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H C Dodson

Publications and source records attributed to H C Dodson.

18 recordsLinked to original sources
PubMed2001

The cytoplasmic tail of alpha 1,2-fucosyltransferase contains a sequence for golgi localization.

The Golgi apparatus has a central role in the glycosylation of proteins and lipids. There is a sequential addition of carbohydrates by glycosyltransferases that are distributed within the Golgi in the order in which the glycosylation occurs. The mechanism of glycosyltransferase retention is considered to involve their transmembrane domains and flanking regions, although we have shown that the cytoplasmic tail of alpha1,2-fucosyltransferase is important for its Golgi localization. Here we show that the removal of the alpha1,2-fucosyltransferase cytoplasmic tail altered its function of fucosylation and its localization site. When the tail was removed, the enzyme moved from the Golgi to the trans Golgi network, suggesting that the transmembrane is responsible for retention and that the cytoplasmic tail is responsible for localization. The cytoplasmic tail of alpha1,2-fucosyltransferase contains 8 amino acids (MWVPSRRH), and mutating these to alanine indicated a role for amino acids 3 to 7 in localization with a particular role of Ser(5). Mutagenesis of Ser(5) to amino acids containing an hydroxyl (Tyr and Thr) demonstrated that the hydroxyl at position 5 is important. Thus, the cytoplasmic tail, and especially a single amino acid, has a predominant role in the localization and thus the function of alpha1,2-fucosyltransferase.

Amino Acid Sequence↗
PubMed2001

PMCA2 mutation causes structural changes in the auditory system in deafwaddler mice.

Homozygous deafwaddler mice (dfw/dfw) have a mutation in the gene encoding plasma membrane Ca2+ATPase isoform 2 (Pmca2). They walk with a hesitant and wobbly gait, display head bobbing and are deaf. Light microscopy and transmission electron microscopy were used to evaluate the nature and relationship of morphological changes in the cochlea, spiral ganglion cells and spherical cells of the cochlear nucleus in homozygous and heterozygous mice of different ages and controls. Ultrastructural findings showed that in 7 week old homozygous (dfw) mice, inner hair cells and their afferent terminals were present although outer hair cells appeared apoptotic. Stereocilia were absent from the second and third rows of outer hair cells. Ganglion cells were also present although abnormal in appearance. In older homozygous mutants there was a loss of hair cells and spiral ganglion cells. Remaining ganglion cells in this group contained very few cytoplasmic organelles apart from a few hypertrophied mitochondria. In the anteroventral cochlear nucleus, spherical cell soma size was smaller in all homozygous (dfw) mutants than in heterozygous mice and controls. The ultrastructural appearance of the end bulbs of Held in homozygous mutants was abnormal compared with controls, and in the younger group were seen to be swollen, with less distinct synaptic densities and containing large numbers of small synaptic vesicles arranged in clumps. In the older group these synapses were distorted and contained hypertrophied mitochondria and no synaptic densities could be seen, suggesting that these synapses may be non-functional. This study has shown that in homozygous (dfw) mice structural abnormalities occurred not only in cochlear hair cells but also in the spiral ganglion neurones and spherical cells in the cochlear nucleus. It seems likely that these changes are the result of the Pmca2 mutation and the subsequent accumulation of toxic levels of calcium that may lead to alterations in their functional integrity.

Animals↗
PubMed2000

Response of spiral ganglion neurones to cochlear hair cell destruction in the guinea pig.

Loss of ganglion cells after hair cell destruction in the mammalian cochlea continues to occur over a long period of time, with the possibility of more than one factor contributing to this process. Despite the absence of hair cells, some ganglion cells are, however, able to survive for considerable periods of time. Because functional ganglion cells are crucial to the successful use of cochlear implants, a better understanding of the response of these cells to injury is required so that their loss can be prevented or ameliorated. Quantitative light microscopy, electron microscopy and immunocytochemical techniques were used to examine the response of type I spiral ganglion neurones to hair cell destruction, in guinea pigs at 1, 3, 6 and 30 weeks survival following intracochlear injection with gentamicin. The time course of ganglion cell loss was determined, while a closer examination of those cells able to survive was carried out. A significant early loss of large numbers of ganglion cells was followed by a further significant loss of these cells by 30-week survival. At the same time a decrease in the numbers of central fibres was also observed. Surviving ganglion cells have little or no perikaryal myelin, an appearance resembling that of type I ganglion cells at 55 days gestation. Ganglion cells surviving the initial loss were also found to have a significantly larger soma size than controls although this was not maintained and at 30 weeks survival the few remaining cells were similar in size to that of controls. The growth associated protein GAP 43 was upregulated in surviving ganglion cells at 3 weeks survival, but appeared diminished by 6 weeks survival. These features may indicate a survival response in ganglion cells and may provide a basis on which to develop appropriate means to prevent their loss.

