Dynamics of interaction between IH and IKLT currents to mediate double resonances of medial superior olive neurons related to sound localization.

Neurons in the medial superior olive (MSO) exhibit high frequency responses such as subthreshold resonance, which is helpful to sensitively detect a small difference in the arrival time of sounds between two ears for precise sound localization. Recently, except for the high frequency depolarization resonance mediated by a low threshold potassium (IKLT) current, a low frequency hyperpolarization resonance mediated by a hyperpolarization-activated cation (IH) current is observed in experiments on the MSO neurons, forming double resonances. The complex dynamics underlying double resonances are studied in an MSO neuron model in the present paper. Firstly, double resonances similar to the experimental observations are simulated as the resting membrane potential is between half-activation voltages of IH and IKLT currents, and stimulation current (IZAP) with large amplitude and exponentially increasing frequency is applied. Secondly, multiple effective factors to modulate double resonances are obtained. Especially, the decrease of time constant of IKLT current and increase of conductance of IH and IKLT currents can enhance the depolarization resonance frequency for precise sound localization. Last, different frequency responses of slow IH and fast IKLT currents in formation of the resonances are acquired. A middle phase difference between IZAP and IKLT currents appears at a high frequency, and the interaction between the positive part of IZAP and the negative IKLT current forms the depolarization resonance. Interaction between the negative part of IZAP and positive IH current with a middle phase difference results in hyperpolarization resonance at a low frequency. Furthermore, the phase difference between IZAP and resonance current can well explain the increase of depolarization resonance frequency modulated by the increase of conductance of IH or IKLT currents. The results present the dynamical and biophysical mechanisms for the double resonances mediated by two currents in the MSO neurons, which is helpful to enhance the depolarization resonance frequency for precise sound localization.

Binaural Processing Deficits Due to Synaptopathy and Myelin Defects.

Hidden hearing loss (HHL) is a deficit in auditory perception and speech intelligibility that occurs despite normal audiometric thresholds and results from noise exposure, aging, or myelin defects. While mechanisms causing perceptual deficits in HHL patients are still unknown, results from animal models indicate a role for peripheral auditory neuropathies in HHL. In humans, sound localization is particularly important for comprehending speech, especially in noisy environments, and its disruption may contribute to HHL. In this study, we hypothesized that neuropathies of cochlear spiral ganglion neurons (SGNs) that are observed in animal models of HHL disrupt the activity of neurons in the medial superior olive (MSO), a nucleus in the brainstem responsible for locating low-frequency sound in the horizontal plane using binaural temporal cues, leading to sound localization deficits. To test our hypothesis, we constructed a network model of the auditory processing system that simulates peripheral responses to sound stimuli and propagation of responses via SGNs to cochlear nuclei and MSO populations. To simulate peripheral auditory neuropathies, we used a previously developed biophysical SGN model with myelin defects at SGN heminodes (myelinopathy) and with loss of inner hair cell-SGN synapses (synaptopathy). Model results indicate that myelinopathy and synaptopathy in SGNs give rise to decreased interaural time difference (ITD) sensitivity of MSO cells, suggesting a possible mechanism for perceptual deficits in HHL patients. This model may be useful to understand downstream impacts of SGN-mediated disruptions on auditory processing and to eventually discover possible treatments for various mechanisms of HHL.

Predicting the Influence of Axon Myelination on Sound Localization Precision Using a Spiking Neural Network Model of Auditory Brainstem.

Spatial hearing allows animals to rapidly detect and localize auditory events in the surrounding environment. The auditory brainstem plays a central role in processing and extracting binaural spatial cues through microsecond-precise binaural integration, especially for detecting interaural time differences (ITDs) of low-frequency sounds at the medial superior olive (MSO). A series of mechanisms exist in the underlying neural circuits for preserving accurate action potential timing across multiple fibers, synapses and nuclei along this pathway. One of these is the myelination of afferent fibers that ensures reliable and temporally precise action potential propagation in the axon. There are several reports of fine-tuned myelination patterns in the MSO circuit, but how specifically myelination influences the precision of sound localization remains incompletely understood. Here we present a spiking neural network (SNN) model of the Mongolian gerbil auditory brainstem with myelinated axons to investigate whether different axon myelination thicknesses alter the sound localization process. Our model demonstrates that axon myelin thickness along the contralateral pathways can substantially modulate ITD detection. Furthermore, optimal ITD sensitivity is reached when the MSO receives contralateral inhibition via thicker myelinated axons compared to contralateral excitation, a result that is consistent with previously reported experimental observations. Our results suggest specific roles of axon myelination for extracting temporal dynamics in ITD decoding, especially in the pathway of the contralateral inhibition.

