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Loss of synapses between spiral ganglion neurons and inner hair cells (IHC synaptopathy) leads to an auditory neuropathy called hidden hearing loss (HHL) characterized by normal auditory thresholds but reduced amplitude of sound-evoked auditory potentials. It has been proposed that synaptopathy and HHL result in poor performance in challenging hearing tasks despite a normal audiogram. However, this has only been tested in animals after exposure to noise or ototoxic drugs, which can cause deficits beyond synaptopathy. Furthermore, the impact of supernumerary synapses on auditory processing has not been evaluated. Here, we studied mice in which IHC synapse counts were increased or decreased by altering neurotrophin 3 (Ntf3) expression in IHC supporting cells. As we previously showed, postnatal Ntf3 knockdown or overexpression reduces or increases, respectively, IHC synapse density and suprathreshold amplitude of sound-evoked auditory potentials without changing cochlear thresholds. We now show that IHC synapse density does not influence the magnitude of the acoustic startle reflex or its prepulse inhibition. In contrast, gap-prepulse inhibition, a behavioral test for auditory temporal processing, is reduced or enhanced according to Ntf3 expression levels. These results indicate that IHC synaptopathy causes temporal processing deficits predicted in HHL. Furthermore, the improvement in temporal acuity achieved by increasing Ntf3 expression and synapse density suggests a therapeutic strategy for improving hearing in noise for individuals with synaptopathy of various etiologies. The auditory neuropathy hidden hearing loss (HHL) is characterised by the loss of cochlear inner hair cell synapses, which reduce the amplitude of sound-evoked auditory potentials. This study shows that loss of these synapses degrades temporal auditory processing and that the generation of supernumerary synapsis results in above-normal temporal auditory processing in mice, potentially improving hearing in HHL patients. [ABSTRACT FROM AUTHOR]

This paper describes the development of shutters, fluidic ribbon cables, and flowmeters for use on bulk-micromachined neural probes. The resulting devices permit electrical recording, stimulation, and chemical drug delivery in the central nervous system at the cellular level. Dielectric shutters reduce unintended drug delivery by a factor of about 25 compared with an open orifice, while silicon fluidic cables are 1.5 times more flexible than the 70 [micro]m-ID polyimide tubing previously used. A pulsed thermal flowmeter integrated on the probe allows verification of drug delivery on a per-channel basis with a resolution of 150 pL/s. Thermal time constants are about 60 [micro]s, allowing multiple measurements within one delivery pulse while restricting ally tissue heating to negligible levels. Finally, test structures have shown the process compatibility of on-chip thermopneumatic microvalves and micropumps. The fabrication of these fluidic structures (microchannels, shutters, cables, valves, and pumps) requires only two masks in addition to the eight normally used for passive probes, providing important new capabilities for use in neurophysiological research and neural prostheses. [1291]

Understanding communication signals, especially in noisy environments, is crucial to social interactions. Yet, as we age, acoustic signals can be disrupted by cochlear damage and the subsequent auditory nerve fibre degeneration. The most vulnerable medium‐ and high‐threshold‐auditory nerve fibres innervate various cell types in the cochlear nucleus, among which the small cells are unique in receiving this input exclusively. Furthermore, small cells project to medial olivocochlear (MOC) neurons, which in turn send branched collaterals back into the small cell cap. Here, we use single‐unit recordings to characterise small cell firing characteristics and demonstrate superior intensity coding in this cell class. We show converse effects when activating/blocking the MOC system, demonstrating that small‐cell unique coding properties are facilitated by direct cholinergic input from the MOC system. Small cells also maintain tone‐level coding in the presence of background noise. Finally, small cells precisely code low‐frequency modulation more accurately than other ventral cochlear nucleus cell types, demonstrating accurate envelope coding that may be important for vocalisation processing. These results highlight the small cell olivocochlear circuit as a key player in signal processing in noisy environments, which may be selectively degraded in ageing or after noise insult. Key points: Cochlear nucleus small cells receive input from low/medium spontaneous rate auditory nerve fibres and medial olivocochlear neurons.Electrical stimulation of medial olivocochlear neurons in the ventral nucleus of the trapezoid body and blocking cholinergic input to small cells using atropine demonstrates an excitatory cholinergic input to small cells, which increases responses to suprathreshold sound.Unique inputs to small cells produce superior sound intensity coding.This coding of intensity is preserved in the presence of background noise, an effect exclusive to this cell type in the cochlear nucleus.These results suggest that small cells serve an essential function in the ascending auditory system, which may be relevant to disorders such as hidden hearing loss. [ABSTRACT FROM AUTHOR]

