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1.  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.
doi:10.1016/j.neuroscience.2008.01.036
PMCID: PMC2478560  PMID: 18343587
cross-correlation; ventral cochlear nucleus; synaptic strength
2.  Electrophysiological Properties of Octopus Neurons of the Cat Cochlear Nucleus: an In Vitro Study 
Electrophysiological studies from mice in vitro have suggested that octopus cells of the mammalian ventral cochlear nucleus (VCN) are anatomically and biophysically specialized for detecting the coincident firing of a population of auditory nerve fibers. Recordings from cats in vivo have shown that octopus cells fire rapidly and with exceptional temporal precision as they convey the timing of that coincidence to higher auditory centers. The current study addresses the question whether the biophysical properties of octopus cells that have until now been examined only in mice, are shared by octopus cells in cats. Whole-cell patch-clamp recordings confirm that octopus cells in brain slices from kittens share the anatomical and biophysical features of octopus cells in mice. As in mice, octopus cells in kittens have large cell bodies and thick dendrites that extend in one direction. Voltage changes produced by depolarizing and hyperpolarizing current injection were small and rapid. Input resistances and membrane time constants in octopus cells of 16-day-old kittens were 15.8 ± 1.5 MΩ (n = 16) and 1.28 ± 0.3 ms (n = 16), respectively. Octopus cells fired only a single action potential at the onset of a depolarizing current pulse; suprathreshold stimuli were greater than 1.8 nA. A tetrodotoxin (TTX)-sensitive sodium conductance (gNa) was responsible for the generation of the action potentials. Octopus cells displayed outward rectification that lasted for the duration of the depolarizing pulses. Hyperpolarizations produced by the injection of current exhibited a depolarizing sag of the membrane potential toward the resting value. A 4-aminopyridine (4-AP) and α-dendrotoxin (α-DTX)-sensitive, low-voltage-activated potassium conductance (gKL) and a ZD7288-sensitive, mixed-cation conductance (gh) were partially activated at rest, giving the octopus cells low input resistances and, as a consequence, brief time constants. In 7-day-old kittens, action potentials were taller and broader, input resistances higher, and both inward and outward rectification was weaker than in 16-day-old kittens. Also as in mice, stellate cells of the VCN fired trains of action potentials with constant interspike intervals when they were depolarized (n = 10) and bushy cells of the VCN fired only a single action potential at the onset of depolarizations (n = 6). In conclusion, the similarity of octopus cells in mice and kittens suggests that the anatomical and biophysical specializations that allow octopus cells to detect and convey synchronous firing among auditory nerve fibers are common to all mammals.
doi:10.1007/s10162-009-0159-x
PMCID: PMC2674202  PMID: 19277784
auditory pathways; cochlear nucleus; octopus cell; patch clamp; cat
3.  Mathematical Models of Cochlear Nucleus Onset Neurons: I. Point Neuron with Many Weak Synaptic Inputs 
The cochlear nucleus (CN) presents a unique opportunity for quantitatively studying input-output transformations by neurons because it gives rise to a variety of different response types from a relatively homogeneous input source, the auditory nerve (AN). Particularly interesting among CN neurons are Onset (On) neurons, which have a prominent response to the onset of sustained sounds followed by little or no response in the steady-state. On neurons contrast sharply with their AN inputs, which respond vigorously throughout stimuli. On neurons can entrain to stimuli (firing once per cycle of a periodic stimulus) at up to 1000 Hz, unlike their AN inputs. To understand the mechanisms underlying these response patterns, we tested whether an integrate-to-threshold point-neuron model with a fixed refractory period can account for On discharge patterns for tones, systematically examining the effect of membrane time constant and the number and strength of the exclusively excitatory AN synaptic inputs. To produce both onset responses to high-frequency tone bursts and entrainment to a broad range of low-frequency tones, the model must have a short time constant (≈0.125 ms) and a large number (>100) of weak synaptic inputs, properties that are consistent with the electrical properties and anatomy of On-responding cells. With these parameters, the model acts like a coincidence detector with a threshold-like relationship between the instantaneous discharge rates of the output and the inputs. Onset responses to high-frequency tone bursts result because the threshold effect enhances the initial response of the AN inputs and suppresses their relatively lower sustained response. However, when the model entrains across a broad range of frequencies, it also produces short interspike intervals at the onset of high-frequency tone bursts, a response pattern not found in all types of On neurons. These results show a tradeoff, that may be a general property of many neurons, between following rapid stimulus fluctuations and responding without short interspike intervals at the onset of sustained stimuli.
