Primary Auditory Afferents Research Articles

Amplification of input differences by dynamic heterogeneity in the spiral ganglion.

A defining feature of type I primary auditory afferents that compose ∼95% of the spiral ganglion is their intrinsic electrophysiological heterogeneity. This diversity is evident both between and within unitary, rapid, and slow adaptation (UA, RA, and SA) classes indicative of specializations designed to shape sensory receptor input. But to what end? Our initial impulse is to expect the opposite: that auditory afferents fire uniformly to represent acoustic stimuli with accuracy and high fidelity. Yet this is clearly not the case. One explanation for this neural signaling strategy is to coordinate a system in which differences between input stimuli are amplified. If this is correct, then stimulus disparity enhancements within the primary afferents should be transmitted seamlessly into auditory processing pathways that utilize population coding for difference detection. Using sound localization as an example, one would expect to observe separately regulated differences in intensity level compared with timing or spectral cues within a graded tonotopic distribution. This possibility was evaluated by examining the neuromodulatory effects of cAMP on immature neurons with high excitability and slow membrane kinetics. We found that electrophysiological correlates of intensity and timing were indeed independently regulated and tonotopically distributed, depending on intracellular cAMP signaling level. These observations, therefore, are indicative of a system in which differences between signaling elements of individual stimulus attributes are systematically amplified according to auditory processing constraints. Thus, dynamic heterogeneity mediated by cAMP in the spiral ganglion has the potential to enhance the representations of stimulus input disparities transmitted into higher level difference detection circuitry.NEW & NOTEWORTHY Can changes in intracellular second messenger signaling within primary auditory afferents shift our perception of sound? Results presented herein lead to this conclusion. We found that intracellular cAMP signaling level systematically altered the kinetics and excitability of primary auditory afferents, exemplifying how dynamic heterogeneity can enhance differences between electrophysiological correlates of timing and intensity.

Dynamic Heterogeneity Shapes Patterns of Spiral Ganglion Activity.

Neural response properties that typify primary sensory afferents are critical to fully appreciate because they establish and, ultimately represent, the fundamental coding design used for higher-level processing. Studies illuminating the center-surround receptive fields of retinal ganglion cells, for example, were ground-breaking because they determined the foundation of visual form detection. For the auditory system, a basic organizing principle of the spiral ganglion afferents is their extensive electrophysiological heterogeneity establishing diverse intrinsic firing properties in neurons throughout the spiral ganglion. Moreover, these neurons display an impressively large array of neurotransmitter receptor types that are responsive to efferent feedback. Thus, electrophysiological diversity and its neuromodulation are a fundamental encoding mechanism contributed by the primary afferents in the auditory system. To place these features into context, we evaluated the effects of hyperpolarization and cAMP on threshold level as indicators of overall afferent responsiveness in CBA/CaJ mice of either sex. Hyperpolarization modified threshold gradients such that distinct voltage protocols could shift the relationship between sensitivity and stimulus input to reshape resolution. This resulted in an "accordion effect" that appeared to stretch, compress, or maintain responsivity across the gradient of afferent thresholds. cAMP targeted threshold and kinetic shifts to rapidly adapting neurons, thus revealing multiple cochleotopic properties that could potentially be independently regulated. These examples of dynamic heterogeneity in primary auditory afferents not only have the capacity to shift the range, sensitivity, and resolution, but to do so in a coordinated manner that appears to orchestrate changes with a seemingly unlimited repertoire.SIGNIFICANCE STATEMENT How do we discriminate the more nuanced qualities of the sound around us? Beyond the basics of pitch and loudness, aspects, such as pattern, distance, velocity, and location, are all attributes that must be used to encode acoustic sensations effectively. While higher-level processing is required for perception, it would not be unexpected if the primary auditory afferents optimized receptor input to expedite neural encoding. The findings reported herein are consistent with this design. Neuromodulation compressed, expanded, shifted, or realigned intrinsic electrophysiological heterogeneity to alter neuronal responses selectively and dynamically. This suggests that diverse spiral ganglion phenotypes provide a rich substrate to support an almost limitless array of coding strategies within the first neural element of the auditory pathway.

