Pattern of degeneration of the spiral ganglion cell and its processes in the C57BL/6J mouse

Although degeneration of spiral ganglion cells has been described as a histopathologic correlate of hearing loss both in animals and humans, the pattern and sequence of this degeneration remain controversial. Degeneration of hair cells and of spiral ganglion cells and their dendritic processes was evaluated in the C57BL/6J mouse, in which there is a genetically determined progressive sensorineural loss starting in the high frequencies that is similar to the pattern commonly seen in the human. Auditory function was evaluated by brainstem evoked responses, and degeneration of hair cells, ganglion cells and their dendrites was evaluated histologically at 3, 8, 12 and 18 months of age. Progressive loss of auditory sensitivity was correlated with the loss of outer and inner hair cells and spiral ganglion cells and their dendritic processes. In addition, dendritic counts were consistently lower at a distal location in the osseous spiral lamina (i.e. near the organ of Corti) than at a proximal location (i.e. near the spiral ganglion), and the difference between the number of distal dendrites and the number of proximal dendrites tended to be greater with advancing age. These observations suggest an age-related progressive retrograde degeneration of spiral ganglion cells. Thus, in degenerating cochleas, some remaining spiral ganglion cells may have no distal dendritic processes near the organ of Corti. This may have implications for successful stimulation of the cochlear neuron in cochlear implantation.     

Cochlear pathology of long term neomycin induced deafness in cats

The long term sequelae of hair cell destruction consequent from administration of the ototoxic aminoglycoside antibiotic, neomycin sulfate, were evaluated in histological and ultrastructural studies of cochlear morphology in cats. Complete hearing loss, as defined by an absence of brainstem evoked responses to click stimulation at 120 dB peak SPL, was induced by intramuscular injections of neomycin at 50 mg/kg body weight/day, and cochlear pathology was studied at 6 months and 1, 3 and 4 years following onset of profound deafness. In these long term ototoxicity cases the organ of Corti was collapsed and resorbed over the basal one-quarter to three-quarters of the cochlear spiral, depending on duration of deafness. Significant progressive reduction in the spiral ganglion cell population and sequential degenerative alterations in the remaining neurons were observed with increasing time elapsed after induced hearing loss. The sequence of pathological alterations in spiral ganglion neurons appeared to be: a) swelling, demyelination and degeneration of the peripheral dendrites; b) demyelination and shrinkage of the cell soma with preservation of the central axon; and c) demyelination of the central axon and degeneration of the cell perikaryon. In apical cochlear regions, severe degeneration of the spiral ganglion preceded the collapse of the tunnel of Corti and regional loss of pillar cells. Residual populations of spiral ganglion neurons were as low as 1-2% of the normal values in the most severely degenerated cochleae in the series. Light microscopic and ultrastructural studies revealed a selective survival advantage for the unmyelinated type II neurons over the myelinated type I neurons with these long survival periods. The prolonged time course and atrophic nature of these pathological alterations suggests that degeneration of spiral ganglion neurons progresses continuously following drug-induced insult to the cochlea. Some possible factors contributing to this long term progressive degeneration will be discussed.     

An original inner ear neuroepithelial degeneration in a deaf Rottweiler puppy.

Histopathological investigation was conducted on both inner ears from a 4.5-month-old Rottweiler puppy with electrophysiologically confirmed bilateral deafness. The lesions were restricted to the organ of Corti and spiral ganglion that both displayed severe degenerative changes. The outer hair cells were less affected than the inner hair cells. The number of spiral ganglion neurons was reduced, and remaining neurons were altered. The basal and middle cochlear turns were more affected than the apical one. The vestibules were normal. Immunostaining with calbindin, calretinin, S100A1 and S100A6 polyclonal antisera was helpful in identifying different cell-types in the degenerated cochlea. The early and severe spiral ganglion cell degeneration is an uncommon finding no matter the species. Such lesions bear significance within the frame of cochlear implants technology for deaf infants.     