PMCID: PMC2280068  PMID: 12435925
integrate-and-fire model; coincidence detection; cochlear nucleus
4.  Enhancement and Distortion in the Temporal Representation of Sounds in the Ventral Cochlear Nucleus of Chinchillas and Cats 
PLoS ONE  2012;7(9):e44286.
A subset of neurons in the cochlear nucleus (CN) of the auditory brainstem has the ability to enhance the auditory nerve's temporal representation of stimulating sounds. These neurons reside in the ventral region of the CN (VCN) and are usually known as highly synchronized, or high-sync, neurons. Most published reports about the existence and properties of high-sync neurons are based on recordings performed on a VCN output tract—not the VCN itself—of cats. In other species, comprehensive studies detailing the properties of high-sync neurons, or even acknowledging their existence, are missing.
Examination of the responses of a population of VCN neurons in chinchillas revealed that a subset of those neurons have temporal properties similar to high-sync neurons in the cat. Phase locking and entrainment—the ability of a neuron to fire action potentials at a certain stimulus phase and at almost every stimulus period, respectively—have similar maximum values in cats and chinchillas. Ranges of characteristic frequencies for high-sync neurons in chinchillas and cats extend up to 600 and 1000 Hz, respectively. Enhancement of temporal processing relative to auditory nerve fibers (ANFs), which has been shown previously in cats using tonal and white-noise stimuli, is also demonstrated here in the responses of VCN neurons to synthetic and spoken vowel sounds.
Along with the large amount of phase locking displayed by some VCN neurons there occurs a deterioration in the spectral representation of the stimuli (tones or vowels). High-sync neurons exhibit a greater distortion in their responses to tones or vowels than do other types of VCN neurons and auditory nerve fibers.
Standard deviations of first-spike latency measured in responses of high-sync neurons are lower than similar values measured in ANFs' responses. This might indicate a role of high-sync neurons in other tasks beyond sound localization.
doi:10.1371/journal.pone.0044286
PMCID: PMC3445608  PMID: 23028514
5.  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
6.  Brainstem Auditory Evoked Potentials Suggest a Role for the Ventral Cochlear Nucleus in Tinnitus 
Numerous studies have demonstrated elevated spontaneous and sound-evoked brainstem activity in animal models of tinnitus, but data on brainstem function in people with this common clinical condition are sparse. Here, auditory nerve and brainstem function in response to sound was assessed via auditory brainstem responses (ABR) in humans with tinnitus and without. Tinnitus subjects showed reduced wave I amplitude (indicating reduced auditory nerve activity) but enhanced wave V (reflecting elevated input to the inferior colliculi) compared with non-tinnitus subjects matched in age, sex, and pure-tone threshold. The transformation from reduced peripheral activity to central hyperactivity in the tinnitus group was especially apparent in the V/I and III/I amplitude ratios. Compared with a third cohort of younger, non-tinnitus subjects, both tinnitus, and matched, non-tinnitus groups showed elevated thresholds above 4 kHz and reduced wave I amplitude, indicating that the differences between tinnitus and matched non-tinnitus subjects occurred against a backdrop of shared peripheral dysfunction that, while not tinnitus specific, cannot be discounted as a factor in tinnitus development. Animal lesion and human neuroanatomical data combine to indicate that waves III and V in humans reflect activity in a pathway originating in the ventral cochlear nucleus (VCN) and with spherical bushy cells (SBC) in particular. We conclude that the elevated III/I and V/I amplitude ratios in tinnitus subjects reflect disproportionately high activity in the SBC pathway for a given amount of peripheral input. The results imply a role for the VCN in tinnitus and suggest the SBC pathway as a target for tinnitus treatment.
doi:10.1007/s10162-012-0344-1
PMCID: PMC3505586  PMID: 22869301
auditory brainstem response (ABR); brainstem auditory evoked potential (BAEP); auditory nerve; ventral cochlear nucleus; spherical bushy cells; inferior colliculus; dorsal cochlear nucleus
7.  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.
