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Responses of cochlear nucleus units in the chinchilla to iterated rippled noises: analysis of neural autocorrelograms.

Temporal encoding of stimulus features related to the pitch of iterated rippled noises was studied for single units in the chinchilla cochlear nucleus. Unlike other periodic complex sounds that produce pitch, iterated rippled noises have neither periodic waveforms nor highly modulated envelopes. Infinitely iterated rippled noise (IIRN) is generated when wideband noise (WBN) is delayed (tau), attenuated, and then added to (+) or subtracted from (-) the undelayed WBN through positive feedback. The pitch of IIRN[+, tau, -1 dB] is at 1/tau, whereas the pitch of IIRN[-, tau, -1 dB] is at 1/2tau. Temporal responses of cochlear nucleus units were measured using neural autocorrelograms. Synchronous responses as shown by peaks in neural autocorrelograms that occur at time lags corresponding to the IIRN tau can be observed for both primarylike and chopper unit types. Comparison of the neural autocorrelograms in response to IIRN[+, tau, -1 dB] and IIRN[-, tau, -1 dB] indicates that the temporal discharge of primarylike units reflects the stimulus waveform fine structure, whereas the temporal discharge patterns of chopper units reflect the stimulus envelope. The pitch of IIRN[+/-, tau, -1 dB] can be accounted for by the temporal discharge patterns of primarylike units but not by the temporal discharge of chopper units. To quantify the temporal responses, the height of the peak in the neural autocorrelogram at a given time lag was measured as normalized rate. Although it is well documented that chopper units give larger synchronous responses than primarylike units to the fundamental frequency of periodic complex stimuli, the largest normalized rates in response to IIRN[+, tau, -1 dB] were obtained for primarylike units, not chopper units. The results suggest that if temporal encoding is important in pitch processing, then primarylike units are likely to be an important cochlear nucleus subsystem that carries the pitch-related information to higher auditory centers.

Acoustic Stimulation↗

Heterogeneous projections of the cat posteroventral cochlear nucleus.

The anterograde tracer Phaseolus vulgaris-leucoagglutinin was used to identify the projections of the posteroventral cochlear nucleus in cats. After labeling predominately cells of the core and multipolar regions, varicose fibers were observed in a variety of auditory nuclei. Ipsilaterally, most varicose fibers were located in periolivary regions situated lateral to the medial superior olive of the superior olivary complex. Contralaterally, the majority of labeled fibers were located in the ventral nucleus of the trapezoid body and the ventral nucleus of the lateral lemniscus. Labeled varicose fibers were also observed in regions not commonly identified as receiving input from the posteroventral cochlear nucleus. These regions included bilaterally the principal nuclei of the superior olivary complex, some periolivary regions, and the sagulum, as well as the ipsilateral intermediate and dorsal nucleus of the lateral lemniscus, inferior colliculus, and lateral pontine nucleus. Both similarities and differences were observed in the projections of the core and multipolar regions. With the exception of calyceal-type endings in the contralateral ventral nucleus of the lateral lemniscus, the varicose fibers in all regions, including the contralateral medial nucleus of the trapezoid body, were beaded, en passant type terminal varicosities.

Animals↗

Recovery of forward-masked responses in ventral cochlear nucleus neurons.

Single unit responses were obtained from 8 classes of cells in the ventral cochlear nucleus: Primarylike, Primarylike with characteristic frequencies below 1 kHz, Primarylike-Notch, Sustained Chopper, Transient-Chopper, Low-intensity Chopper; Onset with later activity and On-Chopper. Stimuli were paired tonebursts, a masker preceding a probe, separated by time delta t ms. The decrement in discharge rate to the probe was measured as a function of delta t and constituted the forward-masking recovery function. The recovery functions of primarylike units were similar to those reported for auditory nerve fibers, but recovered more slowly than all other classes of units in the ventral cochlear nucleus. Some units, such as onset units, were completely masked at short masker-probe intervals, while others, such as the low-intensity choppers, were less affected by the masker. More masking occurred in the first 2 ms of the response (onset rate) than in the overall response (average rate). Using shorter maskers and measuring the onset rate produced greater differences in masking functions between unit classes. Units with high spontaneous activity were more resistant to the effects of the masker than units with low and medium spontaneous activity. This was especially evident at high masker levels and short masker-probe intervals. Units other than primarylike often showed non-monotonic relationships between the firing rate evoked by the masker and the firing rate decrement in response to the probe, suggesting that both adaptation and inhibition are operating to produce the observed effects.

