Synchronous auditory nerve activity in the carboplatin-chinchilla model of auditory neuropathy.
Ontology highlight
ABSTRACT:
SUBMITTER: Cowper-Smith CD
PROVIDER: S-EPMC2905450 | biostudies-other | 2010 Jul
REPOSITORIES: biostudies-other
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Project description:Cochlear implantation has become the standard-of-care for adults and children with severe to profound hearing loss. There is growing evidence that qualitative as well as quantitative deficits in the auditory nerve may affect cochlear implant (CI) outcomes. Auditory neuropathy spectrum disorder (ANSD) is characterized by dysfunctional transmission of sound from the cochlea to the brain due to defective synaptic function or neural conduction. In this review, we examine the precise mechanisms of genetic lesions causing ANSD and the effect of these lesions on CI outcomes. Reviewed data show that individuals with lesions that primarily affect the cochlear sensory system and the synapse, which are bypassed by the CI, have optimal CI outcomes. Individuals with lesions that affect the auditory nerve show poor performance with CIs, likely because neural transmission of the electrical signal from the CI is affected. We put forth a nuanced molecular classification of ANSD that has implications for preoperative counseling for patients with this disorder prior to cochlear implantation. We propose that description of ANSD patients should be based on the molecular site of lesion typically derived from genetic evaluation (synaptopathy vs. neuropathy) as this has implications for expected CI outcomes. Improvements in our understanding of genetic site of lesions and their effects on CI function should lead to better CI outcomes, not just for individuals with auditory neuropathy, but all individuals with hearing loss.
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Project description:This study aimed to (1) characterize temporal response properties of the auditory nerve in implanted children with auditory neuropathy spectrum disorder (ANSD), and (2) compare results recorded in implanted children with ANSD with those measured in implanted children with sensorineural hearing loss (SNHL).Participants included 28 children with ANSD and 29 children with SNHL. All subjects used cochlear nucleus devices in their test ears. Both ears were tested in 6 children with ANSD and 3 children with SNHL. For all other subjects, only one ear was tested. The electrically evoked compound action potential (ECAP) was measured in response to each of the 33 pulses in a pulse train (excluding the second pulse) for one apical, one middle-array, and one basal electrode. The pulse train was presented in a monopolar-coupled stimulation mode at 4 pulse rates: 500, 900, 1800, and 2400 pulses per second. Response metrics included the averaged amplitude, latencies of response components and response width, the alternating depth and the amount of neural adaptation. These dependent variables were quantified based on the last six ECAPs or the six ECAPs occurring within a time window centered around 11 to 12 msec. A generalized linear mixed model was used to compare these dependent variables between the 2 subject groups. The slope of the linear fit of the normalized ECAP amplitudes (re. amplitude of the first ECAP response) over the duration of the pulse train was used to quantify the amount of ECAP increment over time for a subgroup of 9 subjects.Pulse train-evoked ECAPs were measured in all but 8 subjects (5 with ANSD and 3 with SNHL). ECAPs measured in children with ANSD had smaller amplitude, longer averaged P2 latency and greater response width than children with SNHL. However, differences in these two groups were only observed for some electrodes. No differences in averaged N1 latency or in the alternating depth were observed between children with ANSD and children with SNHL. Neural adaptation measured in these 2 subject groups was comparable for relatively short durations of stimulation (i.e., 11 to 12 msec). Children with ANSD showed greater neural adaptation than children with SNHL for a longer duration of stimulation. Amplitudes of ECAP responses rapidly declined within the first few milliseconds of stimulation, followed by a gradual decline up to 64 msec after stimulus onset in the majority of subjects. This decline exhibited an alternating pattern at some pulse rates. Further increases in pulse rate diminished this alternating pattern. In contrast, ECAPs recorded from at least one stimulating electrode in six ears with ANSD and three ears with SNHL showed a clear increase in amplitude over the time course of stimulation. The slope of linear regression functions measured in these subjects was significantly greater than zero.Some but not all aspects of temporal response properties of the auditory nerve measured in this study differ between implanted children with ANSD and implanted children with SNHL. These differences are observed for some but not all electrodes. A new neural response pattern is identified. Further studies investigating its underlying mechanism and clinical relevance are warranted.
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Project description:Spiral ganglion neurons (SGNs) and the associated components of the auditory nerve are primary carriers of auditory information from hair cells to the brain. Loss of SGNs occurs with many pathological conditions, resulting in permanent sensorineural hearing loss. Neural stem/progenitors (NSPs) have been well-characterized in several locations of adult brain and retina. However, it is unclear whether NSPs are present in the adult auditory nerve. Here we examined the self-renewal potential of the adult auditory nerve using ouabain application as a well-established mouse model of acute SGN injury. The observed increase in cell proliferation, alteration in enchromatin/heterochromatin ratio and down-regulation of histone deacetylase expression in glial cells suggest that the quiescent glial cells convert to an activated state after SGN degeneration. This was further confirmed by global gene expression analysis of injured auditory nerves, which showed up-regulation of numerous neurogenesis- and/or development-associated genes shortly after ouabain exposure. These genes include molecular markers commonly used for the identification of NSPs. Under a strict culture regimen, auditory nerve-derived cells of adult mouse ears gave rise to neurospheres, suggesting that multipotent NSPs are present in adult cochlear nerve. Neurosphere assays on Sox2 transgenic mice revealed that Sox2+ glial cells are the source for NSPs. Our data also showed that acute injury or hypoxia enhances neurosphere formation. Taken together, our study revealed that glial cells of adult cochlea exhibit several NSP characteristics, and hence these mature non-neuronal cells may be important targets for promoting self-repair of degenerative auditory nerves. Auditory nerves were removed from the temporal bones of adult CBA/CaJ mice, aged 8 to 12 weeks. Tissues were either collected and used directly as the tissue samples or dissociated and used for the cell culture samples. Dissociated auditory nerve cells were propagated and grown to full confluency (5-7 days), constituting the cultured cell samples. For neurosphere samples, growth medium was changed to neurosphere formation medium and the cells were cultured for an additional 12 days. All samples were prepared in triplicate (n=3).