Cytoarchitecture of the superior olivary complex of three neotropical species of bats (Noctilio leporinus, Phyllostomus hastatus and Carollia perspicillata) with different foraging behavior / Citoarquitetura do complexo olivar superior de três espécies neotropicais de morcegos (Noctilio leporinus, Phyllostomus hastatus e Carollia perspicillata) com diferentes comportamentos de forrageamento

Abstract The understanding of the echolocation by studying different auditory nuclei of echolocating bats can be an important link in elucidating questions arising in relation to their foraging behavior. The superior olivary complex (SOC) is the primary center for processing the binaural cues used in sound localization since echo locating bats rely on acoustic cues to navigate and capture prey while in flight. The present study was taken to test the hypothesis that the SOC of echolocating neotropical bats with different foraging behavior will exhibit morphological variations in relative size, degree of complexity and spatial distribution. The brains were collected from six male adult bats of each species: Noctilio leporinus (fish eating), Phyllostomus hastatus (carnivorous/omnivorous) and Carollia perspicillata (fruit eating). They were double-embedded and transverse serial sections were cut and stained with cresyl fast violet. The SOC measured as 640 ± 70 µm in the N. leporinus bat, 480 ± 50 µm in the P. hastatus and 240 ± 30 µm in the C. perspicillata bat. The principal nuclei of the SOC of in all three bats were the LSO, MSO and MNTB. The MSO and LSO were very well developed in N. leporinus bats. The MSO of N. leporinus bat subdivided into DMSO and VMSO. The main cell type of cells present in MSO and LSO are dark staining multipolar cells in all the bats studied. The well-developed MSO and LSO of N. leporinus bats indicate that these bats are highly sensitive to low frequency sounds and interaural intensity differences, which help these bats to forage over water by using various types of echolocation signals. The average size of SOC in P. hastatus and C. perspicillata bats can be attributed to the fact that these bats use vision and smell along with echolocation to forage the food.

Resumo O entendimento da ecolocalização pelo estudo de diferentes núcleos auditivos de morcegos pode ser um elo importante na elucidação das inúmeras questões que surgem em relação ao seu comportamento de forrageamento. O complexo olivar superior (SOC) é o principal centro de processamento das pistas binaurais usadas na localização do som, já que os morcegos ecolocalizadores contam com sinais acústicos para navegar e capturar as presas durante o vôo. O presente estudo foi realizado para testar a hipótese de que morcegos que usam a ecolocalização para diferentes comportamentos de forrageamento irão variar na estrutura, tamanhos relativos e grau de complexidade e distribuição espacial do grupo SOC. Os cérebros foram coletados de seis machos adultos de morcego de cada espécie: Noctilio leporinus (piscívoro), Phyllostomus hastatus (carnívoros/onívoros) e Carollia perspicillata (frugívoro). Eles foram seccionados em série e transversalmente, cortados e corados com coloração rápida cresil-violeta. tolet. O grupo SOC foi medido como 640 ± 70 µm no morcego N. leporinus, 480 ± 50 µm no P. hastatus e 240 ± 30 µm no morcego C. perspicillata. Os principais núcleos do grupo SOC dos três morcegos foram o LSO e o MSO e o MNTB. O MSO e o LSO foram muito bem desenvolvidos em morcegos N. leporinus. A MSO de N. leporinus foi subdividida em DMSO e VMSO. O principal tipo de células presentes na MSO e LSO são as células multipolares de coloração escura em todos os morcegos. Os MSO bem desenvolvidos e LSO de morcegos N. leporinus indicam que estes morcegos são altamente sensíveis a sons de baixa frequência e diferenças de intensidade interaural, que ajudaram estes morcegos a se alimentarem na superfície da água usando vários tipos de sinais de ecolocalização. O tamanho médio de SOC em morcegos de P. hastatus e C. perspicillata pode ser atribuído ao fato destes morcegos usarem visão e olfato junto com a ecolocalização para forragear.

Activity-Dependent Calcium Signaling in Neurons of the Medial Superior Olive during Late Postnatal Development.