Acoustic Stimulation↗

Neural organization and responses to complex stimuli in the dorsal cochlear nucleus.

The dorsal division of the cochlear nucleus (DCN) is the most complex of its subdivisions in terms of both anatomical organization and physiological response types. Hypotheses about the functional role of the DCN in hearing are as yet primitive, in part because the organizational complexity of the DCN has made development of a comprehensive and predictive model of its input-output processing difficult. The responses of DCN cells to complex stimuli, especially filtered noise, are interesting because they demonstrate properties that cannot be predicted, without further assumptions, from responses to narrow band stimuli, such as tones. In this paper, we discuss the functional organization of the DCN, i.e. the morphological organization of synaptic connections within the nucleus and the nature of synaptic interactions between its cells. We then discuss the responses of DCN principal cells to filtered noise stimuli that model the spectral sound localization cues produced by the pinna. These data imply that the DCN plays a role in interpreting sound localization cues; supporting evidence for such a role is discussed.

Acoustic Stimulation↗

In vivo measures of cochlear length and insertion depth of nucleus cochlear implant electrode arrays.

Three-dimensional cochlear canal lengths, electrode array intracochlear insertion depths, and characteristic frequency ranges were estimated for 20 Nucleus implant recipients on the basis of in vivo computed tomography (CT) scans. Ultra-high resolution images were reconstructed from spiral CT data with 0.1-mm slicing and expanded attenuation scales. Canal length estimates (mean 33.01 mm; SD 2.31) were consistent with previous findings for normal human temporal bones. Intracochlear array insertion depths estimated by 3-dimensional (3-D) spiral calculations (mean 20.19 mm; SD 2.86) and by a computerized array tracking algorithm (mean 20.36 mm; SD 2.66) were not significantly different. Estimates from surgical observations were significantly longer (mean 21.03 mm; SD 2.31) because array compressions were not detectable. Characteristic frequencies at apical electrodes estimated from Greenwood's equations ranged from 387 Hz to 2,596 Hz. The results show that significant variations in cochlear anatomy and array distribution among implant patients that may impact implant performance can be reliably detected and quantified by using in vivo high-resolution CT and 3-D reconstructions.

Adult↗

Fine structure of long-term changes in the cochlear nucleus after acoustic overstimulation: chronic degeneration and new growth of synaptic endings.

The companion study showed that acoustic overstimulation of adult chinchillas, with a noise level sufficient to damage the cochlea, led to cytological changes and degeneration of synaptic endings in the cochlear nucleus within 1-16 weeks. In the present study, the same stimulus was used to study the long-term effects on the fine structure of synaptic endings in the cochlear nucleus. For periods of 6 and 8 months after a single exposure to a damaging noise level, there ensued a chronic, continuing process of neurodegeneration involving excitatory and inhibitory synaptic endings. Electron microscopic observations demonstrated freshly occurring degeneration even as late as 8 months. Degeneration was widespread in the neuropil and included the synapses on the globular bushy cell, which forms part of the main ascending auditory pathway. Neurodegeneration was accompanied by newly formed synaptic endings, which repopulated some of the sites vacated previously by axosomatic endings on globular bushy cells. Many of these synaptic endings must arise from central interneurons. The findings suggest that overstimulation can induce a self-sustaining condition of progressive neurodegeneration accompanied by a new growth of synaptic endings. Noise-induced hearing loss thus may progress as a neurodegenerative disease with the capacity for synaptic reorganization within the cochlear nucleus.

