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1.  Circuitry Underlying Spectrotemporal Integration in the Auditory Midbrain 
Combination sensitivity in central auditory neurons is a form of spectrotemporal integration in which excitatory responses to sounds at one frequency are facilitated by sounds within a distinctly different frequency band. Combination-sensitive neurons respond selectively to acoustic elements of sonar echoes or social vocalizations. In mustached bats, this response property originates in high frequency representations of the inferior colliculus (IC) and depends on low- and high-frequency-tuned glycinergic inputs. To identify source of these inputs, we combined glycine immunohistochemistry with retrograde tract-tracing. Tracers were deposited at high-frequency (>56 kHz), combination-sensitive recording sites in IC. Most glycine-immunopositive, retrogradely labeled cells were in ipsilateral ventral and intermediate nuclei of the lateral lemniscus (VNLL and INLL), with some double-labeling in ipsilateral lateral and medial superior olivary nuclei (LSO and MSO). Generally, double-labeled cells were in expected high-frequency tonotopic areas, but some VNLL and INLL labeling appeared to be in low-frequency representations. To test whether these nuclei provide low-frequency-tuned input to the high-frequency IC, we combined retrograde tracing from IC combination-sensitive sites with anterograde tracing from low-frequency-tuned sites in the anteroventral cochlear nucleus (AVCN). Only VNLL and INLL contained retrogradely labeled cells near (≤50 µm) anterogradely labeled boutons. These cells likely receive excitatory low-frequency input from AVCN. Results suggest that combination-sensitive facilitation arises through convergence of high-frequency glycinergic inputs from VNLL, INLL, or MSO and low-frequency glycinergic inputs from VNLL or INLL. This work establishes an anatomical basis for spectrotemporal integration in the auditory midbrain and a functional role for monaural nuclei of the lateral lemniscus.
PMCID: PMC3226782  PMID: 21976527
combination sensitivity; spectral integration; glycine; mustached bat; nucleus of lateral lemniscus; Pteronotus parnellii
2.  Neurons in the Cochlear Nuclei Controlling the Tensor Tympani Muscle in the Rat: a Study Using Pseudorabies Virus 
Brain research  2007;1154:124-136.
The middle ear muscle reflex has been implicated in modulation of auditory input and protection of the inner ear from acoustic trauma. However, the identification of neurons in the cochlear nuclei participating in this reflex has not been fully elucidated. In the present study, we injected the retrograde transynaptic tracer pseudorabies virus into single tensor tympani (TT) muscles, and identified transynaptically labeled cochlear nucleus neurons at multiple survival times. Motoneurons controlling TT were located ventral to the ipsilateral motor trigeminal nucleus and extended rostrally towards the medial aspect of the lateral lemniscus. Transynaptically-labeled neurons were observed bilaterally in the dorsal and dorso-medial parts of ventral cochlear nuclei as early as 48 h after virus injection, and had morphological features of radiate multipolar cells. After ≥ 69 h, labeled cells of different types were observed in all cochlear nuclei. At those times, labeling was also detected bilaterally in the medial nucleus of the trapezoid body and periolivary cell groups in the superior olivary complex. Based on the temporal course of viral replication, our data strongly suggest the presence of a direct projection of neurons from the ventral cochlear nuclei bilaterally to the TT motoneuron pool in rats. The influence of neurons in the cochlear nuclei upon TT activity through direct and indirect pathways may account for multifunctional roles of this muscle in auditory functions.
PMCID: PMC3005211  PMID: 17482147
direct and indirect acoustic reflex pathways; middle ear muscle; transynaptic transport
3.  Linear coding of complex sound spectra by discharge rate in neurons of the medial nucleus of the trapezoid body (MNTB) and its inputs 
The interaural level difference (ILD) cue to sound location is first encoded in the lateral superior olive (LSO). ILD sensitivity results because the LSO receives excitatory input from the ipsilateral cochlear nucleus and inhibitory input indirectly from the contralateral cochlear nucleus via glycinergic neurons of the ipsilateral medial nucleus of the trapezoid body (MNTB). It is hypothesized that in order for LSO neurons to encode ILDs, the sound spectra at both ears must be accurately encoded via spike rate by their afferents. This spectral-coding hypothesis has not been directly tested in MNTB, likely because MNTB neurons have been mostly described and studied recently in regards to their abilities to encode temporal aspects of sounds, not spectral. Here, we test the hypothesis that MNTB neurons and their inputs from the cochlear nucleus and auditory nerve code sound spectra via discharge rate. The Random Spectral Shape (RSS) method was used to estimate how the levels of 100-ms duration spectrally stationary stimuli were weighted, both linearly and non-linearly, across a wide band of frequencies. In general, MNTB neurons, and their globular bushy cell inputs, were found to be well-modeled by a linear weighting of spectra demonstrating that the pathways through the MNTB can accurately encode sound spectra including those resulting from the acoustical cues to sound location provided by head-related directional transfer functions (DTFs). Together with the anatomical and biophysical specializations for timing in the MNTB-LSO complex, these mechanisms may allow ILDs to be computed for complex stimuli with rapid spectrotemporally-modulated envelopes such as speech and animal vocalizations and moving sound sources.
PMCID: PMC4267272  PMID: 25565971
calyx of held; medial nucleus of the trapezoid body; lateral superior olive; spectrotemporal receptive field; sound localization; temporal processing
4.  Auditory nerve inputs to cochlear nucleus neurons studied with cross-correlation 
Neuroscience  2008;154(1):127-138.