The development of sensory circuits is partially guided by sensory experience. In the medial superior olive (MSO), these refinements generate precise coincidence detection to localize sounds in the azimuthal plane. Glycinergic inhibitory inputs to the MSO, which tune the sensitivity to interaural time differences, undergo substantial structural and functional refinements after hearing onset. Whether excitation and calcium signaling in the MSO are similarly affected by the onset of acoustic experience is unresolved. To assess the time window and mechanism of excitatory and calcium-dependent refinements during late postnatal development, we quantified EPSCs and calcium entry in MSO neurons of Mongolian gerbils of either sex raised in a normal and in an activity altered, omnidirectional white noise environment. Global dendritic calcium transients elicited by action potentials disappeared rapidly after hearing onset. Local synaptic calcium transients decreased, leaving a GluR2 lacking AMPAR-mediated influx as the only activity-dependent source in adulthood. Exposure to omnidirectional white noise accelerated the decrease in calcium entry, leaving membrane properties unaffected. Thus, sound-driven activity accelerates the excitatory refinement and shortens the period of activity-dependent calcium signaling around hearing onset. Together with earlier reports, our findings highlight that excitation, inhibition, and biophysical properties are differentially sensitive to distinct features of sensory experience.SIGNIFICANCE STATEMENT Neurons in the medial superior olive, an ultra-fast coincidence detector for sound source localization, acquire their specialized function through refinements during late postnatal development. The refinement of inhibitory inputs that convey sensitivity to relevant interaural time differences is instructed by the experience of sound localization cues. Which cues instruct the refinement of excitatory inputs, calcium signaling, and biophysical properties is unknown. Here we demonstrate a time window for activity- and calcium-dependent refinements limited to shortly after hearing onset. Exposure to omnidirectional white noise, which suppresses sound localization cues but increases overall activity, accelerates the refinement of calcium signaling and excitatory inputs without affecting biophysical membrane properties. Thus, the refinement of excitation, inhibition, and intrinsic properties is instructed by distinct cues.

Distinct Distribution Patterns of Potassium Channel Sub-Units in Somato-Dendritic Compartments of Neurons of the Medial Superior Olive.

Coincidence detector neurons of the medial superior olive (MSO) are sensitive to interaural time differences in the range of a few tens of microseconds. The biophysical basis for this remarkable acuity is a short integration time constant of the membrane, which is achieved by large low voltage-activated potassium and hyperpolarization-activated inward cation conductances. Additional temporal precision is thought to be achieved through a sub-cellular distribution of low voltage-activated potassium channel expression biased to the soma. To evaluate the contribution of potassium channels, we investigated the presence and sub-cellular distribution profile of seven potassium channel sub-units in adult MSO neurons of gerbils. We find that low- and high voltage-activated potassium channels are present with distinct sub-cellular distributions. Overall, low voltage-activated potassium channels appear to be biased to the soma while high voltage-activated potassium channels are more evenly distributed and show a clear expression at distal dendrites. Additionally, low voltage-activated potassium channel sub-units co-localize with glycinergic inputs while HCN1 channels co-localize more with high voltage-activated potassium channels. Functionally, high voltage-activated potassium currents are already active at low voltages near the resting potential. We describe a possible role of high voltage-activated potassium channels in modulating EPSPs in a computational model and contributing to setting the integration time window of coincidental inputs. Our data shows that MSO neurons express a large set of different potassium channels with distinct functional relevance.

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.

Signatures of Somatic Inhibition and Dendritic Excitation in Auditory Brainstem Field Potentials.

Extracellular voltage recordings (Ve ; field potentials) provide an accessible view of in vivo neural activity, but proper interpretation of field potentials is a long-standing challenge. Computational modeling can aid in identifying neural generators of field potentials. In the auditory brainstem of cats, spatial patterns of sound-evoked Ve can resemble, strikingly, Ve generated by current dipoles. Previously, we developed a biophysically-based model of a binaural brainstem nucleus, the medial superior olive (MSO), that accounts qualitatively for observed dipole-like Ve patterns in sustained responses to monaural tones with frequencies >∼1000 Hz (Goldwyn et al., 2014). We have observed, however, that Ve patterns in cats of both sexes appear more monopole-like for lower-frequency tones. Here, we enhance our theory to accurately reproduce dipole and non-dipole features of Ve responses to monaural tones with frequencies ranging from 600 to 1800 Hz. By applying our model to data, we estimate time courses of paired input currents to MSO neurons. We interpret these inputs as dendrite-targeting excitation and soma-targeting inhibition (the latter contributes non-dipole-like features to Ve responses). Aspects of inferred inputs are consistent with synaptic inputs to MSO neurons including the tendencies of inhibitory inputs to attenuate in response to high-frequency tones and to precede excitatory inputs. Importantly, our updated theory can be tested experimentally by blocking synaptic inputs. MSO neurons perform a critical role in sound localization and binaural hearing. By solving an inverse problem to uncover synaptic inputs from Ve patterns we provide a new perspective on MSO physiology.SIGNIFICANCE STATEMENT Extracellular voltages (field potentials) are a common measure of brain activity. Ideally, one could infer from these data the activity of neurons and synapses that generate field potentials, but this "inverse problem" is not easily solved. We study brainstem field potentials in the region of the medial superior olive (MSO); a critical center in the auditory pathway. These field potentials exhibit distinctive spatial and temporal patterns in response to pure tone sounds. We use mathematical modeling in combination with physiological and anatomical knowledge of MSO neurons to plausibly explain how dendrite-targeting excitation and soma-targeting inhibition generate these field potentials. Inferring putative synaptic currents from field potentials advances our ability to study neural processing of sound in the MSO.