Key points: Inhibitory‐interneuron networks, consisting of multiple forms of circuit motifs including reciprocal (inhibitory interneurons inhibiting other interneurons) and feedforward (inhibitory interneurons inhibiting principal neurons) connections, are crucial in processing sensory information.The present study applies a statistical method to in vivo multichannel spike trains of dorsal cochlear nucleus neurons to disentangle reciprocal and feedforward‐inhibitory motifs.After inducing input‐specific plasticity, reciprocal and feedforward inhibition are found to be differentially regulated, and the combined effect synergistically modulates circuit output.The findings highlight the interplay among different circuit motifs as a key element in neural computation. Inhibitory interneurons play an essential role in neural computations by utilizing a combination of reciprocal (interneurons inhibiting each other) and feedforward (interneuron inhibiting the principal neuron) inhibition to process information. To disentangle the interplay between the two inhibitory‐circuit motifs and understand their effects on the circuit output, in vivo recordings were made from the guinea pig dorsal cochlear nucleus, a cerebellar‐like brainstem circuit. Spikes from inhibitory interneurons (cartwheel cell) and principal output neurons (fusiform cell) were compared before and after manipulating their common multimodal input. Using a statistical model based on the Cox method of modulated renewal process of spike train influence, reciprocal‐ and feedforward‐inhibition motifs were quantified. In response to altered multimodal input, reciprocal inhibition was strengthened while feedforward inhibition was weakened, and the two motifs combined to modulate fusiform cell output and acoustic‐driven responses. These findings reveal the cartwheel cell's role in auditory and multimodal processing, as well as illustrated the balance between different inhibitory‐circuit motifs as a key element in neural computation. Key points: Inhibitory‐interneuron networks, consisting of multiple forms of circuit motifs including reciprocal (inhibitory interneurons inhibiting other interneurons) and feedforward (inhibitory interneurons inhibiting principal neurons) connections, are crucial in processing sensory information.The present study applies a statistical method to in vivo multichannel spike trains of dorsal cochlear nucleus neurons to disentangle reciprocal and feedforward‐inhibitory motifs.After inducing input‐specific plasticity, reciprocal and feedforward inhibition are found to be differentially regulated, and the combined effect synergistically modulates circuit output.The findings highlight the interplay among different circuit motifs as a key element in neural computation. [ABSTRACT FROM AUTHOR]

Accumulating evidence implicates a role for brain structures outside the ascending auditory pathway in tinnitus, the phantom perception of sound. In addition to other factors such as age-dependent hearing loss, high-level sound exposure is a prominent cause of tinnitus. Here, we examined how noise exposure altered the distribution of excitatory and inhibitory synaptic inputs in the guinea pig hippocampus and determined whether these changes were associated with tinnitus. In experiment one, guinea pigs were overexposed to unilateral narrow-band noise (98 dB SPL, 2 h). Two weeks later, the density of excitatory (VGLUT-1/2) and inhibitory (VGAT) synaptic terminals in CA1, CA3, and dentate gyrus hippocampal subregions was assessed by immunohistochemistry. Overall, VGLUT-1 density primarily increased, while VGAT density decreased significantly in many regions. Then, to assess whether the noise-induced alterations were persistent and related to tinnitus, experiment two utilized a noise-exposure paradigm shown to induce tinnitus and assessed tinnitus development which was assessed using gap-prepulse inhibition of the acoustic startle (GPIAS). Twelve weeks after sound overexposure, changes in excitatory synaptic terminal density had largely recovered regardless of tinnitus status, but the recovery of GABAergic terminal density was dramatically different in animals expressing tinnitus relative to animals resistant to tinnitus. In resistant animals, inhibitory synapse density recovered to preexposure levels, but in animals expressing tinnitus, inhibitory synapse density remained chronically diminished. Taken together, our results suggest that noise exposure induces striking changes in the balance of excitatory and inhibitory synaptic inputs throughout the hippocampus and reveal a potential role for rebounding inhibition in the hippocampus as a protective factor leading to tinnitus resilience. [ABSTRACT FROM AUTHOR]

