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Development of mature microcystic lesions in the cochlear nuclei of the Mongolian gerbil, Meriones unguiculatus.

Microcystic lesions are a persistent final stage in a neurodegenerative disorder characteristic of the cochlear nuclei of gerbils. When gerbils of various ages raised under known acoustic conditions were examined, the volume density and number of lesions increased with age, however, the affected region was restricted to the posteroventral cochlear nucleus and adjacent portions of the dorsal cochlear nucleus, interstitial nucleus, and posterior anteroventral cochlear nucleus. Lesions were also noted in a separate locus in the auditory nerve trunk associated with the acoustic nerve nucleus. The fusiform and molecular layers of the dorsal cochlear nucleus were spared at all ages observed. The spherical cell region of the arteroventral cochlear nucleus was also largely spared. A good correlation was observed between the cumulative input from the auditory nerve fibers caused by the ambient acoustic environment acting over the life of the animal and the number of lesions in tonotopic subdivisions of the cochlear nuclei. The earliest microcysts formed in regions receiving auditory nerve fibers most strongly stimulated by the ambient noise. Thereafter, short exposures to higher levels of input or long exposures to lower levels of input were quantitatively equivalent in producing microcystic lesions.

Aging↗

Evidence for a glycinergic pathway connecting the two cochlear nuclei: an immunocytochemical and retrograde transport study.

A combined retrograde transport and immunocytochemical study was carried out to determine the projections of the large glycine-immunoreactive neurons in the ventral cochlear nucleus of the guinea pig. Horseradish peroxidase (HRP) was injected into the contralateral cochlear nucleus, and cochlear nucleus sections were developed for HRP activity followed by staining for glycine using affinity-purified anti-glycine antibodies. These studies show that glycine-immunoreactive neurons in the ventral cochlear nucleus project to the contralateral cochlear nucleus and suggest that this pathway may be glycinergic.

Animals↗

The topographical organization of descending projections from the central nucleus of the inferior colliculus in guinea pig.

We describe the descending projections from the central nucleus of the inferior colliculus (CNIC) in guinea pig. Focal injections of the tracer biocytin, made in physiologically defined frequency regions of the CNIC, labelled laminated axonal terminal fields in the ipsilateral dorsal nucleus of the lateral lemniscus, and bilaterally in the ventral nucleus of the trapezoid body and the dorsal cochlear nucleus. Labelling was also present in the rostral periolivary nucleus, but we could not distinguish a clear border between the terminal fields in this nucleus and those in the ventral nucleus of the trapezoid body. Labelling observed in the ventral nucleus of the lateral lemniscus, and to a lesser extent in the dorsal nucleus of the lateral lemniscus, was accompanied by retrogradely labelled somata and therefore we cannot conclude unequivocally that the CNIC projects to these lemniscal nuclei. Where the labelling was ordered topographically, its position varied as a function of the best frequency at the injection site. High-frequency regions in the CNIC project to the medial parts of the ventral nucleus of the trapezoid body and dorsal cochlear nucleus, while low-frequency regions in the CNIC project to the lateral parts of the ventral nucleus of the trapezoid body and dorsal cochlear nucleus. Additional axonal labelling with terminal boutons, but with no apparent topographical arrangement, was present in the ipsilateral horizontal cell group, sagulum, and also bilaterally in the superficial granule cell layer of the ventral cochlear nucleus and layer 2 of the dorsal cochlear nucleus. Our findings are consistent with the existence of tonotopically organised feedback projections from the CNIC to the brainstem nuclei that project to it.

Animals↗

Afferent projections to the central nucleus of the inferior colliculus in the rat.

The afferent projections to the inferior colliculus of the rat were studied using the method of retrograde transport of horseradish peroxidase (HRP). Following large injections of HRP into the central nucleus, cells within the cochlear nuclei, superior olivary complex and auditory cortex were stained. Within the contralateral dorsal cochlear nucleus, fusiform cells were heavily labeled. Giant cells were also labeled in deeper layers. In the contralateral ventral cochlear nucleus, virtually all major cell types were labeled, with some types being labeled in greater numbers than others. Octopus cells of posteroventral division of ventral cochlear nucleus (PVCN) were never labeled. HRP-positive cells were found in ipsilateral and contralateral lateral superior olivary nucleus (LSO), ipsilateral medial superior olivary nucleus (MSO), ipsilateral and contralateral lateral nucleus of the trapezoid body (LTB), ipsilateral ventral nucleus of the trapezoid body (VTB), and ipsilateral superior paraolivary nucleus (SPN). Pyramidal cells of layer V of auditory cortex were heavily labeled. Small injections of HRP into the central nucleus resulted in labeled cells within restricted regions of the cochlear nuclei, superior olivary complex and auditory cortex. Injections into dorsal regions of the central nucleus resulted in cells labeled in ventral regions of the dorsal and ventral cochlear nuclei, and in lateral regions of LSO. These regions contain neurons which are considered to have low best frequencies. Injections placed in more ventral regions of the central nucleus led to labeling of cells in more dorsal regions of the cochlear nuclei and more medial regions of LSO in agreement with the tonotopical progressions within these structures.

