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1.  Connections of the Auditory Brainstem in a Songbird, Taeniopygia guttata. I. Projections of Nucleus Angularis and Nucleus Laminaris to the Auditory Torus 
The Journal of comparative neurology  2010;518(11):10.1002/cne.22334.
Auditory information is important for social and reproductive behaviors in birds generally, but is crucial for oscine species (songbirds), in particular because in these species auditory feedback ensures the learning and accurate maintenance of song. While there is considerable information on the auditory projections through the forebrain of songbirds, there is no information available for projections through the brainstem. At the latter levels the prevalent model of auditory processing in birds derives from an auditory specialist, the barn owl, which uses time and intensity parameters to compute the location of sounds in space, but whether the auditory brainstem of songbirds is similarly functionally organized is unknown. To examine the songbird auditory brainstem we charted the projections of the cochlear nuclei angularis (NA) and magnocellularis (NM) and the third-order nucleus laminaris (NL) in zebra finches using standard tract-tracing techniques. As in other avian species, the projections of NM were found to be confined to NL, and NL and NA provided the ascending projections. Here we report on differential projections of NA and NL to the torus semicircularis, known in birds as nucleus mesencephalicus lateralis, pars dorsalis (MLd), and in mammals as the central nucleus of the inferior colliculus (ICc). Unlike the case in nonsongbirds, the projections of NA and NL to MLd in the zebra finch showed substantial overlap, in agreement with the projections of the cochlear nuclei to the ICc in mammals. This organization could suggest that the “what” of auditory stimuli is as important as “where.”
doi:10.1002/cne.22334
PMCID: PMC3862038  PMID: 20394061
cochlear nuclei; central nucleus of inferior colliculus; MLd; zebra finch; avian
2.  Preservation of Spectrotemporal Tuning Between the Nucleus Laminaris and the Inferior Colliculus of the Barn Owl 
Journal of neurophysiology  2007;97(5):3544-3553.
Performing sound recognition is a task that requires an encoding of the time-varying spectral structure of the auditory stimulus. Similarly, computation of the interaural time difference (ITD) requires knowledge of the precise timing of the stimulus. Consistent with this, low-level nuclei of birds and mammals implicated in ITD processing encode the ongoing phase of a stimulus. However, the brain areas that follow the binaural convergence for the computation of ITD show a reduced capacity for phase locking. In addition, we have shown that in the barn owl there is a pooling of ITD-responsive neurons to improve the reliability of ITD coding. Here we demonstrate that despite two stages of convergence and an effective loss of phase information, the auditory system of the anesthetized barn owl displays a graceful transition to an envelope coding that preserves the spectrotemporal information throughout the ITD pathway to the neurons of the core of the central nucleus of the inferior colliculus.
doi:10.1152/jn.01162.2006
PMCID: PMC2532515  PMID: 17314241
3.  Developmental Changes Underlying the Formation of the Specialized Time Coding Circuits in Barn Owls (Tyto alba) 
The Journal of Neuroscience  2002;22(17):7671-7679.
Barn owls are capable of great accuracy in detecting the interaural time differences (ITDs) that underlie azimuthal sound localization. They compute ITDs in a circuit in nucleus laminaris (NL) that is reorganized with respect to birds like the chicken. The events that lead to the reorganization of the barn owl NL take place during embryonic development, shortly after the cochlear and laminaris nuclei have differentiated morphologically. At first the developing owl’s auditory brainstem exhibits morphology reminiscent of that of the developing chicken. Later, the two systems diverge, and the owl’s brainstem auditory nuclei undergo a secondary morphogenetic phase during which NL dendrites retract, the laminar organization is lost, and synapses are redistributed. These events lead to the restructuring of the ITD coding circuit and the consequent reorganization of the hindbrain map of ITDs and azimuthal space.
PMCID: PMC3260528  PMID: 12196590
avian development; morphogenesis; auditory; laminaris; evolution; interaural time difference
4.  Comparison of Midbrain and Thalamic Space-Specific Neurons in Barn Owls 
Journal of neurophysiology  2006;95(2):783-790.
