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Neurons of the cochlear nuclei are anatomically and physiologically specialized to optimally encode temporal and spectral information about sound stimuli, in part for binaural auditory processing. The avian cochlear nucleus magnocellularis (NM) integrates excitatory eighth nerve inputs and depolarizing GABAergic inhibition such that temporal fidelity is enhanced across the synapse. The biophysical mechanisms of this depolarizing inhibition, and its role in temporal processing, are not fully understood. We used whole-cell electro-physiology and computational modeling to examine how subthreshold excitatory inputs are integrated and how depolarizing IPSPs affect spike thresholds and synaptic integration by chick NM neurons. We found that both depolarizing inhibition and subthreshold excitatory inputs cause voltage threshold accommodation, nonlinear temporal summation, and shunting. Inhibition caused such large changes in threshold that subthreshold excitatory inputs were followed by a refractory period. We hypothesize that these large shifts in threshold eliminate spikes to asynchronous inputs, providing a mechanism for the enhanced temporal fidelity seen across the eighth nerve/cochlear nucleus synapse. Thus, depolarizing inhibition and threshold shifting hone the temporal response properties of this system so as to enhance the temporal fidelity that is essential for auditory perception.

The nature of the synaptic connection from the auditory nerve onto the cochlear nucleus neurons has a profound impact on how sound information is transmitted. Short-term synaptic plasticity, by dynamically modulating synaptic strength, filters information contained in the firing patterns. In the sound-localization circuits of the brain stem, the synapses of the timing pathway are characterized by strong short-term depression. We investigated the short-term synaptic plasticity of the inputs to the bird’s cochlear nucleus angularis (NA), which encodes intensity information, by using chick embryonic brain slices and trains of electrical stimulation. These excitatory inputs expressed a mixture of short-term facilitation and depression, unlike those in the timing nuclei that only depressed. Facilitation and depression at NA synapses were balanced such that postsynaptic response amplitude was often maintained throughout the train at high firing rates (>100 Hz). The steady-state input rate relationship of the balanced synapses linearly conveyed rate information and therefore transmits intensity information encoded as a rate code in the nerve. A quantitative model of synaptic transmission could account for the plasticity by including facilitation of release (with a time constant of ~40 ms), and a two-step recovery from depression (with one slow time constant of ~8 s, and one fast time constant of ~20 ms). A simulation using the model fit to NA synapses and auditory nerve spike trains from recordings in vivo confirmed that these synapses can convey intensity information contained in natural train inputs.

The strength of synapses between auditory nerve (AN) fibers and ventral cochlear nucleus (VCN) neurons is an important factor in determining the nature of neural integration in VCN neurons of different response types. Synaptic strength was analyzed using cross-correlation of spike trains recorded simultaneously from an AN fiber and a VCN neuron in anesthetized cats. VCN neurons were classified as chopper, primarylike, and onset using previously defined criteria, although onset neurons usually were not analyzed because of their low discharge rates. The correlograms showed an excitatory peak (EP), consistent with monosynaptic excitation, in AN-VCN pairs with similar best frequencies (49% 24/49 of pairs with best frequencies within ±5%). Chopper and primarylike neurons showed similar EPs, except that the primarylike neurons had shorter latencies and shorter-duration EPs. Large EPs consistent with endbulb terminals on spherical bushy cells were not observed, probably because of the low probability of recording from one. The small EPs observed in primarylike neurons, presumably spherical bushy cells, could be derived from small terminals that accompany endbulbs on these cells. EPs on chopper or primarylike-with-notch neurons were consistent with the smaller synaptic terminals on multipolar and globular bushy cells. Unexpectedly, EPs were observed only at sound levels within about 20 dB of threshold, showing that VCN responses to steady tones shift from a 1:1 relationship between AN and VCN spikes at low sound levels to a more autonomous mode of firing at high levels. In the high level mode, the pattern of output spikes seems to be determined by the properties of the postsynaptic spike generator rather than the input spike patterns. The EP amplitudes did not change significantly when the presynaptic spike was preceded by either a short or long interspike interval, suggesting that synaptic depression and facilitation have little effect under the conditions studied here.