doi:10.1371/journal.pgen.1004823
PMCID: PMC4256264  PMID: 25473838
8.  Encoding Intensity in Ventral Cochlear Nucleus Following Acoustic Trauma: Implications for Loudness Recruitment 
Loudness recruitment, an abnormally rapid growth of perceived loudness with sound level, is a common symptom of sensorineural hearing loss. Following acoustic trauma, auditory-nerve rate responses are reduced, and rate grows more slowly with sound level, which seems inconsistent with recruitment (Heinz et al., J. Assoc. Res. Otolaryngol. 6:91–105, 2005). However, rate-level functions (RLFs) in the central nervous system may increase in either slope or saturation value following trauma (e.g., Salvi et al., Hear. Res. 147:261–274, 2000), suggesting that recruitment may arise from central changes. In this paper, we studied RLFs of neurons in ventral cochlear nucleus (VCN) of the cat after acoustic trauma. Trauma did not change the general properties of VCN neurons, and the usual VCN functional classifications remained valid (chopper, primary-like, onset, etc.). After trauma, non-primary-like neurons, most noticeably choppers, exhibited elevated maximum discharge rates and steeper RLFs for frequencies at and near best frequency (BF). Primary-like neurons showed the opposite changes. To relate the neurons’ responses to recruitment, rate-balance functions were computed; these show the sound level required to give equal rates in a normal and a traumatized ear and are analogous to loudness balance functions that show the sound levels giving equal perceptual loudness in the two ears of a monaurally hearing-impaired person. The rate-balance functions showed recruitment-like steepening of their slopes in non-primary-like neurons in all conditions. However, primary-like neurons showed recruitment-like behavior only when rates were summated across neurons of all BFs. These results suggest that the non-primary-like, especially chopper, neurons may be the most peripheral site of the physiological changes in the brain that underlie recruitment.
doi:10.1007/s10162-008-0142-y
PMCID: PMC2644394  PMID: 18855070
ventral cochlear nucleus; acoustic trauma; sensorineural hearing loss; loudness recruitment; hyperacusis; auditory nerve; neuroplasticity; sound intensity; sound level; neural encoding; rate-level function; bushy cell; stellate cell; primary-like units; chopper units
9.  Temporal Measures and Neural Strategies for Detection of Tones in Noise Based on Responses in Anteroventral Cochlear Nucleus 
Journal of neurophysiology  2006;96(5):2451-2464.
To examine possible neural strategies for the detection of tones in broadband noise, single-neuron extracellular recordings were obtained from the anteroventral cochlear nucleus (AVCN) in anesthetized gerbils. Detection thresholds determined by average discharge rate and several temporal metrics were compared with previously reported psychophysical detection thresholds in cats (Costalupes 1985). Because of their limited dynamic range, the average discharge rates of single neurons failed to predict psychophysical detection thresholds for relatively high-level noise at all measured characteristic frequencies (CFs). However, temporal responses changed significantly when a tone was added to a noise, even for neurons with flat masked rate-level functions. Three specific temporal analyses were applied to neural responses to tones in noise. First, temporal reliability, a measure of discharge time consistency across stimulus repetitions, decreased with increasing tone level for most AVCN neurons at all measured CFs. Second, synchronization to the tone frequency, a measure of phase-locking to the tone, increased with tone level for low-CF neurons. Third, rapid fluctuations in the poststimulus time histograms (PSTHs) decreased with tone level for a number of neurons at all CFs. For each of the three temporal measures, some neurons had detection thresholds at or below psychophysical thresholds. A physiological model of a higher-stage auditory neuron that received simple excitatory and inhibitory inputs from AVCN neurons was able to extract the PSTH fluctuation information in a form of decreased rate with tone level.
doi:10.1152/jn.00471.2006
PMCID: PMC2577022  PMID: 16914617
10.  EphB2 signaling regulates lesion-induced axon sprouting but not critical period length in the postnatal auditory brainstem 
Neural Development  2013;8:2.
