On the existence of stimulus-event relations for sensory neurons: A statistical method

Aertsen et al. (1979) studied single unit recordings from the cochlear nucleus and the auditory cortex of the cat using a stimulus with a wide range of natural and technical sounds and discussed the question of the existence of a stimulus-event relation. The existence of such a stimulus-event relation was investigated by presenting the stimulus twice while recording the spike trains and studying the degree of reproducibility of the neural activity under the two presentations of the stimulus. This paper presents a statistical method to decide whether the two recordings of neural activity are similar, and if so to quantify the degree of similarity. The method is of potential use in multi-unit recordings.     

Neural representation of the acoustic biotope

Cats were stimulated with tones and with natural sounds selected from the normal acoustic environment of the animal. Neural activity evoked by the natural sounds and tones was recorded in the cochlear nucleus and in the medial geniculate body. The set of biological sounds proved to be effective in influencing neural activity of single cells at both levels in the auditory system. At the level of the cochlear nucleus the response of a neuron evoked by a natural sound stimulus could be understood reasonably well on the basis of the structure of the spectrograms of the natural sounds and the unit's responses to tones. At the level of the medial geniculate body analysis with tones did not provide sufficient information to explain the responses to natural sounds. At this level the use of an ensemble of natural sound stimuli allows the investigation of neural properties, which are not seen by analysis with simple artificial stimuli. Guidelines for the construction of an ensemble of complex natural sound stimuli, based on the ecology and ethology of the animal under investigation are discussed. This stimulus ensemble is defined as the Acoustic Biotope.     

Spectro-temporal receptive fields of auditory neurons in the grassfrog

The nature of the stimulus-response relation for single auditory neurons is reflected in the properties of the Pre-Event Stimulus Ensemble: the ensemble of stimuli, preceding the occurrence of an action potential (neural event). This paper describes methods to analyse the spectro-temporal properties of this ensemble. These methods are based on the analytic signal representation of acoustic signals and functionals derived from it: the instantaneous amplitude and instantaneous frequency and the dynamic power spectrum. The procedures have been applied to a number of extra-cellular single unit recordings from the grassfrog, Rana temporatia L., recorded during presentation of an ensemble of tonal stimuli. The outcome of this analysis describes the spectro-temporal receptive field of the neuron under the present stimulus conditions. The procedure, based on the dynamic power spectrum is applicable to an arbitrary stimulus ensemble, thus allowing a comparison of the spectrotemporal receptive fields for different types of stimuli.     

Auditory units in the medulla of the marsh frog with unusual patterns of spontaneous activity

Statistical properties of spontaneous firing were studied in 79 single auditory units located in the dorsal medullar (cochlear) nucleus of unanaesthetized curarized marsh frogs (Rana ridibunda). The great majority of these units showed irregular spontaneous activity with mean rates in the range 1–30 spikes · s^–1. In 53% of the cells the auto-renewal functions of the spontaneous activity monotonically rose to an asymptotic value, but 41% of the cells produced auto-renewal functions which showed a pronounced peak after a dead-time period. Five low-frequency auditory neurons revealed periodic firing in the absence of controlled stimuli. The preferred period did not correspond to the unit's best frequency but demonstrated a modest correlation with the best modulation frequency of the unit's response to amplitude-modulated tones and with the duration of the after-onset dip in peri-stimulus time histograms.Abbreviations AM amplitude modulation - ARF auto-renewal function - DMN dorsal medullar nucleus - PST peristimulus time - SA spontaneous activity - TID time interval distribution - RMG response modulation gain     

Corticofugal modulation of initial neural processing of sound information from the ipsilateral ear in the mouse

Background

Cortical neurons implement a high frequency-specific modulation of subcortical nuclei that includes the cochlear nucleus. Anatomical studies show that corticofugal fibers terminating in the auditory thalamus and midbrain are mostly ipsilateral. Differently, corticofugal fibers terminating in the cochlear nucleus are bilateral, which fits to the needs of binaural hearing that improves hearing quality. This leads to our hypothesis that corticofugal modulation of initial neural processing of sound information from the contralateral and ipsilateral ears could be equivalent or coordinated at the first sound processing level.