A simple model of the inner-hair-cell ribbon synapse accounts for mammalian auditory-nerve-fiber spontaneous spike times

The initial neural encoding of acoustic information occurs by means of spikes in primary auditory afferents. Each mammalian primary auditory afferent (type-I auditory-nerve fiber; ANF) is associated with only one ribbon synapse in one receptor cell (inner hair cell; IHC). The properties of ANF spike trains therefore provide an indirect view of the operation of individual IHC synapses. We showed previously that a point process model of presynaptic vesicle pool depletion and deterministic exponential replenishment, combined with short postsynaptic neural refractoriness, accounts for the interspike interval (ISI) distributions, serial ISI correlations, and spike-count statistics of a population of cat-ANF spontaneous spike trains. Here, we demonstrate that this previous synapse model produces unrealistic properties when spike rates are high and show that this problem can be resolved if the replenishment of each release site is stochastic and independent. We assume that the depletion probability varies between synapses to produce differences in spontaneous rate and that the other model parameters are constant across synapses. We find that this model fits best with only four release sites per IHC synapse, a mean replenishment time of 17 ms, and absolute and mean relative refractory periods of 0.6 ms each. This model accounts for ANF spontaneous spike timing better than two influential, comprehensive models of the auditory periphery. It also reproduces ISI distributions from spontaneous and steady-state driven activity from other studies and other mammalian species. Adding fractal noise to the rate of depletion of each release site can yield long-range correlations as typically observed in long spike trains. We also examine two model variants having more complex vesicle cycles, but neither variant yields a markedly improved fit or a different estimate of the number of release sites. In addition, we examine a model variant having both short and long relative refractory components and find that it cannot account for all aspects of the data. These model results will be beneficial for understanding ribbon synapses and ANF responses to acoustic stimulation.

Spike timing in auditory-nerve fibers during spontaneous activity and phase locking.

In vertebrates, all acoustic information transmitted from the inner ear to the central auditory system is relayed by primary auditory afferents (auditory-nerve fibers; ANFs). These neurons are also the most peripheral elements to use action potentials (spikes) to encode the acoustic information. Here, we review what is known about the spiking of ANFs during spontaneous activity, when spike timing might be regarded as largely random, and during stimulation by low-frequency sounds, when spikes are phase locked to the stimulus waveform, a phenomenon generally considered a hallmark of temporal precision and speed in the auditory system. We focus on mammals, in which each ANF is driven by a single ribbon synapse in a single receptor cell, but also cover relevant research on ANFs of vertebrates from other classes. For spontaneous activity, we highlight several spike-history effects in interspike interval distributions, hazard-rate functions, serial interval correlations, and spike-count statistics. We also review models that have attempted to account for these properties. For phase locking, we focus on the responses to low-frequency tones, rather than to low-frequency components of broadband signals such as noise or clicks. We critically review the measures commonly used to quantify phase locking and urge caution when interpreting such measures with respect to spike-timing precision. We also review the dependence of phase locking on stimulus amplitude and frequency. Finally, we identify some open questions.

Basic response properties of auditory nerve fibers: a review.

All acoustic information from the periphery is encoded in the timing and rates of spikes in the population of spiral ganglion neurons projecting to the central auditory system. Considerable progress has been made in characterizing the physiological properties of type-I and type-II primary auditory afferents and understanding the basic properties of type-I afferents in response to sounds. Here, we review some of these properties, with emphasis placed on issues such as the stochastic nature of spike timing during spontaneous and driven activity, frequency tuning curves, spike-rate-versus-level functions, dynamic-range and spike-rate adaptation, and phase locking to stimulus fine structure and temporal envelope. We also review effects of acoustic trauma on some of these response properties.

Dynamic firing properties of type I spiral ganglion neurons.

