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1.  Resolution of interaural time differences in the avian sound localization circuit—a modeling study 
Interaural time differences (ITDs) are a main cue for sound localization and sound segregation. A dominant model to study ITD detection is the sound localization circuitry in the avian auditory brainstem. Neurons in nucleus laminaris (NL) receive auditory information from both ears via the avian cochlear nucleus magnocellularis (NM) and compare the relative timing of these inputs. Timing of these inputs is crucial, as ITDs in the microsecond range must be discriminated and encoded. We modeled ITD sensitivity of single NL neurons based on previously published data and determined the minimum resolvable ITD for neurons in NL. The minimum resolvable ITD is too large to allow for discrimination by single NL neurons of naturally occurring ITDs for very low frequencies. For high frequency NL neurons (>1 kHz) our calculated ITD resolutions fall well within the natural range of ITDs and approach values of below 10 μs. We show that different parts of the ITD tuning function offer different resolution in ITD coding, suggesting that information derived from both parts may be used for downstream processing. A place code may be used for sound location at frequencies above 500 Hz, but our data suggest the slope of the ITD tuning curve ought to be used for ITD discrimination by single NL neurons at the lowest frequencies. Our results provide an important measure of the necessary temporal window of binaural inputs for future studies on the mechanisms and development of neuronal computation of temporally precise information in this important system. In particular, our data establish the temporal precision needed for conduction time regulation along NM axons.
doi:10.3389/fncom.2014.00099
PMCID: PMC4143899  PMID: 25206329
sound localization; interaural time differences; avian brainstem; nucleus laminaris; ITD resolution
2.  Axonal branching patterns as sources of delay in the mammalian auditory brainstem: a reexamination 
In models of temporal processing, time delays incurred by axonal propagation of action potentials play a prominent role. A preeminent model of temporal processing in audition is the binaural model of Jeffress (1948), which has dominated theories regarding our acute sensitivity to interaural time differences (ITDs). In Jeffress’ model a binaural cell is maximally active when the ITD is compensated by an internal delay, which brings the inputs from left and right ears in coincidence, and which would arise from axonal branching patterns of monaural input fibers. By arranging these patterns in systematic and opposite ways for the ipsi- and contralateral inputs, a range of length differences, and thereby of internal delays, is created so that ITD is transformed into a spatial activation pattern along the binaural nucleus. We reanalyze single, labeled and physiologically characterized, axons of spherical bushy cells of the cat anteroventral cochlear nucleus (AVCN) which project to binaural coincidence detectors in the medial superior olive (MSO). The reconstructions largely confirm the observations of two previous reports, but several features are observed which are inconsistent with Jeffress’ model. We found that ipsilateral projections can also form a caudally-directed delay line pattern, which would counteract delays incurred by caudally-directed contralateral projections. Comparisons of estimated axonal delays with binaural physiological data indicate that the suggestive anatomical patterns cannot account for the frequency-dependent distribution of best delays in the cat. Surprisingly, the tonotopic distribution of the afferents endings indicate that low CFs are under- rather than overrepresented in the MSO.
doi:10.1523/JNEUROSCI.5175-10.2011
PMCID: PMC3157295  PMID: 21414923
3.  Interaural timing difference circuits in the auditory brainstem of the emu (Dromaius novaehollandiae) 
In the auditory system, precise encoding of temporal information is critical for sound localization, a task with direct behavioral relevance. Interaural timing differences are computed using axonal delay lines and cellular coincidence detectors in nucleus laminaris (NL). We present morphological and physiological data on the timing circuits in the emu, Dromaius novaehollandiae, and compare these results with those from the barn owl (Tyto alba) and the domestic chick (Gallus gallus). Emu NL was composed of a compact monolayer of bitufted neurons whose two thick primary dendrites were oriented dorsoventrally. They showed a gradient in dendritic length along the presumed tonotopic axis. The NL and nucleus magnocellularis (NM) neurons were strongly immunoreactive for parvalbumin, a calcium-binding protein. Antibodies against synaptic vesicle protein 2 and glutamic acid decarboxlyase revealed that excitatory synapses terminated heavily on the dendritic tufts, while inhibitory terminals were distributed more uniformly. Physiological recordings from brainstem slices demonstrated contralateral delay lines from NM to NL. During whole-cell patch-clamp recordings, NM and NL neurons fired single spikes and were doubly-rectifying. NL and NM neurons had input resistances of 30.0 ± 19.9 MΩ and 49.0 ± 25.6 MΩ, respectively, and membrane time constants of 12.8 ± 3.8 ms and 3.9 ± 0.2 ms. These results provide further support for the Jeffress model for sound localization in birds. The emu timing circuits showed the ancestral (plesiomorphic) pattern in their anatomy and physiology, while differences in dendritic structure compared to chick and owl may indicate specialization for encoding ITDs at low best frequencies.