Methodology/Principal Findings

With the focal electrical stimulation of the auditory cortex and single unit recording, this study examined corticofugal modulation of the ipsilateral cochlear nucleus. The same methods and procedures as described in our previous study of corticofugal modulation of contralateral cochlear nucleus were employed simply for comparison. We found that focal electrical stimulation of cortical neurons induced substantial changes in the response magnitude, response latency and receptive field of ipsilateral cochlear nucleus neurons. Cortical stimulation facilitated auditory response and shortened the response latency of physiologically matched neurons whereas it inhibited auditory response and lengthened the response latency of unmatched neurons. Finally, cortical stimulation shifted the best frequencies of cochlear neurons towards those of stimulated cortical neurons.

Conclusion

Our data suggest that cortical neurons enable a high frequency-specific remodelling of sound information processing in the ipsilateral cochlear nucleus in the same manner as that in the contralateral cochlear nucleus.     

Auditory cortex basal activity modulates cochlear responses in chinchillas

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.     

Modeling inhibition of type II units in the dorsal cochlear nucleus

 Type II units in the dorsal cochlear nucleus (DCN) are characterized by vigorous but nonmonotonic responses to best frequency tones as a function of sound pressure level, and relatively weak responses to noise. A model of DCN neural circuitry was used to explore two hypothetical mechanisms by which neurons may be endowed with type II unit response properties. Both mechanisms assume that type II units receive excitatory input from auditory nerve (AN) fibers and inhibitory input from an unspecified class of cochlear nucleus interneurons that also receive excitatory AN input. The first mechanism, a lateral inhibition (LI) model, supposes that type II units receive inhibitory input from a number of narrowly tuned interneurons whose best frequencies (BFs) flank the BF of the type II unit. Tonal stimuli near BF result in only weak inhibitory input, but broadband stimuli recruit enough lateral inhibitors to greatly weaken the type II unit response. The second mechanism, a wideband inhibition (WBI) model, supposes that type II units receive inhibitory input from interneurons that are broadly tuned so that they respond more vigorously to broadband stimuli than to tones. Physiological and anatomical evidence points to the possible existence of such a class of neurons in the cochlear nucleus. The model extends an earlier computer model of an iso-frequency DCN patch to multiple frequency slices and adds a population of interneurons to provide the inhibition to model type II units (called I2-cells). The results show that both mechanisms accurately simulate responses of type II units to tones and noise. An experimental paradigm for distinguishing the two mechanisms is proposed. Received: 30 December 1996/Accepted in revised form: 13 March 1997     

Postnatal development of central auditory frequency maps

Summary In the early postnatal period of many mammals and in the perihatching period of chicks the auditory ranges are restricted to the species-specific low- and mid-frequency ranges. During subsequent development, the high frequency hearing expands (depending on the species) by 1–4 octaves. Adult-like audition is established between the 4th and the 7th week. It is still discussed controversially, how the extension of the auditory ranges relates to the maturation of orderly frequency representation in the cochleae of the respective species. The present review summarizes investigations of the development of tonotopy in nuclei of the central auditory system, and discusses how the centrally acquired data might contribute to the understanding of the maturation of cochlear stimulus transduction and to the development of frequency maps.Abbreviations ANF auditory nerve fibers - BF best frequency - CN cochlear nucleus - DAB days after birth - DCN dorsal cochlear nucleus - IC inferior colliculus - IHC inner hair cells - HS Hipposideros speoris - LSO lateral superior olive - MGB medial geniculate body (auditory thalamus) - NL Nucleus laminaris - NM Nucleus magnocellularis - OHC outer hair cells - RR Rhinolophus rouxi - SOC superior olivary complex - 2-DG 2-deoxyglucose     