Spiral ganglion neurons, the first neural element in the auditory system, possess complex intrinsic properties, possibly required to process frequency-specific sensory input that is integrated with extensive efferent regulation. Together with their tonotopically-graded sizes, the somata of these neurons reveal a sophisticated electrophysiological profile. Type I neurons, which make up ~95 % of the ganglion, have myriad voltage-gated ion channels that not only vary along the frequency contour of the cochlea, but also can be modulated by regulators such as voltage, calcium, and second messengers. The resultant developmentally- and tonotopically-regulated neuronal firing patterns conform to three distinct response modes (unitary, rapid, and slow) based on threshold and accommodation. This phenotype, however, is not static for any individual type I neuron. Recent observations have shown that, as neurons become less excitable with age, they demonstrate enhanced plasticity enabling them to change from one response mode to another depending upon resting membrane potential and the presence of neurotrophin-3. Thus, the primary auditory afferents utilized to encode dynamic acoustic stimuli possess the intrinsic specializations that allow them dynamically to alter their firing pattern.

Functional specializations of primary auditory afferents on the Mauthner cells: Interactions between membrane and synaptic properties

Primary auditory afferents are usually perceived as passive, timing-preserving, lines of communication. Contrasting this view, a special class of auditory afferents to teleost Mauthner cells, a command neuron that organizes tail-flip escape responses, undergoes potentiation of their mixed (electrical and chemical) synapses in response to high frequency cellular activity. This property is likely to represent a mechanism of input sensitization as these neurons provide the Mauthner cell with essential information for the initiation of an escape response. We review here the anatomical and physiological specializations of these identifiable auditory afferents. In particular, we discuss how their membrane and synaptic properties act in concert to more efficaciously activate the Mauthner cells. The striking functional specializations of these neurons suggest that primary auditory afferents might be capable of more sophisticated contributions to auditory processing than has been generally recognized.

Unmasking effects of olivocochlear efferent activation on responses of inferior colliculus neurons

Behavioural studies suggest a role for the medial olivocochlear (MOC) system in improving detection and discrimination of signals in noise. Physiological studies in the cochlea support this notion, showing unmasking, an improvement of the dynamic range of primary auditory afferents in response to tones in noise after MOC system activation. However, little is known about unmasking effects in higher centres. We investigated the effects of MOC stimulation on the responses of neurons in the guinea pig inferior colliculus to masked tones. In 50% of neurons background noise increased the basal rate and decreased maximum rate, an effect similar to that reported in primary afferents. In 35% of neurons maximum rate was increased by the background noise. Activation of the MOC system caused an increased slope and output dynamic range in the majority of input–output functions. Statistical analysis showed that this increased the discriminability of the tones within the noise. Hence, antimasking effects of olivocochlear activation that have been described in the cochlea can still be observed in the midbrain. However, 27% of neurons showed a variety of effects that have not been described in primary afferents, suggesting involvement of central circuitry in modulating effects of MOC stimulation on higher centres.

Subthreshold Sodium Current Underlies Essential Functional Specializations at Primary Auditory Afferents

Primary auditory afferents are generally perceived as passive, timing-preserving lines of communication. Contrasting this view, identifiable auditory afferents to the goldfish Mauthner cell undergo potentiation of their mixed--electrical and chemical--synapses in response to high-frequency bursts of activity. This property likely represents a mechanism of input sensitization because they provide the Mauthner cell with essential information for the initiation of an escape response. Consistent with this synaptic specialization, we show here that these afferents exhibit an intrinsic ability to respond with bursts of 200-600 Hz and this property critically relies on the activation of a persistent sodium current, which is counterbalanced by the delayed activation of an A-type potassium current. Furthermore, the interaction between these conductances with the membrane passive properties supports the presence of electrical resonance, whose frequency preference is consistent with both the effective range of hearing in goldfish and the firing frequencies required for synaptic facilitation, an obligatory requisite for the induction of activity-dependent changes. Thus our data show that the presence of a persistent sodium current is functionally essential and allows these afferents to translate behaviorally relevant auditory signals into patterns of activity that match the requirements of their fast and highly modifiable synapses. The functional specializations of these neurons suggest that auditory afferents might be capable of more sophisticated contributions to auditory processing than has been generally recognized.

