting diseases and hyperphosphatemia. We sought to uncover the role FGF23 plays in the auditory system due to shared molecular mechanisms and genetic pathways between ear and kidney development, the critical roles multiple FGFs play in auditory development and the known hearing phenotype in mice deficient in klotho (KL), a critical co-factor for FGF23 signaling. Using functional assessments of hearing, we demonstrate that Fgf mice are profoundly deaf. Fgf mice have moderate hearing loss above 20 kHz, consistent with mixed conductive and sensorineural pathology of both middle and inner ear origin. Histology and high-voltage X-ray computed tomography of Fgf mice demonstrate dysplastic bulla and ossicles; Fgf mice have near-normal morphology. The cochleae of mutant mice appear nearly normal on gross and microscopic inspection. In wild type mice, FGF23 is ubiquitously expressed throughout the cochlea. Measurements from Fgf mice do not match the auditory phenotype of Kl−/− mice, suggesting that loss of FGF23 activity impacts the auditory system via mechanisms at least partially independent of KL. Given the extensive middle ear malformations and the overlap of initiation of FGF23 activity and Eustachian tube development...

Swept-sine noise-induced damage as a hearing loss model for preclinical assays

Sanz, Lorena; Murillo-Cuesta, Silvia; Cobo, Pedro; Cediel-Algovia, Rafael; Contreras, Julio; Rivera, Teresa; Varela-Nieto, Isabel; Avendaño, Carlos
Fonte: Frontiers Media S.A. Publicador: Frontiers Media S.A.
Tipo: Artigo de Revista Científica
Publicado em 16/02/2015 EN
Relevância na Pesquisa
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Mouse models are key tools for studying cochlear alterations in noise-induced hearing loss (NIHL) and for evaluating new therapies. Stimuli used to induce deafness in mice are usually white and octave band noises that include very low frequencies, considering the large mouse auditory range. We designed different sound stimuli, enriched in frequencies up to 20 kHz (“violet” noises) to examine their impact on hearing thresholds and cochlear cytoarchitecture after short exposure. In addition, we developed a cytocochleogram to quantitatively assess the ensuing structural degeneration and its functional correlation. Finally, we used this mouse model and cochleogram procedure to evaluate the potential therapeutic effect of transforming growth factor β1 (TGF-β1) inhibitors P17 and P144 on NIHL. CBA mice were exposed to violet swept-sine noise (VS) with different frequency ranges (2–20 or 9–13 kHz) and levels (105 or 120 dB SPL) for 30 min. Mice were evaluated by auditory brainstem response (ABR) and otoacoustic emission tests prior to and 2, 14 and 28 days after noise exposure. Cochlear pathology was assessed with gross histology; hair cell number was estimated by a stereological counting method. Our results indicate that functional and morphological changes induced by VS depend on the sound level and frequency composition. Partial hearing recovery followed the exposure to 105 dB SPL...

Cochlear infrastructure for electrical hearing

Pfingst, Bryan E.; Bowling, Sara A.; Colesa, Deborah J.; Garadat, Soha N.; Raphael, Yehoash; Shibata, Seiji B.; Strahl, Stefan B.; Su, Gina L.; Zhou, Ning
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
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Although the cochlear implant is already the world's most successful neural prosthesis, opportunities for further improvement abound. Promising areas of current research include work on improving the biological infrastructure in the implanted cochlea to optimize reception of cochlear implant stimulation and on designing the pattern of electrical stimulation to take maximal advantage of conditions in the implanted cochlea. In this review we summarize what is currently known about conditions in the cochlea of deaf, implanted humans and then review recent work from our animal laboratory investigating the effects of preserving or reinnervating tissues on psychophysical and electrophysiological measures of implant function. Additionally we review work from our human laboratory on optimizing the pattern of electrical stimulation to better utilize strengths in the cochlear infrastructure. Histological studies of human temporal bones from implant users and from people who would have been candidates for implants show a range of pathologic conditions including spiral ganglion cell counts ranging from approximately 2% to 92% of normal and partial hair cell survival in some cases. To duplicate these conditions in a guinea pig model, we use a variety of deafening and implantation procedures as well as post1-deafening therapies designed to protect neurons and/or regenerate neurites. Across populations of human patients...

Otic Lesions and Congenital Hypothyroidism in the Developing Chick*

Bargman, Gerald J.; Gardner, Lytt I.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /11/1967 EN
Relevância na Pesquisa
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In an effort to elucidate the relation, if any, between thyroid abnormality and congenital deafness in Pendred's syndrome, an experiment was designed to study the effects of hypothyroidism on middle and inner ear hearing structures, including the auditory nerve and its central projection, in developing chick embryos. Propylthiouracil (PTU), 2 mg, was injected into the albumin of fertile chick eggs on the 10th incubation day. Single doses of L-thyroxine (range 1-100μg) were inoculated in a similar manner, either alone or with PTU. Control inocula included sterile saline or water. After hatching, each chick was examined for obvious malformations. The thyroid glands, middle and inner ear mechanisms, auditory nerve, and brainstem were studied grossly and with different histologic staining techniques. When compared to controls, chicks exposed to PTU on their 10th incubation day exhibited: increased mortality, delayed hatching, reduced size, incomplete yolk sac absorption, and death within 5 days unless exogenous thyroid hormone was provided in the first 24-48 hr after hatching. Specific, consistent, morphologic alterations were observed in their thyroid glands as well as in the sensory hair cells of the acoustic papilla and cells of the spiral ganglion of the cochlea. Our data also indicate that if 50-75 μg of L-thyroxine is given simultaneously with (or as long as 120 hr after) the PTU injection on the 10th incubation day...