Exposures to fine particulate matter (PM2.5) and ozone above USA standards are associated with auditory brainstem dysmorphology and abnormal auditory brainstem evoked potentials in healthy young dogs.

BACKGROUND: Delayed central conduction times in the auditory brainstem have been observed in Mexico City (MC) healthy children exposed to fine particulate matter (PM2.5) and ozone (O3) above the current United States Environmental Protection Agency (US-EPA) standards. MC children have α synuclein brainstem accumulation and medial superior olivary complex (MSO) dysmorphology. The present study used a dog model to investigate the potential effects of air pollution on the function and morphology of the auditory brainstem. METHODOLOGY: Twenty-four dogs living in clean air v MC, average age 37.1 ± 26.3 months, underwent brainstem auditory evoked potential (BAEP) measurements. Eight dogs (4 MC, 4 Controls) were analysed for auditory brainstem morphology and histopathology. RESULTS: MC dogs showed ventral cochlear nuclei hypotrophy and MSO dysmorphology with a significant decrease in cell body size, decreased neuronal packing density with regions in the nucleus devoid of neurons and marked gliosis. MC dogs showed significant delayed BAEP absolute wave I, III and V latencies compared to controls. CONCLUSIONS: MC dogs show auditory nuclei dysmorphology and BAEPs consistent with an alteration of the generator sites of the auditory brainstem response waveform. This study puts forward the usefulness of BAEPs to study auditory brainstem neurodegenerative changes associated with air pollution in dogs. Recognition of the role of non-invasive BAEPs in urban dogs is warranted to elucidate novel neurodegenerative pathways link to air pollution and a promising early diagnostic strategy for Alzheimer's Disease.

A Test of the Stereausis Hypothesis for Sound Localization in Mammals.

The relative arrival times of sounds at both ears constitute an important cue for localization of low-frequency sounds in the horizontal plane. The binaural neurons of the medial superior olive (MSO) act as coincidence detectors that fire when inputs from both ears arrive near simultaneously. Each principal neuron in the MSO is tuned to its own best interaural time difference (ITD), indicating the presence of an internal delay, a difference in the travel times from either ear to the MSO. According to the stereausis hypothesis, differences in wave propagation along the cochlea could provide the delays necessary for coincidence detection if the ipsilateral and contralateral inputs originated from different cochlear positions, with different frequency tuning. We therefore investigated the relation between interaural mismatches in frequency tuning and ITD tuning during in vivo loose-patch (juxtacellular) recordings from principal neurons of the MSO of anesthetized female gerbils. Cochlear delays can be bypassed by directly stimulating the auditory nerve; in agreement with the stereausis hypothesis, tuning for timing differences during bilateral electrical stimulation of the round windows differed markedly from ITD tuning in the same cells. Moreover, some neurons showed a frequency tuning mismatch that was sufficiently large to have a potential impact on ITD tuning. However, we did not find a correlation between frequency tuning mismatches and best ITDs. Our data thus suggest that axonal delays dominate ITD tuning.SIGNIFICANCE STATEMENT Neurons in the medial superior olive (MSO) play a unique role in sound localization because of their ability to compare the relative arrival time of low-frequency sounds at both ears. They fire maximally when the difference in sound arrival time exactly compensates for the internal delay: the difference in travel time from either ear to the MSO neuron. We tested whether differences in cochlear delay systematically contribute to the total travel time by comparing for individual MSO neurons the best difference in arrival times, as predicted from the frequency tuning for either ear, and the actual best difference. No systematic relation was observed, emphasizing the dominant contribution of axonal delays to the internal delay.

