Oscillating neurons in the cochlear nucleus: II. Simulation results

A computer model of sustained chopper neurons in the ventral cochlear nucleus is presented and investigated. In the companion paper, the underlying neurophysiological and neuroanatomical data are demonstrated. To explain the preference of chopper neurons for oscillations with periods which are multiples of a 0.4 ms synaptic delay, we suggest a model of circularly connected chopper neurons. In order to simulate chopper neurons within a physiological dynamic range for periodicity encoding, it is necessary to assume that they receive an input from onset neurons. Our computer analysis of the resulting simple neuronal network shows that it can produce stable oscillations. The chopping can be triggered by an amplitude-modulated signal (AM). The dynamic range and the synchronous response of the simulated chopper neurons to AM are enhanced significantly by an additional input from onset neurons. Physiological properties of chopper neurons in the cat, such as mean, standard deviation, and coefficient of variation of the interspike interval are matched precisely by our simulations.     

Parameters for a model of an oscillating neuronal network in the cochlear nucleus defined by genetic algorithms

Chopper neurons in the cochlear nucleus are characterized by intrinsic oscillations with short average interspike intervals (ISIs) and relative level independence of their response (Pfeiffer, Exp Brain Res 1:220–235, 1966; Blackburn and Sachs, J Neurophysiol 62:1303–1329, 1989), properties which are unattained by models of single chopper neurons (e.g., Rothman and Manis, J Neurophysiol 89:3070–3082, 2003a). In order to achieve short ISIs, we optimized the time constants of Rothman and Manis single neuron model with genetic algorithms. Some parameters in the optimization, such as the temperature and the capacity of the cell, turned out to be crucial for the required acceleration of their response. In order to achieve the relative level independence, we have simulated an interconnected network consisting of Rothman and Manis neurons. The results indicate that by stabilization of intrinsic oscillations, it is possible to simulate the physiologically observed level independence of ISIs. As previously reviewed and demonstrated (Bahmer and Langner, Biol Cybern 95:371–379, 2006a), chopper neurons show a preference for ISIs which are multiples of 0.4 ms. It was also demonstrated that the network consisting of two optimized Rothman and Manis neurons which activate each other with synaptic delays of 0.4 ms shows a preference for ISIs of 0.8 ms. Oscillations with various multiples of 0.4 ms as ISIs may be derived from neurons in a more complex network that is activated by simultaneous input of an onset neuron and several auditory nerve fibers.     

A simulation of chopper neurons in the cochlear nucleus with wideband input from onset neurons

The unique temporal and spectral properties of chopper neurons in the cochlear nucleus cannot be fully explained by current popular models. A new model of sustained chopper neurons was therefore suggested based on the assumption that chopper neurons receive input both from onset neurons and the auditory nerve (Bahmer and Langner in Biol Cybern 95:4, 2006). As a result of the interaction of broadband input from onset neurons and narrowband input from the auditory nerve, the chopper neurons in our model are characterized by a remarkable combination of sharp frequency tuning to pure tones and faithful periodicity coding. Our simulations show that the width of the spectral integration of the onset neuron is crucial for both the precision of periodicity coding and their resolution of single components of sinusoidally amplitude-modulated sine waves. One may hypothesize, therefore, that it would be an advantage if the hearing system were able to adapt the spectral integration of onset neurons to varying stimulus conditions.     

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.     

Frequency tuning and response latencies at three levels in the brainstem of the echolocating bat,Eptesicus fuscus

To determine the level at which certain response characteristics originate, we compared monaural auditory responses of neurons in ventral cochlear nucleus, nuclei of lateral lemniscus and inferior colliculus. Characteristics examined were sharpness of frequency tuning, latency variability for individual neurons and range of latencies across neurons.Exceptionally broad tuning curves were found in the nuclei of the lateral lemniscus, while exceptionally narrow tuning curves were found in the inferior colliculus. Neither specialized tuning characteristic was found in the ventral cochlear nuclei.All neurons in the columnar division of the ventral nucleus of the lateral lemniscus maintained low variability of latency over a broad range of stimulus conditions. Some neurons in the cochlear nucleus (12%) and some in the inferior colliculus (15%) had low variability in latency but only at best frequency.Range of latencies across neurons was small in the ventral cochlear nucleus (1.3–5.7 ms), intermediate in the nuclei of the lateral lemniscus (1.7–19.8 ms) and greatest in the inferior colliculus (2.9–42.0 ms).We conclude that, in the nuclei of the lateral lemniscus and in the inferior colliculus, unique tuning and timing properties are built up from ascending inputs.Abbreviations AVCN anteroventral cochlear nucleus - BF best frequency - CV coefficient of variation - DCN dorsal cochlear nucleus - FM frequency modulation - IC inferior colliculus - NLL nuclei of lateral lemniscus - PSTH post stimulus time histogram - PVCN posteroventral cochlear nucleus - SD standard deviation - SPL sound pressure level - VCN ventral cochlear nuclei - VNLLc ventral nucleus of the lateral lemniscus, columnar division     