doi:10.1002/cne.20862
PMCID: PMC2948976  PMID: 16435285
avian; nucleus laminaris; nucleus magnocellularis; dendrite; coincidence detection; sound localization
4.  Biophysical basis of the sound analog membrane potential that underlies coincidence detection in the barn owl 
Interaural time difference (ITD), or the difference in timing of a sound wave arriving at the two ears, is a fundamental cue for sound localization. A wide variety of animals have specialized neural circuits dedicated to the computation of ITDs. In the avian auditory brainstem, ITDs are encoded as the spike rates in the coincidence detector neurons of the nucleus laminaris (NL). NL neurons compare the binaural phase-locked inputs from the axons of ipsi- and contralateral nucleus magnocellularis (NM) neurons. Intracellular recordings from the barn owl's NL in vivo showed that tonal stimuli induce oscillations in the membrane potential. Since this oscillatory potential resembled the stimulus sound waveform, it was named the sound analog potential (Funabiki et al., 2011). Previous modeling studies suggested that a convergence of phase-locked spikes from NM leads to an oscillatory membrane potential in NL, but how presynaptic, synaptic, and postsynaptic factors affect the formation of the sound analog potential remains to be investigated. In the accompanying paper, we derive analytical relations between these parameters and the signal and noise components of the oscillation. In this paper, we focus on the effects of the number of presynaptic NM fibers, the mean firing rate of these fibers, their average degree of phase-locking, and the synaptic time scale. Theoretical analyses and numerical simulations show that, provided the total synaptic input is kept constant, changes in the number and spike rate of NM fibers alter the ITD-independent noise whereas the degree of phase-locking is linearly converted to the ITD-dependent signal component of the sound analog potential. The synaptic time constant affects the signal more prominently than the noise, making faster synaptic input more suitable for effective ITD computation.
doi:10.3389/fncom.2013.00102
PMCID: PMC3821004  PMID: 24265615
phase-locking; sound localization; auditory brainstem; periodic signals; oscillation; owl
5.  Differential Conduction Velocity Regulation in Ipsilateral and Contralateral Collaterals Innervating Brainstem Coincidence Detector Neurons 
The Journal of Neuroscience  2014;34(14):4914-4919.
Information processing in the brain relies on precise timing of signal propagation. The highly conserved neuronal network for computing spatial representations of acoustic signals resolves microsecond timing of sounds processed by the two ears. As such, it provides an excellent model for understanding how precise temporal regulation of neuronal signals is achieved and maintained. The well described avian and mammalian brainstem circuit for computation of interaural time differences is composed of monaural cells in the cochlear nucleus (CN; nucleus magnocellularis in birds) projecting to binaurally innervated coincidence detection neurons in the medial superior olivary nucleus (MSO) in mammals or nucleus laminaris (NL) in birds. Individual axons from CN neurons issue a single axon that bifurcates into an ipsilateral branch and a contralateral branch that innervate segregated dendritic regions of the MSO/NL coincidence detector neurons. We measured conduction velocities of the ipsilateral and contralateral branches of these bifurcating axon collaterals in the chicken by antidromic stimulation of two sites along each branch and whole-cell recordings in the parent neurons. At the end of each experiment, the individual CN neuron and its axon collaterals were filled with dye. We show that the two collaterals of a single axon adjust the conduction velocities individually to achieve the specific conduction velocities essential for precise temporal integration of information from the two ears, as required for sound localization. More generally, these results suggest that individual axonal segments in the CNS interact locally with surrounding neural structures to determine conduction velocity.
doi:10.1523/JNEUROSCI.5460-13.2014
PMCID: PMC3972718  PMID: 24695710
conduction velocity regulation; myelin plasticity; sound localization
6.  Detection of Interaural Time Differences in the Alligator 
The auditory systems of birds and mammals use timing information from each ear to detect interaural time difference (ITD). To determine whether the Jeffress-type algorithms that underlie sensitivity to ITD in birds are an evolutionarily stable strategy, we recorded from the auditory nuclei of crocodilians, who are the sister group to the birds. In alligators, precisely timed spikes in the first-order nucleus magnocellularis (NM) encode the timing of sounds, and NM neurons project to neurons in the nucleus laminaris (NL) that detect interaural time differences. In vivo recordings from NL neurons show that the arrival time of phase-locked spikes differs between the ipsilateral and contralateral inputs. When this disparity is nullified by their best ITD, the neurons respond maximally. Thus NL neurons act as coincidence detectors. A biologically detailed model of NL with alligator parameters discriminated ITDs up to 1 kHz. The range of best ITDs represented in NL was much larger than in birds, however, and extended from 0 to 1000 μs contralateral, with a median ITD of 450 μs. Thus, crocodilians and birds employ similar algorithms for ITD detection, although crocodilians have larger heads.