The brainstem auditory pathway is obligatory for all aural information. Brainstem auditory neurons must encode the level and timing of sounds, as well as their time-dependent spectral properties, the fine structure and envelope, which are essential for sound discrimination. This study focused on envelope coding in the two cochlear nuclei of the barn owl, nucleus angularis (NA) and nucleus magnocellularis (NM). NA and NM receive input from bifurcating auditory nerve fibers and initiate processing pathways specialized in encoding interaural time (ITD) and level (ILD) differences, respectively. We found that NA neurons, though unable to accurately encode stimulus phase, lock more strongly to the stimulus envelope than NM units. The spectrotemporal receptive fields (STRFs) of NA neurons exhibit a pre-excitatory suppressive field. Using multilinear regression analysis and computational modeling, we show that this feature of STRFs can account for enhanced across-trial response reliability, by locking spikes to the stimulus envelope. Our findings indicate a dichotomy in envelope coding between the time and intensity processing pathways as early as at the level of the cochlear nuclei. This allows the ILD processing pathway to encode envelope information with greater fidelity than the ITD processing pathway. Furthermore, we demonstrate that the properties of the neurons’ STRFs can be quantitatively related to spike timing reliability.

Multipolar cells in the ventral cochlear nucleus (VCN) are a structurally and functionally diverse group of projection neurons. Understanding their role in the ascending pathway involves partitioning multipolar cells into distinct populations and determining where in the brain each sends its coded messages. In this study, we used retrograde labeling techniques in rats to identify multipolar neurons that project their axons to the ipsilateral dorsal cochlear nucleus (DCN), the contralateral CN, or to both structures. Three rats received injections of biotinylated dextran amine in the ipsilateral DCN and diamidino yellow in the contralateral CN. Several radiate multipolar neurons (defined by their axonal projections to the ipsilateral DCN and their dendrites that traverse VCN isofrequency sheets) were double labeled but over 70% were not. This result suggests two distinct populations: (1) radiate-commissural (RC-) multipolar cells that project to the ipsilateral DCN and the contralateral CN and (2) radiate multipolar cells that project exclusively (in this context) to the ipsilateral DCN. In a different group of animals, we retrogradely labeled multipolar neurons that project their axons to the contralateral CN and measured the size of their cell bodies. The mean size of this population (266 ± 156 μm2) was significantly smaller than those of RC-multipolar cells (418 ± 140 μm2). We conclude that the CN commissural pathway is composed of at least two components: (1) RC-multipolar cells and (2) commissural multipolar cells that are small and medium-sized neurons that project exclusively (in this context) to the contralateral CN. These results identify separate structural groups of multipolar cells that may correspond to physiological unit types described in the literature. They also provide protocols for isolating and studying different populations of multipolar cells to determine the neural mechanisms that govern their responses to sound.

Amplitude modulation is an important feature of communication sounds. A phenomenological model of the auditory pathway that reproduces amplitude modulation coding from the outer ear to the inferior colliculus is presented. It is based on Hewitt and Meddis’ work. To improve the temporal coding for high level stimuli, high spontaneous rate and low spontaneous rate auditory nerve fibers innervate chopper cells of the cochlear nucleus. Wideband inhibitory interneurons which limit high spontaneous rate fibers connected to chopper units are added in this nucleus. The realistic structure we propose gives results closer to physiological data in terms of synchronization.

The cochlear nucleus (CN) presents a unique opportunity for quantitatively studying input-output transformations by neurons because it gives rise to a variety of different response types from a relatively homogeneous input source, the auditory nerve (AN). Particularly interesting among CN neurons are Onset (On) neurons, which have a prominent response to the onset of sustained sounds followed by little or no response in the steady-state. On neurons contrast sharply with their AN inputs, which respond vigorously throughout stimuli. On neurons can entrain to stimuli (firing once per cycle of a periodic stimulus) at up to 1000 Hz, unlike their AN inputs. To understand the mechanisms underlying these response patterns, we tested whether an integrate-to-threshold point-neuron model with a fixed refractory period can account for On discharge patterns for tones, systematically examining the effect of membrane time constant and the number and strength of the exclusively excitatory AN synaptic inputs. To produce both onset responses to high-frequency tone bursts and entrainment to a broad range of low-frequency tones, the model must have a short time constant (≈0.125 ms) and a large number (>100) of weak synaptic inputs, properties that are consistent with the electrical properties and anatomy of On-responding cells. With these parameters, the model acts like a coincidence detector with a threshold-like relationship between the instantaneous discharge rates of the output and the inputs. Onset responses to high-frequency tone bursts result because the threshold effect enhances the initial response of the AN inputs and suppresses their relatively lower sustained response. However, when the model entrains across a broad range of frequencies, it also produces short interspike intervals at the onset of high-frequency tone bursts, a response pattern not found in all types of On neurons. These results show a tradeoff, that may be a general property of many neurons, between following rapid stimulus fluctuations and responding without short interspike intervals at the onset of sustained stimuli.

Hypothesis

Auditory nerve synapses in ventral cochlear nucleus end on two principal cell types, bushy and stellate cells. While the effects of hearing loss on bushy cells has been well studied, little is known about the effects of hearing loss on synaptic input to the stellate cells. Based on prior observations in bushy cells, we hypothesized that noise-induced hearing loss (NIHL) would decrease quantal release onto stellate cells.