Perceptual organization of sound begins in the auditory periphery

Segmenting the complex acoustic mixture that makes a typical auditory scene into relevant perceptual objects is one of the main challenges of the auditory system [1], for both human and nonhuman species. Several recent studies indicate that perceptual auditory object formation, or "streaming," may be based on neural activity within the auditory cortex and beyond [2, 3]. Here, we find that scene analysis starts much earlier in the auditory pathways. Single units were recorded from a peripheral structure of the mammalian auditory brainstem, the cochlear nucleus. Peripheral responses were similar to cortical responses and displayed all of the functional properties required for streaming, including multisecond adaptation. Behavioral streaming was also measured in human listeners. Neurometric functions derived from the peripheral responses predicted accurately behavioral streaming. This reveals that subcortical structures may already contribute to the analysis of auditory scenes. This finding is consistent with the observation that species lacking a neocortex can still achieve and benefit from behavioral streaming [4]. For humans, we argue that auditory scene analysis of complex scenes is probably based on interactions between subcortical and cortical neural processes, with the relative contribution of each stage depending on the nature of the acoustic cues forming the streams.     

A model of selective processing of auditory-nerve inputs by stellate cells of the antero-ventral cochlear nucleus

Stellate cells in the cat antero-ventral cochlear nucleus (AVCN) maintain a robust rate-place representation of vowel spectra over a wide range of stimulus levels. This rate-place representation resembles that of low threshold, high spontaneous rate (SR) auditory nerve fibers (ANFs)at low stimulus levels, and that of high threshold, lowmedium SR ANFsat high stimulus levels. One hypothesis accounting for this phenomenon is that AVCN stellate cells selectively process inputs from different SR population of ANFs in a level-dependent fashion. In this paper, we investigate a neural mechanism that can support selective processing of ANF inputs by stellate cells. We study a physiologically detailed compartmental model of stellate cells. The model reproduces PST histograms and rate-versus-level functions measured in real cells. These results indicate that simple and plausible distribution patterns of excitatory and inhibitory inputs within the stellate cell dendritic tree can support level dependent selective processing. Factors affecting selective processing are identified. This study thus represents a first step towards the development of a computational model of the AVCN stellate cell receptive field.     

GABA and its related enzymes in the lower auditory system of the guinea pig

The possible existence of GABA-transmitter neurons in the lower auditory system of the guinea pig has been investigated by means of three different experimental approaches: (1) the regional distribution of GABA and its related enzymes, (2) the subcellular distribution of glutamate decarboxylase, and (3) the effect of selected nerve lesions on glutamate decarboxylase concentrations in the auditory nuclei. Within the regions investigated considerable variations in glutamate decarboxylase activity and GABA concentration were found, with the highest values observed in the inferior colliculus. The dorsal cochlear nucleus also contained significant amounts of both glutamate decarboxylase and GABA, in addition to high concentrations of GABA transaminase. The subcellular distribution of glutamate decarboxylase was bimodal in both the cochlear nucleus and inferior colliculus with most enzyme activity recovered in the soluble and synaptosomal fractions. Neither end organ (cochlea) nor trapezoid body lesions induced a significant loss of glutamate decarboxylase activity in either the cochlear nucleus or inferior colliculus. The results suggest the presence of short axon GABAergic interneurons in the cochlear nucleus, most of which appear to terminate within the dorsal cochlear nucleus.     

Tonotopical organization and pure tone response characteristics of single units in the auditory cortex of the Greater Horseshoe Bat

