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PubMed2002

Comparative distribution of NK1, NK2, and NK3 receptors in the rat brainstem auditory nuclei.

While the distribution of substance P in the auditory system is well illustrated, the localization of its receptors has not yet been documented. The goal of our study was to characterize the distribution of the tachykinin receptors NK1-R, NK2-R and NK3-R in the brainstem auditory nuclei of the adult rat using immunohistochemical techniques. The immunoreactivity of the neurokinin receptors was found to be widely distributed in most neurons of the cochlear nucleus (CN), the lateral superior olive (LSO), the medial nucleus of the trapezoid body (MNTB) and in the inferior colliculus (IC). Immunoreactivity was generally confined to post-synaptic targets (neuronal cell body and proximal or primary dendrites) in all auditory nuclei. However, unlike brainstem nuclei, the IC showed, in addition to neuronal cell body staining, a positive axonal immunolabeling (axons and pre-synaptic terminals) with the anti-NK1-R antibody. This axonal staining, revealing a pre-synaptic expression of NK1-R, is in good agreement with the known presence of substance P in the IC neurons. The absence of axonal staining in the superior olivary complex nuclei which projects afferent to the IC indicated that the NK1-R labeled axons are rather intrinsic IC fibers or descending thalamic projections to the IC. Overall, the wide distribution of the three types of tachykinin receptors observed in the present study argues for an important role of tachykinin neuropeptides in the central auditory system.

Animals↗
PubMed1998

Quantification of a neurotrophin receptor from submilligram quantities of brain tissue using western blotting.

The immunodensity of the trkB neurotrophin receptor was quantified from submilligram quantities of brain tissue, using approximately 500 microgram samples dissected from the cochlear nucleus (CN) of adult guinea pigs. Tissue samples were hand-homogenized in a lysis buffer. After complete lysis, an aliquot of the lysate was taken to measure total protein, and the remainder was denatured. Proteins in the denatured aliquot were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and electrophoretically transferred onto an immoblin-P membrane. The membrane was exposed to rabbit anti-trkB and then to anti-rabbit IgG HRP conjugate. The immuno-complex on the membrane was detected by chemiluminescence, which was recorded on autoradiographic film. Autoradiographs were scanned into a computer and the trkB immunobands were quantified by densitometry. This procedure allowed the quantitative comparison of trkB neurotrophin receptor immunodensities between tissue samples. The procedure can be applied to the analysis of small samples of tissue collected from different brain regions or collected from the same region at different times, such as during development or aging, after administering a drug, or after placing a lesion.

Animals↗
PubMed1999

Glutamate receptor phenotypes in the auditory brainstem and mid-brain of the developing rat.

Glutamate receptors mediate most excitatory synaptic transmission in the adult vertebrate brain, but their activation in developing neurons also influences developmental processes. However, little is known about the developmental regulation of the subunits composing these receptors. Here we have studied age-dependent changes in the expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) and N-methyl-D-aspartate (NMDA) receptor subunits in the cochlear nucleus complex (CN), the superior olivary complex (SOC), the nuclei of the lateral lemniscus, and the inferior colliculus of the developing rat. In the lateral superior olive, the medial nucleus of the trapezoid body, and the ventral nucleus of the lateral lemniscus, the distribution of AMPA receptor subunits changed drastically with age. While GluR1 and GluR2 subunits were highly expressed in the first 2 postnatal weeks, GluR4 staining was detectable only thereafter. GluR1 and GluR2 immunoreactivities rapidly decreased during the third postnatal week, with the GluR1 subunits disappearing from most neurons. In contrast, the adult pattern of the distribution of AMPA receptor subunits emerged gradually in most of the other auditory nuclei. Thus, progressive as well as regressive events characterized AMPA receptor development in some nuclei, while a monotonically maturation was seen in other regions. In contrast, the staining patterns of NMDA receptor subunits remained stable or only decreased during the same period. Although our data are not consistent with a generalized pattern of AMPA receptor development, the abundance of GluR1 subunits is a distinctive feature of early AMPA receptors. As similar AMPA receptors are present during plasticity periods throughout the brain, neurons undergoing synaptic and structural remodelling might have a particular need for these receptors.