The strength of synapses between auditory nerve (AN) fibers and ventral cochlear nucleus (VCN) neurons is an important factor in determining the nature of neural integration in VCN neurons of different response types. Synaptic strength was analyzed using cross-correlation of spike trains recorded simultaneously from an AN fiber and a VCN neuron in anesthetized cats. VCN neurons were classified as chopper, primarylike, and onset using previously defined criteria, although onset neurons usually were not analyzed because of their low discharge rates. The correlograms showed an excitatory peak (EP), consistent with monosynaptic excitation, in AN-VCN pairs with similar best frequencies (49% 24/49 of pairs with best frequencies within ±5%). Chopper and primarylike neurons showed similar EPs, except that the primarylike neurons had shorter latencies and shorter-duration EPs. Large EPs consistent with endbulb terminals on spherical bushy cells were not observed, probably because of the low probability of recording from one. The small EPs observed in primarylike neurons, presumably spherical bushy cells, could be derived from small terminals that accompany endbulbs on these cells. EPs on chopper or primarylike-with-notch neurons were consistent with the smaller synaptic terminals on multipolar and globular bushy cells. Unexpectedly, EPs were observed only at sound levels within about 20 dB of threshold, showing that VCN responses to steady tones shift from a 1:1 relationship between AN and VCN spikes at low sound levels to a more autonomous mode of firing at high levels. In the high level mode, the pattern of output spikes seems to be determined by the properties of the postsynaptic spike generator rather than the input spike patterns. The EP amplitudes did not change significantly when the presynaptic spike was preceded by either a short or long interspike interval, suggesting that synaptic depression and facilitation have little effect under the conditions studied here.
PMCID: PMC2478560  PMID: 18343587
cross-correlation; ventral cochlear nucleus; synaptic strength
5.  Relationship between noise-induced hearing-loss, persistent tinnitus and GAP-43 expression in the rat cochlear nucleus: Does synaptic plasticity in ventral cochlear nucleus suppress tinnitus? 
Neuroscience  2011;194:309-325.
Aberrant, lesion-induced neuroplastic changes in the auditory pathway are believed to give rise to the phantom sound of tinnitus. Noise-induced cochlear damage can induce extensive fiber growth and synaptogenesis in the cochlear nucleus, but it is currently unclear if these changes are linked to tinnitus. To address this issue, we unilaterally exposed nine rats to narrowband noise centered at 12 kHz at 126 dB SPL for two hours and sacrificed them 10 weeks later for evaluation of synaptic plasticity (GAP-43 expression) in the cochlear nucleus. Noise-exposed rats along with three age-matched controls were screened for tinnitus-like behavior with gap prepulse inhibition of the acoustic startle (GPIAS) before, 1–10 days after and 8–10 weeks after the noise exposure. All nine noise-exposed rats showed similar patterns of severe hair cell loss at high- and mid-frequency regions in the exposed ear. Eight of the 9 showed strong up-regulation of GAP-43 in auditory nerve fibers and pronounced shrinkage of the ventral cochlear nucleus (VCN) on the noise-exposed side, and strong up-regulation of GAP-43 in the medial ventral VCN, but not in the lateral VCN or the dorsal cochlear nucleus. GAP-43 up-regulation in VCN was significantly greater in Noise-No-Tinnitus rats than in Noise-Tinnitus rats. One Noise-No-Tinnitus rat showed no up-regulation of GAP-43 in auditory nerve fibers and only little VCN shrinkage, suggesting that auditory nerve degeneration plays a role in tinnitus generation. Our results suggest that noise-induced tinnitus is suppressed by strong up-regulation of GAP-43 in the medial VCN. GAP-43 up-regulation most likely originates from medial olivocochlear neurons. Their increased excitatory input on inhibitory neurons in VCN may possibly reduce central hyperactivity and tinnitus.
PMCID: PMC3390756  PMID: 21821100
noise; tinnitus; hair cell loss; growth associated protein-43; ventral cochlear nucleus; dorsal cochlear nucleus
6.  Interaural Phase and Level Difference Sensitivity in Low-Frequency Neurons in the Lateral Superior Olive 
The lateral superior olive (LSO) is believed to encode differences in sound level at the two ears, a cue for azimuthal sound location. Most high-frequency-sensitive LSO neurons are binaural, receiving inputs from both ears. An inhibitory input from the contralateral ear, via the medial nucleus of the trapezoid body (MNTB), and excitatory input from the ipsilateral ear enable level differences to be encoded. However, the classical descriptions of low-frequency-sensitive neurons report primarily monaural cells with no contralateral inhibition. Anatomical and physiological evidence, however, shows that low-frequency LSO neurons receive low-frequency inhibitory input from ipsilateral MNTB, which in turn receives excitatory input from the contralateral cochlear nucleus and low-frequency excitatory input from the ipsilateral cochlear nucleus. Therefore, these neurons would be expected to be binaural with contralateral inhibition. Here, we re-examined binaural interaction in low-frequency (less than ~3 kHz) LSO neurons and phase locking in the MNTB. Phase locking to low-frequency tones in MNTB and ipsilaterally driven LSO neurons with frequency sensitivities < 1.2 kHz was enhanced relative to the auditory nerve. Moreover, most low-frequency LSO neurons exhibited contralateral inhibition: ipsilaterally driven responses were suppressed by raising the level of the contralateral stimulus; most neurons were sensitive to interaural time delays in pure tone and noise stimuli such that inhibition was nearly maximal when the stimuli were presented to the ears in-phase. The data demonstrate that low-frequency LSO neurons of cat are not monaural and can exhibit contralateral inhibition like their high-frequency counterparts.