Background
Studies of developmental plasticity may provide insight into plasticity during adulthood, when neural circuitry is less responsive to losses or changes in input. In the mammalian auditory brainstem, globular bushy cell axons of the ventral cochlear nucleus (VCN) innervate the contralateral medial nucleus of the trapezoid body (MNTB) principal neurons. VCN axonal terminations in MNTB, known as calyces of Held, are very large and specialized for high-fidelity transmission of auditory information. Following unilateral deafferentation during postnatal development, VCN axons from the intact side form connections with novel targets, including the ipsilateral MNTB. EphB signaling has been shown to play a role in this process during the first postnatal week, but mechanisms involved in this reorganization during later developmental periods remain unknown.
Results
We found that EphB2 signaling reduces the number of induced ipsilateral projections to the MNTB after unilateral VCN removal at postnatal day seven (P7), but not after removal of the VCN on one side at P10, after the closure of the critical period for lesion-induced innervation of the ipsilateral MNTB.
Conclusions
Results from this study indicate that molecular mechanisms involved in the development of circuitry may also play a part in rewiring after deafferentation during development, but do not appear to regulate the length of critical periods for plasticity.
doi:10.1186/1749-8104-8-2
PMCID: PMC3575227  PMID: 23379484
MNTB; auditory; brainstem; axon guidance; deafferentation; regeneration
11.  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.
doi:10.1016/j.neuroscience.2011.07.056
PMCID: PMC3390756  PMID: 21821100
noise; tinnitus; hair cell loss; growth associated protein-43; ventral cochlear nucleus; dorsal cochlear nucleus
12.  Computational Diversity in the Cochlear Nucleus Angularis of the Barn Owl 
Journal of Neurophysiology  2002;89(4):2313-2329.
The cochlear nucleus angularis (NA) is widely assumed to form the starting point of a brain stem pathway for processing sound intensity in birds. Details of its function are unclear, however, and its evolutionary origin and relationship to the mammalian cochlear-nucleus complex are obscure. We have carried out extracellular single-unit recordings in the NA of ketamine-anesthetized barn owls. The aim was to re-evaluate the extent of heterogeneity in NA physiology because recent studies of cellular morphology had established several distinct types. Extensive characterization, using tuning curves, phase locking, peristimulus time histograms and rate-level functions for pure tones and noise, revealed five major response types. The most common one was a primary-like pattern that was distinguished from auditory-nerve fibers by showing lower vector strengths of phase locking and/or lower spontaneous rates. Two types of chopper responses were found (chopper-transient and a rare chopper-sustained), as well as onset units. Finally, we routinely encountered a complex response type with a pronounced inhibitory component, similar to the mammalian typeIV. Evidence is presented that this range of response types is representative for birds and that earlier conflicting reports may be due to methodological differences. All five response types defined were similar to well-known types in the mammalian cochlear nucleus. This suggests convergent evolution of neurons specialized for encoding different behaviorally relevant features of the auditory stimulus. It remains to be investigated whether the different response types correlate with morphological types and whether they establish different processing streams in the auditory brain stem of birds.
doi:10.1152/jn.00635.2002
PMCID: PMC3259745  PMID: 12612008
13.  Classification of unit types in the anteroventral cochlear nucleus of laboratory mice 
Hearing Research  2012;289(1-2):13-26.
This report introduces a system for the objective physiological classification of single-unit activity in the anteroventral cochlear nucleus (AVCN) of anesthetized CBA/129 and CBA/CaJ mice. As in previous studies, the decision criteria are based on the temporal properties of responses to short tone bursts that are visualized in the form of peri-stimulus time histograms (PSTHs). Individual unit types are defined by the statistical distribution of quantifiable metrics that relate to the onset latency, regularity, and adaptation of sound-driven discharge rates. Variations of these properties reflect the unique synaptic organizations and intrinsic membrane properties that dictate the selective tuning of sound coding in the AVCN. When these metrics are applied to the mouse AVCN, responses to best frequency (BF) tones reproduce the major PSTH patterns that have been previously demonstrated in other mammalian species. The consistency of response types in two genetically diverse strains of laboratory mice suggests that the present classification system is appropriate for additional strains with normal peripheral function. The general agreement of present findings to established classifications validates laboratory mice as an adequate model for general principles of mammalian sound coding. Nevertheless, important differences are noted for the reliability of specialized endbulb transmission within the AVCN, suggesting less secure temporal coding in this high-frequency species.
doi:10.1016/j.heares.2012.04.019
PMCID: PMC3371138  PMID: 22579638
peri-stimulus time histograms; onset latency; regularity analysis; prepotential; rate adaptation
14.  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.