Acoustic Stimulation↗

Asymmetric uptake of 2-deoxy-D-[14C]glucose in the dorsal cochlear nucleus during Pavlovian conditioning in the rabbit.

Uptake of 2-deoxy-D-[14C]glucose was measured during Pavlovian conditioning of the rabbit's nictitating membrane response by both qualitative autoradiography and by quantitative measurement of radioactivity in samples of brain tissue. Conditioning was accomplished by pairing a tone stimulus delivered to both ears with an air-puff stimulus delivered to the right eye. Infusion of 2-deoxy-D-[14C]glucose during the first day of conditioning when there was no evidence of acquisition or during the 7th day of conditioning when animals demonstrated 68% conditioned responses resulted in a significantly greater uptake of radioactivity by the caudal portions of the left as compared with the right dorsal cochlear nucleus. Similar changes were not observed in other auditory and non-auditory nuclei. Rabbits that had acquired conditioned responses across 6 days of training and were exposed only to the tone-conditioned stimulus on the 7th day of testing exhibited 69% conditioned responses but no asymmetry in the uptake of 2-deoxy-D-[14C]glucose. Control animals receiving unpaired presentations of tone and air puff or no stimulation did not acquire conditioned responses and did not demonstrate asymmetric uptake of radioactivity in the dorsal cochlear nucleus. These results indicate that the asymmetric uptake of radioactivity by the dorsal cochlear nucleus did not result from the effects of stimulation per se or the prior occurrence of learning but was due to the explicit pairing of the tone stimulus with the asymmetric delivery of the air puff. It would appear that the caudal dorsal cochlear nucleus not only serves as a signal transducer for auditory stimuli but also receives inputs from other sensory systems thus allowing it to both recognize when an auditory stimulus is followed by a biologically significant event and to transmit such information to other brain regions that are, in turn, responsible for learning.

Animals↗

Effects of trigeminal ganglion stimulation on unit activity of ventral cochlear nucleus neurons.

The trigeminal ganglion sends a projection to the granule and magnocellular regions of the ventral cochlear nucleus (VCN; [J Comp Neurol 419 (2000) 271]), as well as to the cochlea ([Neuroscience 79 (1997) 605; Neuroscience 84 (1998a) 559]). We investigated the effects of electrically stimulating the trigeminal ganglion on unit responses in the guinea-pig VCN. Responses consisted of one, two or more phases of excitation, sometimes followed by a longer inhibitory phase. The latencies to the first excitation peak ranged between 5 and 17 ms from the onset of stimulation. These responses were preceded by a slow wave potential evoked by the stimulation. Applying kainic acid, which eliminates VIIIth nerve responses, diminished the firing rates of VCN units to trigeminal stimulation, and increased their first spike latencies. Cochlear destruction had a similar effect. The responses in VCN evoked by trigeminal ganglion stimulation therefore appear to result from direct stimulation of the trigeminal ganglion-cochlear nucleus pathway, as well as modulation by the trigeminal ganglion-cochlear pathway. Alternatively, a reduction in spontaneous rate of VCN neurons by removal of VIIIth nerve input could explain the decreased response to trigeminal stimulation after cochlear manipulations. The modulation of firing rate in second order auditory neurons by first order somatosensory neurons could influence central auditory targets and may be involved in generating or modulating perceptions of phantom sounds which can be modified by manipulations of somatic regions of the head and neck ("somatic tinnitus").

Action Potentials↗

Neuronal morphology in the human cochlear nucleus.

Neuronal morphology in the human cochlear nucleus was studied with a Golgi method to better understand the organization of the nucleus. In ventral portions of the nucleus, three principal cell types and two small cell types previously seen in animals were found. In the dorsal portions of the nucleus, predominant cell types found in animals appear to be absent, indicating that cellular organization here is quite different from that in animals. On the other hand, cell morphology in the ventral nucleus suggests that signal processing here is fundamentally similar to that in animals. A review of the organization of these cells in animals is presented to provide a context of present results. The findings have great relevance in light of efforts to implant electrical prostheses in the nucleus.

Cell Nucleus↗

Outward currents in isolated ventral cochlear nucleus neurons.