Spatial receptive fields of neurons in the auditory pathway of the barn owl result from the sensitivity to combinations of interaural time (ITD) and level differences across stimulus frequency. Both the forebrain and tectum of the owl contain such neurons. The neural pathways, which lead to the forebrain and tectal representations of auditory space, separate before the midbrain map of auditory space is synthesized. The first nuclei that belong exclusively to either the forebrain or the tectal pathways are the nucleus ovoidalis (Ov) and the external nucleus of the inferior colliculus (ICx), respectively. Both receive projections from the lateral shell subdivision of the inferior colliculus but are not interconnected. Previous studies indicate that the owl’s tectal representation of auditory space is different from those found in the owl’s forebrain and the mammalian brain. We addressed the question of whether the computation of spatial cues in both pathways is the same by comparing the ITD tuning of Ov and ICx neurons. Unlike in ICx, the relationship between frequency and ITD tuning had not been studied in single Ov units. In contrast to the conspicuous frequency independent ITD tuning of space-specific neurons of ICx, ITD selectivity varied with frequency in Ov. We also observed that the spatially tuned neurons of Ov respond to lower frequencies and are more broadly tuned to ITD than in ICx. Thus there are differences in the integration of frequency and ITD in the two sound-localization pathways. Thalamic neurons integrate spatial information not only within a broader frequency band but also across ITD channels.
doi:10.1152/jn.00833.2005
PMCID: PMC2532520  PMID: 16424454
5.  Difference in response reliability predicted by spectrotemporal tuning in the cochlear nuclei of barn owls 
The brainstem auditory pathway is obligatory for all aural information. Brainstem auditory neurons must encode the level and timing of sounds, as well as their time-dependent spectral properties, the fine structure and envelope, which are essential for sound discrimination. This study focused on envelope coding in the two cochlear nuclei of the barn owl, nucleus angularis (NA) and nucleus magnocellularis (NM). NA and NM receive input from bifurcating auditory nerve fibers and initiate processing pathways specialized in encoding interaural time (ITD) and level (ILD) differences, respectively. We found that NA neurons, though unable to accurately encode stimulus phase, lock more strongly to the stimulus envelope than NM units. The spectrotemporal receptive fields (STRFs) of NA neurons exhibit a pre-excitatory suppressive field. Using multilinear regression analysis and computational modeling, we show that this feature of STRFs can account for enhanced across-trial response reliability, by locking spikes to the stimulus envelope. Our findings indicate a dichotomy in envelope coding between the time and intensity processing pathways as early as at the level of the cochlear nuclei. This allows the ILD processing pathway to encode envelope information with greater fidelity than the ITD processing pathway. Furthermore, we demonstrate that the properties of the neurons’ STRFs can be quantitatively related to spike timing reliability.
doi:10.1523/JNEUROSCI.5422-10.2011
PMCID: PMC3059808  PMID: 21368035
Nucleus angularis; STRF; spectrotemporal tuning; cochlear nuclei; barn owl; response reliability
6.  The Multiple Functions of T Stellate/Multipolar/Chopper Cells in the Ventral Cochlear Nucleus 
Hearing research  2010;276(1-2):61-69.
Acoustic information is brought to the brain by auditory nerve fibers, all of which terminate in the cochlear nuclei, and is passed up the auditory pathway through the principal cells of the cochlear nuclei. A population of neurons variously known as T stellate, type I multipolar, planar multipolar, or chopper cells forms one of the major ascending auditory pathways through the brain stem. T Stellate cells are sharply tuned; as a population they encode the spectrum of sounds. In these neurons, phasic excitation from the auditory nerve is made more tonic by feed forward excitation, coactivation of inhibitory with excitatory inputs, relatively large excitatory currents through NMDA receptors, and relatively little synaptic depression. The mechanisms that make firing tonic also obscure the fine structure of sounds that is represented in the excitatory inputs from the auditory nerve and account for the characteristic chopping response patterns with which T stellate cells respond to tones. In contrast with other principal cells of the ventral cochlear nucleus (VCN), T stellate cells lack a low-voltage-activated potassium conductance and are therefore sensitive to small, steady, neuromodulating currents. The presence of cholinergic, serotonergic and noradrenergic receptors allows the excitability of these cells to be modulated by medial olivocochlear efferent neurons and by neuronal circuits associated with arousal. T Stellate cells deliver acoustic information to the ipsilateral dorsal cochlear nucleus (DCN), ventral nucleus of the trapezoid body (VNTB), periolivary regions around the lateral superior olivary nucleus (LSO), and to the contralateral ventral lemniscal nuclei (VNLL) and inferior colliculus (IC). It is likely that T stellate cells participate in feedback loops through both medial and lateral olivocochlear efferent neurons and they may be a source of ipsilateral excitation of the LSO.
doi:10.1016/j.heares.2010.10.018
PMCID: PMC3078527  PMID: 21056098
ventral cochlear nucleus; brainstem auditory pathways; ion channels; patch-clamp recording
7.  Neural Computation via Neural Geometry: A Place Code for Inter-whisker Timing in the Barrel Cortex? 
PLoS Computational Biology  2011;7(10):e1002188.