Amplitude Normalization of Dendritic EPSPs at the Soma of Binaural Coincidence Detector Neurons of the Medial Superior Olive.

The principal neurons of the medial superior olive (MSO) encode cues for horizontal sound localization through comparisons of the relative timing of EPSPs. To understand how the timing and amplitude of EPSPs are maintained during propagation in the dendrites, we made dendritic and somatic whole-cell recordings from MSO principal neurons in brain slices from Mongolian gerbils. In somatic recordings, EPSP amplitudes were largely uniform following minimal stimulation of excitatory synapses at visualized locations along the dendrites. Similar results were obtained when excitatory synaptic transmission was eliminated in a low calcium solution and then restored at specific dendritic sites by pairing input stimulation and focal application of a higher calcium solution. We performed dual dendritic and somatic whole-cell recordings to measure spontaneous EPSPs using a dual-channel template-matching algorithm to separate out those events initiated at or distal to the dendritic recording location. Local dendritic spontaneous EPSP amplitudes increased sharply in the dendrite with distance from the soma (length constant, 53.6 µm), but their attenuation during propagation resulted in a uniform amplitude of ∼0.2 mV at the soma. The amplitude gradient of dendritic EPSPs was also apparent in responses to injections of identical simulated excitatory synaptic currents in the dendrites. Compartmental models support the view that these results extensively reflect the influence of dendritic cable properties. With relatively few excitatory axons innervating MSO neurons, the normalization of dendritic EPSPs at the soma would increase the importance of input timing versus location during the processing of interaural time difference cues in vivoSIGNIFICANCE STATEMENT The neurons of the medial superior olive analyze cues for sound localization by detecting the coincidence of binaural excitatory synaptic inputs distributed along the dendrites. Previous studies have shown that dendritic voltages undergo severe attenuation as they propagate to the soma, potentially reducing the influence of distal inputs. However, using dendritic and somatic patch recordings, we found that dendritic EPSP amplitude increased with distance from the soma, compensating for dendritic attenuation and normalizing EPSP amplitude at the soma. Much of this normalization reflected the influence of dendritic morphology. As different combinations of presynaptic axons may be active during consecutive cycles of sound stimuli, somatic EPSP normalization renders spike initiation more sensitive to synapse timing than dendritic location.

Cytoarchitecture of the superior olivary complex of three neotropical species of bats (Noctilio leporinus, Phyllostomus hastatus and Carollia perspicillata) with different foraging behavior

Abstract The understanding of the echolocation by studying different auditory nuclei of echolocating bats can be an important link in elucidating questions arising in relation to their foraging behavior. The superior olivary complex (SOC) is the primary center for processing the binaural cues used in sound localization since echo locating bats rely on acoustic cues to navigate and capture prey while in flight. The present study was taken to test the hypothesis that the SOC of echolocating neotropical bats with different foraging behavior will exhibit morphological variations in relative size, degree of complexity and spatial distribution. The brains were collected from six male adult bats of each species: Noctilio leporinus (fish eating), Phyllostomus hastatus (carnivorous/omnivorous) and Carollia perspicillata (fruit eating). They were double-embedded and transverse serial sections were cut and stained with cresyl fast violet. The SOC measured as 640 ± 70 µm in the N. leporinus bat, 480 ± 50 µm in the P. hastatus and 240 ± 30 µm in the C. perspicillata bat. The principal nuclei of the SOC of in all three bats were the LSO, MSO and MNTB. The MSO and LSO were very well developed in N. leporinus bats. The MSO of N. leporinus bat subdivided into DMSO and VMSO. The main cell type of cells present in MSO and LSO are dark staining multipolar cells in all the bats studied. The well-developed MSO and LSO of N. leporinus bats indicate that these bats are highly sensitive to low frequency sounds and interaural intensity differences, which help these bats to forage over water by using various types of echolocation signals. The average size of SOC in P. hastatus and C. perspicillata bats can be attributed to the fact that these bats use vision and smell along with echolocation to forage the food.