Neurons of the ventral cochlear nucleus (VCN) perform diverse information processing tasks on incoming activity from the auditory nerve. We have investigated the cellular basis for functional diversity in VCN cells by characterizing the outward membrane conductances of acutely isolated cells using whole-cell, tight-seal, current- and voltage-clamp techniques. The electrical responses of isolated cells fall into two broad categories. Type 1 cells respond to small depolarizations with a regular train of action potentials. Under voltage clamp, these cells exhibit a noninactivating outward current for voltage steps positive to -35 mV. Analysis of tail currents reveals two exponentially decaying components with slightly different voltage dependence. These currents reverse at -73 mV, near the potassium equilibrium potential of -84 mV, and are blocked by tetraethylammonium (TEA). The major outward current in Type I cells thus appears to be mediated by potassium channels. In contrast to Type I cells, Type II cells respond to small depolarizations with only one to three short-latency action potentials and exhibit strong rectification around -70 mV. Under voltage clamp, these cells exhibit a noninactivating outward current with a threshold near -70 mV. Analysis of tail currents reveals two components with different voltage sensitivity and kinetics. A low-threshold current with slow kinetics is partly activated at rest. This current reverses at -77 mV and is blocked by 4-aminopyridine (4-AP) but is only partly affected by TEA. The other component is a high-threshold current activated by steps positive to -35 mV. This current is blocked by TEA, but not by 4-AP. A simple model based on the voltage dependence and kinetics of the slow low-threshold outward current in Type II cells was developed. The model produces current- and voltage-clamp responses that resemble those recorded experimentally. Our results indicate that the two major classes of acoustic response properties of VCN neurons are in part attributable to the types of outward (potassium) conductances present in these cells. The low-threshold conductance in the Type II (bushy) cells probably plays a role in the preservation of information about the acoustic stimulus phase from the auditory nerve to central auditory nuclei involved in low-frequency sound localization.

4-Aminopyridine↗

Effects of acetylcholine on cochlear nucleus neurons.

Iontophoretic application of acetylcholine (ACh) onto neurons in the dorsal cochlear nucleus (DCN) resulted in an inhibition of the tone-evoked responses of 85% of neurons which were affected. That effect in the DCN contrasts with the predominance of excitatory effects of ACh seen in ventral cochlear nucleus (VCN) neurons. The ACh-induced inhibition in the DCN had a considerably slower onset and time course of recovery than that seen with glycine-induced inhibition. The degree of ACh effects was constant with increasing intensity or attained a maximum effect at 20 to 30 dB above best-frequency threshold in contrast to glycine, which had effects that were relatively greater at low intensities. These findings suggested a modulatory role for ACh at DCN and VCN synapses.

Acetylcholine↗

Physiology of pathway from dorsal cochlear nucleus to inferior colliculus revealed by electrical and auditory stimulation.

The dorsal cochlear nucleus (DCN) projects axons to the contralateral central nucleus of the inferior colliculus (ICC) via the dorsal acoustic stria (DAS). In the anaesthetised cat, when brief electrical stimuli are applied to the caudal surface of DCN, single unit and field activity is evoked preferentially in the ventro-lateral region of ICC. Most single ICC units judged by electrical stimulation to have received a direct input from DCN are excited by contralateral tonal stimulation and inhibited or uninfluenced by ipsilateral tones. The sharp non-monotonic intensity functions of most of these units are similar to those of units in the dorsal cochlear nucleus, but ipsilateral inhibition is likely to be provided by a source other than DCN. Thus, although it is suggested that axons of DAS terminate preferentially in the ventro-lateral aspect of the contralateral ICC, it is likely that at least some neurones in this latter region receive additional input from another source - possibly the lateral superior olivary nucleus.

Acoustic Stimulation↗

Morphological changes in the anteroventral cochlear nucleus that accompany sensorineural hearing loss in DBA/2J and C57BL/6J mice.