doi:10.1523/JNEUROSCI.6154-08.2009
PMCID: PMC3170862  PMID: 19553438
7.  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.
doi:10.3389/fncir.2014.00042
PMCID: PMC4013490  PMID: 24822037
medial superior olive; auditory nerve; input convergence; coincidence window; interaural time difference; interaural correlation; temporal coding; coincidence detection
8.  Neuronal specializations for the processing of interaural difference cues in the chick 
Sound information is encoded as a series of spikes of the auditory nerve fibers (ANFs), and then transmitted to the brainstem auditory nuclei. Features such as timing and level are extracted from ANFs activity and further processed as the interaural time difference (ITD) and the interaural level difference (ILD), respectively. These two interaural difference cues are used for sound source localization by behaving animals. Both cues depend on the head size of animals and are extremely small, requiring specialized neural properties in order to process these cues with precision. Moreover, the sound level and timing cues are not processed independently from one another. Neurons in the nucleus angularis (NA) are specialized for coding sound level information in birds and the ILD is processed in the posterior part of the dorsal lateral lemniscus nucleus (LLDp). Processing of ILD is affected by the phase difference of binaural sound. Temporal features of sound are encoded in the pathway starting in nucleus magnocellularis (NM), and ITD is processed in the nucleus laminaris (NL). In this pathway a variety of specializations are found in synapse morphology, neuronal excitability, distribution of ion channels and receptors along the tonotopic axis, which reduces spike timing fluctuation in the ANFs-NM synapse, and imparts precise and stable ITD processing to the NL. Moreover, the contrast of ITD processing in NL is enhanced over a wide range of sound level through the activity of GABAergic inhibitory systems from both the superior olivary nucleus (SON) and local inhibitory neurons that follow monosynaptic to NM activity.
doi:10.3389/fncir.2014.00047
PMCID: PMC4023016  PMID: 24847212
brainstem auditory nucleus; interaural difference cues; SON; tonic inhibition; phasic inhibition
9.  Responses of Auditory Nerve and Anteroventral Cochlear Nucleus Fibers to Broadband and Narrowband Noise: Implications for the Sensitivity to Interaural Delays 
The quality of temporal coding of sound waveforms in the monaural afferents that converge on binaural neurons in the brainstem limits the sensitivity to temporal differences at the two ears. The anteroventral cochlear nucleus (AVCN) houses the cells that project to the binaural nuclei, which are known to have enhanced temporal coding of low-frequency sounds relative to auditory nerve (AN) fibers. We applied a coincidence analysis within the framework of detection theory to investigate the extent to which AVCN processing affects interaural time delay (ITD) sensitivity. Using monaural spike trains to a 1-s broadband or narrowband noise token, we emulated the binaural task of ITD discrimination and calculated just noticeable differences (jnds). The ITD jnds derived from AVCN neurons were lower than those derived from AN fibers, showing that the enhanced temporal coding in the AVCN improves binaural sensitivity to ITDs. AVCN processing also increased the dynamic range of ITD sensitivity and changed the shape of the frequency dependence of ITD sensitivity. Bandwidth dependence of ITD jnds from AN as well as AVCN fibers agreed with psychophysical data. These findings demonstrate that monaural preprocessing in the AVCN improves the temporal code in a way that is beneficial for binaural processing and may be crucial in achieving the exquisite sensitivity to ITDs observed in binaural pathways.
doi:10.1007/s10162-011-0268-1
PMCID: PMC3123442  PMID: 21567250
coincidence detection; interaural time difference; discrimination; binaural; sound localization
10.  Responses of Auditory Nerve and Anteroventral Cochlear Nucleus Fibers to Broadband and Narrowband Noise: Implications for the Sensitivity to Interaural Delays 
The quality of temporal coding of sound waveforms in the monaural afferents that converge on binaural neurons in the brainstem limits the sensitivity to temporal differences at the two ears. The anteroventral cochlear nucleus (AVCN) houses the cells that project to the binaural nuclei, which are known to have enhanced temporal coding of low-frequency sounds relative to auditory nerve (AN) fibers. We applied a coincidence analysis within the framework of detection theory to investigate the extent to which AVCN processing affects interaural time delay (ITD) sensitivity. Using monaural spike trains to a 1-s broadband or narrowband noise token, we emulated the binaural task of ITD discrimination and calculated just noticeable differences (jnds). The ITD jnds derived from AVCN neurons were lower than those derived from AN fibers, showing that the enhanced temporal coding in the AVCN improves binaural sensitivity to ITDs. AVCN processing also increased the dynamic range of ITD sensitivity and changed the shape of the frequency dependence of ITD sensitivity. Bandwidth dependence of ITD jnds from AN as well as AVCN fibers agreed with psychophysical data. These findings demonstrate that monaural preprocessing in the AVCN improves the temporal code in a way that is beneficial for binaural processing and may be crucial in achieving the exquisite sensitivity to ITDs observed in binaural pathways.