The place theory proposed by Jeffress (1948) is still the dominant model of how the brain represents the movement of sensory stimuli between sensory receptors. According to the place theory, delays in signalling between neurons, dependent on the distances between them, compensate for time differences in the stimulation of sensory receptors. Hence the location of neurons, activated by the coincident arrival of multiple signals, reports the stimulus movement velocity. Despite its generality, most evidence for the place theory has been provided by studies of the auditory system of auditory specialists like the barn owl, but in the study of mammalian auditory systems the evidence is inconclusive. We ask to what extent the somatosensory systems of tactile specialists like rats and mice use distance dependent delays between neurons to compute the motion of tactile stimuli between the facial whiskers (or ‘vibrissae’). We present a model in which synaptic inputs evoked by whisker deflections arrive at neurons in layer 2/3 (L2/3) somatosensory ‘barrel’ cortex at different times. The timing of synaptic inputs to each neuron depends on its location relative to sources of input in layer 4 (L4) that represent stimulation of each whisker. Constrained by the geometry and timing of projections from L4 to L2/3, the model can account for a range of experimentally measured responses to two-whisker stimuli. Consistent with that data, responses of model neurons located between the barrels to paired stimulation of two whiskers are greater than the sum of the responses to either whisker input alone. The model predicts that for neurons located closer to either barrel these supralinear responses are tuned for longer inter-whisker stimulation intervals, yielding a topographic map for the inter-whisker deflection interval across the surface of L2/3. This map constitutes a neural place code for the relative timing of sensory stimuli.
Author Summary
To perceive how stimuli move over sensor surfaces like the retina or the fingertips, neurons in the brain must report the relative timing of signals arriving at different locations on the sensor surface. The rat whisker system is ideal for exploring how the brain performs this computation, because the layout of a small number of sensors (whiskers) maps directly onto the layout of corresponding columns of neurons in the sensory cortex. Previous studies have found that neurons located between adjacent cortical columns are most likely to respond when the corresponding adjacent whiskers are stimulated in rapid succession. These results suggest a link between the location of the neuron and the relative timing of sensory signals reported by its activity. We hypothesized that, if the time taken for whisker signals to arrive at a neuron is related to its distance from each cortical column, then neurons closer to a particular column will report stimuli moving towards that particular whisker. In a model approximating the geometry of cortical connections, responses of artificial neurons matched those of real neurons on a wide range of details. These results suggest an important role for neural geometry in neural computation.
doi:10.1371/journal.pcbi.1002188
PMCID: PMC3192806  PMID: 22022245
8.  Evidence for Opponent Process Analysis of Sound Source Location in Humans 
Research with barn owls suggested that sound source location is represented topographically in the brain by an array of neurons each tuned to a narrow range of locations. However, research with small-headed mammals has offered an alternative view in which location is represented by the balance of activity in two opponent channels broadly tuned to the left and right auditory space. Both channels may be present in each auditory cortex, although the channel representing contralateral space may be dominant. Recent studies have suggested that opponent channel coding of space may also apply in humans, although these studies have used a restricted set of spatial cues or probed a restricted set of spatial locations, and there have been contradictory reports as to the relative dominance of the ipsilateral and contralateral channels in each cortex. The current study used electroencephalography (EEG) in conjunction with sound field stimulus presentation to address these issues and to inform the development of an explicit computational model of human sound source localization. Neural responses were compatible with the opponent channel account of sound source localization and with contralateral channel dominance in the left, but not the right, auditory cortex. A computational opponent channel model reproduced every important aspect of the EEG data and allowed inferences about the width of tuning in the spatial channels. Moreover, the model predicted the oft-reported decrease in spatial acuity measured psychophysically with increasing reference azimuth. Predictions of spatial acuity closely matched those measured psychophysically by previous authors.
doi:10.1007/s10162-012-0356-x
PMCID: PMC3540274  PMID: 23090057
sound source location; opponent process; electroencephalography; continuous stimulation paradigm; computational modeling; minimum audible angle
9.  Functional MRI of Auditory Responses in the Zebra Finch Forebrain Reveals a Hierarchical Organisation Based on Signal Strength but Not Selectivity 
PLoS ONE  2008;3(9):e3184.
Background
Male songbirds learn their songs from an adult tutor when they are young. A network of brain nuclei known as the ‘song system’ is the likely neural substrate for sensorimotor learning and production of song, but the neural networks involved in processing the auditory feedback signals necessary for song learning and maintenance remain unknown. Determining which regions show preferential responsiveness to the bird's own song (BOS) is of great importance because neurons sensitive to self-generated vocalisations could mediate this auditory feedback process. Neurons in the song nuclei and in a secondary auditory area, the caudal medial mesopallium (CMM), show selective responses to the BOS. The aim of the present study is to investigate the emergence of BOS selectivity within the network of primary auditory sub-regions in the avian pallium.