Identification of tuberculo-ventral neurons in the polymorphic layer of the rat dorsal cochlear nucleus

The tuberculo-ventral tract represents a short nervous circuit within the auditory cochlear nuclei. Tuberculo-ventral neurons of the dorsal cochlear nucleus send isofrequency inhibitory inputs to bushy cells of the ventral cochlear nucleus. Injection of wheat germ agglutinin conjugated to horseradish peroxidase into the rat ventral cochlear nucleus, labelled tuberculo-ventral neurons retrogradely in the deep polymorphic layer of the ipsilateral dorsal cochlear nucleus. Five to 20% of the perimeter of these cells was covered by synaptic boutons, most of which contained flat and pleomorphic vesicles. These boutons contained glycine and sometimes GABA. Occasional small axo-somatic boutons contained round vesicles and were immunonegative for both glycine and GABA. This study shows that the synaptic profile of tuberculo-ventral neurons is different from that of other medium-size glycinergic neurons within the polymorphic layer or more superficial regions of the dorsal cochlear nucleus like cartwheel neurons. In fact the latter mostly receive boutons that contain pleomorphic vesicles.     

A rapid form of activity-dependent recovery from short-term synaptic depression in the intensity pathway of the auditory brainstem

Short-term synaptic plasticity acts as a time- and firing rate-dependent filter that mediates the transmission of information across synapses. In the avian auditory brainstem, specific forms of plasticity are expressed at different terminals of the same auditory nerve fibers and contribute to the divergence of acoustic timing and intensity information. To identify key differences in the plasticity properties, we made patch-clamp recordings from neurons in the cochlear nucleus responsible for intensity coding, nucleus angularis, and measured the time course of the recovery of excitatory postsynaptic currents following short-term synaptic depression. These synaptic responses showed a very rapid recovery, following a bi-exponential time course with a fast time constant of ~40 ms and a dependence on the presynaptic activity levels, resulting in a crossing over of the recovery trajectories following high-rate versus low-rate stimulation trains. We also show that the recorded recovery in the intensity pathway differs from similar recordings in the timing pathway, specifically the cochlear nucleus magnocellularis, in two ways: (1) a fast recovery that was not due to recovery from postsynaptic receptor desensitization and (2) a recovery trajectory that was characterized by a non-monotonic bump that may be due in part to facilitation mechanisms more prevalent in the intensity pathway. We tested whether a previously proposed model of synaptic transmission based on vesicle depletion and sequential steps of vesicle replenishment could account for the recovery responses, and found it was insufficient, suggesting an activity-dependent feedback mechanism is present. We propose that the rapid recovery following depression allows improved coding of natural auditory signals that often consist of sound bursts separated by short gaps.     

正常豚鼠耳蜗核一氧化氮合酶阳性神经元的投射

本文采用辣根过氧化物酶（ＨＲＰ）逆行追踪技术结合硫辛酰胺脱氨酸（ＮＡＤＰＨ－ｄ）组织化学方法,研究正常豚鼠耳蜗核一氧化氮合酶（ＮＯＳ）阳性神经元的上行投射特点。探讨耳蜗核ＮＯＳ阳性神经元在听觉信号传递中的可能作用。结果表明,一侧上橄榄复合体加压注射ＨＲＰ后,两侧耳蜗核均出现ＨＲＰ标记细胞,同侧耳蜗核ＮＯＳ－ＨＲＰ双标细胞较多占８２．６３％,并可见ＨＲＰ阳性纤维和终末包绕ＮＯＳ阳性胞体,对侧耳蜗核ＮＯＳ－ＨＲＰ双标细胞相对较少,仅占１４．８７％。一侧下丘加压注入ＨＲＰ后两侧耳蜗核均无ＨＲＰ－ＮＯＳ双标细胞。结果提示,耳蜗核ＮＯＳ阳性神经元向上橄榄复合体投射,可能具有调节听觉声信号传递的作用     

Activation of Metabotropic Glutamate Receptors Regulates Ribosomes of Cochlear Nucleus Neurons