Resumo O entendimento da ecolocalização pelo estudo de diferentes núcleos auditivos de morcegos pode ser um elo importante na elucidação das inúmeras questões que surgem em relação ao seu comportamento de forrageamento. O complexo olivar superior (SOC) é o principal centro de processamento das pistas binaurais usadas na localização do som, já que os morcegos ecolocalizadores contam com sinais acústicos para navegar e capturar as presas durante o vôo. O presente estudo foi realizado para testar a hipótese de que morcegos que usam a ecolocalização para diferentes comportamentos de forrageamento irão variar na estrutura, tamanhos relativos e grau de complexidade e distribuição espacial do grupo SOC. Os cérebros foram coletados de seis machos adultos de morcego de cada espécie: Noctilio leporinus (piscívoro), Phyllostomus hastatus (carnívoros/onívoros) e Carollia perspicillata (frugívoro). Eles foram seccionados em série e transversalmente, cortados e corados com coloração rápida cresil-violeta. tolet. O grupo SOC foi medido como 640 ± 70 µm no morcego N. leporinus, 480 ± 50 µm no P. hastatus e 240 ± 30 µm no morcego C. perspicillata. Os principais núcleos do grupo SOC dos três morcegos foram o LSO e o MSO e o MNTB. O MSO e o LSO foram muito bem desenvolvidos em morcegos N. leporinus. A MSO de N. leporinus foi subdividida em DMSO e VMSO. O principal tipo de células presentes na MSO e LSO são as células multipolares de coloração escura em todos os morcegos. Os MSO bem desenvolvidos e LSO de morcegos N. leporinus indicam que estes morcegos são altamente sensíveis a sons de baixa frequência e diferenças de intensidade interaural, que ajudaram estes morcegos a se alimentarem na superfície da água usando vários tipos de sinais de ecolocalização. O tamanho médio de SOC em morcegos de P. hastatus e C. perspicillata pode ser atribuído ao fato destes morcegos usarem visão e olfato junto com a ecolocalização para forragear.

Physiology and anatomy of neurons in the medial superior olive of the mouse.

In mammals with good low-frequency hearing, the medial superior olive (MSO) computes sound location by comparing differences in the arrival time of a sound at each ear, called interaural time disparities (ITDs). Low-frequency sounds are not reflected by the head, and therefore level differences and spectral cues are minimal or absent, leaving ITDs as the only cue for sound localization. Although mammals with high-frequency hearing and small heads (e.g., bats, mice) barely experience ITDs, the MSO is still present in these animals. Yet, aside from studies in specialized bats, in which the MSO appears to serve functions other than ITD processing, it has not been studied in small mammals that do not hear low frequencies. Here we describe neurons in the mouse brain stem that share prominent anatomical, morphological, and physiological properties with the MSO in species known to use ITDs for sound localization. However, these neurons also deviate in some important aspects from the typical MSO, including a less refined arrangement of cell bodies, dendrites, and synaptic inputs. In vitro, the vast majority of neurons exhibited a single, onset action potential in response to suprathreshold depolarization. This spiking pattern is typical of MSO neurons in other species and is generated from a complement of Kv1, Kv3, and IH currents. In vivo, mouse MSO neurons show bilateral excitatory and inhibitory tuning as well as an improvement in temporal acuity of spiking during bilateral acoustic stimulation. The combination of classical MSO features like those observed in gerbils with more unique features similar to those observed in bats and opossums make the mouse MSO an interesting model for exploiting genetic tools to test hypotheses about the molecular mechanisms and evolution of ITD processing.

Neuronal coupling by endogenous electric fields: cable theory and applications to coincidence detector neurons in the auditory brain stem.

The ongoing activity of neurons generates a spatially and time-varying field of extracellular voltage (Ve). This Ve field reflects population-level neural activity, but does it modulate neural dynamics and the function of neural circuits? We provide a cable theory framework to study how a bundle of model neurons generates Ve and how this Ve feeds back and influences membrane potential (Vm). We find that these "ephaptic interactions" are small but not negligible. The model neural population can generate Ve with millivolt-scale amplitude, and this Ve perturbs the Vm of "nearby" cables and effectively increases their electrotonic length. After using passive cable theory to systematically study ephaptic coupling, we explore a test case: the medial superior olive (MSO) in the auditory brain stem. The MSO is a possible locus of ephaptic interactions: sounds evoke large (millivolt scale)Vein vivo in this nucleus. The Ve response is thought to be generated by MSO neurons that perform a known neuronal computation with submillisecond temporal precision (coincidence detection to encode sound source location). Using a biophysically based model of MSO neurons, we find millivolt-scale ephaptic interactions consistent with the passive cable theory results. These subtle membrane potential perturbations induce changes in spike initiation threshold, spike time synchrony, and time difference sensitivity. These results suggest that ephaptic coupling may influence MSO function.

Behavior and modeling of two-dimensional precedence effect in head-unrestrained cats.