Age Factors↗
PubMed1977

[Clinical and histopathological studies of cases of lafora-like inclusion bodies].

In case 1, 41-year-old male, developed progressive demetia, paretic gait disturbance and pyramidal signs with the duration of three years. The neuropathological study revealed systemic atrophy as type Pick-disease i.e., lobal atrophy in the frontal and the parieto-occipital regions, degenerative changes in the basal ganglia and in the thalamus, nerve cell loss in the substantia nigra and myelin pallor in the pyramidal tract. Lafora-like inclusions were found in the cerebral cortex and in the cochleal nucleus. In case 2, 45-year-old male, showed character change, cerebellar symptomes and mental deteriotation, and ulcers on the oral mucosa during about 15 years long period. Neuropathological examination showed chronic encephalitis in the brain stem, vacuolar change in the neuron in the olivary nucleus and Lafora-like inclusions in the cochlear nucleus. Though neither generalized conversion nor myoclonus were clinicaly observed in these cases, the inclusions showed histochemically strong similarity with that of the Lafora-disease. These Lafora-like inclusions were compared with those in the literatur, which were reported on various disease of CNS. Finally in respect of predilection of the inclusions, it is likely that the inclusions result from same metabolic disturbance in the cochlear neurons in the Lafora-disease as well as in the present cases.

Adult↗
PubMed1995

Effects of myelin or cell body brainstem lesions on 3-channel Lissajous' trajectories of fast and slow components of feline auditory brainstem evoked potentials.

Auditory brainstem evoked potentials (ABEP) were recorded from 16 awake cats using three orthogonal differential electrode pairs before and during a week after inducing neuronal lesions localized to the cochlear nucleus (CN) or the superior olivary complex (SOC), or myelin lesions localized to the fibers of the trapezoid body. ABEPs were digitally filtered to include only the slow ('pedestal') component, or only the faster first to fifth components, and three-channel Lissajous' trajectories (3CLTs) of these fast and slow components of ABEP were obtained. Cell body lesions and myelin lesions induced effects on 3CLT measures of both fast and slow components of ABEP. The results suggest a primary contribution of cell body activity to the slow component, and a primary fiber tract contribution to the fast components. However, the results do not support exclusive generation of the pedestal by cell body and dendritic post-synaptic potentials and of the faster components by action potentials along fibers. The results are consistent with a set of generators for each of the slow and fast components of ABEP, consisting of both cell bodies and their output fibers, that are spatially distributed in the brainstem.

Analysis of Variance↗
PubMed1996

Generators of the brainstem auditory evoked potential in cat. II. Correlating lesion sites with waveform changes.

Brainstem regions involved in generating the brainstem auditory evoked potential (BAEP) were identified by examining the effects of lesions on the click-evoked BAEP in cats. An excitotoxin, kainic acid, was injected into various parts of the cochlear nucleus (CN) or into the superior olivary complex (SOC). The locations of the resulting lesions were correlated with the changes produced in the various extrema of the BAEP waveforms. The results indicate that: (1) the earliest BAEP extrema (P1, N1 (recorded between vertex and the earbar ipsilateral to the stimulus) and P1a, P1b, (vertex to contralateral earbar)) are generated by cells with somata peripheral to the CN; (2) P2 is primarily generated by posterior anteroventral CN (AVCNp) and anterior posteroventral CN (PVCNa) cells; (3) SOC, anterior anteroventral CN (AVCNa), AVCNp, and PVCNa cells are involved in generating P3; (4) AVCNa cells are the main CN cells involved in P4, N4, and P5 generation; (5) both ipsilateral and contralateral SOC cells have a role in generating monaurally evoked P4 and P5; and (6) P5 is generated by cells with characteristic frequencies below 10 kHz. From (2) and (4), it is clear that P2 and P4-P5 are generated by cells in distinct, parallel pathways.

Acoustic Stimulation↗
PubMed2000

AMPA receptor-mediated, calcium-dependent CREB phosphorylation in a subpopulation of auditory neurons surviving activity deprivation.

