Ipsilateral Ventral Cochlear Nucleus Research Articles

Different tonotopic regions of the lateral superior olive receive a similar combination of afferent inputs.

The mammalian lateral superior olive (LSO) codes disparities in the intensity of the sound that reaches the two ears by integrating ipsilateral excitation and contralateral inhibition, but it remains unclear what particular neuron types convey acoustic information to the nucleus. It is also uncertain whether the known conspicuous morphofunctional differences and gradients along the tonotopic axis of the LSO relate to qualitative and/or quantitative regional differences in its afferents. To clarify these issues, we made small, single injections of the neuroanatomical tracer biotinylated dextran amine (BDA) into different tonotopic regions of the LSO of albino rats and analyzed the neurons labeled retrogradely in brainstem auditory nuclei. We demonstrate that the LSO is innervated tonotopically by four brainstem neuron types: spherical bushy cells and planar multipolar neurons of the ipsilateral ventral cochlear nucleus, principal neurons of the ipsilateral medial nucleus of the trapezoid body, and small multipolar neurons of the contralateral ventral nucleus of the trapezoid body. Unexpectedly, the proportion of labeled neurons of each type was virtually identical in all cases, thus indicating that all tonotopic regions of the LSO receive a similar combination of inputs. Even more surprisingly, our data also suggest that the representation of frequencies in the LSO differs from that of the nuclei that innervate it: compared to the latter nuclei, the LSO seems to possess a relatively larger portion of its volume devoted to processing frequencies in the lower-middle part of the spectrum, and a relative smaller portion devoted to higher frequencies. J. Comp. Neurol. 524:2230-2250, 2016. © 2015 Wiley Periodicals, Inc.

Cochlear ablation effects on amino acid levels in the chinchilla cochlear nucleus

Inner ear damage can lead to hearing disorders, including tinnitus, hyperacusis, and hearing loss. We measured the effects of severe inner ear damage, produced by cochlear ablation, on the levels and distributions of amino acids in the first brain center of the auditory system, the cochlear nucleus. Measurements were also made for its projection pathways and the superior olivary nuclei. Cochlear ablation produces complete degeneration of the auditory nerve, which provides a baseline for interpreting the effects of partial damage to the inner ear, such as that from ototoxic drugs or intense sound. Amino acids play a critical role in neural function, including neurotransmission, neuromodulation, cellular metabolism, and protein construction. They include major neurotransmitters of the brain – glutamate, glycine, and γ-aminobutyrate (GABA) – as well as others closely related to their metabolism and/or functions – aspartate, glutamine, and taurine. Since the effects of inner ear damage develop over time, we measured the changes in amino acid levels at various survival times after cochlear ablation. Glutamate and aspartate levels decreased by 2weeks in the ipsilateral ventral cochlear nucleus and deep layer of the dorsal cochlear nucleus, with the largest decreases in the posteroventral cochlear nucleus (PVCN): 66% for glutamate and 63% for aspartate. Aspartate levels also decreased in the lateral part of the ipsilateral trapezoid body, by as much as 50%, suggesting a transneuronal effect. GABA and glycine levels showed some bilateral decreases, especially in the PVCN. These results may represent the state of amino acid metabolism in the cochlear nucleus of humans after removal of eighth nerve tumors, which may adversely result in destruction of the auditory nerve. Measurement of chemical changes following inner ear damage may increase understanding of the pathogenesis of hearing impairments and enable improvements in their diagnosis and treatment.

Modulating central gain in tinnitus: changes in nitric oxide synthase in the ventral cochlear nucleus.