The precedence effect (PE) is an auditory illusion that occurs when listeners localize nearly coincident and similar sounds from different spatial locations, such as a direct sound and its echo. It has mostly been studied in humans and animals with immobile heads in the horizontal plane; speaker pairs were often symmetrically located in the frontal hemifield. The present study examined the PE in head-unrestrained cats for a variety of paired-sound conditions along the horizontal, vertical, and diagonal axes. Cats were trained with operant conditioning to direct their gaze to the perceived sound location. Stereotypical PE-like behaviors were observed for speaker pairs placed in azimuth or diagonally in the frontal hemifield as the interstimulus delay was varied. For speaker pairs in the median sagittal plane, no clear PE-like behavior occurred. Interestingly, when speakers were placed diagonally in front of the cat, certain PE-like behavior emerged along the vertical dimension. However, PE-like behavior was not observed when both speakers were located in the left hemifield. A Hodgkin-Huxley model was used to simulate responses of neurons in the medial superior olive (MSO) to sound pairs in azimuth. The novel simulation incorporated a low-threshold potassium current and frequency mismatches to generate internal delays. The model exhibited distinct PE-like behavior, such as summing localization and localization dominance. The simulation indicated that certain encoding of the PE could have occurred before information reaches the inferior colliculus, and MSO neurons with binaural inputs having mismatched characteristic frequencies may play an important role.

Analytical description of coincidence detection synaptic mechanisms in the auditory pathway.

Localization of sound source azimuth within horizontal plane uses interaural time differences (ITDs) between sounds arriving through the left and right ear. In mammals, ITDs are processed primarily in the medial superior olive (MSO) neurons. These are the first binaural neurons in the auditory pathway. The MSO neurons are notable because they possess high time precision in the range of tens of microseconds. Several theories and experimental studies explain how neurons are able to achieve such precision. In most theories, neuronal coincidence detection processes the ITDs and encodes azimuth in ascending neurons of the auditory pathway using modalities that are more tractable than the ITD. These modalities have been described as firing rate codes, place codes (labeled line codes) and similarly. In this theoretical model it is described how the ITD is processed by coincidence detection and converted into spikes by summing the postsynaptic potentials. Particular postsynaptic conductance functions are used in order to obtain an analytical solution in a closed form. Specifically, postsynaptic response functions are derived from the exponential decay of postsynaptic conductances and the MSO neuron is modeled as a simplified version of the Spike Response Model (SRM0) which uses linear summations of the membrane responses to synaptic inputs. For plausible ratios of time constants, an analytical solution used to describe properties of coincidence detection window is obtained. The parameter space is then explored in the vicinity of the analytical solution. The variation of parameters does not change the solution qualitatively.

A model of the medial superior olive explains spatiotemporal features of local field potentials.

Local field potentials are important indicators of in vivo neural activity. Sustained, phase-locked, sound-evoked extracellular fields in the mammalian auditory brainstem, known as the auditory neurophonic, reflect the activity of neurons in the medial superior olive (MSO). We develop a biophysically based model of the neurophonic that accounts for features of in vivo extracellular recordings in the cat auditory brainstem. By making plausible idealizations regarding the spatial symmetry of MSO neurons and the temporal synchrony of their afferent inputs, we reduce the challenging problem of computing extracellular potentials in a 3D volume conductor to a one-dimensional problem. We find that postsynaptic currents in bipolar MSO neuron models generate extracellular voltage responses that strikingly resemble in vivo recordings. Simulations reproduce distinctive spatiotemporal features of the in vivo neurophonic response to monaural pure tones: large oscillations (hundreds of microvolts to millivolts), broad spatial reach (millimeter scale), and a dipole-like spatial profile. We also explain how somatic inhibition and the relative timing of bilateral excitation may shape the spatial profile of the neurophonic. We observe in simulations, and find supporting evidence in in vivo data, that coincident excitatory inputs on both dendrites lead to a drastically reduced spatial reach of the neurophonic. This outcome surprises because coincident inputs are thought to evoke maximal firing rates in MSO neurons, and it reconciles previously puzzling evoked potential results in humans and animals. The success of our model, which has no axon or spike-generating sodium currents, suggests that MSO spikes do not contribute appreciably to the neurophonic.

Coincidence detection in the medial superior olive: mechanistic implications of an analysis of input spiking patterns.