doi:10.1007/s10162-011-0268-1
PMCID: PMC3123442  PMID: 21567250
coincidence detection; interaural time difference; discrimination; binaural; sound localization
11.  Asymmetric Excitatory Synaptic Dynamics Underlie Interaural Time Difference Processing in the Auditory System 
PLoS Biology  2010;8(6):e1000406.
In order to localize sounds in the environment, the auditory system detects and encodes differences in signals between each ear. The exquisite sensitivity of auditory brain stem neurons to the differences in rise time of the excitation signals from the two ears allows for neuronal encoding of microsecond interaural time differences.
Low-frequency sound localization depends on the neural computation of interaural time differences (ITD) and relies on neurons in the auditory brain stem that integrate synaptic inputs delivered by the ipsi- and contralateral auditory pathways that start at the two ears. The first auditory neurons that respond selectively to ITD are found in the medial superior olivary nucleus (MSO). We identified a new mechanism for ITD coding using a brain slice preparation that preserves the binaural inputs to the MSO. There was an internal latency difference for the two excitatory pathways that would, if left uncompensated, position the ITD response function too far outside the physiological range to be useful for estimating ITD. We demonstrate, and support using a biophysically based computational model, that a bilateral asymmetry in excitatory post-synaptic potential (EPSP) slopes provides a robust compensatory delay mechanism due to differential activation of low threshold potassium conductance on these inputs and permits MSO neurons to encode physiological ITDs. We suggest, more generally, that the dependence of spike probability on rate of depolarization, as in these auditory neurons, provides a mechanism for temporal order discrimination between EPSPs.
Author Summary
Animals can locate the source of a sound by detecting microsecond differences in the arrival time of sound at the two ears. Neurons encoding these interaural time differences (ITDs) receive an excitatory synaptic input from each ear. They can perform a microsecond computation with excitatory synapses that have millisecond time scale because they are extremely sensitive to the input's “rise time,” the time taken to reach the peak of the synaptic input. Current theories assume that the biophysical properties of the two inputs are identical. We challenge this assumption by showing that the rise times of excitatory synaptic potentials driven by the ipsilateral ear are faster than those driven by the contralateral ear. Further, we present a computational model demonstrating that this disparity in rise times, together with the neurons' sensitivity to excitation's rise time, can endow ITD-encoding with microsecond resolution in the biologically relevant range. Our analysis also resolves a timing mismatch. The difference between contralateral and ipsilateral latencies is substantially larger than the relevant ITD range. We show how the rise time disparity compensates for this mismatch. Generalizing, we suggest that phasic-firing neurons—those that respond to rapidly, but not to slowly, changing stimuli—are selective to the temporal ordering of brief inputs. In a coincidence-detection computation the neuron will respond more robustly when a faster input leads a slower one, even if the inputs are brief and have similar amplitudes.
doi:10.1371/journal.pbio.1000406
PMCID: PMC2893945  PMID: 20613857
12.  Maps of interaural time difference in the chicken’s brainstem nucleus laminaris 
Biological cybernetics  2008;98(6):541-559.
Animals, including humans, use interaural time differences (ITDs) that arise from different sound path lengths to the two ears as a cue of horizontal sound source location. The nature of the neural code for ITD is still controversial. Current models differentiate between two population codes: either a map-like rate-place code of ITD along an array of neurons, consistent with a large body of data in the barn owl, or a population rate code, consistent with data from small mammals. Recently, it was proposed that these different codes reflect optimal coding strategies that depend on head size and sound frequency. The chicken makes an excellent test case of this proposal because its physical pre-requisites are similar to small mammals, yet it shares a more recent common ancestry with the owl. We show here that, like in the barn owl, the brainstem nucleus laminaris in mature chickens displayed the major features of a place code of ITD. ITD was topographically represented in the maximal responses of neurons along each isofrequency band, covering approximately the contralateral acoustic hemisphere. Furthermore, the represented ITD range appeared to change with frequency, consistent with a pressure gradient receiver mechanism in the avian middle ear. At very low frequencies, below400 Hz, maximal neural responses were symmetrically distributed around zero ITD and it remained unclear whether there was a topographic representation. These findings do not agree with the above predictions for optimal coding and thus revive the discussion as to what determines the neural coding strategies for ITDs.