A significant challenge in tinnitus research lies in explaining how acoustic insult leads to tinnitus in some individuals, but not others. One possibility is genetic variability in the expression and function of neuromodulators – components of neural signaling that alter the balance of excitation and inhibition in neural circuits. An example is nitric oxide (NO) – a free radical and potent neuromodulator in the mammalian brain – that regulates plasticity via both pre-synaptic and postsynaptic mechanisms. Changes in NO have previously been implicated in tinnitus generation, specifically in the ventral cochlear nucleus (VCN). Here, we examined nitric oxide synthase (NOS) – the enzyme responsible for NO production – in the guinea pig VCN following acoustic trauma. NOS was present in most cell types – including spherical and globular bushy cells, small, medium, and large multipolar cells, and octopus cells – spanning the entire extent of the VCN. The staining pattern was symmetrical in control animals. Unilateral acoustic over-exposure (AOE) resulted in marked asymmetries between ipsilateral and contralateral sides of the VCN in terms of the distribution of NOS across the cochlear nuclei in animals with behavioral evidence of tinnitus: fewer NOS-positive cells and a reduced level of NOS staining was present across the whole extent of the contralateral VCN, relative to the ipsilateral VCN. The asymmetric pattern of NOS-containing cells was observed as early as 1 day after AOE and was also present in some animals at 3, 7, and 21 days after AOE. However, it was not until 8 weeks after AOE, when tinnitus had developed, that asymmetries were significant overall, compared with control animals. Asymmetrical NOS expression was not correlated with shifts in the threshold hearing levels. Variability in NOS expression between animals may represent one underlying difference that can be linked to whether or not tinnitus develops after noise exposure.

Up-regulation of GAP-43 in the chinchilla ventral cochlear nucleus after carboplatin-induced hearing loss: Correlations with inner hair cell loss and outer hair cell loss

Inner ear damage leads to nerve fiber growth and synaptogenesis in the ventral cochlear nucleus (VCN). In this study, we documented the relationship between hair cell loss patterns and synaptic plasticity in the chinchilla VCN using immunolabeling of the growth associated protein-43 (GAP-43), a protein associated with axon outgrowth and modification of presynaptic endings. Unilateral round window application of carboplatin caused hair cell degeneration in which inner hair cells (IHC) were more vulnerable than outer hair cells (OHC). One month after carboplatin treatment (0.5–5 mg/ml), we observed varying patterns of cochlear hair cell loss and GAP-43 expression in VCN. Both IHC loss and OHC loss were strongly correlated with increased GAP-43 immunolabeling in the ipsilateral VCN. We speculate that two factors might promote the expression of GAP-43 in the VCN; one is the loss of afferent input through IHC or the associated type I auditory nerve fibers. The other occurs when the medial olivocochlear efferent neurons lose their cochlear targets, the OHC, and may as compensation increase their synapse numbers in the VCN.

Somatosensory Projections to Cochlear Nucleus Are Upregulated after Unilateral Deafness

The cochlear nucleus (CN) receives innervation from auditory and somatosensory structures, which can be identified using vesicular glutamate transporters, VGLUT1 and VGLUT2. VGLUT1 is highly expressed in the magnocellular ventral CN (VCN), which receives auditory nerve inputs. VGLUT2 is predominantly expressed in the granule cell domain (GCD), which receives nonauditory inputs from somatosensory nuclei, including spinal trigeminal nucleus (Sp5) and cuneate nucleus (Cu). Two weeks after unilateral deafening VGLUT1 is significantly decreased in ipsilateral VCN while VGLUT2 is significantly increased in the ipsilateral GCD (Zeng et al., 2009), putatively reflecting decreased inputs from auditory nerve and increased inputs from nonauditory structures in guinea pigs. Here, we wished to determine whether the upregulation of VGLUT2 represents increases in the number of somatosensory projections to the CN that are maintained for longer periods of time. Thus, we examined concurrent changes in VGLUT levels and somatosensory projections in the CN using immunohistochemistry combined with anterograde tract tracing three and six weeks following unilateral deafening. The data reveal that unilateral deafness leads to increased numbers of VGLUT2-colabeled Sp5 and Cu projections to the ventral and dorsal CN. These findings suggest that Sp5 and Cu play significant and unique roles in cross-modal compensation and that, unlike after shorter term deafness, neurons in the magnocellular regions also participate in the compensation. The enhanced glutamatergic somatosensory projections to the CN may play a role in neural spontaneous hyperactivity associated with tinnitus.