Gentamicin abolishes all cochlear effects of electrical stimulation of the inferior colliculus

Electrical stimulation of the inferior colliculus (IC) has been shown to result in suppression of cochlear output, due to activation of the medial olivocochlear system. This auditory efferent system originates in the brainstem and terminates on the outer hair cells in the cochlea. Recently, excitatory effects of IC stimulation have also been reported, both on cochlear gross potentials and on primary auditory afferents. It has been hypothesized that this excitation is due to co-activation of the lateral olivocochlear system, which synapses on the primary auditory afferent fibres contacting the inner hair cells. If stimulation of the IC leads to the activation of both the medial and lateral olivocochlear system, resulting in a mixture of inhibitory and excitatory effects in the cochlea, then removal of the inhibitory effects, by blocking the medial system, should lead to more pronounced excitatory effects out in the periphery. To investigate this hypothesis, we recorded the effect of IC stimulation on cochlear gross potentials as well as on single auditory primary afferents in guinea pigs following block of the medial olivocochlear system with gentamicin. We found that administration of gentamicin, whether intraperitoneally or by intracochlear perfusion, blocked all effects of IC stimulation, whether inhibitory or excitatory. These data strongly suggest that all effects observed after IC stimulation, both inhibitory as well as excitatory, are due to the activation of the medial olivocochlear system.

Ontogenetic changes in the response properties of individual, primary auditory afferents in the vocal plainfin midshipman fish Porichthys notatus Girard

The auditory system of adult midshipman fish Porichthys notatus Girard is an important sensory receiver system used during intraspecific social communication to encode conspecific vocalizations, but the response properties and function of this system in the pre-adult stages are unknown. Midshipman fish, like other teleosts, use the saccule as the main acoustic end organ of the inner ear. In this study, we examined the discharge properties and the frequency response dynamics of auditory saccular afferent neurons in pre-adult midshipman (approximately 4-12 months of age) to determine whether encoding of auditory information, inclusive of conspecific vocalizations, changes across life history stages. Extracellular single unit recordings were made from saccular afferents while sound was presented via an underwater speaker. Comparisons with adult data show that the resting discharge rate and auditory threshold sensitivity increased with age/size, while temporal encoding of frequency did not show any significant shifts. The results indicate that the saccular afferents of juveniles, like those of non-reproductive adults, are best adapted to temporally encode the low frequency components (<or=100 Hz) of midshipman vocalizations. This report represents the first in vivo investigation of age-related changes in the encoding properties of individual auditory neurons for any fish species.

Mechanism of electrical stimulation-induced neuroprotection: effects of verapamil on protection of primary auditory afferents

In order to assess the role of L-type voltage-gated calcium channels in electrical stimulation-mediated neuroprotection in vivo, we assessed survival of primary auditory afferents (spiral ganglion cells) in systemically deafened guinea pigs following chronic electrical stimulation with or without intracochlear infusion of verapamil, an L-type voltage-gated calcium channel antagonist. Continuous intracochlear drug delivery (0.5 μl/h) was provided using a delivery system developed previously in our laboratory using Alzet ® mini-osmotic pumps. In the absence of chronic stimulation, spiral ganglion cell survival was relatively symmetric in animals treated unilaterally with either artificial perilymph or verapamil (50 μg/ml). In the presence of unilateral chronic electrical stimulation, spiral ganglion cell survival was significantly greater in stimulated, perilymph-infused ears, relative to the contralateral ear. In contrast, spiral ganglion cell survival was bilaterally symmetric in chronically stimulated, verapamil-infused animals. The difference in symmetry of spiral ganglion cell survival between the two groups was statistically significant. In vitro, passive depolarization has been demonstrated to enhance survival of cultured neurons via activation of L-type calcium channels. The results of this study indicate that, as suggested by in vitro depolarization models, in vivo electrical stimulation-mediated neuroprotection requires the activation of L-type voltage-gated calcium channels. Chronic electrical stimulation of the deaf ear is an ideal preparation for further studies in which to extrapolate findings from in vitro depolarization models.

Frequency and directional selectivity in primary auditory afferents in fishes

Coding of frequency and particle motion directionality is described for two fishes; goldfish (a sound-pressure specialist), and oyster toadfish (a hearing generalist). The goldfish hears in a wide bandwidth (&amp;gt;2 kHz) and the toadfish in a narrower one (&amp;lt;400 Hz). Nevertheless, the mechanisms and degree of peripheral frequency analysis appear to be similar. Reverse correlation (revcor) studies of frequency filtering in the auditory nerve reveal two fundamental filter types in both species; one at low and one at higher frequencies. The details of the two filter functions are similar, and one can be transformed into the other by introducing a simple spectral tilt to one of the filters. This suggests that only one fundamental filter exists for each species, and that the second filter type may be derived from it through alterations in the mode of coupling between the hair cell cilia and restraint structures. In spite of this simple filtering, goldfish effectively analyze the frequency components in complex and simple sounds. In both species, primary afferents show directional preferences in 3-D space that correspond to the directionalities of hair cells. Frequency analysis and directional processing in fishes share many fundamental features with those of most other vertebrates.

