Mammalian Medial Superior Olive Research Articles

Neural Maps of Interaural Time Difference in the American Alligator: A Stable Feature in Modern Archosaurs.

Detection of interaural time differences (ITDs) is crucial for sound localization in most vertebrates. The current view is that optimal computational strategies of ITD detection depend mainly on head size and available frequencies, although evolutionary history should also be taken into consideration. In archosaurs, which include birds and crocodiles, the brainstem nucleus laminaris (NL) developed into the critical structure for ITD detection. In birds, ITDs are mapped in an orderly array or place code, whereas in the mammalian medial superior olive, the analog of NL, maps are not found. As yet, in crocodilians, topographical representations have not been identified. However, nontopographic representations of ITD cannot be excluded due to different anatomical and ethological features of birds and crocodiles. Therefore, we measured ITD-dependent responses in the NL of anesthetized American alligators of either sex and identified the location of the recording sites by lesions made after recording. The measured extracellular field potentials, or neurophonics, were strongly ITD tuned, and their preferred ITDs correlated with the position in NL. As in birds, delay lines, which compensate for external time differences, formed maps of ITD. The broad distributions of best ITDs within narrow frequency bands were not consistent with an optimal coding model. We conclude that the available acoustic cues and the architecture of the acoustic system in early archosaurs led to a stable and similar organization in today's birds and crocodiles, although physical features, such as internally coupled ears, head size, or shape, and audible frequency range, vary among the two groups.SIGNIFICANCE STATEMENT Interaural time difference (ITD) is an important cue for sound localization, and the optimal strategies for encoding ITD in neuronal populations are the subject of ongoing debate. We show that alligators form maps of ITD very similar to birds, suggesting that their common archosaur ancestor reached a stable coding solution different from mammals. Mammals and diapsids evolved tympanic hearing independently, and local optima can be reached in evolution that are not considered by global optimal coding models. Thus, the presence of ITD maps in the brainstem may reflect a local optimum in evolutionary development. Our results underline the importance of comparative animal studies and show that optimal models must be viewed in the light of evolutionary processes.

Function and energy consumption constrain neuronal biophysics in a canonical computation: Coincidence detection.

Neural morphology and membrane properties vary greatly between cell types in the nervous system. The computations and local circuit connectivity that neurons support are thought to be the key factors constraining the cells’ biophysical properties. Nevertheless, additional constraints can be expected to further shape neuronal design. Here, we focus on a particularly energy-intense system (as indicated by metabolic markers): principal neurons in the medial superior olive (MSO) nucleus of the auditory brainstem. Based on a modeling approach, we show that a trade-off between the level of performance of a functionally relevant computation and energy consumption predicts optimal ranges for cell morphology and membrane properties. The biophysical parameters appear most strongly constrained by functional needs, while energy use is minimized as long as function can be maintained. The key factors that determine model performance and energy consumption are 1) the saturation of the synaptic conductance input and 2) the temporal resolution of the postsynaptic signals as they reach the soma, which is largely determined by active membrane properties. MSO cells seem to operate close to pareto optimality, i.e., the trade-off boundary between performance and energy consumption that is formed by the set of optimal models. Good performance for drastically lower costs could in theory be achieved by small neurons without dendrites, as seen in the avian auditory system, pointing to additional constraints for mammalian MSO cells, including their circuit connectivity.

Extraction of Inter-Aural Time Differences Using a Spiking Neuron Network Model of the Medial Superior Olive.

The mammalian auditory system is able to extract temporal and spectral features from sound signals at the two ears. One important cue for localization of low-frequency sound sources in the horizontal plane are inter-aural time differences (ITDs) which are first analyzed in the medial superior olive (MSO) in the brainstem. Neural recordings of ITD tuning curves at various stages along the auditory pathway suggest that ITDs in the mammalian brainstem are not represented in form of a Jeffress-type place code. An alternative is the hemispheric opponent-channel code, according to which ITDs are encoded as the difference in the responses of the MSO nuclei in the two hemispheres. In this study, we present a physiologically-plausible, spiking neuron network model of the mammalian MSO circuit and apply two different methods of extracting ITDs from arbitrary sound signals. The network model is driven by a functional model of the auditory periphery and physiological models of the cochlear nucleus and the MSO. Using a linear opponent-channel decoder, we show that the network is able to detect changes in ITD with a precision down to 10 μs and that the sensitivity of the decoder depends on the slope of the ITD-rate functions. A second approach uses an artificial neuronal network to predict ITDs directly from the spiking output of the MSO and ANF model. Using this predictor, we show that the MSO-network is able to reliably encode static and time-dependent ITDs over a large frequency range, also for complex signals like speech.