Study Design

Prospective, randomized animal study.

Methods

CBA/CaJ mice were exposed for 2 hours to 98dBSPL 8–16kHz noise to produce a temporary threshold shift (TTS), or 114dBSPL to produce a permanent threshold shift (PTS). Spontaneous miniature excitatory postsynaptic currents (mEPSCs) were then measured in stellate cells in brain slices of the cochlear nucleus.

Results

Click-evoked auditory brainstem evoked response thresholds were elevated by 35dB in both TTS and PTS mice. Spontaneous mEPSC frequency was found to be five-fold higher than normal in stellate cells of TTS mice and 3-fold higher in PTS mice. mEPSC amplitude was also larger in PTS mice. The mEPSC time course was not different between experimental and control groups.

Conclusions

The dramatic increase in mEPSC frequency after NIHL was not expected. The increase in mEPSC amplitude in PTS mice suggests a post-synaptic remodeling process. Both of these effects could contribute to increased spontaneous firing in the cochlear nucleus in the absence of sound. Our results also suggest that hearing loss may have different effects at auditory nerve synapses on bushy and stellate cells in the VCN.

Level of Evidence

Not applicable.

Introduction

In the auditory system, a specialised subset of sensory neurons are responsible for correctly relaying precise pitch and temporal cues to the brain. In individuals with severe-to-profound sensorineural hearing impairment these sensory auditory neurons can be directly stimulated by a cochlear implant, which restores sound input to the brainstem after the loss of hair cells. This neural prosthesis therefore depends on a residual population of functional neurons in order to function effectively.

Areas covered

In severe cases of sensorineural hearing loss where the numbers of auditory neurons are significantly depleted, the benefits derived from a cochlear implant may be minimal. One way in which to restore function to the auditory nerve is to replace these lost neurons using differentiated stem cells, thus re-establishing the neural circuit required for cochlear implant function. Such a therapy relies on producing an appropriate population of electrophysiologically functional neurons from stem cells, and on these cells integrating and reconnecting in an appropriate manner in the deaf cochlea.

Expert opinion

Here we review progress in the field to date, including some of the key functional features that stem cell-derived neurons would need to possess and how these might be enhanced using electrical stimulation from a cochlear implant.

Anatomical and physiological studies have shown that anteroventral cochlear nucleus (AVCN) neurons receive glycinergic and GABAergic inhibitory inputs. In this study, changes in the temporal responses of AVCN neurons to pure tones and complex sounds after blocking inhibition were analyzed. Blocking inhibition influenced the temporal responses of each type of AVCN neuron. Choppers showed more chopping peaks and shortened chopping cycles after blocking inhibition. Sustained and slowly adapting choppers showed increased regularity throughout the response duration after blocking inhibition, whereas most transient choppers showed increased regularity in the early part of the response. Diverse changes in temporal response patterns were observed in neurons with primary-like and unusual responses, with several neurons showing a large decrease in the first-spike latency after blocking inhibition. This result disagreed with previous findings that onset responses are less affected than sustained responses by manipulating inhibition. Although blocking inhibition had a greater effect on spontaneous activity than that on tone-evoked activity, the change in spontaneous activity was less significant because of larger variability. In addition, for relatively high level masker noises, blocking inhibition had similar effects on responses to noise-alone and noise-plus-tone stimuli, in contrast with previous studies with low-level background noise. In general, inhibition had an enhancing effect on temporal contrast only for responses to amplitude-modulated tones, for which envelope synchrony was enhanced. Results of this study contribute new information about the characteristics, functional roles, and possible sources of inhibitory inputs received by AVCN neurons.

Background

The auditory efferent system has unique neuroanatomical pathways that connect the cerebral cortex with sensory receptor cells. Pyramidal neurons located in layers V and VI of the primary auditory cortex constitute descending projections to the thalamus, inferior colliculus, and even directly to the superior olivary complex and to the cochlear nucleus. Efferent pathways are connected to the cochlear receptor by the olivocochlear system, which innervates outer hair cells and auditory nerve fibers. The functional role of the cortico-olivocochlear efferent system remains debated. We hypothesized that auditory cortex basal activity modulates cochlear and auditory-nerve afferent responses through the efferent system.