doi:10.1007/s00422-008-0220-6
PMCID: PMC3170859  PMID: 18491165
Auditory; Hearing; Sound localization; Sensory
13.  Topography and Morphology of the Inhibitory Projection From Superior Olivary Nucleus to Nucleus Laminaris in Chickens (Gallus gallus) 
The avian nucleus laminaris (NL) is involved in computation of interaural time differences (ITDs) that encode the azimuthal position of a sound source. Neurons in NL are bipolar, with dorsal and ventral dendritic arbors receiving input from separate ears. NL neurons act as coincidence detectors that respond maximally when input from each ear arrives at the two dendritic arbors simultaneously. Computational and physiological studies demonstrated that the sensitivity of NL neurons to coincident inputs is modulated by an inhibitory feedback circuit via the superior olivary nucleus (SON). To understand the mechanism of this modulation, the topography of the projection from SON to NL was mapped, and the morphology of the axon terminals of SON neurons in NL was examined in chickens (Gallus gallus). In vivo injection of AlexaFluor 568 dextran amine into SON demonstrated a coarse topographic projection from SON to NL. Retrogradely labeled neurons in NL were located within the zone of anterogradely labeled terminals, suggesting a reciprocal projection from SON to NL. In vivo extracellular physiological recording further demonstrated that this topography is consistent with tonotopic maps in SON and NL. In addition, three-dimensional reconstruction of single SON axon branches within NL revealed that individual SON neurons innervate a large area of NL and terminate on both dorsal and ventral dendritic arbors of NL neurons. The organization of the projection from SON to NL supports its proposed functions of controlling the overall activity level of NL and enhancing the specificity of frequency mapping and ITD detection.
doi:10.1002/cne.22523
PMCID: PMC3299086  PMID: 21165979
auditory brainstem; axonal projection; γ-aminobutyric acid (GABA); interaural time difference (ITD); tonotopic organization
14.  Bilateral matching of frequency tuning in neural cross-correlators of the owl 
Biological cybernetics  2009;100(6):521-531.
Sound localization requires comparison between the inputs to the left and right ears. One important aspect of this comparison is the differences in arrival time to each side, also called interaural time difference (ITD).A prevalent model of ITD detection, consisting of delay lines and coincidence-detector neurons, was proposed by Jeffress (J Comp Physiol Psychol 41:35–39, 1948). As an extension of the Jeffress model, the process of detecting and encoding ITD has been compared to an effective cross-correlation between the input signals to the two ears. Because the cochlea performs a spectrotemporal decomposition of the input signal, this cross-correlation takes place over narrow frequency bands. Since the cochlear tonotopy is arranged in series, sounds of different frequencies will trigger neural activity with different temporal delays. Thus, the matching of the frequency tuning of the left and right inputs to the cross-correlator units becomes a ‘timing’ issue. These properties of auditory transduction gave theoretical support to an alternative model of ITD-detection based on a bilateral mismatch in frequency tuning, called the ‘stereausis’ model. Here we first review the current literature on the owl’s nucleus laminaris, the equivalent to the medial superior olive of mammals, which is the site where ITD is detected. Subsequently, we use reverse correlation analysis and stimulation with uncorrelated sounds to extract the effective monaural inputs to the cross-correlator neurons. We show that when the left and right inputs to the cross-correlators are defined in this manner, the computation performed by coincidence-detector neurons satisfies conditions of cross-correlation theory. We also show that the spectra of left and right inputs are matched, which is consistent with predictions made by the classic model put forth by Jeffress.
doi:10.1007/s00422-009-0312-y
PMCID: PMC2719282  PMID: 19396457
Barn owl; Interaural time difference; Cross-correlation; Coincidence detection; Cochlear delays; Sound localization; Nucleus laminaris; Stereausis
15.  Adaptation of spike timing precision controls the sensitivity to interaural time difference in the avian auditory brainstem 
While adaptation is widely thought to facilitate neural coding, the form of adaptation should depend on how the signals are encoded. Monaural neurons early in the interaural time difference (ITD) pathway encode the phase of sound input using spike timing rather than firing rate. Such neurons in chicken nucleus magnocellularis (NM) adapt to ongoing stimuli by increasing firing rate and decreasing spike timing precision. We measured NM neuron responses while adapting them to simulated physiological input, and used these responses to construct inputs to binaural coincidence detector neurons in nucleus laminaris (NL). Adaptation of spike timing in NM reduced ITD sensitivity in NL, demonstrating the dominant role of timing in the short-term plasticity as well as the immediate response of this sound localization circuit.
doi:10.1523/JNEUROSCI.1865-12.2012
PMCID: PMC3518488  PMID: 23115186
16.  The analysis of interaural time differences in the chick brain stem 
Physiology & behavior  2005;86(3):297-305.