Although dependence on afferent synaptic activity has been shown for central neurons in every sensory system, the mechanisms of afferent maintenance of target sensory neurons are not understood. Neurons in the cochlear nucleus (CN) require afferent activity for maintenance and survival. One of the earliest changes seen after activity deprivation is an increase in intracellular calcium that leads to the death of 30% of the neuronal population. Sixty minutes after deafferentation, the surviving neurons show increased phosphorylation of the transcription factor calcium/cAMP response element-binding protein (CREB). CREB phosphorylation in activity-deprived CN neurons is dependent on increased intracellular calcium resulting from influx through AMPA receptors and is mediated by calcium/calmodulin-dependent kinases and protein kinase A. We conclude that in CN neurons, the deafferentation-induced increase in calcium activates at least two kinase pathways that phosphorylate CREB in surviving neurons. We hypothesize that this phosphorylation results in the transcription of genes containing the calcium/cAMP response element within their promoter regions, and these genes code for proteins that allow the neurons to compensate for their hypercalcemic, activity-deprived state.

Animals↗
PubMed2000

Differential distribution of glutamate receptors in the cochlear nuclei.

Glutamate receptors are the major excitatory neurotransmitter receptors of the mammalian central nervous system, and include AMPA, kainate, delta, NMDA, and metabotropic types. In the cochlear nucleus (CN), the AMPA receptor subunits GluR2-4 are found in major kinds of neurons, while GluR1 subunit distribution is more restricted. GluR2 is low in the anteroventral CN, suggesting that many AMPA receptors here are calcium-permeable. Delta receptors are most prevalent in cartwheel cells in the dorsal CN. Of the NMDA receptors, NR1 is widespread while the NR2 subunits show more restricted distributions. Of the metabotropic glutamate receptors, mGluR1alpha is most prevalent in the dorsal CN, and mGluR2 is concentrated in Golgi cells and unipolar brush cells. AMPA receptors in endbulb synapses in the anteroventral CN are mainly GluR3+4 complexes: probably an adaptation for rapid auditory neurotransmission. Glutamate receptors are differentially distributed in synapses of fusiform cells of the dorsal CN; GluR4 and mGluR1alpha are present only at basal dendrite synapses (auditory nerve), while other glutamate receptors occupy both apical and basal synapses. Analysis of cytoplasmic distribution suggests that a selective targeting mechanism may restrict movement of GluR4 and mGluR1alpha to basal dendrites, although other targeting mechanisms may be present.

Animals↗
PubMed2006

EphB2 regulates axonal growth at the midline in the developing auditory brainstem.

Eph receptors play important roles in axon guidance at the midline. In the auditory system, growth of axons across the midline is an important determinant of auditory function. The avian cochlear nucleus, n. magnocellularis (NM), makes bilateral projections to its target, n. laminaris (NL). We examined the time course of NM axon growth toward the midline, the expression of Eph proteins at the midline during this growth, and the effects of Eph receptor misexpression on axonal growth across the midline. We found that NM axons reach the midline at E4. At this age, EphB receptors are expressed at the ventral floor plate. Expression extends dorsally to the ventricular zone beginning at E5. NM axons thus grow across the midline at a time when EphB receptor expression levels are low. Overexpression of EphB2 at E2 resulted in misrouted axons that deflected away from transfected midline cells. This effect was observed when midline cells were transfected but not when NM cells alone were transfected, suggesting that EphB2 acts non-cell autonomously and through reverse signaling. These data suggest an inhibitory role for midline Eph receptors, in which low levels permit axon growth and subsequently high levels prohibit growth after axons have crossed the midline.

Animals↗
PubMed2003

Auditory processing of spectral cues for sound localization in the inferior colliculus.

The head-related transfer function (HRTF) of the cat adds directionally dependent energy minima to the amplitude spectrum of complex sounds. These spectral notches are a principal cue for the localization of sound source elevation. Physiological evidence suggests that the dorsal cochlear nucleus (DCN) plays a critical role in the brainstem processing of this directional feature. Type O units in the central nucleus of the inferior colliculus (ICC) are a primary target of ascending DCN projections and, therefore, may represent midbrain specializations for the auditory processing of spectral cues for sound localization. Behavioral studies confirm a loss of sound orientation accuracy when DCN projections to the inferior colliculus are surgically lesioned. This study used simple analogs of HRTF notches to characterize single-unit response patterns in the ICC of decerebrate cats that may contribute to the directional sensitivity of the brain's spectral processing pathways. Manipulations of notch frequency and bandwidth demonstrated frequency-specific excitatory responses that have the capacity to encode HRTF-based cues for sound source location. These response patterns were limited to type O units in the ICC and have not been observed for the projection neurons of the DCN. The unique spectral integration properties of type O units suggest that DCN influences are transformed into a more selective representation of sound source location by a local convergence of wideband excitatory and frequency-tuned inhibitory inputs.