Methods and Findings
Using blood oxygen level-dependent (BOLD) fMRI, we investigated neural responsiveness to natural and manipulated self-generated vocalisations and compared the selectivity for BOS and conspecific song in different sub-regions of the thalamo-recipient area Field L. Zebra finch males were exposed to conspecific song, BOS and to synthetic variations on BOS that differed in spectro-temporal and/or modulation phase structure. We found significant differences in the strength of BOLD responses between regions L2a, L2b and CMM, but no inter-stimuli differences within regions. In particular, we have shown that the overall signal strength to song and synthetic variations thereof was different within two sub-regions of Field L2: zone L2a was significantly more activated compared to the adjacent sub-region L2b.
Conclusions
Based on our results we suggest that unlike nuclei in the song system, sub-regions in the primary auditory pallium do not show selectivity for the BOS, but appear to show different levels of activity with exposure to any sound according to their place in the auditory processing stream.
doi:10.1371/journal.pone.0003184
PMCID: PMC2527133  PMID: 18781203
10.  Estradiol-dependent modulation of auditory processing and selectivity in songbirds 
Frontiers in neuroendocrinology  2010;32(3):287-302.
The steroid hormone estradiol plays an important role in reproductive development and behavior and modulates a wide array of physiological and cognitive processes. Recently, reports from several research groups have converged to show that estradiol also powerfully modulates sensory processing, specifically, the physiology of central auditory circuits in songbirds. These investigators have discovered that (1) behaviorally-relevant auditory experience rapidly increases estradiol levels in the auditory forebrain; (2) estradiol instantaneously enhances the responsiveness and coding efficiency of auditory neurons; (3) these changes are mediated by a non-genomic effect of brain-generated estradiol on the strength of inhibitory neurotransmission; and (4) estradiol regulates biochemical cascades that induce the expression of genes involved in synaptic plasticity. Together, these findings have established estradiol as a central regulator of auditory function and intensified the need to consider brain-based mechanisms, in addition to peripheral organ dysfunction, in hearing pathologies associated with estrogen deficiency.
doi:10.1016/j.yfrne.2010.12.002
PMCID: PMC3119742  PMID: 21146556
17β-Estradiol; Audition; Selectivity; Fadrozole; Estrogen; Aromatase; Behavior; Vocal learning; Selectivity; Auditory coding
11.  The representation of sound localization cues in the barn owl's inferior colliculus 
The barn owl is a well-known model system for studying auditory processing and sound localization. This article reviews the morphological and functional organization, as well as the role of the underlying microcircuits, of the barn owl's inferior colliculus (IC). We focus on the processing of frequency and interaural time (ITD) and level differences (ILD). We first summarize the morphology of the sub-nuclei belonging to the IC and their differentiation by antero- and retrograde labeling and by staining with various antibodies. We then focus on the response properties of neurons in the three major sub-nuclei of IC [core of the central nucleus of the IC (ICCc), lateral shell of the central nucleus of the IC (ICCls), and the external nucleus of the IC (ICX)]. ICCc projects to ICCls, which in turn sends its information to ICX. The responses of neurons in ICCc are sensitive to changes in ITD but not to changes in ILD. The distribution of ITD sensitivity with frequency in ICCc can only partly be explained by optimal coding. We continue with the tuning properties of ICCls neurons, the first station in the midbrain where the ITD and ILD pathways merge after they have split at the level of the cochlear nucleus. The ICCc and ICCls share similar ITD and frequency tuning. By contrast, ICCls shows sigmoidal ILD tuning which is absent in ICCc. Both ICCc and ICCls project to the forebrain, and ICCls also projects to ICX, where space-specific neurons are found. Space-specific neurons exhibit side peak suppression in ITD tuning, bell-shaped ILD tuning, and are broadly tuned to frequency. These neurons respond only to restricted positions of auditory space and form a map of two-dimensional auditory space. Finally, we briefly review major IC features, including multiplication-like computations, correlates of echo suppression, plasticity, and adaptation.
doi:10.3389/fncir.2012.00045
PMCID: PMC3394089  PMID: 22798945
sound localization; central nucleus of the inferior colliculus; auditory; plasticity; adaptation; interaural time difference; interaural level difference; frequency tuning
12.  Micro-rewiring as a substrate for learning 
Trends in neurosciences  2008;31(11):577-584.
How does the brain encode life experiences? Recent results derived from vital imaging, computational modeling, cellular physiology and systems neuroscience have pointed to local changes in synaptic connectivity as a powerful substrate, here termed micro-rewiring. To examine this hypothesis, I first review findings on micro-structural dynamics with focus on the extension and retraction of dendritic spines. Although these observations demonstrate a biological mechanism, they do not inform us of the specific changes in circuit configuration that might occur during learning. Here, computational models have made testable predictions for both the neuronal and circuit levels. Integrative approaches in the mammalian neocortex and the barn owl auditory localization pathway provide some of the first direct evidence in support of these ‘synaptic-clustering’ mechanisms. The implications of these data and the challenges for future research are discussed.
doi:10.1016/j.tins.2008.08.006
PMCID: PMC2581897  PMID: 18817991
13.  Binaural Gain Modulation of Spectrotemporal Tuning in the Interaural Level Difference-Coding Pathway 
The Journal of Neuroscience  2013;33(27):11089-11099.