Low‐voltage activated Kv1.1 subunits are crucial for the processing of sound source location in the lateral superior olive in mice

Voltage-gated potassium (Kv) channels containing Kv1.1 subunits are strongly expressed in neurons that fire temporally precise action potentials (APs). In the auditory system, AP timing is used to localize sound sources by integrating interaural differences in time (ITD) and intensity (IID) using sound arriving at both cochleae. In mammals, the first nucleus to encode IIDs is the lateral superior olive (LSO), which integrates excitation from the ipsilateral ventral cochlear nucleus and contralateral inhibition mediated via the medial nucleus of the trapezoid body. Previously we reported that neurons in this pathway show reduced firing rates, longer latencies and increased jitter in Kv1.1 knockout (Kcna1−/−) mice. Here, we investigate whether these differences have direct impact on IID processing by LSO neurons. Single-unit recordings were made from LSO neurons of wild-type (Kcna1+/+) and from Kcna1−/− mice. IID functions were measured to evaluate genotype-specific changes in integrating excitatory and inhibitory inputs. In Kcna1+/+ mice, IID sensitivity ranged from +27 dB (excitatory ear more intense) to −20 dB (inhibitory ear more intense), thus covering the physiologically relevant range of IIDs. However, the distribution of IID functions in Kcna1−/− mice was skewed towards positive IIDs, favouring ipsilateral sound positions. Our computational model revealed that the reduced performance of IID encoding in the LSO of Kcna1−/− mice is mainly caused by a decrease in temporal fidelity along the inhibitory pathway. These results imply a fundamental role for Kv1.1 in temporal integration of excitation and inhibition during sound source localization.

Ephrin-B Reverse Signaling Is Required for Formation of Strictly Contralateral Auditory Brainstem Pathways

Specificity in the projections from the mammalian ventral cochlear nucleus (VCN) is essential for sound localization. Globular bushy cells project from the VCN to the medial nucleus of the trapezoid body (MNTB) on the contralateral, but not the ipsilateral, side of the brainstem, terminating in large synaptic endings known as calyces of Held. The precision in this pathway is critical for the computation of interaural intensity differences, which are used in sound localization. The mechanisms underlying the development of this projection are not completely understood. In this study, we tested the role of Eph receptor tyrosine kinases and their ephrin ligands in limiting the VCN-MNTB projection to the contralateral side. We found that mice with null mutations in EphB2 and EphB3 had normal contralateral VCN-MNTB projections, yet these projections also had significant numbers of aberrant collateral branches in the ipsilateral MNTB. These aberrant branches ended in calyceal terminations in MNTB. Similar ipsilateral projections were seen in mice with mutations in ephrin-B2. In both of these mouse lines, ipsilateral projections formed concurrently with normal contralateral projections and were not eliminated later in development. However, mice with mutations that affected only the intracellular domain of EphB2 had normal, strictly contralateral VCN-MNTB projections. Expression studies showed that EphB2 is expressed in VCN axons and ephrin-B2 is expressed in MNTB. Together, these data suggest that EphB2-ephrin-B2 reverse signaling is required to prevent the formation of ipsilateral VCN-MNTB projections and that this signaling operates non-cell autonomously.

Central auditory plasticity after carboplatin-induced unilateral inner ear damage in the chinchilla: Up-regulation of GAP-43 in the ventral cochlear nucleus

Inner ear damage may lead to structural changes in the central auditory system. In rat and chinchilla, cochlear ablation and noise trauma result in fiber growth and synaptogenesis in the ventral cochlear nucleus (VCN). In this study, we documented the relationship between carboplatin-induced hair cell degeneration and VCN plasticity in the chinchilla. Unilateral application of carboplatin (5 mg/ml) on the round window membrane resulted in massive hair cell loss. Outer hair cell degeneration showed a pronounced basal-to-apical gradient while inner hair cell loss was more equally distributed throughout the cochlea. Expression of the growth associated protein GAP-43, a well-established marker for synaptic plasticity, was up-regulated in the ipsilateral VCN at 15 and 31 days post-carboplatin, but not at 3 and 7 days. In contrast, the dorsal cochlear nucleus showed only little change. In VCN, the high-frequency area dorsally showed slightly yet significantly stronger GAP-43 up-regulation than the low-frequency area ventrally, possibly reflecting the high-to-low frequency gradient of hair cell degeneration. Synaptic modification or formation of new synapses may be a homeostatic process to re-adjust mismatched inputs from two ears. Alternatively, massive fiber growth may represent a deleterious process causing central hyperactivity that leads to loudness recruitment or tinnitus.