The brain stem auditory system of the chick has proven to be a useful model system for analyzing how the brain encodes temporal information. This paper reviews some of the work on a circuit in the brain stem that compares the timing of information coming from the two ears to determine the location of a sound source. The contralateral projection from the cochlear nucleus, nucleus magnocellularis (NM), to nucleus laminaris (NL) forms a delay line as it proceeds from medial to lateral across NL. NL neurons function like coincidence detectors in that they respond maximally when input from the two ears arrive simultaneously. This arrangement may allow NL to code sound space by the relative level of activity across the nucleus. The head anatomy of the chick allows for enhancement of the functional interaural time differences. Comparing the functional interaural time differences to the length of the neural delay line suggests that each NL can encode approximately one hemifield of sound space. Finally it is suggested that inhibitory input into the NM–NL circuit may provide a means to dynamically adjust the gain of the circuit to allow accurate coding of sound location despite changes in overall sound intensity.
doi:10.1016/j.physbeh.2005.08.003
PMCID: PMC1847356  PMID: 16202434
Auditory system; Sound localization; Nucleus magnocellularis; Nucleus laminaris; Coincidence detection; Interaural canal; GABA
17.  Cross-Correlation in the Auditory Coincidence Detectors of Owls 
Interaural time difference (ITD) plays a central role in many auditory functions, most importantly in sound localization. The classic model for how ITD is computed was put forth by Jeffress (1948). One of the predictions of the Jeffress model is that the neurons that compute ITD should behave as cross-correlators. Whereas cross-correlation-like properties of the ITD-computing neurons have been reported, attempts to show that the shape of the ITD response function is determined by the spectral tuning of the neuron, a core prediction of cross-correlation, have been unsuccessful. Using reverse correlation analysis, we demonstrate in the barn owl that the relationship between the spectral tuning and the ITD response of the ITD-computing neurons is that predicted by cross-correlation. Moreover, we show that a model of coincidence detector responses derived from responses to binaurally uncorrelated noise is consistent with binaural interaction based on cross-correlation. These results are thus consistent with one of the key tenets of the Jeffress model. Our work sets forth both the methodology to answer whether cross-correlation describes coincidence detector responses and a demonstration that in the barn owl, the result is that expected by theory.
doi:10.1523/JNEUROSCI.1969-08.2008
PMCID: PMC2637928  PMID: 18685035
barn owl; interaural time difference; cross-correlation; coincidence detection; sound localization; nucleus laminaris
18.  Theoretical foundations of the sound analog membrane potential that underlies coincidence detection in the barn owl 
A wide variety of neurons encode temporal information via phase-locked spikes. In the avian auditory brainstem, neurons in the cochlear nucleus magnocellularis (NM) send phase-locked synaptic inputs to coincidence detector neurons in the nucleus laminaris (NL) that mediate sound localization. Previous modeling studies suggested that converging phase-locked synaptic inputs may give rise to a periodic oscillation in the membrane potential of their target neuron. Recent physiological recordings in vivo revealed that owl NL neurons changed their spike rates almost linearly with the amplitude of this oscillatory potential. The oscillatory potential was termed the sound analog potential, because of its resemblance to the waveform of the stimulus tone. The amplitude of the sound analog potential recorded in NL varied systematically with the interaural time difference (ITD), which is one of the most important cues for sound localization. In order to investigate the mechanisms underlying ITD computation in the NM-NL circuit, we provide detailed theoretical descriptions of how phase-locked inputs form oscillating membrane potentials. We derive analytical expressions that relate presynaptic, synaptic, and postsynaptic factors to the signal and noise components of the oscillation in both the synaptic conductance and the membrane potential. Numerical simulations demonstrate the validity of the theoretical formulations for the entire frequency ranges tested (1–8 kHz) and potential effects of higher harmonics on NL neurons with low best frequencies (<2 kHz).
doi:10.3389/fncom.2013.00151
PMCID: PMC3821005  PMID: 24265616
phase-locking; sound localization; auditory brainstem; periodic signals; oscillation; owl
19.  Dichotic sound localization properties of duration-tuned neurons in the inferior colliculus of the big brown bat 
Electrophysiological studies on duration-tuned neurons (DTNs) from the mammalian auditory midbrain have typically evoked spiking responses from these cells using monaural or free-field acoustic stimulation focused on the contralateral ear, with fewer studies devoted to examining the electrophysiological properties of duration tuning using binaural stimulation. Because the inferior colliculus (IC) receives convergent inputs from lower brainstem auditory nuclei that process sounds from each ear, many midbrain neurons have responses shaped by binaural interactions and are selective to binaural cues important for sound localization. In this study, we used dichotic stimulation to vary interaural level difference (ILD) and interaural time difference (ITD) acoustic cues and explore the binaural interactions and response properties of DTNs and non-DTNs from the IC of the big brown bat (Eptesicus fuscus). Our results reveal that both DTNs and non-DTNs can have responses selective to binaural stimulation, with a majority of IC neurons showing some type of ILD selectivity, fewer cells showing ITD selectivity, and a number of neurons showing both ILD and ITD selectivity. This study provides the first demonstration that the temporally selective responses of DTNs from the vertebrate auditory midbrain can be selective to binaural cues used for sound localization in addition to having spiking responses that are selective for stimulus frequency, amplitude, and duration.