2015-04-29 | E-GEOD-65249 | biostudies-arrayexpress
Project description:profiles of normal and diseased sciatic nerve of young adult mice Keywords: other
2004-11-12 | E-GEOD-1962 | biostudies-arrayexpress
Project description:Spiral ganglion neurons (SGNs) and the associated components of the auditory nerve are primary carriers of auditory information from hair cells to the brain. Loss of SGNs occurs with many pathological conditions, resulting in permanent sensorineural hearing loss. Neural stem/progenitors (NSPs) have been well-characterized in several locations of adult brain and retina. However, it is unclear whether NSPs are present in the adult auditory nerve. Here we examined the self-renewal potential of the adult auditory nerve using ouabain application as a well-established mouse model of acute SGN injury. The observed increase in cell proliferation, alteration in enchromatin/heterochromatin ratio and down-regulation of histone deacetylase expression in glial cells suggest that the quiescent glial cells convert to an activated state after SGN degeneration. This was further confirmed by global gene expression analysis of injured auditory nerves, which showed up-regulation of numerous neurogenesis- and/or development-associated genes shortly after ouabain exposure. These genes include molecular markers commonly used for the identification of NSPs. Under a strict culture regimen, auditory nerve-derived cells of adult mouse ears gave rise to neurospheres, suggesting that multipotent NSPs are present in adult cochlear nerve. Neurosphere assays on Sox2 transgenic mice revealed that Sox2+ glial cells are the source for NSPs. Our data also showed that acute injury or hypoxia enhances neurosphere formation. Taken together, our study revealed that glial cells of adult cochlea exhibit several NSP characteristics, and hence these mature non-neuronal cells may be important targets for promoting self-repair of degenerative auditory nerves.
2015-04-29 | GSE65249 | GEO
Project description:Several parameters are important when choosing the most appropriate animal to model human obstetrics, including gestation period, number of fetuses per gestation and placental structure. The domesticated long-tailed chinchilla (Chinchilla lanigera) is a well-suited and appropriate animal model of pregnancy that often will carry only one offspring and has a long gestation period of 105-115 days. Furthermore, the chinchilla placenta is of the haemomonochorial labyrinthine type and is therefore comparable to the human villous haemomonochorial placenta. This proof-of-concept study demonstrated the feasibility in laboratory settings, and demonstrated the potential of the pregnant chinchilla as an animal model for obstetric research and its potential usefulness for non-invasive measurements in the placenta. We demonstrate measurements of the placental and fetal metabolism (demonstrated in vivo by hyperpolarized MRI and in vitro by qPCR analyses), placental vessels (demonstrated ex vivo by contrast-enhanced CT angiography) and overall anatomy (demonstrated in vivo by whole-body CT).
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Project description:Overall goal of the study is to identify the molecular regulators of auditory nerve development
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Project description:profiles of normal and diseased sciatic nerve of young adult mice Keywords: other
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Project description:Mutations in OTOF gene, encoding otoferlin, cause DFNB9 deafness and non-syndromic auditory neuropathy (AN). The aim of this study is to identify OTOF mutations in Chinese patients with non-syndromic auditory neuropathy.73 unrelated Chinese Han patients with AN, including one case of temperature sensitive non-syndromic auditory neuropathy (TS-NSRAN) and 92 ethnicity-matched controls with normal hearing were screened. Forty-five pairs of PCR primers were designed to amplify all of the exons and their flanking regions of the OTOF gene. The PCR products were sequenced and analyzed for mutation identification.Five novel possibly pathogenic variants (c.1740delC, c.2975_2978delAG, c.1194T>A, c.1780G>A, c.4819C > T) were identified in the group of 73 AN patients, in which two novel mutant alleles (c.2975_2978delAG + c.4819C > T) were identified in one Chinese TS-NSRAN case. Besides, 10 non-pathogenic variants of the OTOF gene were found in AN patients and controls.Screening revealed that mutations in the OTOF gene account for AN in 4 of 73(5.5%) sporadic AN patients, which shows a lower genetic load of that gene in contrast to the previous studies based on other populations. Notably, we found two novel mutant alleles related to temperature sensitive non-syndromic auditory neuropathy. This mutation screening study further confirms that the OTOF gene contributes to ANs and to TS-NSRAN.
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