Morphological measurements were made on histological sections of the anteroventral cochlear nucleus (AVCN) in mice of the DBA/2J and C57BL/6J strains to determine the effects of sensorineural cochlear pathology on the number, packing density, and size of neurons and on AVCN volume. Both strains possess alleles that cause progressive cochlear pathology initially affecting the organ of Corti: in DBA mice, hearing loss is evident at 4 weeks of age and progresses rapidly; in C57 mice, hearing loss begins after 2 months of age and progresses more slowly. In both strains AVCN volume decreased, some loss of neurons occurred, and these changes paralleled the progression of peripheral hearing loss. Central changes were rapid in DBA mice, but the ultimate magnitude of the changes in 1-year-old mice did not differ between strains. Both strains differed from well-hearing CBA/J mice which exhibited no changes in the AVCN measures. The findings indicate that pathology of the organ of Corti in adult mice results in degenerative changes in the cochlear nucleus. The data also support earlier findings indicating that, if cochlear pathology does not begin prior to young adulthood, the age of onset and duration of sensorineural impairment have little effect on the ultimate magnitude of central effects.

Age Factors↗

Quantitative and cytometric analysis of the ventral cochlear nucleus in man.

A systematic quantitative and cytometric study of the ventral cochlear nucleus has been performed on 3 groups of histologically normal brains, ranging in age from 20 weeks of gestation to adult life. Serial sections, 20 micrometer in thickness, through the length of the nucleus were obtained from paraffin-embedded blocks of the ponto-medullary junction. Every 10th section was analyzed with a Cambridge Imanco Quantimet 720 Image Analyzing system. The surface area of the nucleus was determined on each slide. Cells showing neuronal characteristics were individually counted and classified into 18 pre-determined cell size classes. The raw total number of cells was then corrected for periodicity and split cell error. The total volume of the nucleus and cell packing density were estimated. The mean total number of neurons was 26,098 in premature, 31,802 in full term and 30,440 in adult cases. There was no significant difference among these values. The mean volume of the nucleus was 1.32 mm3 in premature, 3.84 in full term and 5.43 in adult cases. Positive correlation coefficients were found comparing volume versus age. A negative correlation coefficient was detected comparing cell packing density versus age from the full term period to adult life. A significant increase in the number of cells in the largest cell classes was also found with increasing age. The mean neuronal diameter did not change significantly between premature and full term cases but was significantly different between full term and adult cases. These findings are discussed and compared to already reported quantitative studies of the ventral cochlear nucleus in man, which involved manual counting techniques.

Adult↗

Single unit analysis of the posteroventral cochlear nucleus of the decerebrate cat.

Single unit recordings were obtained in the cochlear nuclear complex of the unanesthetized, decerebrate cat. Sixty-six of 282 units were localized to the posteroventral cochlear nucleus, 17 from the multipolar cell area and 49 from the octopus cell area. Spontaneous rates ranged from less than 1 to 75 spikes per second in the multipolar cell area and from less than 1 to 135 spikes per second in the octopus cell area. Poststimulus time histograms revealed four response types, at the best frequency, in the posteroventral cochlear nucleus. These responses were: (1) primary-like (maximum response shortly after the stimulus onset, followed by a reduction in activity to a steady state); (2) chopper (similar to primary-like but with multiple peaks in the first 10-15 milliseconds); (3) onset-ex (onset response followed by a low level of excitation); and (4) onset-in (onset response followed by inhibition). The onset-in responses represented the first observations of inhibition, at best frequency, for onset units in the mammalian cochlear nuclear complex. Analysis of interspike interval distributions showed that both spontaneous and driven activity consisted of irregular intervals for all four response types. Activity-intensity functions for primary-like, chopper and onset-ex units showed monotonic increases with increases in stimulus intensity. Activity-intensity functions for onset-in units were non-monotonic. Latency-intensity functions for primary-like, chopper and onset-ex units exhibited monotonic decreases with increases in intensity. Latency-intensity functions for onset-in units were non-monotonic. In contrast to primary-like, chopper and onset-ex units, onset-in units do not retain the intensity and temporal information coded in the eighth nerve, as least for stimuli above 2 kilohertz. It is hypothesized that a depolarization block, caused by the massive eighth nerve input to octopus cells, is responsible for the inhibition observed from onset-in units.