Electrical stimulation of the cochlear nerve in rats: analysis of c-Fos expression in auditory brainstem nuclei

We investigated functional activation of central auditory brainstem nuclei in response to direct electrical stimulation of the cochlear nerve using c-Fos immunoreactivity as a marker for functional mapping. The cochlear nerve was stimulated in the cerebellopontine angle of Lewis rats applying biphasic electrical pulses (120–250 μA, 5 Hz) for 30 min. In a control group, bilateral cochlectomy was performed in order to assess the basal expression of c-Fos in the auditory brainstem nuclei. The completeness of cochlear ablations and the response of auditory brainstem nuclei to electrical stimulation were electrophysiologically verified. C-Fos immunohistochemistry was performed using the free floating method. In anaesthetized animals with unilateral electrical stimulation of the cochlear nerve, increased expression of c-Fos was detected in the ipsilateral ventral cochlear nucleus (VCN), in the dorsal cochlear nucleus bilaterally (DCN), in the ipsilateral lateral superior olive (LSO) and in the contralateral inferior colliculus (IC). A bilateral slight increase of c-Fos expression in all subdivisions of the lateral lemniscus (LL) did not reach statistical significance. Contralateral inhibition of the nuclei of the trapezoid body (TB) was observed. Our data show that unilateral electrical stimulation of the cochlear nerve leads to increased expression of c-Fos in most auditory brainstem nuclei, similar to monaural auditory stimulation. They also confirm previous studies suggesting inhibitory connections between the cochlear nuclei. C-Fos immunoreactivity mapping is an efficient tool to detect functional changes following direct electrical stimulation of the cochlear nerve on the cellular level. This could be particularly helpful in studies of differential activation of the central auditory system by experimental cochlear and brainstem implants.

Molecular Plasticity in the Rat Auditory Brainstem: Modulation of Expression and Distribution of Phosphoserine, Phospho-CREB and TrkB after Noise Trauma

We induced acoustic trauma by applying click stimuli of 130 dB (SPL) for 30 min to one ear of adult rats. This treatment resulted in an instant and permanent threshold shift of 96 dB in the affected ear. A massive reduction of cochlear nerve fibers in the ventral cochlear nucleus (VCN) was demonstrated by tracing them from the cochlea of rats that survived acoustic overstimulation for 1 year or longer. In the auditory brainstem, we observed a deprivation-dependent appearance of fibers positive for tyrosine receptor kinase B in the ipsilateral VCN between day 3 and day 21 after trauma and an increase in phosphoserine immunostaining in the neuropil of the ipsilateral VCN and in neurons of the contralateral lateral superior olive during the first 30 days after trauma. Immunoreactivity for the cAMP response element binding protein in its phosphorylated form was transiently depressed in the ipsilateral inferior colliculus immediately after trauma and was elevated as late as 7 months after trauma in the ipsilateral VCN. Apparently, a unilateral acoustic overstimulation entails specific regulations of the activity of plasticity-associated molecules through phosphorylation and includes changes to neurotrophin signaling between neurons of the auditory brainstem.