Methodology/Principal Findings

Cochlear microphonics (CM), auditory-nerve compound action potentials (CAP) and auditory cortex evoked potentials (ACEP) were recorded in twenty anesthetized chinchillas, before, during and after auditory cortex deactivation by two methods: lidocaine microinjections or cortical cooling with cryoloops. Auditory cortex deactivation induced a transient reduction in ACEP amplitudes in fifteen animals (deactivation experiments) and a permanent reduction in five chinchillas (lesion experiments). We found significant changes in the amplitude of CM in both types of experiments, being the most common effect a CM decrease found in fifteen animals. Concomitantly to CM amplitude changes, we found CAP increases in seven chinchillas and CAP reductions in thirteen animals. Although ACEP amplitudes were completely recovered after ninety minutes in deactivation experiments, only partial recovery was observed in the magnitudes of cochlear responses.

Conclusions/Significance

These results show that blocking ongoing auditory cortex activity modulates CM and CAP responses, demonstrating that cortico-olivocochlear circuits regulate auditory nerve and cochlear responses through a basal efferent tone. The diversity of the obtained effects suggests that there are at least two functional pathways from the auditory cortex to the cochlea.

The middle ear muscle reflex has been implicated in modulation of auditory input and protection of the inner ear from acoustic trauma. However, the identification of neurons in the cochlear nuclei participating in this reflex has not been fully elucidated. In the present study, we injected the retrograde transynaptic tracer pseudorabies virus into single tensor tympani (TT) muscles, and identified transynaptically labeled cochlear nucleus neurons at multiple survival times. Motoneurons controlling TT were located ventral to the ipsilateral motor trigeminal nucleus and extended rostrally towards the medial aspect of the lateral lemniscus. Transynaptically-labeled neurons were observed bilaterally in the dorsal and dorso-medial parts of ventral cochlear nuclei as early as 48 h after virus injection, and had morphological features of radiate multipolar cells. After ≥ 69 h, labeled cells of different types were observed in all cochlear nuclei. At those times, labeling was also detected bilaterally in the medial nucleus of the trapezoid body and periolivary cell groups in the superior olivary complex. Based on the temporal course of viral replication, our data strongly suggest the presence of a direct projection of neurons from the ventral cochlear nuclei bilaterally to the TT motoneuron pool in rats. The influence of neurons in the cochlear nuclei upon TT activity through direct and indirect pathways may account for multifunctional roles of this muscle in auditory functions.

The dorsal cochlear nucleus (DCN) receives afferent input from the auditory nerve and is thus usually thought of as a monaural nucleus, but it also receives inputs from the contralateral cochlear nucleus as well as descending projections from binaural nuclei. Evidence suggests that some of these commissural and efferent projections are excitatory, whereas others are inhibitory. The goals of this study were to investigate the nature and effects of these inputs in the DCN by measuring DCN principal cell (type IV unit) responses to a variety of contralateral monaural and binaural stimuli. As expected, the results of contralateral stimulation demonstrate a mixture of excitatory and inhibitory influences, although inhibitory effects predominate. Most type IV units are weakly, if at all, inhibited by tones but are strongly inhibited by broadband noise (BBN). The inhibition evoked by BBN is also low threshold and short latency. This inhibition is abolished and excitation is revealed when strychnine, a glycine-receptor antagonist, is applied to the DCN; application of bicuculline, a GABAA-receptor antagonist, has similar effects but does not block the onset of inhibition. Manipulations of discrete fiber bundles suggest that the inhibitory, but not excitatory, inputs to DCN principal cells enter the DCN via its output pathway, and that the short latency inhibition is carried by commissural axons. Consistent with their respective monaural effects, responses to binaural tones as a function of interaural level difference are essentially the same as responses to ipsilateral tones, whereas binaural BBN responses decrease with increasing contralateral level. In comparison to monaural responses, binaural responses to virtual space stimuli show enhanced sensitivity to the elevation of a sound source in ipsilateral space but reduced sensitivity in contralateral space. These results show that the contralateral inputs to the DCN are functionally relevant in natural listening conditions, and that one role of these inputs is to enhance DCN processing of spectral sound localization cues produced by the pinna.

In order to localize sounds in the environment, the auditory system detects and encodes differences in signals between each ear. The exquisite sensitivity of auditory brain stem neurons to the differences in rise time of the excitation signals from the two ears allows for neuronal encoding of microsecond interaural time differences.

Low-frequency sound localization depends on the neural computation of interaural time differences (ITD) and relies on neurons in the auditory brain stem that integrate synaptic inputs delivered by the ipsi- and contralateral auditory pathways that start at the two ears. The first auditory neurons that respond selectively to ITD are found in the medial superior olivary nucleus (MSO). We identified a new mechanism for ITD coding using a brain slice preparation that preserves the binaural inputs to the MSO. There was an internal latency difference for the two excitatory pathways that would, if left uncompensated, position the ITD response function too far outside the physiological range to be useful for estimating ITD. We demonstrate, and support using a biophysically based computational model, that a bilateral asymmetry in excitatory post-synaptic potential (EPSP) slopes provides a robust compensatory delay mechanism due to differential activation of low threshold potassium conductance on these inputs and permits MSO neurons to encode physiological ITDs. We suggest, more generally, that the dependence of spike probability on rate of depolarization, as in these auditory neurons, provides a mechanism for temporal order discrimination between EPSPs.