Animals↗

Presbyacusis and calcium-binding protein immunoreactivity in the cochlear nucleus of BALB/c mice.

The BALB/c mouse is an established model for the early development of sensorineural hearing loss, and is homozygous for the Ahl allele (age-related hearing loss). The present study was designed to determine how auditory peripheral pathology influences calcium-binding protein immunoreactivity in the cochlear nucleus in aged BALB/c mice. To address this issue the loss of hair cells, spiral ganglion neurons (SGN), and neurons in the dorsal (DCN) and posteroventral (PVCN) cochlear nucleus of BALB/c mice at 1 and 24 months of age were quantified using CAST stereological methods. These values were then compared to the percent increase in immunopositive calcium-binding proteins in the cochlear nucleus. By 24 months of age there was a near complete loss of all outer hair cells (OHC). The inner hair cell (IHC) loss was near complete in the more apical and basal regions, while in the mid-regions approximately 50% were missing. The SGN in the apical and middle turns show a 20% loss (re: 1 month) and the basal turn up to 80% loss. A statistically significant decrease in the density of DCN and PVCN neurons (25%) was found at 24 months of age compared to the one month old animals. The percentage of parvalbumin and calretinin positive neurons in the DCN and the PVCN in relation to the density of Nissl stained neurons showed significant increases at 24 months compared to the 1 month old animals. We also determine the relationship between peripheral pathology and the percent increase in calcium-binding protein immunoreactivity. In the DCN, the percent increase of calretinin and parvalbumin was correlated to the loss of SGN, IHCs and OHCs. In the PVCN, parvalbumin was correlated to SGN, IHC, and OHC loss. The percent increase in calbindin immunoreactivity was not correlated to any peripheral pathology. The data here suggest a percent increase in calcium-binding protein immunoreactivity in the cochlea nucleus in the 24 month old mice may reflect an endogenous protective strategy that is designed to counteract calcium overload that is prominent during aging and degeneration. These results will be valuable for understanding the relationship among the peripheral and central auditory system in a model demonstrating a rapidly progressive presbyacusis.

Aging↗

Activation of a metabotropic glutamate receptor increases intracellular calcium concentrations in neurons of the avian cochlear nucleus.

Metabotropic glutamate receptors have been shown to stimulate phosphatidylinositol metabolism, and subsequently liberate Ca2+ from intracellular stores, in a variety of tissue and cell types. We previously demonstrated that glutamate could stimulate phosphatidylinositol metabolism, generating inositol-1,4,5-trisphosphate (IP3), in isolated cochlear nucleus tissue from the chick. Using the calcium indicator dye fura-2 and ratiometric fluorescent imaging, this study examined the ability of glutamate and its analogs to liberate Ca2+ from intracellular stores of neurons of the avian cochlear nucleus, and qualitatively characterized the pharmacological profile of such an action. In normal, Ca(2+)-containing medium, glutamate, kainate (KA), alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA), NMDA, quisqualate (QUIS), and (+/-)-aminocyclopentane-trans-dicarboxylate (ACPD) elicited increases in intracellular calcium concentrations ([Ca2+]i). In the absence of external Ca2+, glutamate, quisqualate, and ACPD evoked increases in [Ca2+]i. In normal medium, the ionotropic glutamate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and the NMDA receptor antagonist 2-amino-5-phosphonovalerate (APV) attenuated but did not abolish the glutamate-evoked response and had no effect on the ACPD-evoked response. The putative metabotropic glutamate receptor antagonist 2-amino-3-phosphonopropionate (AP3) was without effect on the glutamate- and ACPD-evoked increases in [Ca2+]i in Ca(2+)-free medium. We conclude that a metabotropic glutamate receptor (mGluR) is present on cochlear nucleus neurons and is able to stimulate the phosphatidylinositol metabolism--Ca2+ signal transduction cascade.

Animals↗