Acoustic Stimulation↗
PubMed2002

Behavioral audiograms of homozygous med(J) mutant mice with sodium channel deficiency and unaffected controls.

Complete behavioral audiograms were determined for med(J) mice (F1 offspring of C57BL/6JxC3HeB/FeJ) and unaffected controls from the same F1 background. The med(J) mutation results in greatly reduced levels of Scn8a voltage-gated sodium channels, which causes abnormal conduction of action potentials throughout the nervous system and may account for the virtual absence of spontaneous bursting activity in the dorsal cochlear nucleus. The med(J) mice also have tremors, display dystonic postures, and drag their hind legs. The mice were tested using a conditioned suppression/avoidance procedure, with minor modifications of the apparatus made to accommodate the motor-impaired med(J) mice. Thresholds were repeatedly obtained up to the age of 50 weeks to determine if the animals developed a hearing loss with age. The results indicate that med(J) mice have normal thresholds, with the first signs of hearing loss (detectable at 80 kHz) appearing for both the med(J) and normal mice by 48 weeks. Neither the med(J) nor the normal mice could hear below 1 kHz, indicating that house mice fall into the group of mammals with poor low-frequency hearing. The results also demonstrate that the conditioned suppression/avoidance procedure is well suited for assessing hearing in severely impaired, as well as normal, mice and that it can provide for the rapid determination of thresholds necessary to follow changes in hearing that may occur as the result of age, disease, mutation, or drugs.

Aging↗
PubMed2001

Expression of the Kv3.1 potassium channel in the avian auditory brainstem.

The Shaw-like potassium channel Kv3.1, a delayed rectifier with a high threshold of activation, is expressed in the time coding nuclei of the bird auditory brainstem. In both barn owls and chickens, Kv3.1 mRNA was expressed in the cochlear nucleus magnocellularis (NM) and the nucleus laminaris (NL). Western blot analysis showed that an antibody raised against the synthetic peptide sequence of rat Kv3.1 (rKv3.1) specifically recognized the same 92 kDa protein bands in both rat and chicken synaptosomal preparations. Immunohistochemical analyses using this anti-rKv3.1 antibody revealed a prominent gradient in Kv3.1 immunoreactivity along the tonotopic axis of the barn owl NM and NL and a less prominent gradient in the chicken. The precise localization of the Kv3.1 immunoproduct was resolved by electron microscopy. In both the owl and the chicken, Kv3.1 was targeted postsynaptically in NM and NL. The major difference in localization of Kv3.1 protein between the two birds was the expression of Kv3.1 in the NM axons and terminals in the region of the barn owl NL. This location of Kv3.1 channels supports its postulated function in reducing the width of action potentials as they invade the presynaptic terminal. The presynaptic localization may be a specialization for enabling neurons in owl NM to transmit high-frequency temporal information with little jitter.

Alternative Splicing↗
PubMed2003

ERK and SAPK signaling in auditory brainstem neurons after unilateral cochlear ablation.