Purpose
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.
Methods
literature-review, tract-tracing, immunohistochemistry, in vivo electrophysiological recordings
Results
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.
Conclusions
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.
doi:10.1044/1059-0889(2008/07-0045)
PMCID: PMC2760229  PMID: 19056923
Auditory system; Cochlear nucleus; Inferior colliculus; Trigeminal; Reticular formation; Somatosensory; Non-auditory projections; Tinnitus; Deafness; Bimodal plasticity
15.  Hearing Loss Alters Quantal Release at Cochlear Nucleus Stellate Cells 
The Laryngoscope  2010;120(10):2047-2053.
Hypothesis
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1002/lary.21106
PMCID: PMC3091373  PMID: 20824788
16.  Onset Neurones in the Anteroventral Cochlear Nucleus Project to the Dorsal Cochlear Nucleus 
Considerable circumstantial evidence suggests that cells in the ventral cochlear nucleus, that respond predominantly to the onset of pure tone bursts, have a stellate morphology and project, among other places, to the dorsal cochlear nucleus. The characteristics of such cells make them leading candidates for providing the so-called “wideband inhibitory input” which is an essential part of the processing machinery of the dorsal cochlear nucleus. Here we use juxtacellular labeling with biocytin to demonstrate directly that large stellate cells, with onset responses, terminate profusely in the dorsal cochlear nucleus. They also provide widespread local innervation of the anteroventral cochlear nucleus and a small innervation of the posteroventral cochlear nucleus. In addition, some onset cells project to the contralateral dorsal cochlear nucleus.
doi:10.1007/s10162-003-4036-8
PMCID: PMC2538402  PMID: 15357418
stellate cells; anteroventral cochlear nucleus; dorsal cochlear nucleus; wideband inhibitor; onset responses
17.  A bushy cell network in the rat ventral cochlear nucleus 
Geometry of the dendritic tree and synaptic organization of afferent inputs are essential factors in determining how synaptic input is integrated by neurons. This information remains elusive for one of the first brainstem neurons involved in processing of the primary auditory signal from the ear, the bushy cells (BCs) of the ventral cochlear nucleus (VCN). Here, we labeled the BC dendritic trees with retrograde tracing techniques to analyze their geometry and synaptic organization after immunofluorescence for excitatory and inhibitory synaptic markers, electron microscopy, morphometry, double tract-tracing methods, and 3-D reconstructions. Our study revealed that BC dendrites provide space for a large number of compartmentalized excitatory and inhibitory synaptic interactions. The dendritic inputs on BCs are of cochlear and non-cochlear origin, and their proportion and distribution are dependent on the branching pattern and orientation of the dendritic tree in the VCN. Three-dimensional reconstructions showed that BC dendrites branch and cluster with those of other BCs in the core of the VCN. Within the cluster, incoming synaptic inputs establish divergent multiple-contact synapses (dyads and triads) between BCs. Furthermore, neuron-neuron connections including puncta adherentia, sarcoplasmic junctions and gap junctions are common between BCs, which suggests that these neurons are electrically coupled. Together, our study demonstrates the existence of a BC network in the rat VCN. This network may establish the neuroanatomical basis for acoustic information processing by individual BCs, as well as for enhanced synchronization of the output signal of the VCN.