A model of the neuronal processing of interaural time disparities

The auditory system of humans and other mammals is able to use interaural time and intensity differences as well as spectral cues to localize sound sources. One important cue for localizing low-frequency sound sources in the horizontal plane are interaural time differences (ITDs), which are first analyzed in the medial superior olive (MSO) in the brainstem. Results from electrophysiological and psychoacoustic studies suggest ITD encoding in the relative activities of neuronal populations in the two brain hemispheres. This contribution first explores the neuronal encoding of fine-structure ITDs using a physiologically motivated spiking neuronal-network model of the mammalian MSO. Results from this model confirm robust ITD encoding in the relative activity of the MSOs in both hemispheres. Based on the neuronal-network simulations, a simple probabilistic model of subsequent ITD processing is proposed. This simplified model connects the neuronal responses of the two hemispheres with different hearing sensation properties, such as lateral position, spatial extent, or number of spatially separable sensations. First predictions from the model are discussed with regard to the results of a series of psychoacoustic experiments on the lateralization of pure-tone impulses presented via headphones.

Proteomic analyses of nucleus laminaris identified candidate targets of the fragile X mental retardation protein.

The avian nucleus laminaris (NL) is a brainstem nucleus necessary for binaural processing, analogous in structure and function to the mammalian medial superior olive. In chickens (Gallus gallus), NL is a well-studied model system for activity-dependent neural plasticity. Its neurons have bipolar extension of dendrites, which receive segregated inputs from two ears and display rapid and compartment-specific reorganization in response to unilateral changes in auditory input. More recently, fragile X mental retardation protein (FMRP), an RNA-binding protein that regulates local protein translation, has been shown to be enriched in NL dendrites, suggesting its potential role in the structural dynamics of these dendrites. To explore the molecular role of FMRP in this nucleus, we performed proteomic analysis of NL, using micro laser capture and liquid chromatography tandem mass spectrometry. We identified 657 proteins, greatly represented in pathways involved in mitochondria, translation and metabolism, consistent with high levels of activity of NL neurons. Of these, 94 are potential FMRP targets, by comparative analysis with previously proposed FMRP targets in mammals. These proteins are enriched in pathways involved in cellular growth, cellular trafficking and transmembrane transport. Immunocytochemistry verified the dendritic localization of several proteins in NL. Furthermore, we confirmed the direct interaction of FMRP with one candidate, RhoC, by in vitro RNA binding assays. In summary, we provide a database of highly expressed proteins in NL and in particular a list of potential FMRP targets, with the goal of facilitating molecular characterization of FMRP signaling in future studies.

Tonotopic organization of the hyperpolarization-activated current (Ih) in the mammalian medial superior olive

Neuronal membrane properties can largely vary even within distinct morphological cell classes. The mechanisms and functional consequences of this diversity, however, are little explored. In the medial superior olive (MSO), a brainstem nucleus that performs binaural coincidence detection, membrane properties at rest are largely governed by the hyperpolarization-activated inward current (Ih) which enables the temporally precise integration of excitatory and inhibitory inputs. Here, we report that Ih density varies along the putative tonotopic axis of the MSO with Ih being largest in ventral, high-frequency (HF) processing neurons. Also Ih half-maximal activation voltage and time constant are differentially distributed such that Ih of the putative HF processing neurons activate faster and at more depolarized levels. Intracellular application of saturating concentrations of cyclic AMP removed the regional difference in hyperpolarization-activated cyclic nucleotide gated (HCN) channel activation, but not Ih density. Experimental data in conjunction with a computational model suggest that increased Ih levels are helpful in counteracting temporal summation of phase-locked inhibitory inputs which is particularly prominent in HF neurons.