Fine structure and neurotransmitter cytochemistry of neurons in the rat ventral cochlear nucleus projecting to the ipsilateral dorsal cochlear nucleus

The neural tracer wheat germ agglutinin conjugated to horse radish peroxidase was injected into the rat dorsal cochlear nucleus and acoustic stria. Some labelled neurons in the ipsilateral ventral cochlear nucleus were found as a result. These neurons were studied at the ultrastructural level, and their axo-somatic synaptic profile and glycine immunoreactivity were determined. Most neurons were glycine negative and classified as type I multipolar neurons. The latter showed a different synaptic profile from that of neurons projecting to the contralateral inferior colliculus or cochlear nucleus. This suggests the presence of differing populations of multipolar cells based on their synaptic profile. Few labelled multipolar neurons of type II were found, which appeared glycine negative and, rarely, glycine positive. The latter show an ultrastructure and axo-somatic profile similar to that of glycinergic commissural neurons in the dorsal and ventral cochlear nucleus. In particular, about one-third of boutons contained round synaptic vesicles, which are believed to contain an excitatory neurotransmitter. The ultrastructural analysis of the synaptic boutons in the cochlear nucleus confirms the presence of numerous cases of colocalization of glycine and GABA where flat and pleomorphic synaptic vesicles are mixed. The present study is in accordance with previous tract-tracing light microscopic studies which have indicated that large glycinergic neurons in the ventral cochlear nucleus act as broad-band inhibitory neurons in microcircuits of the dorsal cochlear nucleus and contralateral cochlear nucleus.

Lack of growth-associated protein-43 reemergence or of growth-associated protein-43 mRNA modulation in deafferented vestibular nuclei during the first 6 weeks after unilateral inner ear lesion.

We investigated whether a unilateral inner ear lesion that destroyed the labyrinthine receptors, the cochlear receptors, and the spiral ganglion induced collateral sprouting in rat vestibular and auditory brainstem nuclei, using growth-associated protein-43 (GAP-43) as an indicator of synaptic remodeling. Both immunocytochemistry and in situ hybridization were performed to detect a potential modulation of GAP-43 and of its messenger RNA (mRNA) at different times after surgery. We failed to observe a reemergence of GAP-43 or a modulation of its mRNA in the deafferented vestibular nuclei at all survival times tested. In contrast, a substantial increase in the expression of GAP-43 was observed in the neuropil of the ipsilateral deafferented cochlear nuclei and in cell bodies of the ipsilateral superior olive. This increase was associated with an up- and downregulation of the mRNA coding for GAP-43 in the ipsilateral ventral cochlear nucleus and in the ipsilateral superior olive, respectively. These data indicate that synaptic remodeling, as assessed by GAP-43 expression, does not seem to occur in the deafferented vestibular complex during the first 6 weeks after labyrinthectomy, whereas it occurs within the first deafferented auditory relays at times as early as 4 days following spiral ganglion and cochlear receptors removal. We conclude that recovery of a normal resting discharge of the deafferented central vestibular neurons and consequently recovery of a normal resting posture and eye position may not depend on collateral sprouting of the remaining vestibular afferents. In contrast, we confirmed that a reactive synaptogenesis occurs in the brainstem auditory nuclei following cochlea and spiral ganglion removal. Its functional significance remains an open question.

Sources of input to the cochlear granule cell region in the guinea pig

Anterograde and retrograde transport of fluorogold was used to trace input to the superficial granule cell layer of the ventral cochlear nucleus in the guinea pig. Infusion of fluorogold into the labyrinth resulted in heavy labeling of eighth nerve axons and their terminals in the ventral cochlear nucleus, but only a few labeled axons entered the granule cell layer. Injections of fluorogold restricted to the granule cell layer retrogradely labeled neurons in the ipsilateral lateral superior olivary nucleus, in the periolivary region predominantly contralaterally, and in the inferior colliculus predominantly ipsilaterally. Labeled neurons were also present in the ipsilateral ventral cochlear nucleus, but this may be due to interruption of axons of passage in the lateral ventrotubercular tract. Overall this study demonstrates very restricted direct cochlear input to the granule cell region, but provides evidence for projections from several brainstem auditory nuclei.