Animals↗
PubMed1997

Loss and survival of spiral ganglion neurons in the guinea pig after intracochlear perfusion with aminoglycosides.

Loss of cochlear hair cells results in a loss of ganglion cells and further neurodegenerative changes throughout the auditory pathway. Understanding more about the early stages of ganglion cell loss in vivo may lead to ways of ameliorating or preventing the loss of these neurons. To examine these stages, the effects of intracochlear perfusion with aminoglycoside antibiotics on the organ of Corti and spiral ganglion cells were evaluated in young adult guinea pigs at survival periods ranging from 1 hour to 12 weeks, using immunocytochemical and ultrastructural techniques. At 1 hour survival a base-to-apex gradient of damage was indicated in the cochlea by the appearance of severely damaged hair cells and injured ganglion cells in the basal coil while in the apical coil, hair cells were damaged but intact and ganglion cells appeared normal. By 4 hours the appearance of severely disrupted hair cells and damaged ganglion cells had extended throughout the cochlea. The ultrastructural appearance of many injured ganglion cells demonstrated features characteristic of cell death including condensed cytoplasm, non-marginal clumping of nuclear chromatin, and wrinkled nuclear membrane. Despite the loss of many ganglion cells, a population of these cells remained at 12 weeks survival. These contained large amounts of rough endoplasmic reticulum, were unmyelinated apart from the central process and were surrounded by satellite cells. These features are typical of ganglion cells during development, before the onset of hearing. Immunolabelling of cochlear whole mounts after hair cell destruction with protein gene product 9.5 (PGP 9.5) revealed the presence of neural elements in the organ of Corti at up to 12 weeks survival. These may be associated with the remaining ganglion cells. In these surviving ganglion cells, the intense labelling with PGP 9.5 together with the increase in rough endoplasmic reticulum, indicates the presence of active protein synthesis which may be connected with their survival.

Aminoglycosides↗
PubMed1995

Dystrophin expression in the hair cells of the cochlea.

Dystrophin is normally expressed in a number of tissues including muscle, brain and the outer plexiform layer of the retina. In Duchenne and Becker muscular dystrophy abnormal or deficient dystrophin expression leads to muscle degeneration and has been implicated in mental retardation and a form of night blindness. We have examined the expression of dystrophin immunoreactivity in cochlear tissues of normal guinea-pig and mouse, and whether expression is perturbed in the cochlea of the dystrophic MDX mouse. A single band of approximately 427 kDa, corresponding to a full-length isoform of dystrophin was detected in guinea-pig and normal mouse but was absent from the MDX mouse. Cochleae from guinea-pig, normal and MDX mouse also showed a second dystrophin isoform of 116 kDa molecular weight with the C-terminal specific antibody. Immunostained guinea pig cochlear half turns were examined by laser scanning confocal microscopy. Dystrophin was localized in both inner and outer hair cells with staining patterns which were qualitatively similar with both antibodies. In the outer hair cells labelling of the lateral wall was especially distinctive. The synaptic region of both hair cell types was also strongly labelled.

Animals↗
PubMed1995

Changes in acoustic distortion during long term electrical stimulation of the guinea pig cochlea: a preliminary study.

In a preliminary study, acoustic distortion was assessed as a measure of cochlear function in both implanted and contralateral ears of electrically stimulated guinea pigs. Prestimulation distortion levels in implanted ears were below those of unimplanted ears and below those previously reported for guinea pigs. This may have been due to the mechanical or irritant effect of the electrode. In both the ipsilateral and contralateral ears or stimulated animals, distortion levels were depressed during the period of electrical stimulation. In addition, the slope of distortion growth as a function of stimulus level was more gradual in stimulated ears and contralateral ears of the same animals for f2 = 6 kHz and 9 kHz, but was unaffected for f2 = 3 kHz. When the distortion could no longer be recorded in the stimulated ear (4 subjects) or contralateral ear (1 subject) the animal was killed and histological evaluation carried out in both ears. Histological changes were restricted mainly to the efferent terminals in those ears where some distortion was still recordable. In one animal where distortion had become unmeasurable immediately prior to death, the outer hair cells were severely damaged and undergoing lysis. In this preliminary study, intersubject and between-test variability in distortion for implanted (ipsilateral) ears indicated that additional controls are necessary to establish the validity of alterations in acoustic distortion to reflect cochlear pathology.

Acoustics↗
PubMed1994

Effects of unilateral deafening on the cochlear nucleus of the guinea pig at different ages.