PMCID: PMC1449742  PMID: 16291937
lateral superior olive; medial nucleus of the trapezoid body; interaural time delay; interaural level difference; sound localization; phase locking
7.  Target-specific IPSC kinetics promote temporal processing in auditory parallel pathways 
The acoustic environment contains biologically relevant information on time scales from microseconds to tens of seconds. The auditory brainstem nuclei process this temporal information through parallel pathways that originate in the cochlear nucleus from different classes of cells. While the roles of ion channels and excitatory synapses in temporal processing have been well studied, the contribution of inhibition is less well understood. Here, we show in CBA/CaJ mice that the two major projection neurons of the ventral cochlear nucleus, the bushy and T-stellate cells, receive glycinergic inhibition with different synaptic conductance time courses. Bushy cells, which provide precisely timed spike trains used in sound localization and pitch identification, receive slow inhibitory inputs. In contrast, T-stellate cells, which encode slower envelope information, receive inhibition that is eight-fold faster. Both types of inhibition improved the precision of spike timing, but engage different cellular mechanisms and operate on different time scales. Computer models reveal that slow IPSCs in bushy cells can improve spike timing on the scale of tens of microseconds. While fast and slow IPSCs in T-stellate cells improve spike timing on the scale of milliseconds, only fast IPSCs can enhance the detection of narrowband acoustic signals in a complex background. Our results suggest that target-specific IPSC kinetics are critical for the segregated parallel processing of temporal information from the sensory environment.
PMCID: PMC3737999  PMID: 23345233
8.  Identification of Inputs to Olivocochlear Neurons Using Transneuronal Labeling with Pseudorabies Virus (PRV) 
Olivocochlear (OC) neurons respond to sound and provide descending input that controls processing in the cochlea. The identities of neurons in the pathways providing inputs to OC neurons are incompletely understood. To explore these pathways, the retrograde transneuronal tracer pseudorabies virus (Bartha strain, expressing green fluorescent protein) was used to label OC neurons and their inputs in guinea pigs. Labeling of OC neurons began 1 day after injection into the cochlea. On day 2 (and for longer survival times), transneuronal labeling spread to the cochlear nucleus, inferior colliculus, and other brainstem areas. There was a correlation between the numbers of these transneuronally labeled neurons and the number of labeled medial (M) OC neurons, suggesting that the spread of labeling proceeds mainly via synapses on MOC neurons. In the cochlear nucleus, the transneuronally labeled neurons were multipolar cells including the subtype known as planar cells. In the central nucleus of the inferior colliculus, transneuronally labeled neurons were of two principal types: neurons with disc-shaped dendritic fields and neurons with dendrites in a stellate pattern. Transneuronal labeling was also observed in pyramidal cells in the auditory cortex and in centers not typically associated with the auditory pathway such as the pontine reticular formation, subcoerulean nucleus, and the pontine dorsal raphe. These data provide information on the identity of neurons providing input to OC neurons, which are located in auditory as well as non-auditory centers.
PMCID: PMC3767876  PMID: 23728891
superior olive; cochlear nucleus; inferior colliculus; reflex pathway; reticular formation
9.  Planar Multipolar Cells in the Cochlear Nucleus Project to Medial Olivocochlear Neurons in Mouse 
The Journal of comparative neurology  2012;520(7):1365-1375.
Medial olivocochlear (MOC) neurons originate in the superior olivary complex and project to the cochlea, where they act to reduce the effects of noise masking and protect the cochlea from damage. MOC neurons respond to sound via a reflex pathway, however, in this pathway the cochlear nucleus cell type that provides input to MOC neurons is not known. We investigated whether multipolar cells of the ventral cochlear nucleus have projections to MOC neurons, by labeling them with injections into the dorsal cochlear nucleus. The projections of one type of labeled multipolar cell, planar neurons, were traced into the ventral nucleus of the trapezoid body, where they were observed terminating on MOC neurons (labeled in some cases by a second cochlear injection of Fluorogold). These terminations formed what appear to be excitatory synapses, i.e. containing small, round vesicles and prominent postsynaptic densities. These data suggest that cochlear nucleus planar multipolar neurons drive the MOC neuron’s response to sound.
PMCID: PMC3514887  PMID: 22101968
synapse; reflex; superior olivary complex; descending system
10.  Hearing Loss Alters Quantal Release at Cochlear Nucleus Stellate Cells 
The Laryngoscope  2010;120(10):2047-2053.
Auditory nerve synapses in ventral cochlear nucleus end on two principal cell types, bushy and stellate cells. While the effects of hearing loss on bushy cells has been well studied, little is known about the effects of hearing loss on synaptic input to the stellate cells. Based on prior observations in bushy cells, we hypothesized that noise-induced hearing loss (NIHL) would decrease quantal release onto stellate cells.
Study Design
Prospective, randomized animal study.
CBA/CaJ mice were exposed for 2 hours to 98dBSPL 8–16kHz noise to produce a temporary threshold shift (TTS), or 114dBSPL to produce a permanent threshold shift (PTS). Spontaneous miniature excitatory postsynaptic currents (mEPSCs) were then measured in stellate cells in brain slices of the cochlear nucleus.
Click-evoked auditory brainstem evoked response thresholds were elevated by 35dB in both TTS and PTS mice. Spontaneous mEPSC frequency was found to be five-fold higher than normal in stellate cells of TTS mice and 3-fold higher in PTS mice. mEPSC amplitude was also larger in PTS mice. The mEPSC time course was not different between experimental and control groups.
The dramatic increase in mEPSC frequency after NIHL was not expected. The increase in mEPSC amplitude in PTS mice suggests a post-synaptic remodeling process. Both of these effects could contribute to increased spontaneous firing in the cochlear nucleus in the absence of sound. Our results also suggest that hearing loss may have different effects at auditory nerve synapses on bushy and stellate cells in the VCN.