Re-emergence of GAP-43 in cochlear nucleus and superior olive following cochlear ablation in the rat

The effect of cochlear lesion on the expression of the growth associated protein GAP-43 in superior olive and cochlear nucleus was studied in the rat. In normal development of these auditory brainstem nuclei, GAP-43 immunoreactivity is high perinatally but low 10 days postnatally or thereafter. Removal of one spiral ganglion in grown-up animals caused a substantial re-emergence of GAP-43 immunoreactivity in varicose fibers of the ipsilateral ventral cochlear nucleus and cell bodies of the lateral superior olive. These findings suggest that a reactive synaptogenesis takes place in the cochlear nucleus as a consequence of deafening through spiral ganglion loss.

Projections to the medial superior olive from the medial and lateral nuclei of the trapezoid body in rodents and bats

In this study we present direct evidence of axonal projections from both the medial and lateral nuclei of the trapezoid body to the medial superior olive. Projections were traced by intracellularly labeling cells and axons in a tissue slice preparation of two rodent species, Mus musculus and Meriones unguiculatus and two bat species, Eptesicus fuscus and Pteronotus parnellii. The main axon of most principal cells in the medial nucleus of the trapezoid body gives off one or more collateral branches which arborize within the medial superior olive. These collateral axons form small bouton-like swellings which primarily contact somata within the central cell column in the medial superior olive. Likewise, labeled elongate and multipolar cells of the lateral nucleus of the trapezoid body send axons to both the medial and lateral superior olives. These axons also form perisomatic contacts in both target nuclei. These two sets of projections may relay ascending input to the medial superior olive and the lateral superior olive; the medial nucleus of the trapezoid body is known to relay input from the contralateral ventral cochlear nucleus, and the lateral nucleus of the trapezoid body may relay input from the ipsilateral ventral cochlear nucleus. These projections offer two routes for indirect, possibly inhibitory input to reach the medial superior olive from both cochlear nuclei. These indirect, inhibitory pathways may parallel the direct excitatory projections the medial superior olive receives from each cochlear nucleus.

Acoustic chiasm III: Nature, distribution, and sources of afferents to the lateral superior olive in the cat

The outcomes of seven experiments are reported, each directed to the nature and sources of the excitation and inhibition impinging on the lateral superior olive (LSO) in cats. In the first experiment, we used conventional 14C 2-DG methods to determine the specificity, precision, and extent of symmetry in the stimulation reaching LSO from the ipsilateral and contralateral ears. In Experiment 2, we sought the presence of GABA and glycine receptors in LSO using conventional, in vitro receptor-binding methods. On the basis of these results, we used in vitro high-affinity uptake methods in Experiment 3 to seek evidence that some of the terminals as well as the receptors in LSO are glycinergic. In Experiment 4, we used immunocytochemical methods to show that the somata known to supply the contralateral projections to LSO, and their terminals in LSO, are each immunoreactive with an antibody directed to a glycine-protein conjugate. In Experiment 5, we made use of a glycinergic neuron's avidity for transporting glycine retrogradely to label the likely sources of the glycinergic terminals in LSO. In Experiment 6, we used immunocytochemical methods to show that the spherical and globular cells of the ventral cochlear nucleus and terminals in LSO and in MTB are glutamatergic and/or aspartergic. In Experiment 7, we used receptor binding methods to determine whether the glutamate/aspartate receptors in LSO are probably of the kainate or of the quisqualate type. The results of the several experiments suggest that probably glutamate-quisqualate synapses mediate LSO's ipsilaterally driven excitatory responses and glycinergic synapses mediate its contralaterally driven inhibitory responses. The two types of input appear to be well matched in LSO's medial and middle limbs with glycinergic terminals mostly perisomatic and glutamatergic terminals mostly peridendritic. However, LSO's low frequency lateral limb appears to be somewhat different; it receives less stimulation from the contralateral ear. Instead, LSO's lateral limb may receive some of its glycinergic input directly from the ipsilateral ventral cochlear nucleus and/or indirectly via the juxtaposed lateral nucleus of the trapezoid body.