Animals↗

Expression of AMPA receptor subunit flip/flop splice variants in the rat auditory brainstem and inferior colliculus.

The expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor subunit mRNAs and their flip/flop splice variants was evaluated in the rat auditory brainstem and inferior colliculus employing in situ hybridization with radiolabeled oligonucleotide probes. A differential expression of AMPA receptor subunits in auditory nuclei was observed. In general, neurons in all nuclei of the auditory brainstem express high levels of GluR-C flop and GluR-D flop mRNA, but low to very low levels of GluR-A and GluR-B mRNA. The strongest GluR-C and -D flop expression is found in the ventral and medial part of the anteroventral cochlear nucleus, the posteroventral cochlear nucleus, and the medial and the lateral superior olive. These nuclei are part of the binaural auditory pathway which is important for sound localization in space. In contrast, neurons in the central nucleus of the inferior colliculus express high levels of GluR-B flip but only low levels of the other AMPA receptor subunits. From our data, we conclude that neurons of nuclei involved in binaural processing exhibit a specific "auditory AMPA receptor" which consists primarily of GluR-C flop and -D flop and often lacks GluR-B subunits; this indicates fast kinetics and high Ca(2+) permeability of AMPA receptor currents. In contrast, neurons in the central nucleus of the inferior colliculus contain large amounts of GluR-B flip subunits resulting in Ca(2+) impermeable AMPA receptors with slow kinetics.

Animals↗

Apoptosis in auditory brainstem neurons after a severe noise trauma of the organ of Corti: intracochlear GDNF treatment reduces the number of apoptotic cells.

We have studied the morphological and cellular changes in the cochlear nucleus (CN) after cochlear nerve degeneration and whether these changes can be prevented by rescuing the primary cochlear neurons from degeneration with local glial cell line derived neurotrophic factor (GDNF) treatment. Degeneration of spiral ganglion neurons was seen to lead to a reduction of the volume of the anteroventral cochlear nucleus (AVCN); the size of the cell nuclei in the AVCN also was reduced. No differences were observed in cell density. After intrascalar GDNF treatment the volume of the AVCN was significantly larger when compared to the untreated side, and the size of the cell nuclei in the AVCN was significantly larger on the treated side. After degeneration of spiral ganglion neurons, an increased number of apoptotic cell nuclei were seen in ipsilateral CN and superior olivary complex. This increase was significantly smaller after intrascalar GDNF treatment. Degeneration of primary cochlear neurons seems to lead to an increase in the number of CN neurons undergoing apoptotic cell death. This can be prevented partially by rescuing primary cochlear neurons from degeneration with local GDNF treatment.

Animals↗

Diversity and plasticity in amino acid receptor subunits in the rat auditory brain stem.

Glutamate, gamma aminobutyric acid (GABA) and glycine receptors have different properties depending on the specific subunit combination utilized. The subunit composition of amino acid receptors may help to shape the responses of neurons and can provide a diversity of response properties in different neuronal types and regions. This allows a synaptic fine tuning for an optimization of processing requirements and may also allow for changes in response to changes in input. This article reviews the diversity that has been found in the subunit composition of GABA, glycine, alpha amino-3-hydroxy-5-methyl-4 isoxazole propionic acid and N-Methyl, D-aspartate (NMDA) receptors in the mammalian auditory brain stem and provides new data on how the NMDAR1 glutamate receptor subunit changes as a consequence of deafness. In the latter study, quantitative in situ hybridization was used to assess NMDAR1 mRNA expression in six cell types of the rat cochlear nucleus. A unilateral cochlear ablation was performed and expression determined in the ipsilateral and contralateral cochlear nucleus 5 and 20 days later. Significantly decreased expression, compared to normal, was found 5 days following deafness, in ipsilateral spherical bushy cells, octopus cells and shell neurons, but not in fusiform cells, corn cells or granule cells. At 20 days the expression was not significantly different from normal in any of the six cell types.