Developmental changes in spherical cell sizes were measured in the ventral cochlear nucleus (VCN) in normal guinea pigs aged 2 days and 2, 7 and 12 weeks to establish the time course of postnatal neuronal growth, as a baseline for our experimental work. A continued growth of spherical cell size was observed in the VCN up to 7 weeks postnatally. Animals were unilaterally deafened by cochlear perfusion with kanamycin sulphate at ages 1 and 6 weeks. After 6 weeks survival the spherical cells were measured in the VCNs of both sides. Unilateral deafferentation at both ages caused an ipsilateral reduction in spherical cell size, neurons of the younger group being smaller than in the older. On the contralateral side these cells in the older group were larger than age-matched controls while in the younger group there was no difference compared with age-matched controls. These findings suggest that the results of deafferentation are age-dependent, and may indicate an ability of the neural circuitry to adapt to the loss of sensory input on the other side.

Aging↗
PubMed1993

Protein gene product 9.5 in the developing cochlea of the rat: cellular distribution and relation to the cochlear cytoskeleton.

Protein gene product 9.5 was immunolocalized in the adult and early postnatal (P2-P15) rat cochlea, and its distribution compared with a 200 kDa highly phosphorylated neurofilament subunit (neurofilament 200) and alpha-tubulin. In the adult, Protein gene product 9.5 was expressed exclusively in cochlear nerve fibres and ganglion cells, a small percentage of these (Type II ganglion cells and olivocochlear bundle fibres) being intensely positive for both protein gene product and neurofilament 200. In postnatal development, pillar and Deiters' cells were at first (P2-P15) strongly positive for protein gene product 9.5, and hair cells moderately so. At P2, all nerve fibres and ganglion cells showed co-expression of protein gene product 9.5 and neurofilament 200, but at later stages, the subset of intensely co-labelled neurons appeared, nerve fibres at P7 onwards and ganglion cells from P12. There was no overt correlation between the onset of protein gene product 9.5 and alpha-tubulin expression in any cochlear component. Protein gene product 9.5 expression in ganglion cells was at first (P2 and P7) mainly nuclear, and later also cytoplasmic. It is concluded that there is a clear correlation of high levels of protein gene product 9.5 and neurofilament protein expression, and that protein gene product 9.5 is expressed in some non-neuronal cells of the cochlea during its early development, persisting until after hearing has commenced.

Animals↗
PubMed1992

Endocytic pathways in the olfactory and vomeronasal epithelia of the mouse: ultrastructure and uptake of tracers.

Mammalian olfactory neurons possess a well-developed system of endocytic vesicles, endosomes, and lysosomes in their dendrites and perikarya. Vomeronasal neurons are similar and also contain much perikaryal agranular endoplasmic reticulum (AER). Olfactory supporting cells contain endocytic vesicles and endosomes associated closely with abundant fenestrated AER, and vesicles and numerous large dense vacuoles are present basally. Vomeronasal supporting cells have little AER, and few dense vacuoles occur in their bases. In olfactory neurons, ultrastructural tracers (0.08% horseradish peroxidase, thorium dioxide, ferritin) are endocytosed by olfactory receptor endings and transported to the cell body, where their movement is halted in lysosomes. Higher concentrations (1%) of horseradish peroxidase penetrate olfactory receptor plasma membranes and intercellular junctions. In olfactory supporting cells, endocytosed tracers pass through endosomes to accumulate in dense basal vacuoles. These observations indicate that olfactory sensory membranes are rapidly cycled and that endocytosed materials are trapped within the epithelium. It is proposed that in the olfactory epithelium, endocytosis presents redundant odorants to the enzymes of the supporting cell AER to prevent their accumulation, whereas in the vomeronasal epithelium the receptor cells carry out this activity.

Animals↗
PubMed1992

Enhanced horseradish peroxidase uptake in the electrically stimulated cochlea of the guinea pig.

Stimulation with alternating current at the round window causes an accelerated uptake of extracellular HRP by endocytotic vesicles in inner hair cells at the base of the stimulated cochlea, near the site of the electrode, but does not noticeably affect uptake into outer hair cells. After unilateral electrical stimulation, efferent endings on outer hair cells at the cochlear base show increased vesicular and endosomal labelling in both the ipsilateral and contralateral ears. It is concluded that round-window electrical stimulation increases afferent synaptic activity in inner hair cells near the electrode site, and also increases synaptic activity in OHC efferent endings, not only of the ipsilateral cochlea but also of the corresponding region of the contralateral cochlea. Rapid diffuse cytoplasmic labelling of inner and outer hair cells also occurs sporadically in both stimulated and unstimulated cochleae. However, in efferent terminals, diffuse labelling is restricted to stimulated animals, and occurs bilaterally, in corresponding basal regions of the cochlea.