Summary Tonotopical organization and frequency representation in the auditory cortex of Greater Horseshoe Bats was studied using multi-unit recordings.The auditory responsive cortical area can be divided into a primary and a secondary region on the basis of response characteristics forming a core/belt structure.In the primary area units with best frequencies in the range of echolocation signals are strongly overrepresented (Figs. 6–8). There are two separate large areas concerned with the processing of the two components of the echolocation signals. In one area frequencies between the individual resting frequency and about 2 kHz above are represented, which normally occur in the constant frequency (CF) part of the echoes (CF-area), in a second one best frequencies between resting frequency and about 8 kHz below are found (FM-area).In the CF-area tonotopical organization differs from the usual mammalian scheme of dorso-ventral isofrequency slabs. Here isofrequency contours are arranged in a semicircular pattern.The representation of the cochlear partition (cochleotopic organization) was calculated. In the inferior colliculus and auditory cortex there is a disproportionate representation of the basilar membrane. This finding is in contradiction to the current opinion that frequency representation in the auditory system of Horseshoe Bats is only determined by the mechanical tuning properties of the basilar membrane.Response characteristics for single units were studied using pure tone stimuli. Most units showed transient responses. In 25% of units response characteristics depended on the combination of frequency and sound pressure level used.Frequency selectivity of units with best frequencies in the range of echolocation sounds is very high. Q-10dB values of up to 400 were found in a small frequency band just above resting frequency.Abbreviations BF best frequency - CF constant frequency - FM frequency modulated - MT minimal threshold     

Coding of sound location and frequency in the auditory midbrain of diurnal birds of prey,families accipitridae and falconidae

Summary The coding of sound frequency and location in the avian auditory midbrain nucleus (nMLD) was examined in three diurnal raptors: the brown falcon (Falco berigora), the swamp harrier (Circus aeruginosus) and the brown goshawk (Accipiter fasciatus). Previously this nucleus has been studied with free field stimuli in only one other species, the barn owl (Tyto alba).We found some parallels between the organisation of nMLD in the diurnal raptors and that reported in the barn owl in that the central region of nMLD was tonotopically organised and contained cells that did not encode location, and the lateral region (nMLDl) contained cells which were sensitive to stimulus position. However, unlike the barn owl, which has units with circumscribed receptive fields, cells sensitive to stimulus location had large receptive fields which were restricted in azimuth but not in elevation (hemifield units). Such cells could not provide an acoustic space map in which both azimuthal and elevational dimensions were represented, but there was a tendency for units with contralateral borders to be found superficially, and those with ipsilateral borders to be found deep, in nMLDl. Hemifield units displayed receptive field properties consistent with the directional properties of the tympana in the presence of sound transmission through the interaural canal, if there is a central mechanism which is sensitive to interaural intensity differences.Abbreviations nMLD nucleus mesencephalicus lateralis pars dorsalis - SPL sound pressure level re 20 Pa - nMLDl lateral region of nMLD - ICC central nucleus of the inferior colliculus - ICX external nucleus of the inferior colliculus - IID interaural intensity difference - EI excitatory inhibitory     

Physiological characteristics of the tympanic organ in noctuoid moths

Summary We show the variations in the spike activity of both auditory receptors inSpodoptera frugiperda, Mocis latipes, Ascalapha odorata (Noctuidae),Maenas jussiae andEmpyreuma pugione (Arctiidae) immediately after 45 ms and 5 s acoustic stimuli at different intensities. The frequency of the applied stimuli was 34 kHz forE. pugione and 20 kHz for the other species. The electrical activity of the auditory receptors was recorded at the tympanic nerve with a stainless steel hook electrode. When the 45 ms pulses cease there is an afterdischarge from both auditory receptors in all the species. The number of spikes in the afterdischarge activity of both receptor cells (A₁ and A₂) shows a linear relation with stimulus intensity (Table 1). This number increases monotonically with increments in stimulus intensity, except for the A₁ cell activity inE. pugione, which decreases at intensities higher than 55 dB (Fig. 1). There are significant species-specific differences in the slope values of the number of spikes in the afterdischarge of both auditory receptors. After a 5 s stimulusM. latipes andM. jussiae show a rapid recovery of the standard spontaneous A₁-cell discharge level. Poststimulus A₁-cell spike activity inS. frugiperda shows a silent period, the duration of which increases with stimulus intensity (Fig. 3).E. pugione andA. odorata show such a silent period after low and moderately intense stimuli, but at high intensities the post-stimulus activity exceeds the pre-stimulus spontaneous discharge (Fig. 3). We demonstrate statistically that these variations cannot be explained by the random fluctuations of the standard spontaneous discharge. They are thus considered a silent and a rebound period respectively (Fig. 5). The presence and duration of either type of period seem to depend on the magnitude of the response to the acoustic stimulus. They thus seem related to the adaptation rate and the previously suggested existence of peripheral inhibitory interaction between the auditory receptors.     