In the brainstem, the auditory system diverges into two pathways that process different sound localization cues, interaural time differences (ITDs) and level differences (ILDs). We investigated the site where ILD is detected in the auditory system of barn owls, the posterior part of the lateral lemniscus (LLDp). This structure is equivalent to the lateral superior olive in mammals. The LLDp is unique in that it is the first place of binaural convergence in the brainstem where monaural excitatory and inhibitory inputs converge. Using binaurally uncorrelated noise and a generalized linear model, we were able to estimate the spectrotemporal tuning of excitatory and inhibitory inputs to these cells. We show that the response of LLDp neurons is highly locked to the stimulus envelope. Our data demonstrate that spectrotemporally tuned, temporally delayed inhibition enhances the reliability of envelope locking by modulating the gain of LLDp neurons' responses. The dependence of gain modulation on ILD shown here constitutes a means for space-dependent coding of stimulus identity by the initial stages of the auditory pathway.
doi:10.1523/JNEUROSCI.4941-12.2013
PMCID: PMC3718367  PMID: 23825414
14.  Delay Selection by Spike-Timing-Dependent Plasticity in Recurrent Networks of Spiking Neurons Receiving Oscillatory Inputs 
PLoS Computational Biology  2013;9(2):e1002897.
Learning rules, such as spike-timing-dependent plasticity (STDP), change the structure of networks of neurons based on the firing activity. A network level understanding of these mechanisms can help infer how the brain learns patterns and processes information. Previous studies have shown that STDP selectively potentiates feed-forward connections that have specific axonal delays, and that this underlies behavioral functions such as sound localization in the auditory brainstem of the barn owl. In this study, we investigate how STDP leads to the selective potentiation of recurrent connections with different axonal and dendritic delays during oscillatory activity. We develop analytical models of learning with additive STDP in recurrent networks driven by oscillatory inputs, and support the results using simulations with leaky integrate-and-fire neurons. Our results show selective potentiation of connections with specific axonal delays, which depended on the input frequency. In addition, we demonstrate how this can lead to a network becoming selective in the amplitude of its oscillatory response to this frequency. We extend this model of axonal delay selection within a single recurrent network in two ways. First, we show the selective potentiation of connections with a range of both axonal and dendritic delays. Second, we show axonal delay selection between multiple groups receiving out-of-phase, oscillatory inputs. We discuss the application of these models to the formation and activation of neuronal ensembles or cell assemblies in the cortex, and also to missing fundamental pitch perception in the auditory brainstem.
Author Summary
Our brain's ability to perform cognitive processes, such as object identification, problem solving, and decision making, comes from the specific connections between neurons. The neurons carry information as spikes that are transmitted to other neurons via connections with different strengths and propagation delays. Experimentally observed learning rules can modify the strengths of connections between neurons based on the timing of their spikes. The learning that occurs in neuronal networks due to these rules is thought to be vital to creating the structures necessary for different cognitive processes as well as for memory. The spiking rate of populations of neurons has been observed to oscillate at particular frequencies in various brain regions, and there is evidence that these oscillations play a role in cognition. Here, we use analytical and numerical methods to investigate the changes to the network structure caused by a specific learning rule during oscillatory neural activity. We find the conditions under which connections with propagation delays that resonate with the oscillations are strengthened relative to the other connections. We demonstrate that networks learn to oscillate more strongly to oscillations at the frequency they were presented with during learning. We discuss the possible application of these results to specific areas of the brain.
doi:10.1371/journal.pcbi.1002897
PMCID: PMC3567188  PMID: 23408878
15.  The role of auditory feedback in vocal learning and maintenance 
Current Opinion in Neurobiology  2011;22(2):320-327.
Auditory experience is critical for the acquisition and maintenance of learned vocalizations in both humans and songbirds. Despite the central role of auditory feedback in vocal learning and maintenance, where and how auditory feedback affects neural circuits important to vocal control remain poorly understood. Recent studies of singing birds have uncovered neural mechanisms by which feedback perturbations affect vocal plasticity and also have identified feedback-sensitive neurons at or near sites of auditory and vocal motor interaction. Additionally, recent studies in marmosets have underscored that even in the absence of vocal learning, vocalization remains flexible in the face of changing acoustical environments, pointing to rapid interactions between auditory and vocal motor systems. Finally, recent studies show that a juvenile songbird’s initial auditory experience of a song model has long-lasting effects on sensorimotor neurons important to vocalization, shedding light on how auditory memories and feedback interact to guide vocal learning.