Animals↗

Electrophysiological and HRP studies of the direct afferent inputs from the cochlear nuclei to the tensor tympani muscle motoneurons in the cat.

The direct fiber connections from the cochlear nuclei to the tensor tympani muscle (TTM) motoneurons were investigated by means of electrophysiological and horseradish peroxidase (HRP) methods, using cats. When HRP was injected into motoneuron region of the TTM, HRP-labelled cells were found bilaterally in the dorsal cochlear nucleus (DCN) and ventral cochlear nucleus (VCN). When the electrical stimulus was applied to the cochlear nucleus, the TTM motoneurons fired spikes monosynaptically with s short latency. These histological and electrophysiological results indicate the existence of direct fiber connections from the bilateral cochlear nuclei to the TTM motoneurons.

Animals↗

Surgical technique for the Nucleus Contour cochlear implant.

This paper deals with the Nucleus C124R (CS) (Contour) cochlear Implant: its characteristics, differences compared with the previous generation of devices, the perimodiolar electrode, and the surgical technique used for safe insertion. We also discuss the rationale behind perimodiolar electrodes in general, as well as the results of laboratory studies validating the design and safety of this particular electrode array. The differences in surgical technique between this device and prior Nucleus cochlear implants are as follows: the incision and the size of the well, or recess, for the electronics are smaller; the cochleostomy is larger; the posterior portion is placed in a subpericranial pocket, not tied down, before electrode insertion; and the insertion process itself is quite different, due to the nature of the electrode, its size, shape, and stylet. The technique described is that used by one experienced cochlear implant center, and reflect the authors' practice. Clearly, there are other possible variations on this theme, which may be equally satisfactory in other hands. Most surgeons find this device to be easier to place than previous generations: complications to date have been uncommon.

Acoustic Stimulation↗

Projections from the sacculus to the cochlear nuclei in the Mongolian gerbil.

The projections of the saccule, an otolith end organ, to the cochlear nuclei were studied using both transganglionic transport and intracellular injection techniques. Labeled fibers and terminals were observed in the anterior and posterior portions of the ventral cochlear nucleus and the dorsal cochlear nucleus. Most terminals were present in the granule cell domain, especially in the subpeduncular corner between the anteroventral cochlear nucleus and the floccular peduncle of the cerebellum. It has been hypothesized that the cochlea in mammals may have developed phylogenetically from the saccule. The projections from the saccule to the cochlear nuclei were investigated in a mammalian species, the Mongolian gerbil, in an attempt to obtain initial information supporting or refuting this hypothesis. The presence of an otolith end organ projection to the cochlear nuclei in rodents should encourage comparative studies in additional aspects of the evolution of the auditory system.

Animals↗

The development of the Nucleus Freedom Cochlear implant system.

Cochlear Limited (Cochlear) released the fourth-generation cochlear implant system, Nucleus Freedom, in 2005. Freedom is based on 25 years of experience in cochlear implant research and development and incorporates advances in medicine, implantable materials, electronic technology, and sound coding. This article presents the development of Cochlear's implant systems, with an overview of the first 3 generations, and details of the Freedom system: the CI24RE receiver-stimulator, the Contour Advance electrode, the modular Freedom processor, the available speech coding strategies, the input processing options of Smart Sound to improve the signal before coding as electrical signals, and the programming software. Preliminary results from multicenter studies with the Freedom system are reported, demonstrating better levels of performance compared with the previous systems. The final section presents the most recent implant reliability data, with the early findings at 18 months showing improved reliability of the Freedom implant compared with the earlier Nucleus 3 System. Also reported are some of the findings of Cochlear's collaborative research programs to improve recipient outcomes. Included are studies showing the benefits from bilateral implants, electroacoustic stimulation using an ipsilateral and/or contralateral hearing aid, advanced speech coding, and streamlined speech processor programming.

Acoustic Stimulation↗

Quantitative comparison of frequency representation in the auditory brainstem nuclei of the gerbil, Pachyuromys duprasi.