Here, we investigate remodeling of hippocampal cholinergic inputs after noise exposure and determine the relevance of these changes to tinnitus. To assess the effects of noise exposure on the hippocampus, guinea pigs were exposed to unilateral noise for 2 hr and 2 weeks later, immunohistochemistry was performed on hippocampal sections to examine vesicular acetylcholine transporter (VAChT) expression. To evaluate whether the changes in VAChT were relevant to tinnitus, another group of animals was exposed to the same noise band twice to induce tinnitus, which was assessed using gap‐prepulse Inhibition of the acoustic startle (GPIAS) 12 weeks after the first noise exposure, followed by immunohistochemistry. Acoustic Brainstem Response (ABR) thresholds were elevated immediately after noise exposure for all experimental animals but returned to baseline levels several days after noise exposure. ABR wave I amplitude‐intensity functions did not show any changes after 2 or 12 weeks of recovery compared to baseline levels. In animals assessed 2‐weeks following noise‐exposure, hippocampal VAChT puncta density decreased on both sides of the brain by 20–60% in exposed animals. By 12 weeks following the initial noise exposure, changes in VAChT puncta density largely recovered to baseline levels in exposed animals that did not develop tinnitus, but remained diminished in animals that developed tinnitus. These tinnitus‐specific changes were particularly prominent in hippocampal synapse‐rich layers of the dentate gyrus and areas CA3 and CA1, and VAChT density in these regions negatively correlated with tinnitus severity. The robust changes in VAChT labeling in the hippocampus 2 weeks after noise exposure suggest involvement of this circuitry in auditory processing. After chronic tinnitus induction, tinnitus‐specific changes occurred in synapse‐rich layers of the hippocampus, suggesting that synaptic processing in the hippocampus may play an important role in the pathophysiology of tinnitus. [ABSTRACT FROM AUTHOR]

Key points: Dorsal cochlear nucleus fusiform cells receive spectrally relevant auditory input for sound localization. Fusiform cells integrate auditory with other multisensory inputs. Here we elucidate how somatosensory and vestibular stimulation modify the fusiform cell spatial code through activation of an inhibitory interneuron: the ventral cochlear nucleus D‐stellate cell. These results suggests that multisensory cues interact early in an ascending sensory pathway to serve an essential function. Abstract: In the cochlear nucleus (CN), the first central site for coding sound location, numerous multisensory projections and their modulatory effects have been reported. However, multisensory influences on sound location processing in the CN remain unknown. The principal output neurons of the dorsal CN, fusiform cells, encode spatial information through frequency‐selective responses to direction‐dependent spectral features. Here, single‐unit recordings from the guinea pig CN revealed transient alterations by somatosensory and vestibular stimulation in fusiform cell spatial coding. Changes in fusiform cell spectral sensitivity correlated with multisensory modulation of ventral CN D‐stellate cell responses, which provide direct, wideband inhibition to fusiform cells. These results suggest that multisensory inputs contribute to spatial coding in DCN fusiform cells via an inhibitory interneuron, the D‐stellate cell. This early multisensory integration circuit likely confers important consequences on perceptual organization downstream. [ABSTRACT FROM AUTHOR]

Temporal coding of auditory stimuli is critical for understanding communication signals. The bushy cell, a major output neuron of the ventral cochlear nucleus, can "phase-lock" precisely to pure tones and the envelopes of complex stimuli. Bushy cells are also putative recipients of brainstem somatosensory projections and could therefore play a role in perception of communication signals because multisensory integration is required for such complex sound processing. Here, we examine the role of multisensory integration in temporal coding in bushy cells by activating the spinal trigeminal nucleus (Sp5) while recording responses from bushy cells. In normal-hearing guinea pigs of either sex, bushy cell single unit responses to amplitude-modulated (AM) broadband noise were compared with those in the presence of preceding Sp5 electrical stimulation (i.e., bimodal stimuli). Responses to the AM stimuli were also compared with those obtained 45 min after the bimodal stimulation. Bimodal auditory-Sp5 stimulation resulted in enhanced envelope coding for low modulation frequencies, which persisted for up to 45 min. AM detection thresholds were significantly improved 45 min after bimodal auditory-Sp5 stimulation, but not during bimodal auditory-Sp5 stimulation. Anterograde labeling of Sp5 projections was found within the dendritic fields of bushy cells and their inhibitory interneurons, D-stellate cells. Therefore, enhanced AM responses and improved AM sensitivity of bushy cells were likely facilitated by Sp5 neurons through monosynaptic excitatory projections and indirect inhibitory projections. These somatosensory projections may be involved in the improved perception of communication stimuli with multisensory stimulation, consistent with psychophysical studies in humans. [ABSTRACT FROM AUTHOR]

