Graeme Clark Collection
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ItemNeurotrophin survival effects on auditory neurons in vivo [Abstract]( nd)Neurotrophic factors, in particular the neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) are well known to be important for the development and maintenance of the auditory system and have also been reported to act as survival factors for auditory neurons in animal models of deafness. Indeed, numerous studies have demonstrated that intracochlear application of neurotrophins shortly following deafening can prevent auditory neuron degeneration. Following on from these findings, we have investigated two aspects of the time-course of neurotrophin-induced auditory neuron survival. Firstly, we tested the longevity of the survival effects of BDNF on auditory neurons in deaf guinea pigs; specifically we aimed to determine if the survival effects of BDNF are maintained beyond the period of treatment, or if sustained delivery is required. Results from this study indicated that while BDNF prevents auditory neuron degeneration during the treatment period, cessation of the trophic support leads to a rapid loss of survival effects. These findings suggest ongoing neurotrophin treatment may be required for maintained auditory neuron survival. Secondly, we examined the effects of delayed neurotrophin treatment on auditory neuron survival following deafness. Results from this study demonstrated that each of the members of the neurotrophin family BDNF, NT-3, neurotrophin 4/5 (NT-4/5) and nerve growth factor (NGF) - can rescue auditory neurons from degeneration after a two-week period of deafness. These findings show that neurotrophins can be effective survival agents even when the degenerative processes are well underway. The results of these studies provide further support to the theory that neurotrophic factors may ultimately be able to be used as therapeutic agents for the benefit of the hearing impaired community, but suggest that ongoing treatment, or combined use of alternative therapies, may be necessary.
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ItemExpression of the guidance molecule netrin-1 in the postnatal rat cochlea [Abstract]( nd)Purpose: Neurotrophic factors have been demonstrated to stimulate axonal growth from auditory neurons in both in vitro and in vivo animal models of deafness. These findings may be important to improving cochlear implant performance via an enhanced electro-neural interface, or ultimately for a regenerated auditory system. Numerous molecules exist which are involved in axon guidance during embryogenesis for the construction of a functional neural network. The netrins are a family of such guidance molecules, and are expressed within the developing cochlea. It remains to be determined, however, if these molecules are expressed in the developed mammalian cochlea, and therefore if they may be of potential use for guiding regenerated axons within the mammalian auditory system. This study seeks to investigate the expression patterns of the netrin-l protein in postnatal rats. Methods: Cochlear tissue samples were taken from rats at postnatal day I (PI), P3, P5, P7, Pl0, Pl5 and P22. Samples from each age group were separated using SDS-PAGE and protein expression was determined by western immunoblot analysis. Results: Preliminary findings suggest that the netrin-l protein may be present in the postnatal cochlea, however not in its full form. Spinal cord samples, used as positive controls, reveal an ~75kD immunoreactive band, consistent with the molecular weight (MW) of netrin-l. Cochlear samples displayed bands at a slightly lower MW, and may therefore represent proteolytic fragments of the full-length netrin-l protein. The signal showed decreasing intensity following P7, with no signal seen at P22. Conclusions: These results suggest that netrin-l may be present in the postnatal cochlea, and in decreasing levels with increasing age. Netrin-l may therefore have the potential to control new axonal growth in the adult mammalian cochlea. Further studies investigating the expression patterns of the netrin-l receptors, DCC and neogenin, will give a greater indication of the presence and role of this guidance cue within the damaged auditory system.
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ItemNeurotrophins support auditory neuron survival in vivo following an extended period of deafness [Abstract]( nd)Neurotrophic factors are important for the development and maintenance of the auditory system, and have also been reported to act as survival factors for auditory neurons in animal deafness models. Indeed, studies have demonstrated that application of neurotrophins into the inner ear shortly following deafening can prevent auditory neuron degeneration. However, little is known about the survival effects of delayed neurotrophin treatment, which is a clinically more realistic model. This study examined the capacity of various neurotrophins to support auditory neuron survival after an extended period of deafness in vivo. Specifically, we aimed to determine if the neurotrophins BDNF, NT-3, NT-4/5 and NGF could rescue neurons from degeneration after a two-week period of deafness. Normal hearing guinea pigs were bilaterally deafened; two weeks later the left cochleae were implanted with a mini-osmotic pump, which delivered 200µl of neurotrophin (62.5µg/ml) over a period of 28 days. The right cochleae acted as deafened and untreated internal controls. For all surgical procedures, guinea pigs were anaesthetised using ketamine (40mg/kg) and xylazil (4mg/kg). Delayed treatment with each of the four neurotrophins halted the degeneration of auditory neurons that is normally seen following loss of hair cells, resulting in neuronal survival rates of between 79-87% of normal hearing animals, as compared to only 52% survival in deafened, untreated controls. These results indicate that neurotrophins have the capacity to rescue auditory neurons from degeneration following an extended period of deafness. These findings suggest that neurotrophins may play a role as therapeutic agents in long-term deaf patients.
