Role of Inhibition in Binaural Processing

The medial and lateral superior olives (MSO, LSO) are the lowest order cell groups in the mammalian auditory circuit to receive massive binaural input. The MSO functions in part to encode interaural time differences (ITD), the predominant cue for localization of low frequency sounds. Binaural inputs to the MSO consist of excitatory projections from the cochlear nuclei (CN) and inhibitory projections from both the medial nucleus of the trapezoid body (MNTB) and lateral nucleus of the trapezoid body (LNTB). The interaction of excitatory and inhibitory currents within an MSO cell\u27s soma and dendrites over the backdrop of its intrinsic ionic conductances imbues ITD sensitivity to these neurons. Lloyd Jeffress proposed a coincidence detection circuit in which arrays of neurons receive sub-threshold excitatory inputs via delay lines that represent sound location as a place code of activity patterns within the cell group (Jeffress, 1948). The Jeffress place code model later found a neural instantiation in the MSO. Recent in vivo (McAlpine et al., 2001; Brand et al., 2002) studies have shown that peak discharge rates do not fall within the ecological range as the Jeffress model predicts but instead ITD is coded by changes in discharge rate. The timing of inhibition relative to excitation modulates the discharge rates of MSO cells (Brand et al., 2002; Chirila et al., 2007); however, the details of this circuit, such as the onset time of inhibition, are not well known. Although the MNTB and LNTB have been investigated in vivo and in vitro , they have not been well characterized with respect to their function in ITD processing in larger mammals. Additionally, inhibition is modulated by anesthesia and confounds in vivo experiments that examine the careful interplay of excitatory and inhibitory effects in the MSO. For this reason, these physiological experiments were performed on decerebrate unanaesthetized animals. Further investigation of the anatomical organization of inhibitory inputs was carried out as the basis for a comprehensive model of the MSO that incorporates the effects of binaural inhibiting projections to MSO neurons.;Unbiased stereological counts of the MNTB, MSO and subdivisions of the LNTB showed that the MSO and MNTB contain approximately the same number of cells. The main (m)LNTB, posteroventral (pv)LNTB and the hilus (h)LNTB are estimated to contain 3800, 1400, and 200 neurons respectively. Tonotopic organization of the MNTB and MSO show that in the low frequency area, MSO cells outnumber MNTB cells 2 to 1, suggesting a divergent innervation of the MSO from the MNTB. Injection of the retrograde tracer, biotinylated dextrane amine, in the MSO, labeled cells in the MNTB, pvLNTB and mLNTB and defines the important role that these sub-nuclei, and in particular the pvLNTB, have in ITD coding. Computational modeling of a single MSO cell suggests that when two sources of inhibition temporally frame excitation the coincidence detection window is refined and less sensitive to temporal fluctuations that otherwise might degrade ITD sensitivity. Finally, physiological properties of MNTB cells reveal a heterogeneous population of responses and less precise temporal coding than are found in their inputs, globular bushy cells

Mapping the functional connectivity of the mouse anteroventral cochlear nucleus

The cochlear nucleus is the first central processor of auditory information and provides afferent input to most of the major brainstem and midbrain auditory nuclei. Presently, the lack of detailed data describing connectivity within the circuitry of the cochlear nucleus poses a major barrier to understanding its role in auditory processing, and thus complicates attempts to understand the auditory system as a whole. We have applied a novel, quantitative approach to mapping local circuits in the anteroventral cochlear nucleus (AVCN) using laser-scanning photostimulation. This approach included the development of new software and techniques that will allow more efficient acquisition and analysis of functional connectivity. Evoked responses to glutamate uncaging were analyzed to measure the amplitude and kinetics of individual synaptic events, providing a detailed description of connectivity and synaptic properties. We found that the majority of cells, including all three AVCN principal cell types, receive input from both D-stellate and tuberculoventral cells. Additionally, a small fraction of cells receive inhibitory input from an unidentified cell population at the dorsal-medial boundary of the AVCN, or excitatory input from within the AVCN. In agreement with previous reports, AVCN cells integrate from tuberculoventral cells occupying a narrow corresponding isofrequency region of the dorsal cochlear nucleus. In contrast, D-stellate inputs to the same cells arise from a much larger area which spans a wider frequency range. Furthermore, T-stellate cells integrate these inputs from an area that spans twice the frequency range of that integrated by bushy cells. Our results suggest that inhibitory circuits, even from a single presynaptic class, have patterns of convergence for each cell type that can support different kinds of spectral and temporal processing.Doctor of Philosoph