Effects of Hearing Preservation on Psychophysical Responses to Cochlear Implant Stimulation

Previous studies have shown that residual acoustic hearing supplements cochlear implant function to improve speech recognition in noise as well as perception of music. The current study had two primary objectives. First, we sought to determine how cochlear implantation and electrical stimulation over a time period of 14 to 21 months influence cochlear structures such as hair cells and spiral ganglion neurons. Second, we sought to investigate whether the structures that provide acoustic hearing also affect the perception of electrical stimulation. We compared psychophysical responses to cochlear implant stimulation in two groups of adult guinea pigs. Group I (11 animals) received a cochlear implant in a previously untreated ear, while group II (ten animals) received a cochlear implant in an ear that had been previously infused with neomycin to destroy hearing. Psychophysical thresholds were measured in response to pulse-train and sinusoidal stimuli. Histological analysis of all group I animals and a subset of group II animals was performed. Nine of the 11 group I animals showed survival of the organ of Corti and spiral ganglion neurons adjacent to the electrode array. All group I animals showed survival of these elements in regions apical to the electrode array. Group II animals that were examined histologically showed complete loss of the organ of Corti in regions adjacent and apical to the electrode array and severe spiral ganglion neuron loss, consistent with previous reports for neomycin-treated ears. Behaviorally, group II animals had significantly lower thresholds than group I animals in response to 100 Hz sinusoidal stimuli. However, group I animals had significantly lower thresholds than group II animals in response to pulse-train stimuli (0.02 ms/phase; 156 to 5,000 pps). Additionally, the two groups showed distinct threshold versus pulse rate functions. We hypothesize that the differences in detection thresholds between groups are caused by the electrical activation of the hair cells in group I animals and/or differences between groups in the condition of the spiral ganglion neurons.     

Progressive degeneration in the cochlear nucleus after chemical destruction of the cochlea

In the guinea pig, the organ of Corti and the spiral ganglion cells were destroyed by administering gentamicin into the inner ear. The antero-ventral cochlear nucleus (AVCN) was studied with electron microscopy 15 and 30 days after treatment. There does not seem to be a specific type of degeneration induced by the drug. For nerve terminals, a progressive degeneration occurred: after 15 days, clear and swollen boutons appeared and after 30 days an electron-dense type of degeneration was observed. The cell bodies of the AVCN did not seem altered infirming a rapid, direct or indirect, neurotoxic effect of the drug.     

Histopathologic features of the temporal bone in usher syndrome type I

Temporal bones of 2 patients with Usher syndrome type I were examined using light microscopy. In both patients, findings from histopathologic examination of the cochlea were characterized by degeneration of the organ of Corti, which was most marked in the basal turn, atrophy of the stria vascularis, and a decrease in the number of spiral ganglion cells. The cochlear nerve appeared to be diminished. The sensory epithelium of the saccular and utricular maculae of patient 1 was normal for age. The left temporal bone of patient 2, classified as Usher syndrome genetic subtype USH1D or USH1F, demonstrated the typical signs of severe cochleosaccular degeneration. Present cases and cases from the literature were reviewed in search of an explanation for the above-described differences in histologic findings.     

Degeneration of cochlear neurons after amikacin intoxication in the rat

Summary Intoxication with high doses of the aminoglycoside antibiotic amikacin in a supranormal sensitive period in the rat induces complete destruction of the inner and outer hair cells in the organ of Corti in all turns, whereas the supporting cells remain partially preserved in the upper turns. With increasing survival time, the number of ganglion cells in the spiral ganglion decreases progressively, reaching a minimum of about 10% surviving cells after 12 months. Both type I and type II neurons are subject to retrograde degeneration, although type-II cells degenerate more slowly than type-I cells. The presence or absence of supporting cells in the organ of Corti does not seem to influence neuronal degeneration. This retrograde degeneration is similar in all animals so far studied but its time course is different for different species. Retrograde degeneration after destruction of Corti's organ is a long-lasting process and is never completed at once. This must be taken into consideration in the treatment of total deafness with electric stimulation of surviving neurons.     

The effect of organ of corti loss on ganglion cell survival in humans.