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ItemDelayed neurotrophin treatment supports auditory neuron survival in deaf guinea pigs [Abstract]( nd)The cochlear implant provides auditory cues to patients with a severe profound hearing loss by direct electrical stimulation of the auditory nerve. As such, the total number and integrity of the surviving auditory neuron population may govern the benefits that patients can derive from the implants. Therefore, the rescue of auditory neurons from degeneration following the loss of hair cells is of great therapeutic significance. Neurotrophic factors are known to be important for the development and maintenance of the auditory system I, and have also been rep6rted to act as survival factors for auditory neurons in animal models of deafness. However, while studies have demonstrated that the application of neurotrophins into the inner ear shortly following deafening can prevent auditory neuron degeneration2,3, much less is known about the survival effects of delayed neurotrophin treatment, which is a clinically more realistic model. This study therefore examined the effects of delayed neurotrophin treatment on auditory neuron survival following deafening. Specifically, we aimed to determine if any or all of the neurotrophins -BDNF, NT -3, NT-4/5 and NGF -could rescue neurons from degeneration after a period of two weeks of deafuess. Normal hearing guinea pigs were bilaterally deafened J using a combination of the aminoglycoside kanamycin and the loop diuretic frusemide. Two weeks later the left cochleae were implanted with a cannula attached to a mini-osmotic pump, which delivered 10Ilg of neurotrophin over a period of 28 days. The right cochleae acted as deafened and untreated controls. Despite the delayed treatments, each of the four neurotrophins prevented the degeneration of auditory neurons that is normally seen following loss of hair cells. When compared to normal hearing animals, the neuronal survival rates of deafened, neurotrophin-treated animals ranged between 79 87%; in contrast, deafened, untreated controls displayed only 52% neuronal survival. Current work is also investigating the expression patterns of the neurotrophin Trk receptors in relation to these findings, and these results will also be discussed. The results of this study provide further support to the theory that neurotrophic factors may be able to be used as therapeutic agents for the benefit of the hearing impaired community.
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ItemTraining place pitch perception in cochlear implant users [Abstract]( 1997)The study has aimed at determining whether the ability to use place coded vowel formant information could be enhanced with analytical vowel training in a group of -congenitally deafened patients, who showed limited speech perception skills after cochlear implant experience ranging from 1y8m to 6y11m. It has investigated whether improvements in vowel perception after training can carry over to word recognition. A further objective was to see whether poorer vowel perception was associated with poorer electrode position difference limens. Three children, one adolescent and one young adult were assessed with synthesized versions of the words /hid, head, had, hud, hod, hood/ and a natural version of these words as well as with a closed-set monosyllabic word task. The change in performance after 10 training sessions was compared to the change in performance during a non-training period. Four of the five patients showed a significant gain in synthetic vowel perception post-training on at least one assessment, but only two patients showed gains across a number of tests post-training. For one of these 2 children improvements in vowel perception generalized to word perception. Patients’ electrode limens ranged from 1 to 3 electrodes except for 1 adolescent whose minimal progress post-training could be partly explained by poorer apical electrode discrimination. The findings are discussed with reference to a number of factors, including the notion of a "critical period" for neural plasticity.
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ItemChronic electrical stimulation of the auditory nerve at high rates: I. Effect on residual hearing [Abstract]( 1996)In addition to direct excitation of auditory nerve fibres, cochlear implant patients with small amounts of residual hearing may receive important additional auditory cues via electrophonic activation of hair cells 1. Before incorporating electrophonic hearing into speech processing strategies, the extent of hair cell survival following cochlear implantation must first be determined. We have recently demonstrated widespread survival of hair cells apical to electrode arrays implanted for periods of up to three years, the present report describes the effects of chronic electrical stimulation on hair cell survival.
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ItemChronic electrical stimulation of the auditory nerve at high rates: II. Cochlear pathophysiology [Abstract]( 1996)A major factor in the improved performance of cochlear implant patients has been the use of high stimulus rate speech processing strategies. While these strategies show clear clinical advantage, we know little of their long-term safety. Indeed, recent studies have indicated that high stimulus rates at intensities above clinical limits, can result in neural damage as a result of prolonged neuronal hyperactivity. The present study was designed to evaluate the effects of chronic electrical stimulation of the auditory nerve at high rates, using intensities within clinical limits.
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ItemSpatial representation of the cochlea within the inferior colliculus of neonatally deafened kittens following chronic electrical stimulation of the auditory nerve [Abstract]( 1995)The orderly tonotopic representation of the cochlea is accurately reproduced within the central auditory system of normal hearing animals. Any degradation of this representation as a result of a neonatal hearing loss or chronic electrical stimulation during development could have important implications for the use of multichannel cochlear implants in young children. In the present study we have used 2-deoxyglucose autoradiography (2-00) to examine the topographic representation of the cochlea within the inferior colliculus (IC) of neonatally deafened kittens following periods of chronic intracochlear electrical stimulation.
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ItemIntrinsic connections of the rat cochlear nucleus [Abstract]( 1996)In mammals three subdivisions of the cochlear nucleus can be distinguished: the dorsal (DCN), the posterior (PVCN) and the anteroventral (AVCN) cochlear nucleus (CN) I. The intrinsic connections between and within these areas have not been well defined. Wickesberg et al.2 revealed that projections from DCN to AVCN in the mouse are frequency specific and tonotopic. In contrast Synder and Leake in the cat revealed projections from AVCN to PVCN and DCN but only modest projections from PVCN and DCN to AVCN with no frequency specificity observed. These previous studies utilized the retrograde tracer horseradish peroxidase. We investigated this apparent contradiction further, using neurobiotin, a retrograde and anterograde tracer, to examine connections within the cochlear nucleus of the rat, with emphasis on the AVCN subdivision.
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ItemIntracellular responses of anteroventral cochlear nucleus neurones to intracochlear electrical stimulation in the rat [Abstract]( 1996)The anterior division of the ventral cochlear nucleus (AVCN) is the first relay station of the auditory pathway. Currently little is known about the intracellular physiological responses of neurones in the AVCN to electrical stimulation of the cochlea. We investigated the effect of cochlear electrical stimulation in the rat AVCN using in vivo intracellular recordings. Male rats were anaesthetised with urethane (1.3g/kg i.p), placed in a stereotaxic frame, the crania and dura removed and the cochlear nucleus exposed.