doi:10.1016/j.conb.2011.11.006
PMCID: PMC3297733  PMID: 22137567
16.  Population-wide bias of surround suppression in auditory spatial receptive fields of the owl’s midbrain 
The physical arrangement of receptive fields (RFs) within neural structures is important for local computations. Nonuniform distribution of tuning within populations of neurons can influence emergent tuning properties, causing bias in local processing. This issue was studied in the auditory system of barn owls. The owl’s external nucleus of the inferior colliculus (ICx) contains a map of auditory space where the frontal region is overrepresented. We measured spatiotemporal RFs of ICx neurons using spatial white noise. We found a population-wide bias in surround suppression such that suppression from frontal space was stronger. This asymmetry increased with laterality in spatial tuning. The bias could be explained by a model of lateral inhibition based on the overrepresentation of frontal space observed in ICx. The model predicted trends in surround suppression across ICx that matched the data. Thus, the uneven distribution of spatial tuning within the map could explain the topography of time-dependent tuning properties. This mechanism may have significant implications for the analysis of natural scenes by sensory systems.
doi:10.1523/JNEUROSCI.0047-12.2012
PMCID: PMC3447633  PMID: 22855796
Sound localization; spatiotemporal receptive field; inferior colliculus; barn owl; surround bias
17.  Microsecond Precision of Phase Delay in the Auditory System of the Barn Owl 
Journal of Neurophysiology  2005;94(2):1655-1658.
The auditory system encodes time with sub-millisecond accuracy. To shed new light on the basic mechanism underlying this precise temporal neuronal coding, we analyzed the neurophonic potential, a characteristic multiunit response, in the barn owl’s nucleus laminaris. We report here that the relative time measure of phase delay is robust against changes in sound level, with a precision sharper than 20 µs. Absolute measures of delay, such as group delay or signal-front delay, had much greater temporal jitter, for example due to their strong dependence on sound level. Our findings support the hypothesis that phase delay underlies the sub-millisecond precision of the representation of interaural time difference needed for sound localization.
doi:10.1152/jn.01226.2004
PMCID: PMC3268176  PMID: 15843477
18.  Fast Detection of Unexpected Sound Intensity Decrements as Revealed by Human Evoked Potentials 
PLoS ONE  2011;6(12):e28522.
The detection of deviant sounds is a crucial function of the auditory system and is reflected by the automatically elicited mismatch negativity (MMN), an auditory evoked potential at 100 to 250 ms from stimulus onset. It has recently been shown that rarely occurring frequency and location deviants in an oddball paradigm trigger a more negative response than standard sounds at very early latencies in the middle latency response of the human auditory evoked potential. This fast and early ability of the auditory system is corroborated by the finding of neurons in the animal auditory cortex and subcortical structures, which restore their adapted responsiveness to standard sounds, when a rare change in a sound feature occurs. In this study, we investigated whether the detection of intensity deviants is also reflected at shorter latencies than those of the MMN. Auditory evoked potentials in response to click sounds were analyzed regarding the auditory brain stem response, the middle latency response (MLR) and the MMN. Rare stimuli with a lower intensity level than standard stimuli elicited (in addition to an MMN) a more negative potential in the MLR at the transition from the Na to the Pa component at circa 24 ms from stimulus onset. This finding, together with the studies about frequency and location changes, suggests that the early automatic detection of deviant sounds in an oddball paradigm is a general property of the auditory system.
doi:10.1371/journal.pone.0028522
PMCID: PMC3232232  PMID: 22163029
19.  Mechanistic Basis and Functional Roles of Long-Term Plasticity in Auditory Neurons Induced by a Brain-Generated Estrogen 
The Journal of Neuroscience  2012;32(46):16478-16495.
The classic estrogen 17β-estradiol (E2) was recently identified as a novel modulator of hearing function. It is produced rapidly, in an experience-dependent fashion, by auditory cortical neurons of both males and females. This brain-generated E2 enhances the efficiency of auditory coding and improves the neural and behavioral discrimination of auditory cues. Remarkably, the effects of E2 are long-lasting and persist for hours after local rises in hormone levels have subsided. The mechanisms and functional consequences of this E2-induced plasticity of auditory responses are unknown. Here, we addressed these issues in the zebra finch model by combining intracerebral pharmacology, biochemical assays, in vivo neurophysiology in awake animals, and computational and information theoretical approaches. We show that auditory experience activates the MAPK pathway in an E2-dependent manner. This effect is mediated by estrogen receptor β (ERβ), which directly associates with MEKK1 to sequentially modulate MEK and ERK activation, where the latter is required for the engagement of downstream molecular targets. We further show that E2-mediated activation of the MAPK cascade is required for the long-lasting enhancement of auditory-evoked responses in the awake brain. Moreover, a functional consequence of this E2/MAPK activation is to sustain enhanced information handling and neural discrimination by auditory neurons for several hours following hormonal challenge. Our results demonstrate that brain-generated E2 engages, via a nongenomic interaction between an estrogen receptor and a kinase, a persistent form of experience-dependent plasticity that enhances the neural coding and discrimination of behaviorally relevant sensory signals in the adult vertebrate brain.