Frequency representation in the auditory brainstem nuclei of the fattailed gerbil (Pachyuromys duprasi) was studied by focal iontophoretic HRP injections into the cochlear nucleus at physiologically characterized positions. Tuning curves of cochlear nucleus neurons were determined by extracellular recording of multi-unit spike activity prior to HRP application. Neurons with characteristic frequencies of 0.55 to 17.5 kHz were recorded. Anterograde labeling of synaptic terminal fields demonstrated a tonotopic arrangement of frequencies within the cochlear nucleus subdivisions and the lateral and medial superior olivary nuclei. In all nuclei investigated terminal fields were arranged in isofrequency planes. In the subdivisions of the cochlear nucleus and in the lateral superior olive the frequency range from 0.55 to 17.5 kHz was represented. In the medial superior olive on the other hand, frequency representation was restricted to frequencies below 3.5 kHz. Quantitative evaluation of tonotopy showed that the frequency representation in the anteroventral and posteroventral cochlear nucleus and lateral superior olive were very similar. The amount of tissue-volume processing one octave varied within the hearing range. The frequency range of highest auditory sensitivity (between 1 and 5 kHz) occupied up to 25% nuclear tissue/octave, while at the upper and lower limits of the hearing range, frequencies were represented by a ratio of 10-15% nuclear tissue/octave. The frequency representation pattern in these brainstem nuclei reflected exactly the frequency place map of the cochlea.

Animals↗

Incomplete maturation of brainstem auditory nuclei in genetically induced early postnatal cochlear degeneration.

In the Shaker-2 mouse mutant, a cochleo-saccular type of genetically induced inner ear degeneration occurs. Morphological signs of degeneration are evident in the 3rd postnatal week and a severe and almost total degeneration has occurred by the age of 6-9 weeks. There are no qualitative differences between the brain of the normal CBA/J mouse and that of the Shaker-2 mouse. The growth of the auditory brainstem nuclei (dorsal cochlear nucleus and ventral cochlear nucleus) in the mutant Sh-2 mouse has stopped by 14 days of age--but not in the normal CBA/J mouse. The brainstem as a whole continues to grow between 14 and 140 days of age in both strains. The early cochlear degeneration coincides with the critical period when a normal input from the peripheral receptor organ is necessary for the maturation of the central auditory pathway.

Animals↗

Auditory neuronal sizes after a unilateral conductive hearing loss.

The left external auditory meatus was removed in 4-day-old CBA/J mice; after killing at 45 days, serial sections of the cochleae and brain stem were prepared. From these, the cross-sectional areas of spiral ganglion neurons and of 14 auditory brain stem neuronal types were measured, using a total of 210 neurons of each of the 15 types from both the right and left sides. Nine neuronal types were significantly smaller (P less than 0.01) on the left side: spiral ganglion neurons; globular, small spherical, large spherical, octopus, multipolar, and granule cells of the ventral cochlear nucleus; Purkinje-like cells of the dorsal cochlear nucleus; and spindle cells of the lateral superior olivary nucleus. Two neuronal types were significantly smaller (P less than 0.01) on the right: principal cells of the medial nucleus of the trapezoid body (superior olivary complex), and spindle-shape principal neurons of the central nucleus of the inferior colliculus. The left ventral cochlear nucleus had significantly smaller volume (P less than 0.01) than the right but right and left dorsal cochlear nuclear volumes did not differ significantly (P greater than 0.05). Right and left sides were not significantly different (P greater than 0.05) for the following neuronal types: fusiform cells and coarse- and fine-Nissl deep cells of the dorsal cochlear nucleus, and rostral bipolar cells of the medial superior olivary nucleus. Neurons affected by unilateral conductive loss were not significantly different (P greater than 0.05) from the same cells in mice with bilateral conductive losses; neurons not affected by unilateral conductive loss were not significantly different (P greater than 0.05) from the same cells in normal mice.

Animals↗

Transcription factor modulation and expression in the rat auditory brainstem following electrical intracochlear stimulation.

Neuronal activity in sensory organs elicited by adequate or electrical stimulation not only invokes fast electrical responses but may also trigger complex molecular changes inside central neurons. Following electrical intracochlear stimulation with a cochlear implant under urethane anesthesia, we observed changes in the phosphorylation state of the cAMP response element binding protein (CREB) and the expression of the immediate-early genes c-fos and egr-1, molecules known to act as transcription factors, in a tonotopically precise pattern in central auditory neurons. These neurons resided in the posteroventral and anteroventral cochlear nucleus, the dorsal cochlear nucleus, the lateral superior olive, the medial nucleus of the trapezoid body, the dorsal and ventral nucleus of the lateral lemniscus, and the central nucleus of the inferior colliculus. Moreover, effects of electrical stimulation were identified in the medial vestibular nucleus and the lateral parabrachial nucleus. Regionally, CREB was dephosphorylated wherever immediate-early gene expression went up. These massive stimulation-dependent modulations of transcription factors in the ascending auditory system are indicative of ongoing changes that modify the chemistry and structure of the affected cells and, consequently, their response characteristics to subsequent stimulation of the inner ear.