Unilateral cochlear ablation (UCA) in adults deafferented one cochlear nucleus (CN) and induced several plasticities in central auditory pathways. To assess whether signal transduction could contribute to these changes, we determined if UCA induced activity in the extracellular signal-regulated kinase (ERK) and the stress-activated protein kinase (SAPK) signal transduction pathways. Using Western blots, we measured phosphorylated ERK1 (ERK1-P), ERK2 (ERK2-P), p46 and p54 SAPK (SAPK-P) and c-Jun (c-Jun-P) levels in the major subdivisions of the CN, the principal nuclei of the superior olivary complex (SOC) and the central nucleus of the inferior colliculus (ICc) for up to 145 days postablation. ERK1-P and ERK2-P were typically elevated at 7 and 145 days but depressed at 30 days, 60 days, or both. In addition, ERK1-P and ERK2-P were elevated at 3 days in the anteroventral (AVCN) and posteroventral CN (PVCN). Immunohistochemical labeling indicated that after 5 days, most ERK1/2-P in the CN was in neuronal nuclei. Only minor changes were evident in total ERK1 and ERK2 levels. Several correlations were evident between the postablation plasticities observed previously and altered ERK1-P and ERK2-P levels. Few changes were found in SAPK-P and c-Jun-P levels. Concomitant elevations of SAPK-P and c-Jun-P were not evident, except in the superficial dorsal CN (DCN) at postablation day 3, consistent with a cell-stress response. These findings suggest that signals induced as a consequence of UCA are transduced mainly through the neuronal ERK pathway. This activity probably influenced gene expression and cytoplasmic regulatory mechanisms that contributed to the plasticities induced by UCA.

Animals↗
PubMed2001

Expression of a voltage-dependent potassium channel protein (Kv3.1) in the embryonic development of the auditory system.

The present study traces the development of a voltage-dependent potassium channel protein (Kv3.1) in the avian homologue of the cochlear nucleus, in the cochleovestibular ganglion, and in the otic epithelium from early developmental stages until near hatching. Immunohistochemistry with antibodies to the carboxy terminus (recognizing the Kv3.1b splice variant) and to the amino terminus (recognizing either form of Kv3.1) was used on Hamburger-Hamilton-staged chicken embryos. There were three periods in the relative levels of immunostaining in these regions. Early (E2-6), when precursor cells proliferate, migrate, and form axons, there was staining when using either antibody. In the middle period (E6-11), marked by hair cell differentiation, dendritic growth, and early synapse formation, staining levels decreased. In the late period (E11-19), when auditory function begins, staining increased rapidly, especially for Kv3.1b. Early Kv3.1 expression occurs in neuronal and hair cell precursors before they differentiate or function. Later, in the otic epithelium, a high level of Kv3.1 in cilia may precede or coincide with the onset of hair cell function. In neurons, some features of its localization correlate with axon outgrowth and synapse formation, others with the onset of neural activity and function.

Animals↗
PubMed2002

Morphology, GluR1 and GRIP-C localization differ in octopus cells of C57BL6 and B6Cast mice.

The C57BL6 mouse (B6) is homozygous for the gene for age-related hearing loss (ahl/ahl) and shows normal adult-like hearing before subtle changes in hearing begin at about 30 days of age. The B6Cast mouse is congenic to B6, having the wild type allele for normal hearing from Castaneous Ei on a B6 background. It has normal hearing throughout most of its lifespan. This study characterized the morphology of octopus cell (OC) somata in the posterior-ventral cochlear nucleus and of synaptic terminals on the OC somata in 8-week-old B6 and B6Cast mice, and the immunolocalization of antibodies to GluR1 (glutamate receptor subunit 1) and GRIP-C (glutamate receptor interacting protein-C terminus). By 8 weeks of age there are significant changes in the morphology of OCs and synaptic terminals around their somata in B6 mice compared to B6Cast mice. The distribution of immunoreactivity for the proteins GluR1 and GRIP is also significantly different in B6 mice from that in B6Cast mice. The modest degenerative changes reported in some B6 outer hair cells of the basal turn at this age do not seem adequate to explain the major changes observed in most OCs at a time when physiological studies show that many measures of the animals' hearing are still near normal. The findings suggest that changes in the alpha-amino-3-hydroxy-5-methyl-4-isoxazole glutamate receptor subunits and/or their binding proteins are part of the phenotype of ahl, and may reflect a role of the glutamate receptor pathway in the mechanism of ahl.

Adaptor Proteins, Signal Transducing↗
PubMed1994

Effects of electrical brainstem stimulation on tinnitus.