doi:10.1523/JNEUROSCI.3233-12.2012
PMCID: PMC3752145  PMID: 23152630
20.  STIMULUS-DRIVEN COMPETITION IN A CHOLINERGIC MIDBRAIN NUCLEUS 
Nature neuroscience  2010;13(7):889-895.
The mechanisms by which the brain selects a particular stimulus as the next target for gaze are poorly understood. A cholinergic nucleus in the owl’s midbrain exhibits functional properties that suggest its role in bottom-up stimulus selection. Neurons in the nucleus isthmi pars parvocellularis (Ipc) respond to wide ranges of visual and auditory features, but they are not tuned to particular values of those features. Instead, they encode the relative strengths of stimuli across the entirety of space. Many neurons exhibit switch-like properties, abruptly increasing their responses to a stimulus in their receptive field when it becomes the strongest stimulus. This information propagates directly to the optic tectum, a structure involved in gaze control and stimulus selection, as periodic (25–50 Hz) bursts of cholinergic activity. The functional properties of Ipc neurons resemble those of a “salience map”, a core component in computational models for spatial attention and gaze control.
doi:10.1038/nn.2573
PMCID: PMC2893238  PMID: 20526331
21.  Noise-invariant Neurons in the Avian Auditory Cortex: Hearing the Song in Noise 
PLoS Computational Biology  2013;9(3):e1002942.
Given the extraordinary ability of humans and animals to recognize communication signals over a background of noise, describing noise invariant neural responses is critical not only to pinpoint the brain regions that are mediating our robust perceptions but also to understand the neural computations that are performing these tasks and the underlying circuitry. Although invariant neural responses, such as rotation-invariant face cells, are well described in the visual system, high-level auditory neurons that can represent the same behaviorally relevant signal in a range of listening conditions have yet to be discovered. Here we found neurons in a secondary area of the avian auditory cortex that exhibit noise-invariant responses in the sense that they responded with similar spike patterns to song stimuli presented in silence and over a background of naturalistic noise. By characterizing the neurons' tuning in terms of their responses to modulations in the temporal and spectral envelope of the sound, we then show that noise invariance is partly achieved by selectively responding to long sounds with sharp spectral structure. Finally, to demonstrate that such computations could explain noise invariance, we designed a biologically inspired noise-filtering algorithm that can be used to separate song or speech from noise. This novel noise-filtering method performs as well as other state-of-the-art de-noising algorithms and could be used in clinical or consumer oriented applications. Our biologically inspired model also shows how high-level noise-invariant responses could be created from neural responses typically found in primary auditory cortex.
Author Summary
Birds and humans excel at the task of detecting important sounds, such as song and speech, in difficult listening environments such as in a large bird colony or in a crowded bar. How our brains achieve such a feat remains a mystery to both neuroscientists and audio engineers. In our research, we found a population of neurons in the brain of songbirds that are able to extract a song signal from a background of noise. We explain how the neurons are able to perform this task and show how a biologically inspired algorithm could outperform the best noise-reduction methods proposed by engineers.
doi:10.1371/journal.pcbi.1002942
PMCID: PMC3591274  PMID: 23505354
22.  Auditory Spatial Acuity Approximates the Resolving Power of Space-Specific Neurons 
PLoS ONE  2007;2(8):e675.
The relationship between neuronal acuity and behavioral performance was assessed in the barn owl (Tyto alba), a nocturnal raptor renowned for its ability to localize sounds and for the topographic representation of auditory space found in the midbrain. We measured discrimination of sound-source separation using a newly developed procedure involving the habituation and recovery of the pupillary dilation response. The smallest discriminable change of source location was found to be about two times finer in azimuth than in elevation. Recordings from neurons in its midbrain space map revealed that their spatial tuning, like the spatial discrimination behavior, was also better in azimuth than in elevation by a factor of about two. Because the PDR behavioral assay is mediated by the same circuitry whether discrimination is assessed in azimuth or in elevation, this difference in vertical and horizontal acuity is likely to reflect a true difference in sensory resolution, without additional confounding effects of differences in motor performance in the two dimensions. Our results, therefore, are consistent with the hypothesis that the acuity of the midbrain space map determines auditory spatial discrimination.
doi:10.1371/journal.pone.0000675
PMCID: PMC1925148  PMID: 17668055
23.  GABA Immunoreactivity in Auditory and Song Control Brain Areas of Zebra Finches 
Journal of chemical neuroanatomy  2007;34(1-2):1-21.