Author Summary

Animals can locate the source of a sound by detecting microsecond differences in the arrival time of sound at the two ears. Neurons encoding these interaural time differences (ITDs) receive an excitatory synaptic input from each ear. They can perform a microsecond computation with excitatory synapses that have millisecond time scale because they are extremely sensitive to the input's “rise time,” the time taken to reach the peak of the synaptic input. Current theories assume that the biophysical properties of the two inputs are identical. We challenge this assumption by showing that the rise times of excitatory synaptic potentials driven by the ipsilateral ear are faster than those driven by the contralateral ear. Further, we present a computational model demonstrating that this disparity in rise times, together with the neurons' sensitivity to excitation's rise time, can endow ITD-encoding with microsecond resolution in the biologically relevant range. Our analysis also resolves a timing mismatch. The difference between contralateral and ipsilateral latencies is substantially larger than the relevant ITD range. We show how the rise time disparity compensates for this mismatch. Generalizing, we suggest that phasic-firing neurons—those that respond to rapidly, but not to slowly, changing stimuli—are selective to the temporal ordering of brief inputs. In a coincidence-detection computation the neuron will respond more robustly when a faster input leads a slower one, even if the inputs are brief and have similar amplitudes.

The bushy cells of the anterior ventral cochlear nucleus (AVCN) preserve or improve the temporal coding of sound information arriving from auditory nerve fibers (ANF). The critical cellular mechanisms entailed in this process include the specialized nerve terminals, the endbulbs of Held, and the membrane conductance configuration of the bushy cell. In one strain of mice (DBA/2J), an early-onset hearing loss can cause a reduction in neurotransmitter release probability, and a smaller and slower spontaneous miniature excitatory postsynaptic current (EPSC) at the endbulb synapse. In the present study, by using a brain slice preparation, we tested the hypothesis that these changes in synaptic transmission would degrade the transmission of timing information from the ANF to the AVCN bushy neuron. We show that the electrical excitability of bushy cells in hearing-impaired old DBA mice was different from that in young, normal-hearing DBA mice. We found an increase in the action potential (AP) firing threshold with current injection; a larger AP afterhyperpolarization; and an increase in the number of spikes produced by large depolarizing currents. We also tested the temporal precision of bushy cell responses to high-frequency stimulation of the ANF. The standard deviation of spikes (spike jitter) produced by ANF-evoked excitatory postsynaptic potentials (EPSPs) was largely unaffected in old DBA mice. However, spike entrainment during a 100-Hz volley of EPSPs was significantly reduced. This was not a limitation of the ability of bushy cells to fire APs at this stimulus frequency, because entrainment to trains of current pulses was unaffected. Moreover, the decrease in entrainment is not attributable to increased synaptic depression. Surprisingly, the spike latency was 0.46 ms shorter in old DBA mice, and was apparently attributable to a faster conduction velocity, since the evoked excitatory postsynaptic current (EPSC) latency was shorter in old DBA mice as well. We also tested the contribution of the low-voltage-activated K+ conductance (gKLV) on the spike latency by using dynamic clamp. Alteration in gKLV had little effect on the spike latency. To test whether these changes in DBA mice were simply a result of continued postnatal maturation, we repeated the experiments in CBA mice, a strain that shows normal hearing thresholds through this age range. CBA mice exhibited no reduction in entrainment or increased spike jitter with age. We conclude that the ability of AVCN bushy neurons to reliably follow ANF EPSPs is compromised in a frequency-dependent fashion in hearing-impaired mice. This effect can be best explained by an increase in spike threshold.