doi:10.3389/fphys.2014.00215
PMCID: PMC4050336  PMID: 24959149
auditory neurophysiology; binaural hearing; dichotic stimulation; Eptesicus fuscus; sound localization
20.  Modeling coincidence detection in nucleus laminaris 
Biological Cybernetics  2003;89(5):388-396.
A biologically detailed model of the binaural avian nucleus laminaris is constructed, as a two-dimensional array of multicompartment, conductance-based neurons, along tonotopic and interaural time delay (ITD) axes. The model is based primarily on data from chick nucleus laminaris. Typical chick-like parameters perform ITD discrimination up to 2 kHz, and enhancements for barn owl perform ITD discrimination up to 6 kHz. The dendritic length gradient of NL is explained concisely. The response to binaural out-of-phase input is suppressed well below the response to monaural input (without any spontaneous activity on the opposite side), implicating active potassium channels as crucial to good ITD discrimination.
doi:10.1007/s00422-003-0444-4
PMCID: PMC3269635  PMID: 14669019
21.  The relative contributions of MNTB and LNTB neurons to inhibition in the medial superior olive assessed through single and paired recordings 
The medial superior olive (MSO) senses microsecond differences in the coincidence of binaural signals, a critical cue for detecting sound location along the azimuth. An important component of this circuit is provided by inhibitory neurons of the medial and lateral nuclei of the trapezoid body (MNTB and LNTB, respectively). While MNTB neurons are fairly well described, little is known about the physiology of LNTB neurons. Using whole cell recordings from gerbil brainstem slices, we found that LNTB and MNTB neurons have similar membrane time constants and input resistances and fire brief action potentials, but only LNTB neurons fire repetitively in response to current steps. We observed that LNTB neurons receive graded excitatory and inhibitory synaptic inputs, with at least some of the latter arriving from other LNTB neurons. To address the relative timing of inhibition to the MSO from the LNTB versus the MNTB, we examined inhibitory responses to auditory nerve stimulation using a slice preparation that retains the circuitry from the auditory nerve to the MSO intact. Despite the longer physical path length of excitatory inputs driving contralateral inhibition, inhibition from both pathways arrived with similar latency and jitter. An analysis of paired whole cell recordings between MSO and MNTB neurons revealed a short and reliable delay between the action potential peak in MNTB neurons and the onset of the resulting IPSP (0.55 ± 0.01 ms, n = 4, mean ± SEM). Reconstructions of biocytin-labeled neurons showed that MNTB axons ranged from 580 to 858 μm in length (n = 4). We conclude that while both LNTB and MNTB neurons provide similarly timed inhibition to MSO neurons, the reliability of inhibition from the LNTB at higher frequencies is more constrained relative to that from the MNTB due to differences in intrinsic properties, the strength of excitatory inputs, and the presence of feedforward inhibition.
doi:10.3389/fncir.2014.00049
PMCID: PMC4030206  PMID: 24860434
inhibition; auditory brainstem; timing; sound localization; axon
22.  Formation and Maturation of the Calyx of Held 
Hearing research  2010;276(1-2):70-78.
Sound localization requires precise and specialized neural circuitry. A prominent and well-studied specialization is found in the mammalian auditory brainstem. Globular bushy cells of the ventral cochlear nucleus (VCN) project contralaterally to neurons of the medial nucleus of the trapezoid body (MNTB), where their large axons terminate on cell bodies of MNTB principal neurons, forming the calyces of Held. The VCN-MNTB pathway is necessary for the accurate computation of interaural intensity and time differences; MNTB neurons provide inhibitory input to the lateral superior olive, which compares levels of excitation from the ipsilateral ear to levels of tonotopically matched inhibition from the contralateral ear, and to the medial superior olive, where precise inhibition from MNTB neurons tunes the delays of binaural excitation. Here we review the morphological and physiological aspects of the development of the VCN-MNTB pathway and its calyceal termination, along with potential mechanisms that give rise to its precision. During embryonic development, VCN axons grow towards the midline, cross the midline into the region of the presumptive MNTB and then form collateral branches that will terminate in calyces of Held. In rodents, immature calyces of Held appear in MNTB during the first few days of postnatal life. These calyces mature morphologically and physiologically over the next three postnatal weeks, enabling fast, high fidelity transmission in the VCN-MNTB pathway.
doi:10.1016/j.heares.2010.11.004
PMCID: PMC3109188  PMID: 21093567
23.  Glycinergic inhibition tunes coincidence detection in the auditory brainstem 
Nature Communications  2014;5:3790.