Discharge properties of identified cochlear nucleus neurons and auditory nerve fibers in response to repetitive electrical stimulation of the auditory nerve

Using the in vitro isolated whole brain preparation of the guinea pig maintained at 29°C, we intracellularly recorded and stained cochlear nucleus (CN) neurons and auditory nerve (AN) fibers. Discharge properties of CN cells and AN axons were tested in response to 50-ms trains of electrical pulses delivered to the AN at rates ranging from 100 to 1000 pulses per second (pps). At low stimulation rates (200-300pps), the discharges of AN fibers and a large proportion of principal cells (bushy, octopus, stellate) in the ventral cochlear nucleus (VCN) followed with high probability each pulse in the train, resulting in synchronization of discharges within large populations of AN fibers and CN cells. In contrast, at high stimulation rates (500pps and higher), AN fibers and many VCN cells exhibited "primary-like", "onset" and some other discharge patterns resembling those produced by natural sound stimuli. Unlike cells in the VCN, principal cells (pyramidal, giant) of the dorsal CN did not follow the stimulating pulses even at low rates. Instead, they often showed "pauser" and "build-up" patterns of activity, characteristic for these cells in conditions of normal hearing. We hypothesize that, at low stimulation rates, the response behavior of AN fibers and VCN cells is different from the patterns of neuronal activity related to normal auditory processing, whereas high stimulation rates produce more physiologically meaningful discharge patterns. The observed differences in discharge properties of AN fibers and CN cells at different stimulation rates can contribute to significant advantages of high- versus low-rate electrical stimulation of the AN used for coding sounds in modern cochlear implant

Anatomical and physiological properties of the superior paraolivary nucleus in the rat

The superior paraolivary nucleus (SPON) is a group of neurons located within the superior olivary complex, a constellation of brainstem nuclei involved in auditory processing. The major inputs to the SPON arise from the contralateral ear and SPON axons target primarily the ipsilateral inferior colliculus. However, little is known regarding the neurochemical phenotypes present in the SPON and how these neurons respond to auditory stimuli. Understanding the neurochemical and physiological properties of the constituent neurons will provide insight into the functional role of the SPON and will contribute to our understanding of the neural circuitry involved in hearing. Immunocytochemical, stereological, physiological and pharmacological techniques were used to characterize SPON neurons in the rat. The presence of inhibitory neurotransmitters was investigated with immunocytochemistry and provides evidence that the SPON contains a morphologically homogeneous population of GABAergic neurons and further that these neurons receive a robust inhibitory innervation in the form of glycinergic and GABAergic inputs. Stereological estimates of total neuron number in eighteen subcortical auditory nuclei provide evidence that the SPON is a prominent brainstem cell group and a major source of ascending inhibition to the inferior colliculus. Extracellular in vivo recordings provide evidence that nearly all SPON neurons respond to sound played in the contralateral ear with spike activity timed to the stimulus offset and phase lock to amplitude modulations in complex sounds. Pharmacologically blocking glycinergic input abolished the offset response (indicating that offset activity is a rebound from glycinergic inhibition); blockade of glycinergic and GABAergic input simultaneously, resulted in broader receptive fields and reduced phase locking capabilities. Taken together, these data indicate the rat SPON is a prominent auditory cell group that provides GABAergic inhibition to the ipsilateral inferior colliculus indicating the sound offset. GABAergic inhibition has been implicated in numerous aspects of auditory physiology, including sound localization and sensitivity to stimulus duration. Therefore, the SPON plays an important role in auditory processing and offset inhibition may be involved in processing complex sounds and in creating sensitivity to stimulus duration, both important features of animal and human communication