The bushy cells of the anterior ventral cochlear nucleus (AVCN) preserve or improve the temporal coding of sound information arriving from auditory nerve fibers (ANF). The critical cellular mechanisms entailed in this process include the specialized nerve terminals, the endbulbs of Held, and the membrane conductance configuration of the bushy cell. In one strain of mice (DBA/2J), an early-onset hearing loss can cause a reduction in neurotransmitter release probability, and a smaller and slower spontaneous miniature excitatory postsynaptic current (EPSC) at the endbulb synapse. In the present study, by using a brain slice preparation, we tested the hypothesis that these changes in synaptic transmission would degrade the transmission of timing information from the ANF to the AVCN bushy neuron. We show that the electrical excitability of bushy cells in hearing-impaired old DBA mice was different from that in young, normal-hearing DBA mice. We found an increase in the action potential (AP) firing threshold with current injection; a larger AP afterhyperpolarization; and an increase in the number of spikes produced by large depolarizing currents. We also tested the temporal precision of bushy cell responses to high-frequency stimulation of the ANF. The standard deviation of spikes (spike jitter) produced by ANF-evoked excitatory postsynaptic potentials (EPSPs) was largely unaffected in old DBA mice. However, spike entrainment during a 100-Hz volley of EPSPs was significantly reduced. This was not a limitation of the ability of bushy cells to fire APs at this stimulus frequency, because entrainment to trains of current pulses was unaffected. Moreover, the decrease in entrainment is not attributable to increased synaptic depression. Surprisingly, the spike latency was 0.46 ms shorter in old DBA mice, and was apparently attributable to a faster conduction velocity, since the evoked excitatory postsynaptic current (EPSC) latency was shorter in old DBA mice as well. We also tested the contribution of the low-voltage-activated K+ conductance (gKLV) on the spike latency by using dynamic clamp. Alteration in gKLV had little effect on the spike latency. To test whether these changes in DBA mice were simply a result of continued postnatal maturation, we repeated the experiments in CBA mice, a strain that shows normal hearing thresholds through this age range. CBA mice exhibited no reduction in entrainment or increased spike jitter with age. We conclude that the ability of AVCN bushy neurons to reliably follow ANF EPSPs is compromised in a frequency-dependent fashion in hearing-impaired mice. This effect can be best explained by an increase in spike threshold.

Purpose

This review outlines the anatomical and functional bases of somatosensory influences on auditory processing in the normal brainstem and midbrain. Thereafter, it explores how interactions between the auditory and somatosensory system are modified through deafness and their impact on tinnitus is discussed.

Methods

literature-review, tract-tracing, immunohistochemistry, in vivo electrophysiological recordings

Results

Somatosensory input originates in the dorsal root ganglia (DRG) and trigeminal ganglia (TG) and is transmitted directly and indirectly through second order nuclei to the ventral and dorsal cochlear nucleus (VCN, DCN) and inferior colliculus (IC). The glutamatergic somatosensory afferents can be segregated from auditory nerve inputs by the type of vesicular glutamate transporters present in their terminals. Electrical stimulation of the somatosensory input results in a complex combination of excitation and inhibition and alters the rate and timing of responses to acoustic stimulation.

Deafness increases the spontaneous rates of those neurons that receive excitatory somatosensory input, and results in a greater sensitivity of DCN neurons to trigeminal stimulation.

Conclusions

Auditory-somatosensory bimodal integration is already present in first order auditory nuclei. The balance of excitation and inhibition elicited by somatosensory input is altered following deafness. The increase in somatosensory influence on auditory neurons when their auditory input is diminished could be due to cross modal re-innervation or increased synaptic strength, and may contribute to mechanisms underlying somatic tinnitus.

Sensory deprivation has been shown to exert detrimental effects on the structure and function of central sensory systems. Congenital deafness represents an extreme form of auditory deprivation, and in the adult white cat, synapses between auditory nerve endings and resident cells of the anteroventral cochlear nucleus exhibited abnormal structure. Endbulbs of Held were reduced in branching and displayed striking hypertrophy of their postsynaptic densities. So-called modified endbulbs showed no change in branching complexity but did exhibit hypertrophy of their postsynaptic densities. These differential pre- and postsynaptic effects prompted the question of how deafness might affect other primary endings and synapses. Thus, we studied type I and type II multipolar cells that receive bouton endings from auditory nerve fibers. Type I multipolar cells project to the contralateral inferior colliculus and have relatively few axosomatic endings; type II multipolar cells project to the contralateral cochlear nucleus and have many axosomatic endings. Compared with normal-hearing cats, bouton endings of congenitally deaf cats were smaller but there was no difference in synaptic vesicle density or size of postsynaptic densities. These data reveal that different classes of primary endings and second-order neurons exhibit different degrees of synaptic anomalies to deafness.

Objectives/Hypothesis

One limitation with cochlear implants is the difficulty stimulating spatially discrete spiral ganglion cell groups because of electrode interactions. Multipolar electrodes have improved on this some, but also at the cost of much higher device power consumption. Recently, it has been shown that spatially selective stimulation of the auditory nerve is possible with a mid-infrared laser aimed at the spiral ganglion via the round window. However, these neurons must be driven at adequate rates for optical radiation to be useful in cochlear implants. We herein use single-fiber recordings to characterize the responses of auditory neurons to optical radiation.