Neural adaptation to tone sequences in the songbird forebrain: patterns, determinants, and relation to the build-up of auditory streaming

Neural responses to tones in the mammalian primary auditory cortex (A1) exhibit adaptation over the course of several seconds. Important questions remain about the taxonomic distribution of multi-second adaptation and its possible roles in hearing. It has been hypothesized that neural adaptation could explain the gradual “build-up” of auditory stream segregation. We investigated the influence of several stimulus-related factors on neural adaptation in the avian homologue of mammalian A1 (field L2) in starlings (Sturnus vulgaris). We presented awake birds with sequences of repeated triplets of two interleaved tones (ABA–ABA–…) in which we varied the frequency separation between the A and B tones (ΔF), the stimulus onset asynchrony (time from tone onset to onset within a triplet), and tone duration. We found that stimulus onset asynchrony generally had larger effects on adaptation compared with ΔF and tone duration over the parameter range tested. Using a simple model, we show how time-dependent changes in neural responses can be transformed into neurometric functions that make testable predictions about the dependence of the build-up of stream segregation on various spectral and temporal stimulus properties.     

Resonance phenomena in the cochlea of the mustache bat and their contribution to neuronal response characteristics in the cochlear nucleus

Summary The cochlea of the mustache bat, Pteronotus parnellii, is very sensitive and sharply tuned to the frequency range of the dominant second harmonic of the echolocation call around 61 kHz. About 900 Hz above this frequency the cochlear microphonic potential (CM) reaches its maximum amplitude and lowest threshold. At exactly the same frequency, pronounced evoked otoacoustic emissions (OAE) can be measured in the outer ear canal, indicating mechanical resonance. The CM amplitude maximum and the OAE are most severely masked by simultaneous exposure to tones within the range from about 61–62 kHz up to about 70 kHz. The data suggest that the mechanism of mechanical resonance involves cochlear loci basal to the 61 kHz position.The resonance contributes to auditory sensitivity and sharp tuning: At the frequency of the OAE, single unit responses in the cochlear nucleus have the lowest thresholds. Maximum tuning sharpness occurs at frequencies about 300 Hz below the OAE-frequency, where the threshold is about 10 dB less sensitive than at the OAE-frequency. In addition, in the frequency range around the OAE-frequency several specialized neuronal response features can be related to mechanical resonance: Long lasting excitation after the end of the stimulus, asymmetrical tuning curves with a shallow high frequency slope and phasic on-off neuronal response patterns. In particular the latter phenomenon indicates the occurrence of local mechanical cancellations in the cochlea.Abbreviations CF constant frequency component of echolocation calls - CM cochlear microphonic potential - FM frequency modulated component of echolocation calls - N1 compound action potential of the auditory nerve - OAE octoacoustic emission - SEOAE synchronous evoked OAE     

Egr2::Cre Mediated Conditional Ablation of Dicer Disrupts Histogenesis of Mammalian Central Auditory Nuclei