Transformations of an Auditory Temporal Code in the Medulla of a Sound-Producing Fish

The fish auditory system provides important insights into the evolution and mechanisms of vertebrate hearing. Fish have relatively simple auditory systems, without a cochlea for mechanical frequency analysis. However, as in all vertebrates, the primary auditory afferents of fish represent sounds as stimulus-entrained spike trains. Thus, fish provide important models for studying how temporal spiking patterns are used in higher level neural computations. In this paper we demonstrate that one of the fundamental transformations of information in the auditory system of a sound-producing fish, Pollimyrus, takes place in the auditory medulla. We discovered a class of neurons in which evoked spiking patterns were relatively independent of the stimulus fine structure and appeared to reflect intrinsic properties of the neurons. These neurons generated sustained responses but were poorly phase-locked to tones compared with the primary afferents. The interval histograms showed that spike timing was regular. However, in contrast to primary afferents, the mode of the interspike interval distribution was independent of the period of tonal stimuli. The tuning of the neurons was broad, with best sensitivity in the same spectral region where these animals concentrate energy in their communication sounds. The physiology of these neurons was similar to that of the chopper neurons known in the auditory brainstem of mammals. Our findings suggest that this medullary transformation, from phase-locked afferent input to chopper-like physiology, is basic to vertebrate auditory processing, even within lineages that have not evolved a cochlea.

Recruitment of the Auditory Cortex in Congenitally Deaf Cats by Long-Term Cochlear Electrostimulation

In congenitally deaf cats, the central auditory system is deprived of acoustic input because of degeneration of the organ of Corti before the onset of hearing. Primary auditory afferents survive and can be stimulated electrically. By means of an intracochlear implant and an accompanying sound processor, congenitally deaf kittens were exposed to sounds and conditioned to respond to tones. After months of exposure to meaningful stimuli, the cortical activity in chronically implanted cats produced field potentials of higher amplitudes, expanded in area, developed long latency responses indicative of intracortical information processing, and showed more synaptic efficacy than in naïve, unstimulated deaf cats. The activity established by auditory experience resembles activity in hearing animals.

Spatial resolution of cochlear implants: the electrical field and excitation of auditory afferents

This paper investigates the spatial resolution of electrical intracochlear stimulation in order to enable further refinement of cochlear implants. For this purpose electrical potential distributions around a conventional human intracochlear electrode (NUCLEUS-22) were measured in a tank, in cat cadaver cochleae and in living cat cochleae. Potential gradients were calculated where of importance. The values were compared to spatial tuning curves from cat primary auditory afferents in electrical mono-, bi-, and various tripolar stimulation modes. Finally, a lumped element model was developed to elucidate the single fiber data. Tank potential measurements show the principal features of the different stimulation modes but are not sufficient to explain all the features of experimental data from single fibers. Intracochlear potential measurements indicate an increase in spatial resolution in an apical direction. The single fiber data also confirm that a tripolar stimulus configuration provides significantly better spatial resolution than any other stimulation mode presently in use.

The number of primary auditory afferents in the rat

Published estimates of the number of primary auditory afferents in the rat differ by as much as 30%. We undertook to determine if the widely varying estimates were related to methodological differences, especially the difference between counting cells in Rosenthal's canal and fibers in the cochlear nerve. Type I ganglion cells and myelinated cochlear nerve fibers in the same ears were counted in Long-Evans and Sprague-Dawley strains. Type II spiral ganglion cells were also counted. In each strain the numbers of myelinated fibers and type I ganglion cells were essentially the same. Means for the Long-Evans were 18,036 fibers and 17,749 cells. Means for Sprague-Dawleys were higher: 19,444 fibers and 19,229 cells. The mean number of type II ganglion cells was also greater in Sprague-Dawley than in Long-Evans rats: 1,388 and 1,170, respectively. Cell and fiber counts from the two ears of the same animal differed on average by only 1%. The number of auditory afferents did not change with age over the range (2–10 months) studied here. Several methodological differences have probably contributed to the varying estimates of type I primary auditory afferents, but the discrepancies are not inherent in counts of fibers and spiral ganglion cells.