HYPOTHESIS: Severe spiral ganglion cell loss does not necessarily follow loss of hair cells or supporting cells in humans. BACKGROUND: Despite some publications to the contrary, statements that loss of hair cells and/or supporting cells of the organ of Corti results in a severe loss of spiral ganglion cells in humans still appear in the literature, especially in respect to cochlear implants. This assumption is apparently based on studies in animals or cell culture and not from studies of human temporal bones. METHODS: Morphological analysis of archival temporal bones with microscopic and statistical analysis of ganglion cell, hair cell, and supporting cell populations was performed in 33 ears with total hearing losses of varying causes and durations of deafness. None of the ears had remaining hair cells. Six ears had had cochlear implants. RESULTS: Ganglion cell counts ranging from 2,889 to 34,299 and the corresponding percentage of remaining ganglion cells based on age-normative data were not significantly related to the duration of hearing loss (r = -0.13 and 0.02, respectively, p > 0.05) or to remaining supporting cell populations (r's from 0.15 to 0.27, p > 0.05). More than half of ears (51.5%) had ganglion cell counts within two standard deviations of age-normative means. Mean ganglion cell counts and percentage of remaining ganglion cells of ears with surviving peripheral processes (dendrites) did not differ significantly from those of ears with no peripheral processes. CONCLUSION: The loss of hair and supporting cells in the organ of Corti in humans does not necessarily result in as significant a loss of spiral ganglion cells as has been reported animals. In fact, our results suggest that ganglion cell loss may be a primary concomitant loss due to the disease process.     

Pathological findings in the human auditory system following long-standing gentamicin ototoxicity

Summary The clinical, audiovestibular and histopathological findings in a patient who suffered from a long-standing gentamicin-induced deafness are reported. In both temporal bones, the organ of Corti was completely absent, with only a few nerve fibres remaining in the apical part of the cochlea. Regenerative ingrowth of nerve fibers into the area of the degenerative organ of Corti was present apically in both ears. The stria vascularis exhibited considerable degeneration in all turns and loss of microvasculature was found in the basilar membrane. The spiral ganglion cells, the cochlear nerve and the central auditory pathways and nuclei appeared to be unaffected.     

Pathological findings in the human auditory system following long-standing gentamicin ototoxicity

The clinical, audiovestibular and histopathological findings in a patient who suffered from a long-standing gentamicin-induced deafness are reported. In both temporal bones, the organ of Corti was completely absent, with only a few nerve fibres remaining in the apical part of the cochlea. Regenerative ingrowth of nerve fibers into the area of the degenerative organ of Corti was present apically in both ears. The stria vascularis exhibited considerable degeneration in all turns and loss of microvasculature was found in the basilar membrane. The spiral ganglion cells, the cochlear nerve and the central auditory pathways and nuclei appeared to be unaffected.     

Expression of EphA4 in developing inner ears of the mouse and guinea pig

The expression of EphA4, an Eph-class receptor tyrosine kinase, was determined by immunohistochemistry in developing inner ears of the mouse and the guinea pig. In the mouse, EphA4 expression was visible in the fibroblasts of the spiral ligament and in the structures that were to become the osseous spiral lamina. Cochlear nerve ganglion cells expressed ephrin-B2, and the modiolus expressed mRNA coding for ephrin-B3, both transmembrane ligands for EphA4. In contrast, in the guinea pig, cells of the cochlear nerve ganglion expressed EphA4, as did supporting cells of the organ of Corti (Hensen's cells and inner pillar cells). There was also some expression in fibroblasts of the spiral ligament but none in the structures that were to become the osseous spiral lamina. It is suggested that in the mouse, EphA4 may help direct the cochlear innervation towards the organ of Corti by a repulsive interaction, but that this is highly species dependent.     