Study Design

In vivo study using normal-hearing adult gerbils.

Methods

Two diode lasers were used for stimulation of the auditory nerve. They operated between 1.844 μm and 1.873 μm, with pulse durations of 35 μs to 1,000 μs, and at repetition rates up to 1,000 pulses per second (pps). The laser outputs were coupled to a 200-μm-diameter optical fiber placed against the round window membrane and oriented toward the spiral ganglion. The auditory nerve was exposed through a craniotomy, and recordings were taken from single fibers during acoustic and laser stimulation.

Results

Action potentials occurred 2.5 ms to 4.0 ms after the laser pulse. The latency jitter was up to 3 ms. Maximum rates of discharge averaged 97 ± 52.5 action potentials per second. The neurons did not strictly respond to the laser at stimulation rates over 100 pps.

Conclusions

Auditory neurons can be stimulated by a laser beam passing through the round window membrane and driven at rates sufficient for useful auditory information. Optical stimulation and electrical stimulation have different characteristics; which could be selectively exploited in future cochlear implants.

Level of Evidence

Not applicable.

Deaf people who use cochlear implants show surprisingly poor sensitivity to the temporal fine structure of sounds. One possible reason is that conventional cochlear implants cannot activate selectively the auditory-nerve fibers having low characteristic frequencies (CFs), which, in normal hearing, phase lock to stimulus fine structure. Recently, we tested in animals an alternative mode of auditory prosthesis employing penetrating auditory-nerve electrodes that permit frequency-specific excitation in all frequency regions. We present here measures of temporal transmission through the auditory brainstem – from pulse trains presented with various auditory-nerve electrodes to phase-locked activity of neurons in the central nucleus of the inferior colliculus (ICC). On average, intraneural stimulation resulted in significant ICC phase locking at higher pulse rates (i.e., higher “limiting rates”) than did cochlear-implant stimulation. That could be attributed, however, to the larger percentage of low-CF neurons activated selectively by intraneural stimulation. Most ICC neurons with limiting rates >500 pulses per second had CFs <1.5 kHz, whereas neurons with lower limiting rates tended to have higher CFs. High limiting rates also correlated strongly with short first-spike latencies. It follows that short latencies correlated significantly with low CFs, opposite to the correlation observed with acoustical stimulation. These electrical-stimulation results reveal a high-temporal-acuity brainstem pathway characterized by low CFs, short latencies, and high-fidelity transmission of periodic stimulation. Frequency-specific stimulation of that pathway by intraneural stimulation might improve temporal acuity in human users of a future auditory prosthesis, which in turn might improve musical pitch perception and speech reception in noise.

Hearing loss has been attributed to many factors, including degeneration of sensory neurons in the auditory pathway and demyelination along the cochlear nerve. Fibroblast growth factors (FGFs), which signal through four receptors (Fgfrs), are produced by auditory neurons and play a key role in embryonic development of the cochlea and in neuroprotection against sound-induced injury. However, the role of FGF signaling in the maintenance of normal auditory function in adult and aging mice remains to be elucidated. Furthermore, the contribution of glial cells, which myelinate the cochlear nerves, is poorly understood. To address these questions, we generated transgenic mice in which Fgfr1 and Fgfr2 were specifically inactivated in Schwann cells and oligodendrocytes but not in neurons. Adult mutant mice exhibited late onset of hearing impairment, which progressed markedly with age. The hearing impairment was accompanied by significant loss of myelinated spiral ganglion neurons. The pathology extended into the cochlear nucleus, without apparent loss of myelin or of the deletion-bearing glial cells themselves. This suggests that perturbation of FGF receptor-mediated glial function leads to the attenuation of glial support of neurons, leading to their loss and impairment of auditory functions. Thus, FGF/FGF receptor signaling provides a potentially novel mechanism of maintaining reciprocal interactions between neurons and glia in adult and aging animals. Dysfunction of glial cells and FGF receptor signaling may therefore be implicated in neurodegenerative hearing loss associated with normal aging.