Level of Evidence
Not applicable.
PMCID: PMC3091373  PMID: 20824788
11.  Assembly of the Auditory Circuitry by a Hox Genetic Network in the Mouse Brainstem 
PLoS Genetics  2013;9(2):e1003249.
Rhombomeres (r) contribute to brainstem auditory nuclei during development. Hox genes are determinants of rhombomere-derived fate and neuronal connectivity. Little is known about the contribution of individual rhombomeres and their associated Hox codes to auditory sensorimotor circuitry. Here, we show that r4 contributes to functionally linked sensory and motor components, including the ventral nucleus of lateral lemniscus, posterior ventral cochlear nuclei (VCN), and motor olivocochlear neurons. Assembly of the r4-derived auditory components is involved in sound perception and depends on regulatory interactions between Hoxb1 and Hoxb2. Indeed, in Hoxb1 and Hoxb2 mutant mice the transmission of low-level auditory stimuli is lost, resulting in hearing impairments. On the other hand, Hoxa2 regulates the Rig1 axon guidance receptor and controls contralateral projections from the anterior VCN to the medial nucleus of the trapezoid body, a circuit involved in sound localization. Thus, individual rhombomeres and their associated Hox codes control the assembly of distinct functionally segregated sub-circuits in the developing auditory brainstem.
Author Summary
Sound perception and sound localization are controlled by two distinct circuits in the central nervous system. However, the cellular and molecular determinants underlying their development are poorly understood. Here, we show that a spatially restricted region of the brainstem, the rhombomere 4, and two members of the Hox gene family, Hoxb1 and Hoxb2, are directly implicated in the development of the circuit leading to sound perception and sound amplification. In the absence of Hoxb1 and Hoxb2 function, we found severe morphological defects in the hair cell population implicated in transducing the acoustic signal, leading ultimately to severe hearing impairments in adult mutant mice. In contrast, the expression in the cochlear nucleus of another Hox member, Hoxa2, regulates the guidance receptor Rig1 and contralateral connectivity in the sound localization circuit. Some of the auditory dysfunctions described in our mouse models resemble pathological hearing conditions in humans, in which patients have an elevated hearing threshold sensitivity, as recorded in audiograms. Thus, this study provides mechanistic insight into the genetic and functional regulation of Hox genes during development and assembly of the auditory system.
PMCID: PMC3567144  PMID: 23408898
12.  A Map of Functional Synaptic Connectivity in the Mouse Anteroventral Cochlear Nucleus 
The Journal of Neuroscience  2014;34(6):2214-2230.
The cochlear nuclei are the first central processors of auditory information and provide inputs to all the major brainstem and midbrain auditory nuclei. Although the local circuits within the cochlear nuclei are understood at a cellular level, the spatial patterns of connectivity and the connection strengths in these circuits have been less well characterized. We have applied a novel, quantitative approach to mapping local circuits projecting to cells in the mouse anteroventral cochlear nucleus (AVCN) using laser-scanning photostimulation and glutamate uncaging. The amplitude and kinetics of individual evoked synaptic events were measured to reveal the patterns and strengths of synaptic connections. We found that the two major excitatory projection cell classes, the bushy and T-stellate cells, receive a spatially broad inhibition from D-stellate cells in the AVCN, and a spatially confined inhibition from the tuberculoventral cells of the dorsal cochlear nucleus. Furthermore, T-stellate cells integrate D-stellate inhibition from an area that spans twice the frequency range of that integrated by bushy cells. A subset of both bushy and T-stellate cells receives inhibition from an unidentified cell population at the dorsal–medial boundary of the AVCN. A smaller subset of cells receives local excitation from within the AVCN. Our results show that inhibitory circuits can have target-specific patterns of spatial convergence, synaptic strength, and receptor kinetics, resulting in different spectral and temporal processing capabilities.
PMCID: PMC3913869  PMID: 24501361
brain mapping; glutamate uncaging; inhibitory function; laser photostimulation; local circuits; topography
13.  Dendrites of Medial Olivocochlear (MOC) Neurons in Mouse 
Neuroscience  2008;154(1):147-159.
Stains for acetylcholinesterase (AChE) and retrograde labeling with Fluorogold (FG) were used to study olivocochlear neurons and their dendritic patterns in mice. The two methods gave similar results for location and number of somata. The total number of medial olivocochlear (MOC) neurons in the ventral nucleus of the trapezoid body (VNTB) is about 170 per side. An additional dozen large olivocochlear neurons are located in the dorsal periolivary nucleus (DPO). Dendrites of all of these neurons are long and extend in all directions from the cell bodies, a pattern that contrasts with the sharp frequency tuning of their responses. For VNTB neurons, there were greater numbers of dendrites directed medially than laterally and those directed medially were longer (on average, 25– 50% longer). Dendrite extensions were most pronounced for neurons located in the rostral portion of the VNTB. When each dendrite from a single neuron was represented as a vector, and all the vectors summed, the result was also skewed toward the medial direction. DPO neurons, however, had more symmetric dendrites that projected into more dorsal parts of the trapezoid body, suggesting that this small group of olivocochlear neurons has very different physiological properties. Dendrites of both types of neurons were somewhat elongated rostrally, about 20% longer than those directed caudally. These results can be interpreted as extensions of dendrites of olivocochlear neurons toward their synaptic inputs: medially to meet crossing fibers from the cochlear nucleus that are part of the MOC reflex pathway, and rostrally to meet descending inputs from higher centers.