Animals↗
PubMed1987

Structural effects of short term and chronic extracochlear electrical stimulation on the guinea pig spiral organ.

To assess the effects of extracochlear electrical stimulation on cochlear structure, guinea pigs were implanted and stimulated with single middle ear electrodes either at round window or promontory sites, and their cochleae examined by transmission electron microscopy. Implanted but unstimulated, or unimplanted control animals were examined in the same way. Alternating current stimulation at the promontory for 2 h at 150 Hz, 500 microA, caused outer hair cell efferent endings to become dense and vacuolated, but no hair cells were damaged. With direct current stimulation at 500 microA for 2 h the basal regions of the stimulated cochlea were badly damaged and many outer hair cells lysed. Long term (up to 1200 h) round window stimulation at 100 or 141 Hz, 15-91 microA rms, did not cause cell death or inner hair cell damage, but basal outer hair cells and their efferent endings were badly affected in both ipsilateral and contralateral cochleae. The compound action potential of the auditory evoked response to broad band click stimuli was not altered by chronic electrical stimulation. It is concluded that chronic stimulation with the parameters used does not threaten cochlear survival, and it is proposed that the bilateral structural changes induced by chronic stimulation are caused by excessive activation of the cochlear efferent pathways.

Animals↗
PubMed1976

Effects of incubator noise on the cochlea of the newborn.

The possible effects of incubator noise on the hearing of premature babies have long been debated. The type of hearing loss found in 12 low-birthweight children was examined; and the variable noise level in regularly used incubators was measured. This noise, applied to guinea pigs continuously during their second week after birth, was shown histologically to destroy a proportion of the sensory cells in the cochlea. Adult guinea pigs, however, were not vulnerable in this way. The conclusion is that there is definite circumstantial evidence of the damaging effect of many incubators on the hearing of premature infants.

Animals↗
PubMedDate not supplied

Structural alteration of hair cells in the contralateral ear resulting from extracochlear electrical stimulation.

Chronic electrical stimulation of the auditory nerve in patients with profound sensori-neural deafness is becoming increasingly routine. Therefore, it is important to understand more about the long-term consequences of this procedure. Hitherto, structural studies in animals after electrocochlear stimulation have concentrated on the stimulated cochlea. Here we have examined the effects of unilateral extracochlear electrical stimulation on the spiral organ of both the ipsilateral and contralateral ears of the mature guinea pig, and have found alterations in the structure of the outer hair cells and their efferent nerve terminals in the contralateral as well as the ipsilateral cochlea. This is the first evidence for a structural influence of efferent activity on the cochlea. Although the importance of the efferent system, consisting of the crossed and uncrossed olivo-cochlear bundles, is well established in providing central control of the sensory pathways, its exact role in hearing is incompletely understood. However, it is known that the outer hair cells and their efferent innervation are important in their contribution to inner hair cell responses and in modulating the micromechanics of the whole cochlea. These efferent functions now appear to be related to an important part of cochlear morphology, and are also relevant to our understanding of cochlear neurobiology, normal development and the management of hearing disability in both adult and child.

Afferent Pathways↗
PubMedDate not supplied

Further studies of the effects of continuous white noise of moderate intensity (70--80 dB SPL) on the cochlea in young guinea pigs. Time course and distribution of hair cell degeneration.

Guinea pigs aged one week were exposed to white noise at a maximum of 76 dB SPL for 7 days and were then killed 3, 8 and 16 weeks later for histological examination of the cochlea by the surface preparation method. Appreciable increases in outer hair cell losses were observed in the apical turn 3/3 1/2, chiefly in the outer two rows, between the 3rd and 8th week, but not between the 8th and 16th week. No significant losses were seen in control groups corresponding to 3- and 8-week periods, although in the control group of 16 weeks' survival, small deficits, attributable to natural ageing, were seen in the apical half-turn, 3 1/2.

Acoustic Stimulation↗
PubMedDate not supplied

The effects of combined gentamicin and white noise on the spiral organ of young guinea pigs. A structural study.

The present work describes the effects on the spiral organ of very young guinea pigs, of continuous white noise (76 dB SPL, 7 days) combined with gentamicin, using surface preparations and both transmission and scanning electron microscopy to analyse structural changes. Gentamicin only, at 80 mg/kg/day for 5 days did not cause any perceptible loss of hair cells, and only minimal structural changes. When combined with 7 days of white noise, there was a widespread effect on outer hair cells throughout the cochlea, some changes being similar to those induced by sound alone, others being seen only in the combined experiments. Outer hair cell losses with sound and gentamicin treatment were highly variable, but in addition to apical damage, also seen in sound-treated animals, a more basal area of cell loss appeared in the spiral organ.

Animals↗