Mutations in the gene that encodes espins can cause deafness and vestibular disorders; mice that are homozygous for the autosomal recessive, jerker mutation in the espin gene never hear. Extracellular injections of biocytin into the anteroventral cochlear nucleus (AVCN) revealed that although the cochlear nuclei are smaller in je/je mice, the topography in its innervation resembles that in wild type mice. Auditory nerve fibers innervate narrow, topographically organized, “isofrequency” bands in deaf animals over the ages examined, P18–P70. The projection of tuberculoventral cells was topographic in je/je as in wild type mice. Terminals of auditory nerve fibers in the multipolar cell area included both large and small endings whereas in the octopus cell area they were exclusively small boutons in je/je as in wild type mice but end bulbs near the nerve root of je/je animals were smaller than in hearing animals. In whole-cell recordings from targets of auditory nerve fibers, octopus and T stellate cells, miniature excitatory postsynaptic currents (mEPSCs) had similar shapes as in +/+, indicating that the properties of AMPA receptors were not affected by the mutation. In je/je animals the frequency of spontaneous mEPSCs was elevated and synaptic depression in responses to trains of shocks delivered at between 100 and 333 Hz was greater than in wild type mice indicating that the probability of neurotransmitter release was increased. The frequency of spontaneous mEPSCs and extent of synaptic depression were greater in octopus than in T stellate cells, in both wild type and je/je mice.

Octopus cells, located in the mammalian auditory brainstem, receive their excitatory synaptic input exclusively from auditory nerve fibers (ANFs). They respond with accurately timed spikes but are broadly tuned for sound frequency. Since the representation of information in the auditory nerve is well understood, it is possible to pose a number of questions about the relationship between the intrinsic electrophysiology, dendritic morphology, synaptic connectivity, and the ultimate functional role of octopus cells in the brainstem. This study employed a multi-compartmental Hodgkin-Huxley model to determine whether dendritic delay in octopus cells improves synaptic input coincidence detection in octopus cells by compensating for the cochlear traveling wave delay. The propagation time of post-synaptic potentials from synapse to soma was investigated. We found that the total dendritic delay was approximately 0.275 ms. It was observed that low-threshold potassium channels in the dendrites reduce the amplitude dependence of the dendritic delay of post-synaptic potentials. As our hypothesis predicted, the model was most sensitive to acoustic onset events, such as the glottal pulses in speech when the synaptic inputs were arranged such that the model's dendritic delay compensated for the cochlear traveling wave delay across the ANFs. The range of sound frequency input from ANFs was also investigated. The results suggested that input to octopus cells is dominated by high frequency ANFs.

A hallmark of brain organization is the integration of primary and modulatory pathways by principal neurons. Primary sensory inputs are usually not plastic, while modulatory inputs converging to the same principal neuron can be plastic. However, the mechanisms determining this input specific expression of synaptic plasticity remain unknown. We investigated this problem in the dorsal cochlear nucleus (DCN), where principal cells integrate primary auditory nerve input with plastic, parallel fiber input. Our previous DCN studies have shown that parallel fiber inputs exhibit short- and long-term plasticities mediated by endocannabinoid signaling. Here we show that auditory nerve inputs to principal cells do not show short- or long-term endocannabinoid-mediated synaptic plasticity. Electrophysiological and electron microscopy studies indicate that input specificity arises from selective expression of presynaptic cannabinoid (CB1) receptors in parallel fiber terminals, but not in auditory nerve terminals. However, pairing of parallel fiber activity with auditory nerve activity elicits plasticity in parallel fiber inputs, thus suggesting a role for synaptic plasticity in multisensory integration.

In the ascending auditory pathway, the inferior colliculus (IC) receives and integrates excitatory and inhibitory inputs from many lower auditory nuclei, intrinsic projections within the IC, contralateral IC through the commissure of the IC and from the auditory cortex. All these connections make the IC a major center for subcortical temporal and spectral integration of auditory information. In this study, we examine bilateral collicular interaction in modulating amplitude-domain signal processing using electrophysiological recording, acoustic and focal electrical stimulation. Focal electrical stimulation of one (ipsilateral) IC produces widespread inhibition (61.6%) and focused facilitation (9.1%) of responses of neurons in the other (contralateral) IC, while 29.3% of the neurons were not affected. Bilateral collicular interaction produces a decrease in the response magnitude and an increase in the response latency of inhibited IC neurons but produces opposite effects on the response of facilitated IC neurons. These two groups of neurons are not separately located and are tonotopically organized within the IC. The modulation effect is most effective at low sound level and is dependent upon the interval between the acoustic and electric stimuli. The focal electrical stimulation of the ipsilateral IC compresses or expands the rate-level functions of contralateral IC neurons. The focal electrical stimulation also produces a shift in the minimum threshold and dynamic range of contralateral IC neurons for as long as 150 minutes. The degree of bilateral collicular interaction is dependent upon the difference in the best frequency between the electrically stimulated IC neurons and modulated IC neurons. These data suggest that bilateral collicular interaction mainly changes the ratio between excitation and inhibition during signal processing so as to sharpen the amplitude sensitivity of IC neurons. Bilateral interaction may be also involved in acoustic-experience-dependent plasticity in the IC. Three possible neural pathways underlying the bilateral collicular interaction are discussed.