Cholinergic modulation contributes to adaptive sensory processing by controlling spontaneous and stimulusevoked neural activity and long-term synaptic plasticity. In the dorsal cochlear nucleus (DCN), in vitro activation of muscarinic acetylcholine receptors (mAChRs) alters the spontaneous activity of DCN neurons and interacts with N-methyl-D-aspartate (NMDA) and endocannabinoid receptors to modulate the plasticity of parallel fiber synapses onto fusiform cells by converting Hebbian long-term potentiation to anti-Hebbian long-term depression. Because noise exposure and tinnitus are known to increase spontaneous activity in fusiform cells as well as alter stimulus timing-dependent plasticity (StTDP), it is important to understand the contribution of mAChRs to in vivo spontaneous activity and plasticity in fusiform cells. In the present study, we blocked mAChRs actions by infusing atropine, a mAChR antagonist, into the DCN fusiform cell layer in normal hearing guinea pigs. Atropine delivery leads to decreased spontaneous firing rates and increased synchronization of fusiform cell spiking activity. Consistent with StTDP alterations observed in tinnitus animals, atropine infusion induced a dominant pattern of inversion of StTDP mean population learning rule from a Hebbian to an anti-Hebbian profile. Units preserving their initial Hebbian learning rules shifted toward more excitatory changes in StTDP, whereas units with initial suppressive learning rules transitioned toward a Hebbian profile. Together, these results implicate muscarinic cholinergic modulation as a factor in controlling in vivo fusiform cell baseline activity and plasticity, suggesting a central role in the maladaptive plasticity associated with tinnitus pathology. [ABSTRACT FROM AUTHOR]

Tinnitus, the perception of phantom sounds, is thought to arise from increased neural synchrony, which facilitates perceptual binding and creates salient sensory features in the absence of physical stimuli. In the auditory cortex, increased spontaneous cross-unit synchrony and single-unit bursting are de facto physiological correlates of tinnitus. However, it is unknown whether neurons in the dorsal cochlear nucleus (DCN), the putative tinnitus-induction site, exhibit increased synchrony. Using a temporary-threshold shift model and gap-prepulse inhibition of the acoustic startle to assess tinnitus, we recorded spontaneous activity from fusiform cells, the principle neurons of the DCN, in normal hearing, tinnitus, and non-tinnitus guinea pigs. Synchrony and bursting, as well as spontaneous firing rate (SFR), correlated with behavioral evidence of tinnitus, and increased synchrony and bursting were associated with SFR elevation. The presence of increased synchrony and bursting in DCN fusiform cells suggests that a neural code for phantom sounds emerges in this brainstem location and likely contributes to the formation of the tinnitus percept. [ABSTRACT FROM AUTHOR]

Central auditory circuits are influenced by the somatosensory system, a relationship that may underlie tinnitus generation. In the guinea pig dorsal cochlear nucleus (DCN), pairing spinal trigeminal nucleus (Sp5) stimulation with tones at specific intervals and orders facilitated or suppressed subsequent tone-evoked neural responses, reflecting spike timing-dependent plasticity (STDP). Furthermore, after noiseinduced tinnitus, bimodal responses in DCN were shifted from Hebbian to anti-Hebbian timing rules with less discrete temporal windows, suggesting a role for bimodal plasticity in tinnitus. Here, we aimed to determine if multisensory STDP principles like those in DCN also exist in primary auditory cortex (A1), and whether they change following noise-induced tinnitus. Tone-evoked and spontaneous neural responses were recorded before and 15 min after bimodal stimulation in which the intervals and orders of auditory-somatosensory stimuli were randomized. Tone-evoked and spontaneous firing rates were influenced by the interval and order of the bimodal stimuli, and in sham-controls Hebbian-like timing rules predominated as was seen in DCN. In noise-exposed animals with and without tinnitus, timing rules shifted away from those found in sham-controls to more anti-Hebbian rules. Only those animals with evidence of tinnitus showed increased spontaneous firing rates, a purported neurophysiological correlate of tinnitus in A1. Together, these findings suggest that bimodal plasticity is also evident in A1 following noise damage and may have implications for tinnitus generation and therapeutic intervention across the central auditory circuit. [ABSTRACT FROM AUTHOR]