Neurons in the medial superior olive (MSO) detect microsecond differences in the arrival time of sounds between the ears (interaural time differences or ITDs), a crucial binaural cue for sound localization. Synaptic inhibition has been implicated in tuning ITD sensitivity, but the cellular mechanisms underlying its influence on coincidence detection are debated. Here we determine the impact of inhibition on coincidence detection in adult Mongolian gerbil MSO brain slices by testing precise temporal integration of measured synaptic responses using conductance-clamp. We find that inhibition dynamically shifts the peak timing of excitation, depending on its relative arrival time, which in turn modulates the timing of best coincidence detection. Inhibitory control of coincidence detection timing is consistent with the diversity of ITD functions observed in vivo and is robust under physiologically relevant conditions. Our results provide strong evidence that temporal interactions between excitation and inhibition on microsecond timescales are critical for binaural processing.
Coincidence detector neurons in the mammalian brainstem encode interaural time differences (ITDs) that are implicated in auditory processing. Myoga et al. study a previously developed neuronal model and find that inhibition is crucial for sound localization, but more dynamically than previously thought.
doi:10.1038/ncomms4790
PMCID: PMC4024823  PMID: 24804642
24.  Noise Reduction of Coincidence Detector Output by the Inferior Colliculus of the Barn Owl 
A recurring theme in theoretical work is that integration over populations of similarly tuned neurons can reduce neural noise. However, there are relatively few demonstrations of an explicit noise reduction mechanism in a neural network. Here we demonstrate that the brainstem of the barn owl includes a stage of processing apparently devoted to increasing the signal-to-noise ratio in the encoding of the interaural time difference (ITD), one of two primary binaural cues used to compute the position of a sound source in space. In the barn owl, the ITD is processed in a dedicated neural pathway that terminates at the core of the inferior colliculus (ICcc). The actual locus of the computation of the ITD is before ICcc in the nucleus laminaris (NL), and ICcc receives no inputs carrying information that did not originate in NL. Unlike in NL, the rate-ITD functions of ICcc neurons require as little as a single stimulus presentation per ITD to show coherent ITD tuning. ICcc neurons also displayed a greater dynamic range with a maximal difference in ITD response rates approximately double that seen in NL. These results indicate that ICcc neurons perform a computation functionally analogous to averaging across a population of similarly tuned NL neurons.
doi:10.1523/JNEUROSCI.0220-06.2006
PMCID: PMC2492673  PMID: 16738236
interaural time difference; sound localization; inferior colliculus; nucleus laminaris; barn owl; pooling
25.  Kcna1 gene deletion lowers the behavioral sensitivity of mice to small changes in sound location and increases asynchronous brainstem auditory evoked potentials, but does not affect hearing thresholds 
The Journal of Neuroscience  2012;32(7):2538-2543.
Sound localization along the azimuth depends on the sensitivity of binaural nuclei in the auditory brainstem to small differences in interaural level and timing occurring within a sub-millisecond epoch, and on monaural pathways that transmit level and timing cues with high temporal fidelity to insure their coincident arrival at the binaural targets. The soma and axons of these brainstem neurons are heavily invested with ion channels containing the low-threshold potassium channel subunit Kv1.1, which previous in-vitro and in-vivo studies suggest are important for regulating their high input-output correspondence and temporal synchrony. We compared awake Kcna1 null mutant (−/−) mice lacking Kv1.1 with +/+ mice to determine if Kv1.1 activity contributes to sound localization, and examined anesthetized mice for absolute hearing thresholds for suprathreshold differences that may be revealed in the waveforms of auditory brainstem response potentials. The awake −/− mice tested with reflex modification audiometry had reduced sensitivity to an abrupt change in the location of a broad band noise compared to +/+ mice, while anesthetized −/− mice had normal absolute thresholds for tone pips but a high level of stimulus-evoked but asynchronous background activity. Evoked potential waveforms had progressively earlier peaks and troughs in −/− mice but the amplitude excursions between adjacent features were identical in the two groups. Their greater excitability and asynchrony in suprathreshold evoked potentials coupled with their normal thresholds suggests that a disruption in central neural processing in −/− mice and not peripheral hearing loss is responsible for their poor sound localization.
doi:10.1523/JNEUROSCI.1958-11.2012
PMCID: PMC3297021  PMID: 22396426

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