The spiral ganglion and cochlear nuclei of deafness mice

Deafness mice (dn/dn) never develop hearing, but, except for the associated physical defects, have no other known abnormalities. For this study, cochleas and brains of five adult homozygotes (dn/dn) and five adult heterozygotes (+/dn), matched by weight and sex, were prepared for serial section light microscopy. In the homozygotes, the organ of Corti was totally degenerated basally, gradually improving toward the apex where supporting cells, border cells and pillar cells were present; however, the stria vascularis was dystrophic in the apex. The saccular macula was atrophied or dystrophic in seven of the ten homozygote ears. The homozygotes had only 23% of the number of spiral ganglion cells found in the heterozygotes, but they appeared robust. In six of the ears of each group there was clumping of apical spiral ganglion neurons. In the homozygotes, the volume of Rosenthal's canal was 121%, that of the dorsal nuclei was 90%, and that of the ventral cochlear nuclei was 63% of the comparable volumes in heterozygotes. The globular cells of the homozygote ventral cochlear nucleus were 72% of the size of those of heterozygotes. These quantitative morphological abnormalities of the homozygote spiral ganglion and cochlear nuclei may result from organ of Corti atrophy.     

Vector-mediated delivery of bcl-2 prevents degeneration of auditory hair cells and neurons after injury

OBJECTIVE: To test the hypothesis that bcl-2 prevents oxidative stress-induced apoptosis of auditory sensory cells in explants of the organ of Corti and dissociated cell cultures of the spiral ganglion. METHODS: Organ of Corti explants and dissociated spiral ganglion cell cultures obtained from 3-day-old (P3) rats or adult spiral ganglion cell cultures from 28-day-old (P28) rats were transduced with vectors containing a human bcl-2 gene. Cultures were then exposed to neomycin, cisplatin or subjected to withdrawal of neurotrophin supplementation. Outcome measures included hair cell and neuron counts, mitochondrial membrane potential and a histological measure of apoptosis. RESULTS: Expression of bcl-2 in the organ of Corti explants and neuronal cell cultures provided a significant level of protection against cell death. Bcl-2 expression in the organ of Corti explants also protected mitochondria from loss of membrane potential and blocked an early step in the commitment of hair cells to apoptosis. CONCLUSION: Expression of bcl-2 in cochlear tissues protects sensory cells from a variety of insults that have been demonstrated to damage the inner ear.     

Cochlear pathology of the circling mouse: a new mouse model of DFNB6

CONCLUSION: The circling mouse (cir/cir) has phenotypes which follow the pattern of neuroepithelial defects of deafness from 10 days after birth. The cir mouse is defective in Tmie gene, the function of which should be further elucidated. OBJECTIVES: We previously reported a recessive mutation of deafness called circling mice (cir/cir). The present study focused on investigating phenotypes and histological findings of the cochlea in circling mice with respect to age. MATERIALS AND METHODS: In order to analyze cochlear pathology over time, five different age groups of circling mice were examined (10, 18, 21, 35, and 90 days old). The organs of Corti and spiral ganglion neurons in basal and middle turns were evaluated. RESULTS: The pathology of the organ of Corti followed the pattern of neuroepithelial defects. Hair cells in organs of Corti had degenerated in circling mice at 10 days old, in a time-dependent manner. Scanning electron microscopy (SEM) showed that stereociliary bundles were irregular in size and had shortened at 10 days, and that this degeneration was complete at 21 days. The number of spiral ganglion neurons significantly reduced with age. RT-PCR analysis indicated that the transmembrane inner ear gene (Tmie) was absent in various organs in circling mice.     

Localization of the NO/cGMP-pathway in the cochlea of guinea pigs.

The presence of nitric oxide synthase (NOS) in substructures of the cochlea of guinea pigs is an issue of current focus. Moreover, information concerning the localization of cells effected by the NO/cGMP-pathway are rare. Paraffin sections of guinea pig cochlea were incubated with specific antibodies to the three known NOS isoforms, soluble guanylyl cyclase (sGC) and cyclic guanosine-monophosphate (cGMP), the second messenger system of NO. While detection of inducible iNOS failed in all cochlear structures, expression of endothelial eNOS was found in the spiral ligament, in the stria vascularis, in cells of the organ of Corti, in nerve fibers and in some perikaryia of the spiral ganglion. The cochlear nerve showed an accentuated affinity for immunostaining in distal, basal segments of the cochlea. Neuronal bNOS was found predominantly in the endosteum of the modiolus and cochlea and was less intensively present in all perikaryia of the spiral ganglion and in the spiral ligament. Supporting cells of the organ of Corti and cells in the limbus spiralis displayed only modest immunostaining, while bNOS was not found in outer and inner hair cells. NOS detection was accompanied by immunoreactivity to sGC and to cGMP. The presence of NOS and its second messenger system gives evidence for a possible involvement in neurotransmission, regulation of the cochlear amplifier and in homeostasis.     