doi:10.1002/cne.22139
PMCID: PMC2841288  PMID: 19634178
cochlear nucleus; electron microscopy; gap junctions; immunofluorescence; synchronization; 3D-Reconstruction
18.  Mathematical Models of Cochlear Nucleus Onset Neurons: II. Model with Dynamic Spike-Blocking State 
Onset (On) neurons in the cochlear nucleus (CN), characterized by their prominent response to the onset followed by little or no response to the steady-state of sustained stimuli, have a remarkable ability to entrain (firing 1 spike per cycle of a periodic stimulus) to low-frequency tones up to 1000 Hz. In this article, we present a point-neuron model with independent, excitatory auditory-nerve (AN) inputs that accounts for the ability of On neurons to both produce onset responses for high-frequency tone bursts and entrain to a wide range of low-frequency tones. With a fixed-duration spike-blocking state after a spike (an absolute refractory period), the model produces entrainment to a broad range of low-frequency tones and an On response with short interspike intervals (chopping) for high-frequency tone bursts. To produce On response patterns with no chopping, we introduce a novel, more complex, active membrane model in which the spike-blocking state is maintained until the instantaneous membrane voltage falls below a transition voltage. During the sustained depolarization for a high-frequency tone burst, the new model does not chop because it enters a spike-blocking state after the first spike and fails to leave this state until the membrane voltage returns toward rest at the end of the stimulus. The model entrains to low-frequency tones because the membrane voltage falls below the transition voltage on every cycle when the AN inputs are phase-locked. With the complex membrane model, On response patterns having moderate steady-state activity for high-frequency tone bursts (On-L) are distinguished from those having no steady-state activity (On-I) by requiring fewer AN inputs. Voltage-gated ion channels found in On-responding neurons of the CN may underlie the hypothesized dynamic spike-blocking state. These results provide a mechanistic rationale for distinguishing between the different physiological classes of CN On neurons.
PMCID: PMC2270482  PMID: 12435926
refractory period; state-dependent spike discharge; voltage-gated ion channels; cochlear nucleus
19.  A new auditory threshold estimation technique for low frequencies: Proof of concept 
Ear and hearing  2013;34(1):42-51.
Objectives
Presently available non-behavioral methods to estimate auditory thresholds perform less well at frequencies below 1 kHz than at 1 kHz and above. For many uses, such as providing accurate infant hearing aid amplification for low-frequency vowels, we need an accurate non-behavioral method to estimate low-frequency thresholds. Here we develop a novel technique to estimate low-frequency cochlear thresholds based on the use of a previously-reported waveform. We determine how well the method works by comparing the resulting thresholds to thresholds from onset-response compound action potentials (CAPs) and single auditory-nerve (AN) fibers in cats. A long-term goal is to translate this technique for use in humans.
Design
An electrode near the cochlea records a combination of cochlear microphonic (CM) and neural responses. In response to low-frequency, near threshold-level tones, the CM is almost sinusoidal while the neural responses occur preferentially at one phase of the tone. If the tone is presented again but with its polarity reversed, the neural response keeps the same shape, but shifts ½ cycle in time. Averaging responses to tones presented separately at opposite polarities overlaps and interleaves the neural responses and yields a waveform in which the CM is cancelled and the neural response appears twice each tone cycle, i.e. the resulting neural response is mostly at twice the tone frequency. We call the resultant waveform “the auditory nerve overlapped waveform” (ANOW). ANOW level functions were measured in anesthetized cats from 10 to 80 dB SPL in 10 dB steps using tones between 0.3 and 1 kHz. As a response metric, we calculated the magnitude of the ANOW component at twice the tone frequency (ANOW2f). The ANOW threshold was the sound level where the interpolated ANOW2f crossed a statistical criterion that was higher than 95% of the noise floor distribution. ANOW thresholds were compared to onset-CAP thresholds from the same recordings and single-AN-fiber thresholds from the same animals.
Results
We obtained ANOW and onset-CAP level functions for 0.3 to 1 kHz tones, and single-AN-fiber responses from cats. Except at 1 kHz, typical ANOW thresholds were mostly 10-20 dB more sensitive than onset-CAP thresholds and 10-20 dB less sensitive than the most sensitive single-AN-fiber thresholds.
Conclusions
ANOW provides frequency-specific estimates of cochlear neural thresholds over a frequency range that is important for hearing but is not well accessed by non-behavioral, non-invasive methods. Our results suggest that, with further targeted development, the ANOW low-frequency threshold estimation technique can be useful both clinically in humans and in basic-science animal experiments.
doi:10.1097/AUD.0b013e31825f9bd3
PMCID: PMC3495092  PMID: 22874644
audiogram; auditory nerve neurophonic; compound action potential; neural synchrony; phase locking
20.  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.