The brain stem auditory system of the chick is an advantageous model for examining changes that occur as a result of deafness. Elimination of acoustic input through cochlear ablation results in the eventual death of approximately 30% of neurons in the chick cochlear nucleus, nucleus magnocellularis (NM). One early change following deafness is an alteration in NM ribosomes, evidenced both by a decrease in protein synthesis and reduction in antigenicity for Y10B, a monoclonal antibody that recognizes a ribosomal epitope. Previous studies have shown that mGluR activation is necessary to maintain Y10B antigenicity and NM viability. What is still unclear, however, is whether or not mGluR activation is sufficient to prevent deafness-induced changes in these neurons, or if other activity-dependent factors are also necessary. The current study investigated the ability of mGluR activation to regulate cochlear nucleus ribosomes in the absence of auditory nerve input. In vitro methods were employed to periodically pressure eject glutamate or mGluR agonists over neurons on one side of a slice preparation leaving the opposite side of the same slice untreated. Immunohistochemistry was then performed using Y10B in order to assess ribosomal changes. Application of glutamate and both group I and II selective mGluR agonists effectively rescued ribosomal antigenicity on the treated side of the slice in comparison to ribosomes on the untreated side. These findings suggest that administration of mGluR agonists is sufficient to reduce the early interruption of normal ribosomal integrity that is typically seen following loss of auditory nerve activity.     

Auditory responses in the vocal motor system of budgerigars

Budgerigars (Melopsittacus undulatus) are small Australian parrots that can imitate novel sounds in adulthood and therefore serve as a convenient model system for the study of vocal learning in adult animals. Previous anatomical studies had indicated that known auditory regions in the telencephalon of budgerigars are connected, albeit indirectly and rather sparsely, to vocal motor nuclei. Physiological evidence for connections between the auditory and vocal motor systems in budgerigars had been lacking, however. Here, we show that neurons in a telencephalic vocal motor region, i.e., the central nucleus of the lateral neostriatum (NLc), are responsive to auditory stimuli in isoflurane-anesthetized budgerigars. These responses are highly variable from trial to trial and frequently have latencies in excess of 100 ms. Neurons in NLc generally respond better to a budgerigar's own contact call than to a white noise stimulus, but the response preferences of NLc neurons in budgerigars are generally weaker and more diverse than the response preferences of neurons in the high vocal center of songbirds, which is probably analogous to NLc. These data indicate that parrots and songbirds, which have evolved the ability to learn vocalizations independently of one another, have both evolved physiologically effective connections between their auditory and vocal motor systems. Interestingly, however, the anatomical pathways by which the auditory and vocal motor systems interact, and the physiological details of how they communicate, appear to be significantly different between the two taxa.     

Vestibular efferent neurons forming projections to the saccule in the guinea pig

A comparative analysis was made of the distribution of vestibular efferent neurons projecting to the saccule and efferent cells sending out axons to the auditory nerve ("cochlear efferent neurons") in the guinea pig, using retrograde horseradish peroxidase axonal transport techniques. Saccular efferent neurons were discovered bilaterally in the subependymal granular layer at the base of the fourth cerebral ventricle and laterally to the facial nerve genu ispsilaterally in the parvocellular reticular nucleus, as well as nuclei of the superior olivary complex: the lateral olivary nucleus and lateral nucleus of the trapezoid body. Cochlear efferent neurons are located ipsilaterally in the pontine reticular caudal nucleus, in the anteroventral cochlear nucleus, and in the lateral and medial olivary nuclei. Neurons were found contralaterally in the medial nucleus of the trapezoid body. It thus emerged that location zones of vestibular saccular efferent neurons and those of cochlear efferent units partially overlapped. The possible involvement of saccular vestibular efferent neurons in the mechanisms of auditory perception is discussed.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 22, No. 5, pp. 657–665, September–October, 1990.     

猫耳蜗电图中N_2波起源的分析

在35只猫进行了耳蜗电图、听觉脑干电反应及耳蜗核局部电位的同时描记,将普鲁卡因或海人酸微量注入耳蜗核内,观察电位的变化,以分析耳蜗电图中N_2 波的起源。实验结果表明:猫的 N_2 波来源于外周第一级神经元冲动的成分和耳蜗核电活动的成分。     

Delay Line Models of Sound Localization in the Barn Owl

SYNOPSIS. The detection of interaural time differences underliesazimuthal sound localization in the barn owl. Sensitivity tothese time differences arises in the brainstem nucleus laminaris.Auditory information reaches the nucleus laminaris via bilateralprojections from the cochlear nucleus magnocellularis. The magnocellularinputs to the nucleus laminaris act as delay lines to createmaps of interaural time differences. These delay lines are tappedby postsynaptic coincidence detectors that encode interauraltime differences. The entire circuit, from the auditory nerveto the nucleus magnocellularis to the nucleus laminaris, isspecialized for the encoding and preservation of temporal information.A mathematical model of this circuit (Grun et al., 1990) providesuseful predictions.     