The primary aim of the auditory brainstem implant (ABI), an investigational device, is to restore auditory sensations in neurofibromatosis-2 patients deafened by bilateral acoustic neuroma surgery. An electrode is placed on the dorsal cochlear nucleus after the tumor is removed through the translabyrinthine approach. This procedure was performed on 18 patients: 13 were completely deafferentated after bilateral tumor removal and had received the ABI during surgery on the second-sided tumor; 5 were implanted at first-sided tumor removal. Three of these 5 patients had usable hearing remaining on the side of the second acoustic neuroma and were stimulated only during laboratory sessions. All patients had tinnitus. We used a questionnaire to assess the effects of brainstem stimulation on this symptom. Of the 18 patients, one early patient deceased, and one patient with no follow-up was not included in this study. Six patients who were unable to use the ABI because of temporary hardware problems or side effects from electrical stimulation were also excluded. Thus, we studied 10 patients. Of 7 patients who used their implant daily, 6 reported noticeable tinnitus reduction; the ABI had no effect in the remaining case. Of 3 recently implanted patients who used this implant only during laboratory testing, one patient reported complete suppression of tinnitus, one described worse tinnitus, and one reported no effect.

Adolescent↗
PubMed2006

Phosphorylated cAMP response element-binding protein levels in guinea pig brainstem auditory nuclei after unilateral cochlear ablation.

After left unilateral cochlear ablation (UCA) in young adult guinea pigs, the appearance of plasticities in auditory pathways suggested altered gene expression and modified phenotypic behaviors of auditory neurons. Because phosphorylated cyclic-AMP response element-binding protein (CREB-P) is a transcription factor that binds to certain genes to facilitate their expression, CREB-P levels were measured after UCA and correlated with postablation plasticities. After UCA, Western blotting was employed to quantify CREB-P levels and illustrate CREB levels in the anteroventral (AVCN), posteroventral (PVCN), and dorsal (DCN) cochlear nucleus; the lateral (LSO) and medial superior olive (MSO); the medial nucleus of the trapezoid body (MNTB); and the central nucleus of the inferior colliculus (ICc) for up to 145 days. We also quantified the levels of several protein synthesis regulators and synaptic markers in the AVCN at 60 days. Sucrose-based extraction buffer improved CREB-P recovery. CREB-P levels became depressed at 3 and 7 postablation days, except in the PVCN, where they were elevated at 7 days, and in the ICc, where they were elevated at both times. At 60 days, CREB-P levels in all the nuclei were elevated. In the AVCN, levels of the protein synthesis regulators and synaptic markers were also elevated at 60 days. By 145 days, CREB-P levels again declined, except in the AVCN, where elevations persisted and increased on the ablated side, and in the ICc, where CREB-P elevations remained. The changes in CREB-P levels coincided with several plasticities in glutamatergic and glycinergic transmitter release and receptor activities, and alterations in neurotrophic support, that developed after UCA. These findings suggest that UCA altered CREB-P levels, which in turn might have contributed to plasticities that appear after UCA.

Animals↗
PubMed1999

Differential distribution of intracellular glutamate receptors in dendrites.

Glutamate receptors are synthesized in the cell body and transported in intracellular compartments to the target synapse. The objective of the present study was to analyze the intracellular pool of glutamate receptors and determine whether the intracellular pool was related to the synaptic distribution of the receptors. As a model system, we chose the fusiform cell of the dorsal cochlear nucleus for which we have previously demonstrated that receptors are selectively targeted to synapses on apical and basal dendrites. A combination of retrograde tracing and postembedding immunogold labeling was used to quantify intracellular receptors in segments of apical and basal dendrites. Immunolabeling for GluR4 and mGluR1alpha is present at synapses on basal dendrites but not on apical dendrites, whereas immunolabeling for GluR2/3 is present at both populations of synapses. In the analysis of intracellular pools, we find that GluR2/3 is equally distributed in apical and basal dendrites, whereas GluR4 and mGluR1alpha are more concentrated in basal dendrites than in apical dendrites. These findings indicate that the distribution of intracellular receptors is related to that of synaptic receptors and suggest that a mechanism exists in neurons to target proteins to dendritic domains soon after synthesis. We found no evidence for the existence of a pool of intracellular receptors, which could represent a receptor reserve, near the postsynaptic density. Receptors were often found in clusters associated with tubulovesicular membranes of the endoplasmic reticulum, identified with immunoglobulin binding protein (BIP) or calnexin, suggesting that this organelle is involved in receptor transport in dendrites.

Amino Acid Sequence↗