Animals↗

Connections between the cochlear nuclei in guinea pig.

This study provides a detailed analysis of the appearances and distributions of neurons projecting from one cochlear nucleus to the other. Injections of wheatgerm agglutinin conjugated to horseradish peroxidase were made into ventral or dorsal cochlear nucleus of the guinea pig. Retrogradely labeled cells in the opposite cochlear nucleus were examined and quantified. Three major categories of labeled cells were discerned on the basis of their soma shape: elongate, round-to-oval, and polygonal. All injections resulted in widespread labeling of cells in all of these categories, but especially round-to-oval cells, in the opposite ventral cochlear nucleus and sparse labeling in the dorsal cochlear nucleus. The results suggest that there is a significant cochlear nucleus commissural projection involving heterogeneous cell types which could have diverse functions in binaural auditory signal processing.

Animals↗

The c-Fos transcription factor in the auditory pathway of the juvenile rat: effects of acoustic deprivation and repetitive stimulation.

The expression of the inducible transcription factors (ITF) c-Fos and JunB was investigated in the dorsal cochlear nucleus (DCN), ventral cochlear nucleus (VCN) and inferior colliculus (IC) of juvenile and adult rats following deprivation and repetitive stimulation paradigms using 8 kHz tone bursts at 5 min duration and 70 dB, 90 dB or 120 dB sound pressure level (SPL). (1) During postnatal development without stimulation, c-Fos is absent in DCN and VCN from postnatal day (P) 12 to adulthood, but shows a strong expression in the IC which declines during maturation. A similar decrease was also seen in the pons. (2) Between P15 and P35 stimulation of rats with 8 kHz for 5 min at 70 dB SPL evoked expression of c-Fos in a moderate number of cells of DCN, VCN and IC. Higher sound pressure levels increased the number of c-Fos immunoreactive neurons as studied at P21. (3) Deprivation of acoustic stimulation up to P21 reduced the expression of c-Fos when rats were stimulated with 90 dB immediately after the restoration of acoustic input. In contrast to 90 dB SPL, c-Fos immunoreactivity (IR) did not significantly differ between deprived and normal rats following application of 120 dB SPL at P21. Stimulation at P28, i.e., 7 days after the end of the deprivation, evoked an increase of c-Fos only in the IC compared to otherwise normally stimulated rats. At P35, effects of the former deprivation on the c-Fos expression were not longer detectable. (4) In a repetitive stimulation paradigm, 8 kHz tone bursts 5 min in duration were applied each second day between P23 and P35 or each day between P29 and P35. When compared with acutely stimulated rats at P35, both repetitive acoustic stimulation protocols reduced the c-Fos immunoreactivity by 50%-75% in the DCN, VCN and IC. In adult 4-month-old rats, repetitive stimulation did not reduce the c-Fos immunoreactivity from its moderate levels as compared with acute stimulation. (5) In some experiments, we studied also the expression of the JunB protein. JunB paralleled the expression of c-Fos following single acoustic stimulation, but was expressed in a substantially lower number of cells. In contrast to c-Fos, however, repetitive stimulation as described in section 4 did not evoke a decrease of JunB in the lower acoustic pathway.

Acoustic Stimulation↗

Decreased expression of the c-Fos, but not Jun B, transcription factor in the auditory pathway of the rat after repetitive acoustic stimulation.

Between the 21st and 34th postnatal days, male rats received an acoustic stimulus every second day, and the expression of c-Fos and Jun B proteins was compared with rats that received only a single acoustic stimulus at postnatal day 34. For acoustic stimulation, 8-kHz pure-tone bursts (100 ms duration at a rate of 6.3 Hz) were applied for 5 min. The numbers of neurons immunoreactive to c-Fos and Jun B were studied 2 h after the last or acute stimulus, respectively, in the ventral cochlear nucleus (VCN), dorsal cochlear nucleus (DCN) and inferior colliculus (IC). Compared with the single stimulus, repetitive stimulation significantly reduced the number of c-Fos labeled neurons in the VCN by 51%, in the DCN by 75% and in the IC by 48%. In contrast to c-Fos, repetitive stimulation did not significantly lower the number of Jun-B-expressing neurons. These findings indicate that independent intraneuronal pathways terminate on the induction of c-Fos- and Jun-B-expressing genes during the juvenile maturation of the acoustic pathway and that chronic exposure of acoustic events alters the program of intraneuronal gene expression by reducing transcriptional activities with subsequent stabilization at the genetic level.

Acoustic Stimulation↗