Histogenesis of the auditory system requires extensive molecular orchestration. Recently, Dicer1, an essential gene for generation of microRNAs, and miR-96 were shown to be important for development of the peripheral auditory system. Here, we investigated their role for the formation of the auditory brainstem. Egr2::Cre-mediated early embryonic ablation of Dicer1 caused severe disruption of auditory brainstem structures. In adult animals, the volume of the cochlear nucleus complex (CNC) was reduced by 73.5%. This decrease is in part attributed to the lack of the microneuronal shell. In contrast, fusiform cells, which similar to the granular cells of the microneural shell are derived from Egr2 positive cells, were still present. The volume reduction of the CNC was already present at birth (67.2% decrease). The superior olivary complex was also drastically affected in these mice. Nissl staining as well as Vglut1 and Calbindin 1 immunolabeling revealed that principal SOC nuclei such as the medial nucleus of the trapezoid body and the lateral superior olive were absent. Only choline acetyltransferase positive neurons of the olivocochlear bundle were observed as a densely packed cell group in the ventrolateral area of the SOC. Mid-embryonic ablation of Dicer1 in the ventral cochlear nucleus by Atoh7::Cre-mediated recombination resulted in normal formation of the cochlear nucleus complex, indicating an early embryonic requirement of Dicer1. Quantitative RT-PCR analysis of miR-96 demonstrated low expression in the embryonic brainstem and up-regulation thereafter, suggesting that other microRNAs are required for proper histogenesis of the auditory brainstem. Together our data identify a critical role of Dicer activity during embryonic development of the auditory brainstem.     

Effects of Antioxidant Treatment on Blast-Induced Brain Injury

Blast-induced traumatic brain injury has dramatically increased in combat troops in today’s military operations. We previously reported that antioxidant treatment can provide protection to the peripheral auditory end organ, the cochlea. In the present study, we examined biomarker expression in the brains of rats at different time points (3 hours to 21 days) after three successive 14 psi blast overpressure exposures to evaluate antioxidant treatment effects on blast-induced brain injury. Rats in the treatment groups received a combination of antioxidants (2,4-disulfonyl α-phenyl tertiary butyl nitrone and N-acetylcysteine) one hour after blast exposure and then twice a day for the following two days. The biomarkers examined included an oxidative stress marker (4-hydroxy-2-nonenal, 4-HNE), an immediate early gene (c-fos), a neural injury marker (glial fibrillary acidic protein, GFAP) and two axonal injury markers [amyloid beta (A4) precursor protein, APP, and 68 kDa neurofilament, NF-68]. The results demonstrate that blast exposure induced or up-regulated the following: 4-HNE production in the dorsal hippocampus commissure and the forceps major corpus callosum near the lateral ventricle; c-fos and GFAP expression in most regions of the brain, including the retrosplenial cortex, the hippocampus, the cochlear nucleus, and the inferior colliculus; and NF-68 and APP expression in the hippocampus, the auditory cortex, and the medial geniculate nucleus (MGN). Antioxidant treatment reduced the following: 4-HNE in the hippocampus and the forceps major corpus callosum, c-fos expression in the retrosplenial cortex, GFAP expression in the dorsal cochlear nucleus (DCN), and APP and NF-68 expression in the hippocampus, auditory cortex, and MGN. This preliminary study indicates that antioxidant treatment may provide therapeutic protection to the central auditory pathway (the DCN and MGN) and the non-auditory central nervous system (hippocampus and retrosplenial cortex), suggesting that these compounds have the potential to simultaneously treat blast-induced injuries in the brain and auditory system.     

Spectro-temporal receptive fields of auditory neurons in the grassfrog

The stimulus-event relation of single units in the auditory midbrain area, the torus semicircularis, of the anaesthetized grassfrog (Rana temporaria L.) during stimulation with a wide ensemble of natural stimuli, was analysed using first and second order statistical analysis techniques. The average stimulus preceding the occurrence of action potentials, in general, did not prove to give very informative results. The second order procedure consisted in the determination of the average dynamic power spectrum of the pre-event stimuli, following procedures as described elsewhere (Aertsen and Johannesma, 1980; Aertsen et al., 1980). The outcome of this analysis was filtered with the overall power spectrum of the complete stimulus ensemble in order to correct for its non-uniform spectral composition. The stimulus-filtered average pre-event dynamic spectrum gives a first indication of the spectro-temporal receptive field of a neuron under natural stimulus conditions. Results for a limited number of recordings are presented and, globally, compared to the outcome of an analogous analysis of experiments with tonal stimuli.