PMCID: PMC2587447  PMID: 18313859
superior olive; cochlear nucleus; efferent; descending pathway; auditory reflex
14.  Auditory Cortex Basal Activity Modulates Cochlear Responses in Chinchillas 
PLoS ONE  2012;7(4):e36203.
The auditory efferent system has unique neuroanatomical pathways that connect the cerebral cortex with sensory receptor cells. Pyramidal neurons located in layers V and VI of the primary auditory cortex constitute descending projections to the thalamus, inferior colliculus, and even directly to the superior olivary complex and to the cochlear nucleus. Efferent pathways are connected to the cochlear receptor by the olivocochlear system, which innervates outer hair cells and auditory nerve fibers. The functional role of the cortico-olivocochlear efferent system remains debated. We hypothesized that auditory cortex basal activity modulates cochlear and auditory-nerve afferent responses through the efferent system.
Methodology/Principal Findings
Cochlear microphonics (CM), auditory-nerve compound action potentials (CAP) and auditory cortex evoked potentials (ACEP) were recorded in twenty anesthetized chinchillas, before, during and after auditory cortex deactivation by two methods: lidocaine microinjections or cortical cooling with cryoloops. Auditory cortex deactivation induced a transient reduction in ACEP amplitudes in fifteen animals (deactivation experiments) and a permanent reduction in five chinchillas (lesion experiments). We found significant changes in the amplitude of CM in both types of experiments, being the most common effect a CM decrease found in fifteen animals. Concomitantly to CM amplitude changes, we found CAP increases in seven chinchillas and CAP reductions in thirteen animals. Although ACEP amplitudes were completely recovered after ninety minutes in deactivation experiments, only partial recovery was observed in the magnitudes of cochlear responses.
These results show that blocking ongoing auditory cortex activity modulates CM and CAP responses, demonstrating that cortico-olivocochlear circuits regulate auditory nerve and cochlear responses through a basal efferent tone. The diversity of the obtained effects suggests that there are at least two functional pathways from the auditory cortex to the cochlea.
PMCID: PMC3340362  PMID: 22558383
15.  Commissural Axons of the Mouse Cochlear Nucleus 
The Journal of comparative neurology  2013;521(7):1683-1696.
The axons of commissural neurons that project from one cochlear nucleus to the other were studied after labeling with anterograde tracer. Injections were made into the dorsal subdivision of the cochlear nucleus in order to restrict labeling only to the group of commissural neurons that gave off collaterals to, or were located in, this subdivision. The number of labeled commissural axons in each injection was correlated with the number of labeled radiate multipolar neurons, suggesting radiate neurons as the predominant origin of the axons. The radiate commissural axons are thick and myelinated, and they exit the dorsal acoustic stria of the injected cochlear nucleus to cross the brainstem in the dorsal half, near the crossing position of the olivocochlear bundle. They enter the opposite cochlear nucleus via the dorsal and ventral acoustic stria and at its medial border. Reconstructions of single axons demonstrate that terminations are mostly in the core and typically within a single subdivision of the cochlear nucleus. Extents of termination range from narrow to broad along both the dorso-ventral (i.e. tonotopic) and rostro-caudal dimensions. In the electron microscope, labeled swellings form synapses that are symmetric (in that there is little postsynaptic density), a characteristic of inhibitory synapses. Our labeled axons do not appear to include excitatory commissural axons that end in edge regions of the nucleus. Radiate commissural axons could mediate the broad-band inhibition observed in responses to contralateral sound, and they may balance input from the two ears on a quick time course.
PMCID: PMC3573222  PMID: 23124982
auditory brainstem; inhibitory synapse; glycine; electron microscopy; binaural balance; multipolar cell
16.  GABAergic and glycinergic inhibitory synaptic transmission in the ventral cochlear nucleus studied in VGAT channelrhodopsin-2 mice 
Both glycine and GABA mediate inhibitory synaptic transmission in the ventral cochlear nucleus (VCN). In mice, the time course of glycinergic inhibition is slow in bushy cells and fast in multipolar (stellate) cells, and is proposed to contribute to the processing of temporal cues in both cell types. Much less is known about GABAergic synaptic transmission in this circuit. Electrical stimulation of the auditory nerve or the tuberculoventral pathway evokes little GABAergic synaptic current in brain slice preparations, and spontaneous GABAergic miniature synaptic currents occur infrequently. To investigate synaptic currents carried by GABA receptors in bushy and multipolar cells, we used transgenic mice in which channelrhodopsin-2 and EYFP is driven by the vesicular GABA transporter (VGAT-ChR2-EYFP) and is expressed in both GABAergic and glycinergic neurons. Light stimulation evoked action potentials in EYFP-expressing presynaptic cells, and evoked inhibitory postsynaptic potentials (IPSPs) in non-expressing bushy and planar multipolar cells. Less than 10% of the IPSP amplitude in bushy cells arose from GABAergic synapses, whereas 40% of the IPSP in multipolar neurons was GABAergic. In voltage clamp, glycinergic IPSCs were significantly slower in bushy neurons than in multipolar neurons, whereas there was little difference in the kinetics of the GABAergic IPSCs between two cell types. During prolonged stimulation, the ratio of steady state vs. peak IPSC amplitude was significantly lower for glycinergic IPSCs. Surprisingly, the reversal potentials of GABAergic IPSCs were negative to those of glycinergic IPSCs in both bushy and multipolar neurons. In the absence of receptor blockers, repetitive light stimulation was only able to effectively evoke IPSCs up to 20 Hz in both bushy and multipolar neurons. We conclude that local GABAergic release within the VCN can differentially influence bushy and multipolar cells.
