Rapid disruption of cochlear function and structure by trimethyltin in the guinea pig.

Trimethyltin (TMT) is a potent ototoxicant which acutely disrupts generation of the action potential evoked by a broad range of tone frequencies and subsequently produces selective high frequency impairment and outer hair cell (OHC) damage in the extreme basal turn of the cochlea. We investigated the development of TMT ototoxicity in the guinea pig 6-48 h following treatment using the compound action potential (CAP), cochlear microphonic (CM), endocochlear potential (EP) and light and electron microscopic examinations. At all time intervals studied, TMT reduced CAP sensitivity and CM amplitude. The effect was relatively broad across test frequencies at 6 h and subsequently became restricted to higher frequencies. No disruption of the EP was observed between 6 and 24 h following TMT. OHC pathology in the basal turn of the cochlea 12 h following TMT consisted of vacuolization in the supranuclear region and disruption of the cuticular plate; some mitochondria exhibited dark inclusions. Type 1 spiral ganglion cells appeared swollen at 24 h with separation of myelin from the cell bodies. No pathological changes were observed in the inner hair cells (IHC). The present data identify the OHC as targets responsible for the loss of CM sensitivity after TMT as the EP was unaffected. These data suggest that CAP and CM recovery at low and middle frequencies following acute TMT administration is accompanied by recovery of neurotransmission at the IHC or Type 1 SGC level and OHC recovery at apical regions of the cochlea.

Unusual morphology of the stria vascularis in pigmented strain 2/NCR guinea pigs.

This paper reports an abnormality in the morphology of the apical stria vascularis of inbred 2/NCR guinea pigs as compared to outbred animals. Cochleas were embedded in plastic, sectioned, and examined in the light and electron microscopes. In the 2/NCR animals, the apical stria vascularis consisted of a cuboidal epithelium composed of a monolayer of poorly differentiated cells. Few or no capillaries were associated with this epithelium. No melanin pigment was present in the abnormal region of the stria in these animals, although pigmentation appeared normal in lower turns of the cochlea. Measurements of compound action potential thresholds between 2 and 40 kHz revealed no differences in auditory function between the two strains.

Trimethyltin disrupts auditory function and cochlear morphology in pigmented rats.

Trimethyltin (TMT) produces auditory deficits, presumably of cochlear origin, in rats. The present study identified pathological changes in the cochlea following treatment with TMT and correlated them with auditory threshold changes. Thresholds were determined by reflex-modulation audiometry, before and after treatment with TMT or with saline vehicle. Animals were then perfused and their cochleas embedded for examination as block-surface preparations or radial sections. In the first week following treatment, all TMT-treated rats showed threshold shifts of 40 to 60 dB at 40 kHz, and smaller threshold shifts (10-25 dB) at 2.5 and 10 kHz. At 3 weeks they showed threshold shifts similar to those identified one week following treatment, but with some recovery at 10 kHz. At 10 weeks, one animal showed complete recovery and three showed recovery of function at 10 but not at 40 kHz. TMT-treated animals showed losses of outer hair cells (OHC) in the basal turn of the cochlea as early as 48 hours following exposure. Comparable OHC pathology was seen at 9 days, along with some losses of inner hair cells. More extensive pathology occurred at longer survival times including the loss of type 1 spiral ganglion cells. The loss of auditory sensitivity at high frequencies was closely related to the loss of outer hair cells in the basal turn of the cochlea.

Morphology of the cochlear nerve in Sprague-Dawley and brown Norway rats.

Cochlear nerve morphology was studied in young adult albino (Sprague-Dawley) and pigmented (Brown Norway) rats. Analysis of the material included counts of normal and degenerating fibers and of glial cell nuclei, and measurements of vascularity and of the nerves' cross-sectional areas. The median number of normal fibers in the Sprague-Dawley rats was 21,216, and, in the Brown Norway rats, it was 20,186. There were no statistically significant differences between the two strains in numbers of normal fibers, degenerating myelin sheaths, or glial cell nuclei, or in the cross-sectional areas of the nerves. The area density of blood vessels was significantly higher in nerves from the Sprague-Dawley rats. The median area density in that strain was 0.0149, while in the Brown Norway rats the median area density was 0.0105.

Changes with age in the morphology of the cochlear nerve in rats: light microscopy.

Cochlear nerve morphology was examined in a series of rats ranging in age from young adulthood to advanced age in order to assess the extent of fiber loss and the nature of degenerative changes with age. The animals were perfused via the aorta with mixed aldehydes. Blocks including the cochlear nerves were removed, embedded in Araldite, and sectioned in a plane transverse to the longitudinal axis of the nerve. Analysis of the material included counts of normal and degenerating fibers and of glial cells, maps of fiber packing densities, and measurements of the cross-sectional area of the nerve. The median number of normal fibers in the young adult animals (2-3 months) was 21,218. This number was reduced by 21% at 26.5 months and by 24% in the oldest group (35-36 months). The number of degenerating myelin sheaths was first seen to be significantly increased at 6 months, reached a peak at 26.5 months, and declined at 35-36 months. There was an age-related increase in the cross-sectional area of the nerve, amounting to about 60% at 26.5 months and to about 50% at 35-36 months. Fiber packing density decreased evenly with age over the area of the nerve. The increased cross-sectional area and decreased fiber packing density appeared to be related to increases in the thickness of myelin sheaths and in the area occupied by interneural elements.

Degeneration in the cochlear nerve of the rat following cochlear lesions.

Left unilateral cochlear lesions were performed on 26 albino rats at 1.5 months of age. After survival times ranging from 1 h to 6 months, the animals were perfused via the aorta with mixed aldehydes. Blocks including the cochlear nerves were removed, embedded in Araldite, sectioned in a plane transverse to the longitudinal axis of the nerve, and analyzed in the light microscope. Degenerating fiber profiles were grouped into 4 categories, and their relative frequencies were counted, as were numbers of normal fibers and glial cell nuclei. The cross-sectional areas of the nerves were measured. Lesion extent was evaluated by means of sections through operated cochleas from short and long survival times, and right cochlear nerves from 11 of the animals were used as controls. In the left nerves, segmental swelling of fibers occurred as early as 16 h survival, followed by collapse of fibers and breakdown of myelin sheaths. Starting at 36 h survival, increased numbers of glial cells were seen in the nerve. At longer survival times there were decreases in the cross-sectional area of the nerve and in the packing density of degenerating fiber profiles. At the longest survival times, a substantial amount of debris remained which resembled that seen in early stages. Finally, there was evidence of continued loss of nerve fibers occurring over a period of weeks to months.

Auditory discrimination: role of time and intensity in the precedence effect.

Rats were trained to respond on a lever adjacent to a sounding speaker (the sound source) when a single click was emitted. A second click (the artificial echo) was presented through a second speaker on the opposite side. In Condition I, the echo (equal in intensity to the source) was delayed from .015 to 32 milliseconds; greater than 75% correct responses were given for delay times between about .040 milliseconds (lower threshold) and 8 milliseconds (upper threshold). In Condition II, the echo (simultaneous with the source) was reduced in intensity relative to the source over a range from 2.5 decibels to 40 decibels; greater than 75% correct responses occurred for intensity reductions greater than 5 decibels. In Condition III, both the intensity and the delay time of the echo were manipulated in a manner analogous to that which would occur under natural conditions; greater than 95% correct responses were given for delay times from 1 to 32 milliseconds. These data indicate that both time and intensity differences are necessary for localization of primary sources, with delay time contributing more at short echo path distances, and intensity differences at long distances.