Localization of glucocorticoid receptors and glucocorticoid receptor mRNAs in the rat cochlea

The distribution of glucocorticoid (GR) receptor messenger RNAs (mRNAs) and GR receptors was studied by in situ hybridization histochemistry and immunocytochemistry, respectively. In situ hybridization histochemistry was performed with a biotin-labeled riboprobe complementary to rat GR receptor mRNA. GR receptor mRNAs were demonstrated in spiral ligament cells, spiral limbus cells, and spiral ganglion cells. GR receptor mRNAs were demonstrated neither in cells of the stria vascularis nor in cells of the organ of Corti region. With the use of a monoclonal and a polyclonal antibody, GR receptors were observed in the spiral ligament cells, stria vascularis cells, spiral limbus cells, and spiral ganglion cells by immunocytochemistry. Binding of anti-GR-receptor antibodies to a lesser extent was observed in the organ of Corti region; however, cellular distribution of the GR receptors could not be resolved with the applied techniques. These results suggest that the GR receptor is expressed differently in the heterogeneous cochlear tissues.     

Inner ear histopathology in "nervous Pointer dogs" with severe hearing loss

Ten puppy dogs (82, 131 or 148 days-old) from a Pointer cross-colony, exhibiting a juvenile severe hearing loss transmitted as an autosomal recessive trait, were used for histopathological characterization of the inner ear lesion. Immunostaining with calbindin, Na,K-ATPase, cytokeratins, S100, S100A1 and S100A6 antisera were helpful in identifying the different cell types in the degenerated cochleae.

Lesions, restricted to the Corti’s organ and spiral ganglion, were bilateral but sometimes slightly asymmetrical. Mild to severe lesions of the Corti’s organ were unevenly distributed among the different parts of the middle and basal cochlear turns while the apical turn remained unaffected at 148 days.

In 82 day-old puppies (n = 2), severe lesions of the Corti’s organ, meaning that it was replaced by a layer of unidentifiable cells, involved the lower middle and upper basal turns junction area, extending in the upper basal turn. Mild lesions of the Corti’s organ, with both hair and supporting cells abnormalities, involved the lower middle turn and extended from the rest of upper basal turn into the lower basal turn. The outer hair cells (ohc) were more affected than the inner hair cell (ihc). The lesions extended towards the basal end of the cochlea in the 131 (n = 5) and 148 (n = 3) day-old puppies. Additionally, the number of spiral ganglion neurons was reduced in the 131 and 148 day-old puppies; it is earlier than observed in most other canine hereditary deafness. These lesions were interpreted as a degeneration of the neuroepithelial type. This possible animal model might provide information about progressive juvenile hereditary deafness and neuronal retrograde degeneration investigations in human.     

Spiral ganglion cell density in young and old gerbils

The Mongolian gerbil, like other mammalian species, has a decreased number of spiral ganglion cells as a function of age. This loss of cells was first seen in 24- to 30-month old animals in the basal end of the ganglion. In the oldest individuals the apical end of the ganglion was also affected. There were approximately 15-25% fewer cells in the affected areas in the 36- to 42-month old animals. In the oldest animals degeneration of the stria vascularis was seen in the apical turn and some degenerative changes in the organ of Corti were seen throughout the length of the cochlear duct. The aging pattern in the gerbil cochlea, is similar to that described for other species. Vacuoles, previously described in the gerbil cochlear nucleus, were also seen in the auditory nerve within the modiolus, but central to the Schwann-glial border in all animals. Vacuoles were not present within the spiral ganglion or the peripheral processes of the ganglion cells. Because the ganglion cell axons should be similar on either side of the Schwann-glial border, but the vacuoles were confined to the central nervous system, it is concluded that the degenerative process affects glial cells as opposed to neurons.