doi:10.1016/j.heares.2013.05.002
PMCID: PMC3905197  PMID: 23707995
carboplatin; growth associated protein-43; cochlear nucleus; chinchilla; hearing loss; hair cells
21.  Contralateral Effects and Binaural Interactions in Dorsal Cochlear Nucleus 
The dorsal cochlear nucleus (DCN) receives afferent input from the auditory nerve and is thus usually thought of as a monaural nucleus, but it also receives inputs from the contralateral cochlear nucleus as well as descending projections from binaural nuclei. Evidence suggests that some of these commissural and efferent projections are excitatory, whereas others are inhibitory. The goals of this study were to investigate the nature and effects of these inputs in the DCN by measuring DCN principal cell (type IV unit) responses to a variety of contralateral monaural and binaural stimuli. As expected, the results of contralateral stimulation demonstrate a mixture of excitatory and inhibitory influences, although inhibitory effects predominate. Most type IV units are weakly, if at all, inhibited by tones but are strongly inhibited by broadband noise (BBN). The inhibition evoked by BBN is also low threshold and short latency. This inhibition is abolished and excitation is revealed when strychnine, a glycine-receptor antagonist, is applied to the DCN; application of bicuculline, a GABAA-receptor antagonist, has similar effects but does not block the onset of inhibition. Manipulations of discrete fiber bundles suggest that the inhibitory, but not excitatory, inputs to DCN principal cells enter the DCN via its output pathway, and that the short latency inhibition is carried by commissural axons. Consistent with their respective monaural effects, responses to binaural tones as a function of interaural level difference are essentially the same as responses to ipsilateral tones, whereas binaural BBN responses decrease with increasing contralateral level. In comparison to monaural responses, binaural responses to virtual space stimuli show enhanced sensitivity to the elevation of a sound source in ipsilateral space but reduced sensitivity in contralateral space. These results show that the contralateral inputs to the DCN are functionally relevant in natural listening conditions, and that one role of these inputs is to enhance DCN processing of spectral sound localization cues produced by the pinna.
doi:10.1007/s10162-005-0008-5
PMCID: PMC2504593  PMID: 16075189
dorsal cochlear nucleus; contralateral inputs; binaural interactions; sound localization
22.  EphB signaling regulates target innervation in the developing and deafferented auditory brainstem 
Developmental neurobiology  2012;72(9):1243-1255.
Precision in auditory brainstem connectivity underlies sound localization. Cochlear activity is transmitted to the ventral cochlear nucleus (VCN) in the mammalian brainstem via the auditory nerve. VCN globular bushy cells project to the contralateral medial nucleus of the trapezoid body (MNTB), where specialized axons terminals, the calyces of Held, encapsulate MNTB principal neurons. The VCN-MNTB pathway is an essential component of the circuitry used to compute interaural intensity differences that are used for localizing sounds. When input from one ear is removed during early postnatal development, auditory brainstem circuitry displays robust anatomical plasticity. The molecular mechanisms that control the development of auditory brainstem circuitry and the developmental plasticity of these pathways are poorly understood. In this study we examined the role of EphB signaling in the development of the VCN-MNTB projection and in the reorganization of this pathway after unilateral deafferentation. We found that EphB2 and EphB3 reverse signaling are critical for the normal development of the projection from VCN to MNTB, but that successful circuit assembly most likely relies upon the coordinated function of many EphB proteins. We have also found that ephrin-B reverse signaling repels induced projections to the ipsilateral MNTB after unilateral deafferentation, suggesting that similar mechanisms regulate these two processes.
doi:10.1002/dneu.20990
PMCID: PMC3418463  PMID: 22021100
EphB; ephrin-B; VCN; MNTB; deafferentation
23.  Responses of cochlear nucleus neurons to harmonic and mistuned complex tones 
Hearing research  2007;238(1-2):39-48.
Preliminary measurements of the representation in the cochlear nucleus (CN) of harmonic tones, harmonic tones with mistuned components, and double harmonic tones are reported. These data indicate that, unlike auditory nerve fibers and IC neurons, neurons in the CN may exhibit one of several qualitatively-different response patterns when stimulated with mistuned tones. Primarylike neurons synchronized their discharges to 2–3 individual stimulus components, much like auditory nerve fibers do. Chopper neurons tended to respond with the periodicity of envelopes produced by interactions between adjacent stimulus components but exhibited little or no response synchronized to individual stimulus components. A small proportion of CN neurons exhibited complex slowly-modulated discharge patterns similar to those that are commonly observed in the inferior colliculus (IC). The patterns obtained from CN neurons with different pure-tone discharge patterns were generally consistent with expectations based on previous studies with other stimuli. The measurements provided additional insight into the hierarchical processing stages that result in the highly patterned responses of IC neurons to harmonic and mistuned tones.