PMCID: PMC4109614  PMID: 25104925
IPSC; target-specific inhibition; bushy; multipolar; stellate
17.  Up-regulation of GAP-43 in the chinchilla ventral cochlear nucleus after carboplatin-induced hearing loss: Correlations with inner hair cell loss and outer hair cell loss 
Hearing research  2013;302:74-82.
Inner ear damage leads to nerve fiber growth and synaptogenesis in the ventral cochlear nucleus (VCN). In this study, we documented the relationship between hair cell loss patterns and synaptic plasticity in the chinchilla VCN using immunolabeling of the growth associated protein-43 (GAP-43), a protein associated with axon outgrowth and modification of presynaptic endings. Unilateral round window application of carboplatin caused hair cell degeneration in which inner hair cells (IHC) were more vulnerable than outer hair cells (OHC). One month after carboplatin treatment (0.5 to 5 mg/ml), we observed varying patterns of cochlear hair cell loss and GAP-43 expression in VCN. Both IHC loss and OHC loss were strongly correlated with increased GAP-43 immunolabeling in the ipsilateral VCN. We speculate that two factors might promote the expression of GAP-43 in the VCN; one is the loss of afferent input through IHC or the associated type I auditory nerve fibers. The other occurs when the medial olivocochlear efferent neurons lose their cochlear targets, the OHC, and may as compensation increase their synapse numbers in the VCN.
PMCID: PMC3905197  PMID: 23707995
carboplatin; growth associated protein-43; cochlear nucleus; chinchilla; hearing loss; hair cells
18.  Selective removal of lateral olivocochlear efferents increases vulnerability to acute acoustic injury 
Journal of neurophysiology  2006;97(2):1775-1785.
Cochlear sensory cells and neurons receive efferent feedback from the olivocochlear (OC) system. The myelinated medial component of the OC system, and its effects on outer hair cells (OHCs), has been implicated in protection from acoustic injury. The unmyelinated lateral (L)OC fibers target ipsilateral cochlear nerve dendrites, and pharmacological studies suggest the LOC's dopaminergic component may protect these dendrites from excitotoxic effects of acoustic overexposure. Here, we explore LOC function in vivo via selective stereotaxic destruction of LOC cell bodies in mouse. Lesion success in removing the LOC, and sparing the MOC, was assessed by histological analysis of brainstem sections and cochlear whole-mounts. Auditory brainstem responses (ABR), a neural-based metric, and distortion product otoacoustic emissions (DPOAEs), an OHC-based metric, were measured in control and surgical mice. In cases where the LOC was at least partially destroyed, there were increases in suprathreshold neural responses that were frequency- and level-independent, and not attributable to OHC-based effects. These interaural response asymmetries were not found in controls, or in cases where the lesion missed the LOC. In LOC-lesion cases, after exposure to a traumatic stimulus, temporary threshold shifts were greater in the ipsilateral ear, but only when measured in the neural response; OHC-based measurements were always bilaterally symmetric, suggesting OHC vulnerability was unaffected. Interaural asymmetries in threshold shift were not found in either unlesioned controls or in cases which missed the LOC. These findings suggest that the LOC modulates cochlear nerve excitability and protects the cochlea from neural damage in acute acoustic injury.
PMCID: PMC1805782  PMID: 17093118
Cochlea; Excitotoxicity; Noise-induced hearing loss; Feedback control
19.  Connections and synaptic function in the posteroventral cochlear nucleus of deaf jerker mice 
Mutations in the gene that encodes espins can cause deafness and vestibular disorders; mice that are homozygous for the autosomal recessive, jerker mutation in the espin gene never hear. Extracellular injections of biocytin into the anteroventral cochlear nucleus (AVCN) revealed that although the cochlear nuclei are smaller in je/je mice, the topography in its innervation resembles that in wild type mice. Auditory nerve fibers innervate narrow, topographically organized, “isofrequency” bands in deaf animals over the ages examined, P18–P70. The projection of tuberculoventral cells was topographic in je/je as in wild type mice. Terminals of auditory nerve fibers in the multipolar cell area included both large and small endings whereas in the octopus cell area they were exclusively small boutons in je/je as in wild type mice but end bulbs near the nerve root of je/je animals were smaller than in hearing animals. In whole-cell recordings from targets of auditory nerve fibers, octopus and T stellate cells, miniature excitatory postsynaptic currents (mEPSCs) had similar shapes as in +/+, indicating that the properties of AMPA receptors were not affected by the mutation. In je/je animals the frequency of spontaneous mEPSCs was elevated and synaptic depression in responses to trains of shocks delivered at between 100 and 333 Hz was greater than in wild type mice indicating that the probability of neurotransmitter release was increased. The frequency of spontaneous mEPSCs and extent of synaptic depression were greater in octopus than in T stellate cells, in both wild type and je/je mice.
PMCID: PMC2553045  PMID: 18634002
brain stem; auditory pathway; auditory nerve; hearing impairment; espin
20.  Mutation of Npr2 Leads to Blurred Tonotopic Organization of Central Auditory Circuits in Mice 
PLoS Genetics  2014;10(12):e1004823.