Histological study of long-term effects induced by systemic administration of KA at different developing ages : G.F. Ricci, L. Rocchi, G. Cusimano, G. Palladini (Roma-Italy)

Principal cells of the lateral superior olivary nucleus (LSO) are thought to receive a direct excitatory input from spherical bushy cells located in the ipsilateral ventral cochlear nucleus (VCN) and an indirect input from the contralateral VCN globular bushy cells via a secure synapse in the medial nucleus of the trapezoid body (MNTB). MNTB bushy cells project to the somata and proximal dendrites of LSO principal cells. LSO neurons display phasic ‘chopper’ temporal response patterns to ipsilateral tone-burst stimuli at characteristic frequency (CF), while binaural stimuli suppress this ipsilaterally evoked activity. This suppression is sensitive to interaural differences in intensity, phase and time, suggesting a role for these neurons in the localization of sound in space. In the present study, the nature of the neurotransmitter mediating fast ipsilateral excitation of LSO neurons was examined using iontophoretic application of excitant amino acid (EAA) agonists and antagonists. N-methyl-d-aspartate (NMDA) and quisqualate (QUIS) were used as agonists, while the selective NMDA receptor antagonists d. l-2-amino-5-phosphonovaleric acid (APV), and the non-selective receptor EAA antagonist cis-2,3-piperidine-dicarboxylic acid (PDA) were used to study ipsilaterally evoked neuronal responses. In 3 additional experiments the selective non-NMDA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX) replaced PDA. Ipsilateral, tone-evoked and spontaneous activities were generally enhanced by EAA agonists while partial blockade of tone-evoked, ipsilateral excitation was observed with EAA antagonists. Both PDA and DNQX more effectively blocked ipsilateral tone-evoked excitations and spontaneous activity than did the NMDA-receptor antagopnist, APV, QUIS application enhanced both spontaneous and tone-evoked responses to a greater extent than did NMDA application. These findings indicate that EAA receptors are present on LSO principal cells and suggest that if an EAA mediates fast ipsilateral excitatory responses in LSO it is unlikely to utilize slow NMDA receptors but is acting through non-NMDA receptors of the QUIS or kainate receptors types.

Formula omitted] receptors may mediate ipsilateral excitation at lateral superior olivary synapses

Principal cells of the lateral superior olivary nucleus (LSO) are thought to receive a direct excitatory input from spherical bushy cells located in the ipsilateral ventral cochlear nucleus (VCN) and an indirect input from the contralateral VCN globular bushy cells via a secure synapse in the medial nucleus of the trapezoid body (MNTB). MNTB bushy cells project to the somata and proximal dendrites of LSO principal cells. LSO neurons display phasic ‘chopper’ temporal response patterns to ipsilateral tone-burst stimuli at characteristic frequency (CF), while binaural stimuli suppress this ipsilaterally evoked activity. This suppression is sensitive to interaural differences in intensity, phase and time, suggesting a role for these neurons in the localization of sound in space. In the present study, the nature of the neurotransmitter mediating fast ipsilateral excitation of LSO neurons was examined using iontophoretic application of excitant amino acid (EAA) agonists and antagonists. N- methyl- d-aspartate (NMDA) and quisqualate (QUIS) were used as agonists, while the selective NMDA receptor antagonists d. l-2-amino-5-phosphonovaleric acid (APV), and the non-selective receptor EAA antagonist cis-2,3-piperidine-dicarboxylic acid (PDA) were used to study ipsilaterally evoked neuronal responses. In 3 additional experiments the selective non-NMDA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX) replaced PDA. Ipsilateral, tone-evoked and spontaneous activities were generally enhanced by EAA agonists while partial blockade of tone-evoked, ipsilateral excitation was observed with EAA antagonists. Both PDA and DNQX more effectively blocked ipsilateral tone-evoked excitations and spontaneous activity than did the NMDA-receptor antagopnist, APV, QUIS application enhanced both spontaneous and tone-evoked responses to a greater extent than did NMDA application. These findings indicate that EAA receptors are present on LSO principal cells and suggest that if an EAA mediates fast ipsilateral excitatory responses in LSO it is unlikely to utilize slow NMDA receptors but is acting through non-NMDA receptors of the QUIS or kainate receptors types.