The role of intrinsic neuronal properties in the encoding of auditory information in the cochlear nuclei.

It is now possible to relate the intrinsic electrical properties of particular cells in the cochlear nuclei of mammals with their biological function. In the layered dorsal cochlear nucleus, information concerning the location of a sound source seems to be contained in the spatial pattern of activation of a population of neurons. In the unlayered, ventral cochlear nucleus, however, neurons carry information in their temporal firing patterns. The voltage-sensitive conductances that make responses to synaptic current brief enable bushy cells to convey signals from the auditory nerve to the superior olivary complex with a temporal precision of at least 120 microseconds.     

Design principles of sensory processing in cerebellum-like structures

Cerebellum-like structures are compared for two sensory systems: electrosensory and auditory. The electrosensory lateral line lobe of mormyrid electric fish is reviewed and the neural representation of electrosensory objects in this structure is modeled and discussed. The dorsal cochlear nucleus in the auditory brainstem of mammals is reviewed and new data are presented that characterize the responses of neurons in this structure in the mouse. Similarities between the electrosensory and auditory cerebellum-like structures are shown, in particular adaptive processes that may reduce responses to predictable stimuli. We suggest that the differences in the types of sensory objects may drive the differences in the anatomical and physiological characteristics of these two cerebellum-like structures.     

A Model of the Peripheral Auditory System Responding to Low-Frequency Tones

A model of the peripheral auditory system responding to low-frequency tone stimulation is given. The model is of the type previously introduced by Weiss (1966). It includes three interconnected parts: a linear model of the ear's mechanical system, a model of the cochlear transducer, and a stochastic model of an auditory nerve fiber. The output of the model accurately mimics many characteristics of the output of some auditory nerve neurons responding to sinusoidal stimuli but is unable to successfully match all reported aspects of data obtained from other of these neurons. Characteristics of the model neurons are discussed.     

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.     

Specialized sound reception in dolphins—a hint for the function of the dorsal cochlear nucleus in mammals

Dolphins have developed a specialized system for sound reception. Their pinnae are reduced and shifted under the skin, and sound is transduced via the lower jaw to the auditory ossicles. In line with their auditory functions (notably echolocation), most auditory nuclei in the brain stem of dolphins are extremely well‐developed. In contrast, the dorsal cochlear nucleus is drastically reduced. In the La Plata dolphin the volume of the dorsal cochlear nucleus is 4 mm³, while that of the ventral cochlear nucleus is 98 mm³. The reduction in size of the dorsal cochlear nucleus is also seen in baleen whales, which do not echolocate and are, in contrast to dolphins, tuned to deep frequencies. However, dolphins and baleen whales have the reduction of the outer ear in common. In humans, cats, bats and seals, there is a correlation between the development of pinnae and the dorsal cochlear nucleus. So, we conclude that the function of the dorsal cochlear nucleus in mammals could be to eliminate “auditory artifacts”; arising from the operation of the pinnae.     

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.     

Spatial cross-correlation

We propose in this paper a new class of model processes for the extraction of spectral information from the neural representation of acoustic signals in mammals. We are concerned particularly with mechanisms for detecting the phase-locked activity of auditory neurons in response to frequencies and intensities of sound associated with speech perception. Recent psychophysical tests on deaf human subjects implanted with intracochlear stimulating electrodes as an auditory prosthesis have produced results which are in conflict with the predictions of the classical place-pitch and periodicity-pitch theories. In our model, the detection of synchronicity between two phase-locked signals derived from sources spaced a finite distance apart on the basilar membrane can be used to extract spectral information from the spatiotemporal pattern of basilar membrane motion. Computer simulations of this process suggest an optimal spacing of about 0.3–0.4 of the wavelength of the frequency to be detected. This interval is consistent with a number of psychophysical, neurophysiological, and anatomical observations, including the results of high resolution frequency-mapping of the anteroventral cochlear nucleus which are presented here. One particular version of this model, invoking the binaurally sensitive cells of the medial superior olive as the critical detecting elements, has properties which are useful in accounting for certain complex binaural psychophysical observations.