Directional hearing by mechanical coupling in the parasitoid fly Ormia ochracea.

Sound localization is a basic processing task of the auditory system. The directional detection of an incident sound impinging on the ears relies on two acoustic cues: interaural amplitude and interaural time differences. In small animals, with short interaural distances both amplitude and time cues can become very small, challenging the directional sensitivity of the auditory system. The ears of a parasitoid fly Ormia ochracea, are unusual in that both acoustic sensors are separated by only 520 microns and are contained within an undivided air-filled chamber. This anatomy results in minuscule differences in interaural time cues (ca. 2 microseconds) and no measurable difference in interaural intensity cues generated from an incident sound wave. The tympana of both ears are anatomically coupled by a cuticular bridge. This bridge also mechanically couples the tympanana, providing a basis for directional sensitivity. Using laser vibrometry, it is shown that the mechanical response of the tympanal membranes has a pronounced directional sensitivity. Interaural time and intensity differences in the mechanical response of the ears are significantly larger than those available in the acoustic field. The tympanal membranes vibrate with amplitude differences of about 12 dB and time differences on the order of 50 microseconds to sounds at 90 degrees off the longitudinal body axis. The analysis of the deflection shapes of the tympanal vibrations shows that the interaural differences in the mechanical response are due to the dynamic properties of the tympanal system and reflect its intrinsic sensitivity to the direction of a sound source. Using probe microphones and extracellular recording techniques, we show that the primary auditory afferents encode sound direction with a time delay of about 300 microseconds. Our data point to a novel mechanism for directional hearing in O. ochracea based on intertympanal mechanical coupling, a process that amplifies small acoustic cues into interaural time and amplitude differences that can be reliably processed at the neural level. An intuitive description of the mechanism is proposed using a simple mechanical model in which the ears are coupled through a flexible lever.

Naturalistic stimuli increase the rate and efficiency of information transmission by primary auditory afferents

Natural sounds, especially communication sounds, have highly structured amplitude and phase spectra. We have quantified how structure in the amplitude spectrum of natural sounds affects coding in primary auditory afferents. Auditory afferents encode stimuli with naturalistic amplitude spectra dramatically better than broad-band stimuli (approximating white noise); the rate at which the spike train carries information about the stimulus is 2-6 times higher for naturalistic sounds. Furthermore, the information rates can reach 90% of the fundamental limit to information transmission set by the statistics of the spike response. These results indicate that the coding strategy of the auditory nerve is matched to the structure of natural sounds; this 'tuning' allows afferent spike trains to provide higher processing centres with a more complete description of the sensory world.

A common neural code for frequency- and amplitude-modulated sounds.

Most naturally occurring sounds are modulated in amplitude or frequency; important examples include animal vocalizations and species-specific communication signals in mammals, insects, reptiles, birds and amphibians. Deciphering the information from amplitude-modulated (AM) sounds is a well-understood process, requiring a phase locking of primary auditory afferents to the modulation envelopes. The mechanism for decoding frequency modulation (FM) is not as clear because the FM envelope is flat (Fig. 1). One biological solution is to monitor amplitude fluctuations in frequency-tuned cochlear filters as the instantaneous frequency of the FM sweeps through the passband of these filters. This view postulates an FM-to-AM transduction whereby a change in frequency is transmitted as a change in amplitude. This is an appealing idea because, if such transduction occurs early in the auditory pathway, it provides a neurally economical solution to how the auditory system encodes these important sounds. Here we illustrate that an FM and AM sound must be transformed into a common neural code in the brain stem. Observers can accurately determine if the phase of an FM presented to one ear is leading or lagging, by only a fraction of a millisecond, the phase of an AM presented to the other ear. A single intracranial image is perceived, the spatial position of which is a function of this phase difference.