GABAB receptors sharpen tuning of a sound localization circuit

GABA_B receptors sharpen tuning of a sound localization circuit

Spike timing jitter is beneficial in neural spike coding - A case of the mammalian MSO sound localization circuit

Auditory brainstem calculates horizontal direction (azimuth) of sound from the ITD (interaural time delay). Jeffress proposed in 1948 that sound source azimuth is computed by a neural circuit consisting of an array of delay lines [1]. This is the case in birds, but probably not in mammals [2]. We studied how the ITD-s (shorter than typical action potential duration) are processed within a stochastic model of the MSO (medial superior olive), mammalian azimuth decoder circuit [3]. The MSO circuit makes use of its intrinsic noise, yet spike timing precision in the circuit is essential. Therefore a classification of dynamical observables is needed. Most of them can be described as random variables. Introducing noisy, from trial to trial non-repetitive stimulation in binaural cochlear implants sometimes leads to a better performance [4]. Part of it can be attributed to stochastic processing. We present our current results as a case study showing multitude of roles of (random versus deterministic) spike timing in a neural circuit. In particular, either phenomenological (excitatory-excitatory and excitatory-inhibitory units), or electrophysiological (excitatory and inhibitory synapses) classification of individual elements of the circuit might be abstracted in an explanation stressing the neural computation in the circuit. We study various parameters of the MSO model and their influence on the output of the model. Finally we evaluate the performance of the model using the concept of ideal observer.

Influence of inhibitory synaptic kinetics on the interaural time difference sensitivity in a linear model of binaural coincidence detection

Temporal correlations between the sound waves arriving at the two ears are used to extract the azimuthal position of sound sources. Nerve cells in the mammalian medial superior olive (MSO) that extract these binaural correlations are sensitive to interaural time differences (ITDs) in the range of about 10 micros. These neurons receive inputs from the two ears via four pathways, two excitatory and two inhibitory ones. In this paper, a simple linear model is fitted to the frequency dependence of ITD sensitivity of MSO neurons, which is quantified by the two parameters, characteristic phase and characteristic delay. The fit parameters are the relative delays and the relative strengths of the two inhibitory pathways and thus specify the underlying ITD-detecting circuit assuming a non-Jeffress-like situation, i.e., no excitatory delay lines but phase-locked inhibition. The fitting procedure finds the parameters of these inhibitory pathways such that they account for a desired frequency dependence of ITD sensitivity. It is found that positive characteristic delays require a finite amount of ipsilateral inhibition that arrives at roughly the same time as ipsilateral excitation as well as contralateral inhibition that lags contralateral excitation so much that it effectively leads excitation of the next cycle.

Quantification of the three‐dimensional morphology of coincidence detector neurons in the medial superior olive of gerbils during late postnatal development

In the mammalian medial superior olive (MSO), neurons compute the azimuthal location of sound sources by temporally precise coincidence detection. It is assumed that the dendritic morphology of MSO neurons plays a crucial role in this computational process. However, few quantitative data about the morphology of these neuronal coincidence detectors are available, limiting theoretical approaches. Such a quantitative morphological description of neurons of the mammalian MSO would also allow a comparative analysis with its avian analog, the nucleus laminaris. We used single-cell electroporation, microscopic reconstruction, and compartmentalization to extract anatomical parameters of MSO neurons and quantitatively describe their morphology and development between postnatal day 9 and 36. We found that developmental refinement occurs until P27, generating morphologically compact, cylinder-like cells with axons originating from the soma. The complexity of higher order dendrites decreases between postnatal days 9 and 21. This decrease in dendritic complexity is judged from counting and analyzing the location of dendritic branches and determining the distribution of the surface area and total length of neurons. During this developmental period, the average length of terminal branches increases about twofold, indicating an elimination of predominantly small branches. The cell volume increases more than 1.5-fold between P9 and P27, a change that can be attributed to an increase in dendritic diameter during this developmental period. The developmental profile of the morphology of MSO neurons obtained indicates that maturation is reached 2 weeks after hearing onset.

Evolution of sound localisation in land vertebrates

The story of the evolution of hearing in land vertebrates is fascinating but complex. The water-to-land transition changed the physical environment in which hearing happens so dramatically that both the peripheral receptor structures and the central auditory circuits underwent a revolution, leading to the sensitive hearing of higher-frequency airborne sound. This (r)evolution took a very long time indeed. Most of it happened after the early divergence of the major clades of land vertebrates. Hearing, at least hearing as we commonly understand it today, is the youngest of the major senses and much of its evolutionary history is not shared between amphibians, lepidosauromorphs (lizards and snakes), archosauromorphs (birds and crocodilians) and mammals. There was no linear evolution of complexity from 'lower' to 'higher' vertebrates. We are only just beginning to appreciate the implications of this for central auditory processing. There is no consensus, yet, on the evolution of sound localisation. The multitude of physical cues involved in sound localisation means that different selective pressures interact and need to be considered. The use and neural processing of interaural time differences is just one example. It has taught us that long-standing assumptions, such as the homology of the mammalian medial superior olive and the avian nucleus laminaris, need to be questioned and that important insights may arise from unexpected directions, such as the paleontology of middle-ear ossicles. There is still much to discover.