Auditory information relayed by auditory nerve fibers and somatosensory information relayed by granule cell parallel fibers converge on the fusiform cells (FCs) of the dorsal cochlear nucleus, the first brain station of the auditory pathway. In vitro, parallel fiber synapses on FCs exhibit spike-timing-dependent plasticity with Hebbian learning rules, partially mediated by the NMDA receptor (NMDAr). Well-timed bimodal auditorysomatosensory stimulation, in vivo equivalent of spike-timing-dependent plasticity, can induce stimulus-timing-dependent plasticity (StTDP) of the FCs spontaneous and toneevoked firing rates. In healthy guinea pigs, the resulting distribution of StTDP learning rules across a FC neural population is dominated by a Hebbian profile while anti- Hebbian, suppressive and enhancing LRs are less frequent. In this study, we investigate in vivo, the NMDAr contribution to FC baseline activity and long term plasticity. We find that blocking the NMDAr decreases the synchronization of FC- spontaneous activity and mediates differential modulation of FC rate-level functions such that low, and high threshold units are more likely to increase, and decrease, respectively, their maximum amplitudes. Three significant alterations in mean learning-rule profiles were identified: transitions from an initial Hebbian profile towards (1) an anti-Hebbian; (2) a suppressive profile; and (3) transitions from an anti-Hebbian to a Hebbian profile. FC units preserving their learning rules showed instead, NMDAr-dependent plasticity to unimodal acoustic stimulation, with persistent depression of tone-evoked responses changing to persistent enhancement following the NMDAr antagonist. These results reveal a crucial role of the NMDAr in mediating FC baseline activity and long-term plasticity which have important implications for signal processing and auditory pathologies related to maladaptive plasticity of dorsal cochlear nucleus circuitry. [ABSTRACT FROM AUTHOR]

The cochlear nucleus (CN) is the first site of multisensory integration in the ascending auditory pathway. The principal output neurons of the dorsal cochlear nucleus (DCN), fusiform cells, receive somatosensory information relayed by the CN granule cells from the trigeminal and dorsal column pathways. Integration of somatosensory and auditory inputs results in long-term enhancement or suppression in a stimulus-timing-dependent manner. Here, we demonstrate that stimulus-timing-dependent plasticity (STDP) can be induced in DCN fusiform cells using paired auditory and transcutaneous electrical stimulation of the face and neck to activate trigeminal and dorsal column pathways to the CN, respectively. Long-lasting changes in fusiform cell firing rates persisted for up to 2 h after this bimodal stimulation, and followed Hebbian or anti-Hebbian rules, depending on tone duration, but not somatosensory stimulation location: 50 ms paired tones evoked predominantly Hebbian, while 10 ms paired tones evoked predominantly anti-Hebbian plasticity. The tone-duration-dependent STDP was strongly correlated with first inter-spike intervals, implicating intrinsic cellular properties as determinants of STDP. This study demonstrates that transcutaneous stimulation with precise auditory- somatosensory timing parameters can non-invasively induce fusiform cell long-term modulation, which could be harnessed in the future to moderate tinnitus-related hyperactivity in DCN. [ABSTRACT FROM AUTHOR]

Tinnitus has been associated with enhanced central gain manifested by increased spontaneous activity and sound-evoked firing rates of principal neurons at various stations of the auditory pathway. Yet, the mechanisms leading to these modifications are not well understood. In a recent in vivo study, we demonstrated that stimulus-timing-dependent bimodal plasticity mediates modifications of spontaneous and tone-evoked responses of fusiform cells in the dorsal cochlear nucleus (DCN) of the guinea pig. Fusiform cells from sham animals showed primarily Hebbian learning rules while noise-exposed animals showed primarily anti-Hebbian rules, with broadened profiles for the animals with behaviorally verified tinnitus (Koehler SD, Shore SE. J Neurosci 33: 19647-19656, 2013a). In the present study we show that well-timed bimodal stimulation induces alterations in the rate-level functions (RLFs) of fusiform cells. The RLF gains and maximum amplitudes show Hebbian modifications in sham and no-tinnitus animals but anti-Hebbian modifications in noise-exposed animals with evidence for tinnitus. These findings suggest that stimulus-timing bimodal plasticity produced by the DCN circuitry is a contributing mechanism to enhanced central gain associated with tinnitus. [ABSTRACT FROM AUTHOR]