Tonotopy is a fundamental organizational feature of the auditory system. Sounds are encoded by the spatial and temporal patterns of electrical activity in spiral ganglion neurons (SGNs) and are transmitted via tonotopically ordered processes from the cochlea through the eighth nerve to the cochlear nuclei. Upon reaching the brainstem, SGN axons bifurcate in a stereotyped pattern, innervating target neurons in the anteroventral cochlear nucleus (aVCN) with one branch and in the posteroventral and dorsal cochlear nuclei (pVCN and DCN) with the other. Each branch is tonotopically organized, thereby distributing acoustic information systematically along multiple parallel pathways for processing in the brainstem. In mice with a mutation in the receptor guanylyl cyclase Npr2, this spatial organization is disrupted. Peripheral SGN processes appear normal, but central SGN processes fail to bifurcate and are disorganized as they exit the auditory nerve. Within the cochlear nuclei, the tonotopic organization of the SGN terminal arbors is blurred and the aVCN is underinnervated with a reduced convergence of SGN inputs onto target neurons. The tonotopy of circuitry within the cochlear nuclei is also degraded, as revealed by changes in the topographic mapping of tuberculoventral cell projections from DCN to VCN. Nonetheless, Npr2 mutant SGN axons are able to transmit acoustic information with normal sensitivity and timing, as revealed by auditory brainstem responses and electrophysiological recordings from VCN neurons. Although most features of signal transmission are normal, intermittent failures were observed in responses to trains of shocks, likely due to a failure in action potential conduction at branch points in Npr2 mutant afferent fibers. Our results show that Npr2 is necessary for the precise spatial organization typical of central auditory circuits, but that signals are still transmitted with normal timing, and that mutant mice can hear even with these deficits.
Author Summary
Millions of people suffer from debilitating hearing defects, ranging from a complete inability to detect sound to more subtle changes in how sounds are encoded by the nervous system. Many forms of deafness are due to mutations in genes that impair the development or function of hair cells, which are responsible for changing sound into electrical signals that can be processed by the brain. Both mice and humans carrying these mutations fail standard hearing tests. In contrast, very little is known about the genetic basis of central auditory processing disorders, which are poorly defined and difficult to diagnose, since these patients can still detect sounds. By finding genes that are required for the normal wiring of central auditory circuits in mice, we can investigate how changes at the circuit level affect circuit function and therefore improve our understanding of central auditory processing disorders. Here, we show that the natriuretic peptide receptor Npr2 is required to establish frequency maps in the mouse central auditory system. Surprisingly, despite a dramatic change in circuit organization, Npr2 mutant mice are still able to respond to sounds with normal sensitivity and timing, underscoring the need for better hearing diagnostic methods in mice as in humans.
PMCID: PMC4256264  PMID: 25473838
21.  Efferent Feedback Minimizes Cochlear Neuropathy from Moderate Noise Exposure 
Although protective effects of the cochlea’s efferent feedback pathways have been well documented, prior work has focused on hair cell damage and cochlear threshold elevation and, correspondingly, on the high sound pressure levels (> 100 dB SPL) necessary to produce them. Here we explore the noise-induced loss of cochlear neurons that occurs with lower intensity exposures and in the absence of permanent threshold shifts. Using confocal microscopy to count synapses between hair cells and cochlear nerve fibers, and using measurement of auditory brainstem responses and otoacoustic emissions to assess cochlear pre- and post-synaptic function, we compare the damage from a weeklong exposure to moderate-level noise (84 dB SPL) in mice with varying degrees of cochlear de-efferentation induced by surgical lesion to the olivocochlear pathway. Such exposure causes minimal acute threshold shift and no chronic shifts in mice with normal efferent feedback. In de-efferented animals, there was up to 40% loss of cochlear nerve synapses and a corresponding decline in the amplitude of the auditory brainstem response. Quantitative analysis of the de-efferentation in inner vs. outer hair cell areas suggested that outer hair cell efferents are most important in minimizing this neuropathy, presumably by virtue of their sound-evoked feedback reduction of cochlear amplification. The moderate nature of this acoustic overexposure suggests that cochlear neurons are at risk even in everyday acoustic environments, and, thus, that the need for cochlear protection is plausible as a driving force in the design of this feedback pathway.
PMCID: PMC3640841  PMID: 23536069
Auditory neuropathy; olivocochlear; hair cells; cochlea; noise; acoustic injury; feedback
22.  Cross-modal interactions of auditory and somatic inputs in the brainstem and midbrain and their imbalance in tinnitus and deafness 
American journal of audiology  2008;17(2):S193-S209.
This review outlines the anatomical and functional bases of somatosensory influences on auditory processing in the normal brainstem and midbrain. Thereafter, it explores how interactions between the auditory and somatosensory system are modified through deafness and their impact on tinnitus is discussed.
literature-review, tract-tracing, immunohistochemistry, in vivo electrophysiological recordings
Somatosensory input originates in the dorsal root ganglia (DRG) and trigeminal ganglia (TG) and is transmitted directly and indirectly through second order nuclei to the ventral and dorsal cochlear nucleus (VCN, DCN) and inferior colliculus (IC). The glutamatergic somatosensory afferents can be segregated from auditory nerve inputs by the type of vesicular glutamate transporters present in their terminals. Electrical stimulation of the somatosensory input results in a complex combination of excitation and inhibition and alters the rate and timing of responses to acoustic stimulation.
Deafness increases the spontaneous rates of those neurons that receive excitatory somatosensory input, and results in a greater sensitivity of DCN neurons to trigeminal stimulation.
Auditory-somatosensory bimodal integration is already present in first order auditory nuclei. The balance of excitation and inhibition elicited by somatosensory input is altered following deafness. The increase in somatosensory influence on auditory neurons when their auditory input is diminished could be due to cross modal re-innervation or increased synaptic strength, and may contribute to mechanisms underlying somatic tinnitus.