Inhibitory transmission is critical to sensory and motor processing and is believed to play a role in experience-dependent plasticity. The main inhibitory neurotransmitter in vertebrates, GABA, has been implicated in both sensory and motor aspects of vocalization in songbirds. To understand the role of GABAergic mechanisms in vocal communication, GABAergic elements must be characterized fully. Hence, we investigated GABA immunohistochemistry in the zebra finch brain, emphasizing auditory areas and song control nuclei. Several nuclei of the ascending auditory pathway showed a moderate to high density of GABAergic neurons including the cochlear nuclei, nucleus laminaris, superior olivary nucleus, mesencephalic nucleus lateralis pars dorsalis, and nucleus ovoidalis. Telencephalic auditory areas, including field L subfields L1, L2a and L3, as well as the caudomedial nidopallium (NCM) and mesopallium (CMM), contained GABAergic cells at particularly high densities. Considerable GABA labeling was also seen in the shelf area of caudodorsal nidopallium, and the cup area in the arcopallium, as well as in area X, the lateral magnocellular nucleus of the anterior nidopallium, the robust nucleus of the arcopallium and nidopallial nucleus HVC. GABAergic cells were typically small, most likely local inhibitory interneurons, although large GABA-positive cells that were sparsely distributed were also identified. GABA-positive neurites and puncta were identified in most nuclei of the ascending auditory pathway and in song control nuclei. Our data are in accordance with a prominent role of GABAergic mechanisms in regulating the neural circuits involved in song perceptual processing, motor production, and vocal learning in songbirds.
doi:10.1016/j.jchemneu.2007.03.005
PMCID: PMC2778006  PMID: 17466487
GAD; Avian; NCM; Songbird; Plasticity; HVC
24.  Localization of KCNC1 (Kv3.1) Potassium Channel Subunits in the Avian Auditory Nucleus Magnocellularis and Nucleus Laminaris during Development 
Journal of Neurobiology  2003;55(2):165-178.
The KCNC1 (previously Kv3.1) potassium channel, a delayed rectifier with a high threshold of activation, is highly expressed in the time coding nuclei of the adult chicken and barn owl auditory brainstem. The proposed role of KCNC1 currents in auditory neurons is to reduce the width of the action potential and enable neurons to transmit high frequency temporal information with little jitter. Because developmental changes in potassium currents are critical for the maturation of the shape of the action potential, we used immunohistochemical methods to examine the developmental expression of KCNC1 subunits in the avian auditory brainstem. The KCNC1 gene gives rise to two splice variants, a longer KCNC1b and a shorter KCNC1a that differ at the carboxy termini. Two antibodies were used: an antibody to the N-terminus that does not distinguish between KCNC1a and b isoforms, denoted as panKCNC1, and another antibody that specifically recognizes the C terminus of KCNC1b. A comparison of the staining patterns observed with the pan-KCNC1 and the KCNC1b specific antibodies suggests that KCNC1a and KCNC1b splice variants are differentially regulated during development. Although pan-KCNC1 immunoreactivity is observed from the earliest time examined in the chicken (E10), a subcellular redistribution of the immunoproduct was apparent over the course of development. KCNC1b specific staining has a late onset with immunostaining first appearing in the regions that map high frequencies in nucleus magnocellularis (NM) and nucleus laminaris (NL). The expression of KCNC1b protein begins around E14 in the chicken and after E21 in the barn owl, relatively late during ontogeny and at the time that synaptic connections mature morphologically and functionally.
doi:10.1002/neu.10198
PMCID: PMC3268178  PMID: 12672015
chicken; barn owl; ontogeny; time coding; outward current; high threshold
25.  Spatial hearing in echoic environments: The role of the envelope in owls 
Neuron  2010;67(4):643-655.
Summary
In the precedence effect, sounds emanating directly from the source are localized preferentially over their reflections. Although most studies have focused on the delay between the onset of a sound and its echo, humans still experience the precedence effect when this onset delay is removed. We tested in barn owls the hypothesis that an ongoing delay, equivalent to the onset delay, is discernible from the envelope features of amplitude-modulated stimuli and may be sufficient to evoke this effect. With sound pairs having only envelope cues, owls localized direct sounds preferentially and neurons in their auditory space-maps discharged more vigorously to them, but only if the sounds were amplitude modulated. Under conditions that yielded the precedence effect, acoustical features known to evoke neuronal discharges were more abundant in the envelopes of the direct sounds than of the echoes, suggesting that specialized neural mechanisms for echo suppression were unnecessary.
doi:10.1016/j.neuron.2010.07.014
PMCID: PMC2930190  PMID: 20797540

Results 1-25 (780950)