Tinnitus and cochlear damage have been associated with changes in somatosensory-auditory integration and plasticity in the dorsal cochlear nucleus (DCN). Recently, we demonstrated in vivo that DCN bimodal plasticity is stimulus timing-dependent, with Hebbian and anti-Hebbian timing rules that reflect in vitro spike timing-dependent plasticity. In this in vivo study, we assessed the stimulus timing dependence of bimodal plasticity in a tinnitus model. Guinea pigs were exposed to a narrowband noise that produced a temporary elevation of auditory brainstem response thresholds. A total of 60% of the guinea pigs developed tinnitus as indicated by gap-induced prepulse inhibition of the acoustic startle. After noise exposure and tinnitus induction, stimulus timing-dependent plasticity was mea-sured by comparing responses to sound before and after paired somatosensory and auditory stimulation presented with varying intervals and orders. In comparison with Sham and noise-exposed animals that did not develop tinnitus, timing rules in verified tinnitus animals were more likely to be anti-Hebbian and broader for those bimodal intervals in which the neural activity showed enhancement. Further-more, units from exposed animals with tinnitus were more weakly suppressed than either Sham animals or exposed animals without tinnitus. The broadened timing rules in the enhancement phase in animals with tinnitus, and in the suppressive phase in exposed animals without tinnitus was in contrast to narrow, Hebbian-like timing rules in Sham animals. These findings implicate alterations in DCN bimodal spike timing-dependent plasticity as underlying mechanisms in tinnitus, opening the way for a therapeutic target. [ABSTRACT FROM AUTHOR]

Multisensory neurons in the dorsal cochlear nucleus (DCN) show long-lasting enhancement or suppression of sound-evoked responses when stimulated with combined somatosensory-auditory stimulation. By varying the intervals between sound and somatosensory stimuli we show for the first time in vivo that DCN bimodal responses are influenced by stimulus-timing dependent plasticity. The timing rules and time courses of the observed stimulus-timing dependent plasticity closely mimic those of spike-timing dependent plasticity that have been demonstrated in vitro at parallel-fiber synapses onto DCN principal cells. Furthermore, the degree of inhibition in a neuron influences whether that neuron has Hebbian or anti-Hebbian timing rules. As demonstrated in other cerebellar-like circuits, anti-Hebbian timing rules reflect adaptive filtering, which in the DCN would result in suppression of sound-evoked responses that are predicted by activation of somatosensory inputs, leading to the suppression of body-generated signals such as self-vocalization. [ABSTRACT FROM AUTHOR]

Tinnitus or ringing of the ears is a subjective phantom sensation necessitating behavioral models that objectively demonstrate the existence and quality of the tinnitus sensation. The gap detection test uses the acoustic startle response elicited by loud noise pulses and its gating or suppression by preceding sub-startling prepulses. Gaps in noise bands serve as prepulses, assuming that ongoing tinnitus masks the gap and results in impaired gap detection. This test has shown its reliability in rats, mice, and gerbils. No data exists for the guinea pig so far, although gap detection is similar across mammals and the acoustic startle response is a well-established tool in guinea pig studies of psychiatric disorders and in pharmacological studies. Here we investigated the startle behavior and prepulse inhibition (PPI) of the guinea pig and showed that guinea pigs have a reliable startle response that can be suppressed by 15 ms gaps embedded in narrow noise bands preceding the startle noise pulse. After recovery of auditory brainstem response (ABR) thresholds from a unilateral noise over-exposure centered at 7 kHz, guinea pigs showed diminished gap-induced reduction of the startle response in frequency bands between 8 and 18 kHz. This suggests the development of tinnitus in frequency regions that showed a temporary threshold shift (TTS) after noise over-exposure. Changes in discharge rate and synchrony, two neuronal correlates of tinnitus, should be reflected in altered ABR waveforms, which would be useful to objectively detect tinnitus and its localization to auditory brainstem structures. Therefore, we analyzed latencies and amplitudes of the first five ABR waves at suprathreshold sound intensities and correlated ABR abnormalities with the results of the behavioral tinnitus testing. Early ABR wave amplitudes up to N3 were increased for animals with tinnitus possibly stemming from hyperactivity and hypersynchrony underlying the tinnitus percept. Animals that did not develop tinnitus after noise exposure showed the opposite effect, a decrease in wave amplitudes for the later waves P4-P5. Changes in latencies were only observed in tinnitus animals, which showed increased latencies. Thus, tinnitus-induced changes in the discharge activity of the auditory nerve and central auditory nuclei are represented in the ABR. [ABSTRACT FROM AUTHOR]