PMCID: PMC2760229  PMID: 19056923
Auditory system; Cochlear nucleus; Inferior colliculus; Trigeminal; Reticular formation; Somatosensory; Non-auditory projections; Tinnitus; Deafness; Bimodal plasticity
23.  Structural and Functional Classes of Multipolar Cells in the Ventral Cochlear Nucleus 
Multipolar cells in the ventral cochlear nucleus (VCN) are a structurally and functionally diverse group of projection neurons. Understanding their role in the ascending pathway involves partitioning multipolar cells into distinct populations and determining where in the brain each sends its coded messages. In this study, we used retrograde labeling techniques in rats to identify multipolar neurons that project their axons to the ipsilateral dorsal cochlear nucleus (DCN), the contralateral CN, or to both structures. Three rats received injections of biotinylated dextran amine in the ipsilateral DCN and diamidino yellow in the contralateral CN. Several radiate multipolar neurons (defined by their axonal projections to the ipsilateral DCN and their dendrites that traverse VCN isofrequency sheets) were double labeled but over 70% were not. This result suggests two distinct populations: (1) radiate-commissural (RC-) multipolar cells that project to the ipsilateral DCN and the contralateral CN and (2) radiate multipolar cells that project exclusively (in this context) to the ipsilateral DCN. In a different group of animals, we retrogradely labeled multipolar neurons that project their axons to the contralateral CN and measured the size of their cell bodies. The mean size of this population (266 ± 156 μm2) was significantly smaller than those of RC-multipolar cells (418 ± 140 μm2). We conclude that the CN commissural pathway is composed of at least two components: (1) RC-multipolar cells and (2) commissural multipolar cells that are small and medium-sized neurons that project exclusively (in this context) to the contralateral CN. These results identify separate structural groups of multipolar cells that may correspond to physiological unit types described in the literature. They also provide protocols for isolating and studying different populations of multipolar cells to determine the neural mechanisms that govern their responses to sound.
PMCID: PMC2566305  PMID: 16550550
hearing; ascending pathways; classifying neurons; naming neurons; double labeling
24.  Projections from the dorsal and ventral cochlear nuclei to the medial geniculate body 
Direct projections from the cochlear nucleus (CN) to the medial geniculate body (MG) mediate a high-speed transfer of acoustic information to the auditory thalamus. Anderson etal. (2006) used anterograde tracers to label the projection from the dorsal CN (DCN) to the MG in guinea pigs. We examined this pathway with retrograde tracers. The results confirm a pathway from the DCN, originating primarily from the deep layers. Labeled cells included a few giant cells and a larger number of small cells of unknown type. Many more labeled cells were present in the ventral CN (VCN). These cells, identifiable as multipolar (stellate) or small cells, were found throughout much of the VCN. Most of the labeled cells were located contralateral to the injection site. The CN to MG pathway bypasses the inferior colliculus (IC), where most ascending auditory information is processed. Anderson etal. (2006) hypothesized that CN-MG axons are collaterals of axons that reach the IC. We tested this hypothesis by injecting different fluorescent tracers into the MG and IC and examining the CN for double-labeled cells. After injections on the same side of the brain, double-labeled cells were found in the contralateral VCN and DCN. Most double-labeled cells were in the VCN, where they accounted for up to 37% of the cells labeled by the MG injection. We conclude that projections from the CN to the MG originate from the VCN and, less so, from the DCN. A significant proportion of the cells send a collateral projection to the IC. Presumably, the collateral projections send the same information to both the MG and the IC. The results suggest that T-stellate cells of the VCN are a major source of direct projections to the auditory thalamus.
PMCID: PMC3942891  PMID: 24634646
thalamus; multipolar cells; T-stellate; magnocellular pathway; fear conditioning; lemniscal pathway; multimodal processing; collateral projections
25.  Origins of Glutamatergic Terminals in the Inferior Colliculus Identified by Retrograde Transport and Expression of VGLUT1 and VGLUT2 Genes 
Terminals containing vesicular glutamate transporter (VGLUT) 2 make dense axosomatic synapses on tectothalamic GABAergic neurons. These are one of the three types of glutamatergic synapses in the inferior colliculus (IC) identified by one of three combinations of transporter protein: VGLUT1 only, VGLUT2 only, or both VGLUT1 and 2. To identify the source(s) of these three classes of glutamatergic terminals, we employed the injection of Fluorogold (FG) into the IC and retrograde transport in combination with in situ hybridization for VGLUT1 and VGLUT2 mRNA. The distribution of FG-positive soma was consistent with previous reports. In the auditory cortex, all FG-positive cells expressed only VGLUT1. In the IC, the majority of FG-positive cells expressed only VGLUT2. In the intermediate nucleus of the lateral lemniscus, most FG-positive cells expressed VGLUT2, and a few FG-positive cells expressed both VGLUT1 and 2. In the superior olivary complex (SOC), the majority of FG-positive cells expressing VGLUT2 were in the lateral superior olive, medial superior olive, and some periolivary nuclei. Fewer FG-positive cells expressed VGLUT1&2. In the ventral cochlear nucleus, almost all FG-positive cells expressed VGLUT1&2. On the other hand in the dorsal cochlear nucleus, the vast majority of FG-positive cells expressed only VGLUT2. Our data suggest that (1) the most likely sources of VGLUT2 terminals in the IC are the intermediate nucleus of the lateral lemniscus, the dorsal cochlear nucleus, the medial and lateral superior olive, and the IC itself, (2) VGLUT1 terminals in the IC originate only in the ipsilateral auditory cortex, and (3) VGLUT1&2 terminals in IC originate mainly from the VCN with minor contributions from the SOC and the lateral lemniscal nuclei.
PMCID: PMC2967334  PMID: 21048892
vesicular glutamate transporter; in situ hybridization; retrograde transport; auditory system

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