From quantification of 3D morphology of coincidence detector neurons in the MSO to a multi-compartmental model

In the medial superior olive (MSO), neurons compute the azimuthal location of low frequency sound sources by a temporally precise mechanism of coincidence detection. This type of neuronal processing has been subject to various model predictions based on in vivo and in vitro data obtained in mammalian MSO and an avian analog brain structure. It is assumed that dendritic morphology of MSO neurons affects this computational process. However, few quantitative data about the morphology of these neuronal coincidence detectors are available from mammals, limiting theoretical approaches. We used single cell electroporation, microscopic reconstruction and compartmentalization to extract anatomical parameters of MSO neurons and quantitatively describe their morphology and their development between postnatal day 9 and 36. The dendritic arborization of higher order dendrites decreases between postnatal day 9 and 21, whereas the dendritic radius increased until P27. The developmental profile of the morphology of MSO neurons shows that maturation is reached two weeks after hearing onset. In general, we find that at postnatal days older than P27 the neurons of the gerbil MSO are bipolar, morphologically compact, cylinder-like cells with axons originating from the soma. The obtained geometry of these cells was then used to establish multi-compartmental models to quantify the influence of morphological and developmental changes on the integration of synaptic currents. To increase computational and programming efficiency of the simulations, we developed a Python-based object-oriented library. from Eighteenth Annual Computational Neuroscience Meeting: CNS*2009 Berlin, Germany. 18–23 July 2009

Interaural Time Difference Processing in the Mammalian Medial Superior Olive: The Role of Glycinergic Inhibition

The dominant cue for localization of low-frequency sounds are microsecond differences in the time-of-arrival of sounds at the two ears [interaural time difference (ITD)]. In mammals, ITD sensitivity is established in the medial superior olive (MSO) by coincidence detection of excitatory inputs from both ears. Hence the relative delay of the binaural inputs is crucial for adjusting ITD sensitivity in MSO cells. How these delays are constructed is, however, still unknown. Specifically, the question of whether inhibitory inputs are involved in timing the net excitation in MSO cells, and if so how, is controversial. These inhibitory inputs derive from the nuclei of the trapezoid body, which have physiological and structural specializations for high-fidelity temporal transmission, raising the possibility that well timed inhibition is involved in tuning ITD sensitivity. Here, we present physiological and pharmacological data from in vivo extracellular MSO recordings in anesthetized gerbils. Reversible blockade of synaptic inhibition by iontophoretic application of the glycine antagonist strychnine increased firing rates and significantly shifted ITD sensitivity of MSO neurons. This indicates that glycinergic inhibition plays a major role in tuning the delays of binaural excitation. We also tonically applied glycine, which lowered firing rates but also shifted ITD sensitivity in a way analogous to strychnine. Hence tonic glycine application experimentally decoupled the effect of inhibition from the timing of its inputs. We conclude that, for proper ITD processing, not only is inhibition necessary, but it must also be precisely timed.

Interaural time difference processing in the mammalian medial superior olive

The dominant cue for localization of low-frequency sounds are microsecond differences in the time-of-arrival of sounds at the two ears [interaural time difference (ITD)]. In mammals, ITD sensitivity is established in the medial superior olive (MSO) by coincidence detection of excitatory inputs from both ears. Hence the relative delay of the binaural inputs is crucial for adjusting ITD sensitivity in MSO cells. How these delays are constructed is, however, still unknown. Specifically, the question of whether inhibitory inputs are involved in timing the net excitation in MSO cells, and if so how, is controversial. These inhibitory inputs derive from the nuclei of the trapezoid body, which have physiological and structural specializations for high-fidelity temporal transmission, raising the possibility that well timed inhibition is involved in tuning ITD sensitivity. Here, we present physiological and pharmacological data from in vivo extracellular MSO recordings in anesthetized gerbils. Reversible blockade of synaptic inhibition by iontophoretic application of the glycine antagonist strychnine increased firing rates and significantly shifted ITD sensitivity of MSO neurons. This indicates that glycinergic inhibition plays a major role in tuning the delays of binaural excitation. We also tonically applied glycine, which lowered firing rates but also shifted ITD sensitivity in a way analogous to strychnine. Hence tonic glycine application experimentally decoupled the effect of inhibition from the timing of its inputs. We conclude that, for proper ITD processing, not only is inhibition necessary, but it must also be precisely timed.