A 3-D application-specific microelectrode array has been developed for physiological studies in guinea pig cochlear nucleus (CN). The batch-fabricated silicon probes contain integrated parylene cables and use a boron etch-stop to define 15μm-thick shanks and limit tissue displacement. Targeting the ventral (three probes) and dorsal (two probes) subnuclei, the custom four-shank 32-site probes are combined in a slotted block platform having a 1.18-mm^2 footprint. The device has permitted, for the first time, high-density 3-D in vivo studies of ventral CN to dorsal CN connections, stimulating with 1000 μm^2 sites in one subnucleus while recording with 177 μm^2 sites in the other. Through these experiments, it has demonstrated the efficacy of bimodal silicon arrays to better understand the central nervous system at the circuit level. The 160 electrode sites also provide a high-density neural interface, which is an essential aspect of auditory prosthesis prototypes. [ABSTRACT FROM AUTHOR]

Tinnitus is a phantom sound (ringing of the ears) that affects quality of life for millions around the world and is associated in most cases with hearing impairment. This symposium will consider evidence that deafferentation of tonotopically organized central auditory structures leads to increased neuron spontaneous firing rates and neural synchrony in the hearing loss region. This region covers the frequency spectrum of tinnitus sounds, which are optimally suppressed following exposure to band-limited noise covering the same frequencies. Cross-modal compensations in subcortical structures may contribute to tinnitus and its modulation by jaw-clenching and eye movements. Yet many older individuals with impaired hearing do not have tinnitus, possibly because age-related changes in inhibitory circuits are better preserved.Abrain network involving limbic and other nonauditory regions is active in tinnitus and may be driven when spectrotemporal information conveyed by the damaged ear does not match that predicted by central auditory processing. [ABSTRACT FROM AUTHOR]

The auditory compound action potential (CAP) represents synchronous VIIIth nerve activity. Clicks or impulses have been used in the past to produce this synchrony under the assumption that the wide spectral spread inherent in transient signals will activate a large portion of the cochlear partition. However, the observation that only auditory nerve units tuned above 3 kHz contribute to synchronous activity in the N1P1 complex of the CAP [Dolan et al., J. Acoust. Soc. Am. 73, 580-591 (1983)] suggests that temporal delays imposed by the traveling wave result in an asynchronous pattern of VIIIth nerve activation. In order to determine if units tuned below 3 kHz could be recruited into the CAP response, the present study uses tone bursts of exponentially rising frequency to hypothetically activate synchronous discharges of VIIIth nerve fibers along the length of the cochlear partition. The equations defining the frequency sweeps are calculated to be the inverse of the delay-line characteristics of the guinea pig cochlear partition. The resultant sweeps theoretically cause a constant phase displacement of a large portion of the cochlear partition at one time. Compound action potentials recorded in response to the rising frequency sweeps were compared to CAPs evoked by corresponding falling frequency sweeps and clicks. Analysis of the CAP waveforms showed narrower N1 widths and larger N1 and P1 amplitudes for rising sweeps when compared to falling sweeps. This is consistent with the hypothesis of increased synchrony. A further test of the hypothesis was made by using high-pass masking noise to evaluate the contributions of discrete cochlear locations to the CAP (''derived'' CAP). Latency functions of the derived CAPs for clicks and falling frequency sweeps showed progressive increases in latency as the cutoff frequency of the high-pass filter was lowered. The latency of the derived CAP for these stimulus conditions reflects traveling wave delays [Aran and Cazals, ''Electrocochleography: Animal studies,'' in Evoked Electrical Activity in The Auditory Nervous System (Academic, New York, 1978)]. In contrast, derived CAPs obtained from rising sweeps showed no change in latency for any cutoff frequencies, indicating a constant delay of response for fibers with different characteristic frequencies (CFs). These results support the theoretical premise underlying the derivation of the rising sweep: Spectral energy with the appropriate temporal organization, dictated by basilar membrane traveling wave properties, will increase CAP synchrony. [ABSTRACT FROM AUTHOR]