Neural Models of Subcortical Auditory Processing

An important feature of the auditory system is its ability to distinguish many simultaneous sound sources. The primary goal of this work was to understand how a robust, preattentive analysis of the auditory scene is accomplished by the subcortical auditory system. Reasonably accurate modelling of the morphology and organisation of the relevant auditory nuclei, was seen as being of great importance. The formulation of plausible models and their subsequent simulation was found to be invaluable in elucidating biological processes and in highlighting areas of uncertainty. In the thesis, a review of important aspects of mammalian auditory processing is presented and used as a basis for the subsequent modelling work. For each aspect of auditory processing modelled, psychophysical results are described and existing models reviewed, before the models used here are described and simulated. Auditory processes which are modelled include the peripheral system, and the production of tonotopic maps of the spectral content of complex acoustic stimuli, and of modulation frequency or periodicity. A model of the formation of sequential associations between successive sounds is described, and the model is shown to be capable of emulating a wide range of psychophysical behaviour. The grouping of related spectral components and the development of pitch perception is also investigated. Finally a critical assessment of the work and ideas for future developments are presented. The principal contributions of this work are the further development of a model for pitch perception and the development of a novel architecture for the sequential association of those groups. In the process of developing these ideas, further insights into subcortical auditory processing were gained, and explanations for a number of puzzling psychophysical characteristics suggested.Royal Naval Engineering College, Manadon, Plymout

Dorsal cochlear nucleus responses to somatosensory stimulation are enhanced after noise-induced hearing loss

Multisensory neurons in the dorsal cochlear nucleus (DCN) achieve their bimodal response properties [Shore (2005) Eur. J. Neurosci. , 21 , 3334–3348] by integrating auditory input via VIIIth nerve fibers with somatosensory input via the axons of cochlear nucleus granule cells [Shore et al. (2000) J. Comp. Neurol. , 419 , 271–285; Zhou & Shore (2004) J. Neurosci. Res. , 78 , 901–907]. A unique feature of multisensory neurons is their propensity for receiving cross-modal compensation following sensory deprivation. Thus, we investigated the possibility that reduction of VIIIth nerve input to the cochlear nucleus results in trigeminal system compensation for the loss of auditory inputs. Responses of DCN neurons to trigeminal and bimodal (trigeminal plus acoustic) stimulation were compared in normal and noise-damaged guinea pigs. The guinea pigs with noise-induced hearing loss had significantly lower thresholds, shorter latencies and durations, and increased amplitudes of response to trigeminal stimulation than normal animals. Noise-damaged animals also showed a greater proportion of inhibitory and a smaller proportion of excitatory responses compared with normal. The number of cells exhibiting bimodal integration, as well as the degree of integration, was enhanced after noise damage. In accordance with the greater proportion of inhibitory responses, bimodal integration was entirely suppressive in the noise-damaged animals with no indication of the bimodal enhancement observed in a sub-set of normal DCN neurons. These results suggest that projections from the trigeminal system to the cochlear nucleus are increased and/or redistributed after hearing loss. Furthermore, the finding that only neurons activated by trigeminal stimulation showed increased spontaneous rates after cochlear damage suggests that somatosensory neurons may play a role in the pathogenesis of tinnitus.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73500/1/j.1460-9568.2007.05983.x.pd

Temporal coding of the periodicity of monaural and binaural complex tones in the guinea pig auditory brainstem