EphA4 signaling promotes axon segregation in the developing auditory system

Precision of synaptic connections within neural circuits is essential for the accurate processing of sensory information. Specificity is exemplified at cellular and subcellular levels in the chick auditory brainstem, where nucleus magnocellularis (NM) neurons project bilaterally to nucleus laminaris (NL). Dorsal dendrites of NL neurons receive input from ipsilateral, but not contralateral, branches of NM axons whereas ventral dendrites are innervated by contralateral NM axons. This organization is analogous to that of the mammalian medial superior olive (MSO) and represents an important component of the circuitry underlying sound localization. However, the molecular mechanisms that establish segregated inputs to individual regions of NL neurons have not been identified. During synapse formation in NL, the EphA4 receptor is expressed in dorsal, but not ventral NL, neuropil, suggesting a potential role in targeting synapses to appropriate termination zones. Here, we directly tested this role by ectopically expressing EphA4 and disrupting EphA4 signaling using in ovo electroporation. We found that both misexpression of EphA4 and disruption of EphA4 signaling resulted in an increase in the number of NM axons that grow aberrantly across NL cell bodies into inappropriate regions of NL neuropil. EphA4 signaling is thus essential for targeting axons to distinct subsets of dendrites. Moreover, loss of EphA4 function resulted in morphological abnormalities of NL suggestive of errors in cell migration. These results suggest that EphA4 has multiple roles in the formation of auditory brainstem nuclei and their projections.

Simple neuron models of ITD sensitive neurons

Neurons which show sensitivity to interaural time delay (ITD) exist in both mammalian medial superior olive (MSO), and bird nucleus laminaris (NL). In this study, we examine simple mathematical models of single MSO and NL cells which respond probabilistically to a pair of isolated inputs with a response probability that depends on the input interpulse interval. Inputs are either isolated pulse pairs or pairs of periodic trains, with or without random jitter added to their event times. Refractoriness is incorporated in the input description and/or in the cell model in specified simulations. We find that periodic rate-ITD shapes are shaped by three interacting factors: the cell’s temporal response (described by the paired-pulse response), input frequency, and the degree of input synchrony. Paired-pulse responses are able to predict the widths of rate-ITD curves obtained from deterministic periodic input simulations. Reduced input synchrony predictably smears rate-ITD curves. Larger numbers of weaker inputs yield stronger rate-ITD modulation than a few strong inputs. Model response is compared with in vivo and in vitro MSO and NL physiological data. Comparisons with published analytical models as well as more complex and realistic physiological cell models are examined.

The function of the medial superior olive in small mammals: temporal receptive fields in auditory analysis.

Traditionally, the medial superior olive, a mammalian auditory brainstem structure, is considered to encode interaural time differences, the main cue for localizing low-frequency sounds. Detection of binaural excitatory and inhibitory inputs are considered as an underlying mechanism. Most small mammals, however, hear high frequencies well beyond 50 kHz and have small interaural distances. Therefore, they can not use interaural time differences for sound localization and yet possess a medial superior olive. Physiological studies in bats revealed that medial superior olive cells show similar interaural time difference coding as in larger mammals tuned to low-frequency hearing. Their interaural time difference sensitivity, however, is far too coarse to serve in sound localization. Thus, interaural time difference sensitivity in medial superior olive of small mammals is an epiphenomenon. We propose that the original function of the medial superior olive is a binaural cooperation causing facilitation due to binaural excitation. Lagging inhibitory inputs, however, suppress reverberations and echoes from the acoustic background. Thereby, generation of antagonistically organized temporal fields is the basic and original function of the mammalian medial superior olive. Only later in evolution with the advent of larger mammals did interaural distances, and hence interaural time differences, became large enough to be used as cues for sound localization of low-frequency stimuli.