Coincidence detection by binaural neurons in the medial superior olive underlies sensitivity to interaural time difference (ITD) and interaural correlation (ρ). It is unclear whether this process is akin to a counting of individual coinciding spikes, or rather to a correlation of membrane potential waveforms resulting from converging inputs from each side. We analyzed spike trains of axons of the cat trapezoid body (TB) and auditory nerve (AN) in a binaural coincidence scheme. ITD was studied by delaying "ipsi-" vs. "contralateral" inputs; ρ was studied by using responses to different noises. We varied the number of inputs; the monaural and binaural threshold and the coincidence window duration. We examined physiological plausibility of output "spike trains" by comparing their rate and tuning to ITD and ρ to those of binaural cells. We found that multiple inputs are required to obtain a plausible output spike rate. In contrast to previous suggestions, monaural threshold almost invariably needed to exceed binaural threshold. Elevation of the binaural threshold to values larger than 2 spikes caused a drastic decrease in rate for a short coincidence window. Longer coincidence windows allowed a lower number of inputs and higher binaural thresholds, but decreased the depth of modulation. Compared to AN fibers, TB fibers allowed higher output spike rates for a low number of inputs, but also generated more monaural coincidences. We conclude that, within the parameter space explored, the temporal patterns of monaural fibers require convergence of multiple inputs to achieve physiological binaural spike rates; that monaural coincidences have to be suppressed relative to binaural ones; and that the neuron has to be sensitive to single binaural coincidences of spikes, for a number of excitatory inputs per side of 10 or less. These findings suggest that the fundamental operation in the mammalian binaural circuit is coincidence counting of single binaural input spikes.

Emphasis of spatial cues in the temporal fine structure during the rising segments of amplitude-modulated sounds II: single-neuron recordings.

Recently, with the use of an amplitude-modulated binaural beat (AMBB), in which sound amplitude and interaural-phase difference (IPD) were modulated with a fixed mutual relationship (Dietz et al. 2013b), we demonstrated that the human auditory system uses interaural timing differences in the temporal fine structure of modulated sounds only during the rising portion of each modulation cycle. However, the degree to which peripheral or central mechanisms contribute to the observed strong dominance of the rising slope remains to be determined. Here, by recording responses of single neurons in the medial superior olive (MSO) of anesthetized gerbils and in the inferior colliculus (IC) of anesthetized guinea pigs to AMBBs, we report a correlation between the position within the amplitude-modulation (AM) cycle generating the maximum response rate and the position at which the instantaneous IPD dominates the total neural response. The IPD during the rising segment dominates the total response in 78% of MSO neurons and 69% of IC neurons, with responses of the remaining neurons predominantly coding the IPD around the modulation maximum. The observed diversity of dominance regions within the AM cycle, especially in the IC, and its comparison with the human behavioral data suggest that only the subpopulation of neurons with rising slope dominance codes the sound-source location in complex listening conditions. A comparison of two models to account for the data suggests that emphasis on IPDs during the rising slope of the AM cycle depends on adaptation processes occurring before binaural interaction.

Intense and specialized dendritic localization of the fragile X mental retardation protein in binaural brainstem neurons: a comparative study in the alligator, chicken, gerbil, and human.

Neuronal dendrites are structurally and functionally dynamic in response to changes in afferent activity. The fragile X mental retardation protein (FMRP) is an mRNA binding protein that regulates activity-dependent protein synthesis and morphological dynamics of dendrites. Loss and abnormal expression of FMRP occur in fragile X syndrome (FXS) and some forms of autism spectrum disorders. To provide further understanding of how FMRP signaling regulates dendritic dynamics, we examined dendritic expression and localization of FMRP in the reptilian and avian nucleus laminaris (NL) and its mammalian analogue, the medial superior olive (MSO), in rodents and humans. NL/MSO neurons are specialized for temporal processing of low-frequency sounds for binaural hearing, which is impaired in FXS. Protein BLAST analyses first demonstrate that the FMRP amino acid sequences in the alligator and chicken are highly similar to human FMRP with identical mRNA-binding and phosphorylation sites, suggesting that FMRP functions similarly across vertebrates. Immunocytochemistry further reveals that NL/MSO neurons have very high levels of dendritic FMRP in low-frequency hearing vertebrates including alligator, chicken, gerbil, and human. Remarkably, dendritic FMRP in NL/MSO neurons often accumulates at branch points and enlarged distal tips, loci known to be critical for branch-specific dendritic arbor dynamics. These observations support an important role for FMRP in regulating dendritic properties of binaural neurons that are essential for low-frequency sound localization and auditory scene segregation, and support the relevance of studying this regulation in nonhuman vertebrates that use low frequencies in order to further understand human auditory processing disorders.