Humans report a strong pitch percept in response to a complex tone – the sum of a series of harmonics – presented to either a single ear (‘monaurally’) or both ears (‘diotically’). Interspike interval histograms of responses of neurons in the auditory system to monaural complex tones show a peak at the period of the pitch reported by humans – a ‘neural correlate of pitch’. However, the same pitch percept can be generated by presenting complexes with harmonics distributed across both ears (‘dichotically’). This requires combination of the neural signals underlying pitch from both sides of the auditory system, termed ‘binaural fusion’. Temporal coding generally deteriorates along the auditory pathway; binaural fusion should occur at a relatively early stage. One of the prime candidates is in the superior olivary complex (SOC). Although the guinea pig auditory system has been extensively studied, this work is the first in vivo investigation of the guinea pig SOC. Cells of the lateral superior olive (LSO) show sensitivity to interaural level differences; medial superior olive (MSO) cells show sensitivity to interaural time differences. Additionally, cells with responses similar to the medial nucleus of the trapezoid body (MNTB) and superior paraolivary nucleus (SPN) of other species were found in the guinea pig SOC. Presumed MNTB cells showed a three-component spike waveform shape; presumed SPN cells responded at the offset of contralaterally-presented stimuli. MSO and LSO cells respond to the overall pitch of complex tones, even if the monaural waveforms presented to each ear differ; this is consistent with the perception of humans. In contrast, cells of the ventral cochlear nucleus, which provide the main input to MSO and LSO cells, do not show evidence of a binaural pitch response. In conclusion, SOC cells are able to encode the pitch of binaural complex tones in their spike timing patterns.MRC Studentshi

Coincidence detection in the cochlear nucleus : implications for the coding of pitch

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 2011.Cataloged from PDF version of thesis.Includes bibliographical references (p. 165-177).The spatio-temporal pattern in the auditory nerve (AN), i.e. the temporal pattern of AN fiber activity across the tonotopic axis, provides cues to important features in sounds such as pitch, loudness, and spatial location. These spatio-temporal cues may be extracted by central neurons in the cochlear nucleus (CN) that receive inputs from AN fibers innervating different cochlear regions and are sensitive to their relative timing. One possible mechanism for this extraction is cross-frequency coincidence detection (CD), in which a central neuron converts the degree of cross-frequency coincidence in the AN into a rate response by preferentially firing when its AN inputs across the tonotopic axis discharge in synchrony. We implemented a CD model receiving AN inputs from varying extents of the tonotopic axis, and compared responses of model CD cells with those of single units recorded in the CN of the anesthetized cat. We used Huffman stimuli, which have flat magnitude spectra and a single phase transition, to systematically manipulate the relative timing across AN fibers and to evaluate the sensitivity of model CD cells and CN units to the spatiotemporal pattern of AN discharges. Using a maximum likelihood approach, we found that certain unit types (primary-like-with-notch and some phase lockers) had responses consistent with cross-frequency CD cell. Some of these CN units provide input to neurons in a binaural circuit that process cues for sound localization and are sensitive to interaural level differences. A possible functional role of a cross-frequency CD mechanism in the CN is to increase the dynamic range of these binaural neurons. However, many other CN units had responses more consistent with AN fibers than with CD cells. We hypothesized that CN units resembling cross-frequency CD cells (as determined by their responses to Huffman stimuli) would convert spatio-temporal cues to pitch in the AN into rate cues that are robust with level. We found that, in response to harmonic complex tones, cross-frequency CD cells and some CN units (primary-like-with-notch and choppers) maintained robust rate cues at high levels compared to AN fibers, suggesting that at least some CN neurons extend the dynamic range of rate representations of pitch beyond that found in AN fibers. However, there was no obvious correlation between robust rate cues in individual CN units and similarity to cross-frequency CD cells as determined by responses to Huffman stimuli. It is likely that a model including more realistic inputs, membrane channels, and spiking mechanism, or other mechanisms such as lateral inhibition or spatial and temporal summation over spatially distributed inputs would provide insight into the neural mechanisms that give rise to the robust rate cues observed in some CN units.by Grace I. Wang.Ph.D