doi:10.1016/j.heares.2007.11.001
PMCID: PMC2323903  PMID: 18078726
cochlear nucleus; chinchilla; complex sounds; spectral segregation; auditory scene analysis
24.  Postsynaptic Targets of Type II Auditory Nerve Fibers in the Cochlear Nucleus.  
Type II auditory nerve fibers, which provide the primary afferent innervation of outer hair cells of the cochlea, project thin fibers centrally and form synapses in the cochlear nucleus. We investigated the postsynaptic targets of these synapses, which are unknown. Using serial-section electron microscopy of fibers labeled with horseradish peroxidase, we examined the border of the granule-cell lamina in mice, an area of type II termination that receives branches having swellings with complex shapes. About 70% of the swellings examined with the electron microscope formed morphological synapses, which is a much higher value than found in previous studies of type II swellings in other parts of the cochlear nucleus. The high percentage of synapses enabled a number of postsynaptic targets to be identified. Most of the targets were small dendrites. Two of these dendrites were traced to their somata of origin, which were cochlear-nucleus “small cells” situated at the border of the granule-cell lamina. These cells did not appear to receive any terminals containing synaptic vesicles that were large and round, indicating a lack of input from type I auditory nerve fibers. Nor did type II swellings or targets participate in the synaptic glomeruli formed by mossy terminals and the dendrites of granule cells. Other type II synapses were axosomatic and their targets were large cells, which were presumed multipolar cells and one cell with characteristics of a globular bushy cell. These large cells almost certainly receive additional input from type I auditory nerve fibers, which provide the afferent innervation of the cochlear inner hair cells. A few type II postsynaptic targets—the two small cells as well as a large dendrite—received synapses that had accompanying postsynaptic bodies, a likely marker for synapses of medial olivocochlear branches. These targets thus probably receive convergent input from type II fibers and medial olivocochlear branches. The diverse nature of the type II targets and the examples of segregated convergence of other inputs illustrates the synaptic complexity of type II input to the cochlear nucleus.
doi:10.1007/s10162-003-4012-3
PMCID: PMC2538406  PMID: 15357415
outer hair cell; olivocochlear; small cell; multipolar cell; granule cell
25.  Cochlear nucleus neurons redistribute synaptic AMPA and glycine receptors in response to monaural conductive hearing loss 
Neuroscience  2009;163(4):1264-1276.
Neurons restore their function in response to external or internal perturbations and maintain neuronal or network stability through a homeostatic scaling mechanism. Homeostatic responses at synapses along the auditory system would be important for adaptation to normal and abnormal fluctuations in the sensory environment. We investigated at the electron microscopic level and after postembedding immunogold labeling whether projection neurons in the cochlear nucleus responded to modifications of auditory nerve activity. After unilaterally reducing the level of auditory inputs by ~ 20 dB by monaural earplugging, auditory nerve synapses on bushy cells somata and basal dendrites of fusiform cells of the ventral and dorsal cochlear nucleus, respectively, upregulated GluR3 AMPA receptor subunit, while inhibitory synapses decreased the expression of GlyRα1 subunit. These changes in expression levels were fully reversible once the earplug was removed, indicating that activity affects the trafficking of receptors at synapses. Excitatory synapses on apical dendrites of fusiform cells (parallel fibers) with different synaptic AMPA receptor subunit composition, were not affected by sound attenuation, as the expression levels of AMPA receptor subunits were the same as in normal hearing littermates. GlyRα1 subunit expression at inhibitory synapses on apical dendrites of fusiform cells was also found unaffected. Furthermore, fusiform and bushy cells of the contralateral side to the earplugging upregulated the GluR3 subunit at auditory nerve synapses. These results show that cochlear nucleus neurons innervated by the auditory nerve, are able to respond to small changes in sound levels by redistributing specific AMPA and glycine receptor subunits.
doi:10.1016/j.neuroscience.2009.07.049
PMCID: PMC2760652  PMID: 19646510
earplugging; glutamate receptors; glycine α1 subunit; postembedding immunogold labeling; ultrastructure

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