The effects of lowered cochlear temperature on eighth-nerve tuning were assessed by using forward masking of whole nerve action potential (AP) responses to generate AP tuning curves (APTCs) at cochlear temperatures ranging from 38.5° to 30 °C for probe frequencies from 8 to 36 kHz. The data indicate that subnormal cochlear temperatures result in: (a) broadened APTCs for probe frequencies above 10 kHz which are interpreted as resulting from reduced hair-cell frequency selectivity, (b) lowered or more sensitive APTC tips where tone-burst thresholds are unchanged, and (c) raised or less sensitive tips where thresholds to tone bursts were elevated. Increased tip sensitivity is explained in terms of enhanced eighth-nerve adaptation which occurred during hypothermia. Experiments directly addressing adaptation were performed, in which the masker-probe interval (Δt) was systematically lengthened. The normalized AP decrement versus Δt functions indicate an enhancement of both the amount and duration of adaptation during hypothermia. Functions relating the growth of response to the masker (AP decrement versus masker intensity functions) were reduced at low temperatures. [ABSTRACT FROM AUTHOR]

When responses to one part of a sequence of auditory signals reduce the responses to a subsequent portion of the signal, 'forward masking' results. Although forward masking occurs in the auditory nerve, that observed in the ventral cochlear nucleus (VCN) more closely resembles psychophysical forward masking. In contrast to the auditory nerve in which the amount of forward masking is proportional to the amount of excitation produced by the masker, most VCN neurons show a poor correlation between forward masking and excitation produced by the masker, indicating a more complex interaction between responses to adjacent signals. This study tested the hypothesis that one component of forward masking is produced by inputs from centrifugal neural connections to the VCN. The centrifugal pathways were interrupted with knife-cut lesions medial to the CN. Responses of single units obtained 60 minutes after the lesions were compared to those obtained before the lesions. In primarylike, sustained chopper and on units the lesions resulted in a reduction in forward masking and enhanced recovery. In contrast, lesions resulted in increased masking in primarylike-notch and low-intensity chopper units. The relationship between masker-elicited excitation and forward masking became more monotonic for transient choppers and on units, approaching that observed for auditory nerve fibers. These effects are probably the result of removal of both inhibitory and excitatory inputs, ultimately reflecting a balance of excitation and inhibition to each neural population in the VCN. © 1998 Acoustical Society of America. [ABSTRACT FROM AUTHOR]

This study examines the encoding of rapid frequency sweeps in single units of the ventral cochlear nucleus (VCN). Sweeps were designed to explore the role of cochlear mechanics in shaping the temporal responses across cells in the VCN. The time course of frequency change for rapidly rising frequency sweeps theoretically produced simultaneous displacement maxima by canceling travel time along the cochlear partition. Rising sweeps with longer time courses only partially canceled travel time, while falling sweeps had time courses of frequency change equal to or greater than travel time. Falling sweeps thus augmented normal travel time. Latency of unit firing to sweeps across unit characteristic frequency (CF) reflected cochlear delay-line mechanics. The latency-CF functions agreed with predictions from travel-time estimates for rising-frequency sweeps, but responses to falling sweeps were less predictable. [ABSTRACT FROM AUTHOR]

• Stimulus-timing-dependent plasticity is altered in animals administered salicylate. • Cross-unit spontaneous synchrony and firing rates are increased in salicylate-induced tinnitus. • GPIAS and operant conditioning both indicate tinniutus in animals administered salicylate. • Salicylate-induced tinnitus and noise-exposure-induced tinnitus could have a similar mechanism. Following noise overexposure and tinnitus-induction, fusiform cells of the dorsal cochlear nucleus (DCN) show increased spontaneous firing rates (SFR), increased spontaneous synchrony and altered stimulus-timing-dependent plasticity (StDP), which correlate with behavioral measures of tinnitus. Sodium salicylate, the active ingredient in aspirin, which is commonly used to induce tinnitus, increases SFR and activates NMDA receptors in the ascending auditory pathway. NMDA receptor activation is required for StDP in many brain regions, including the DCN. Blocking NMDA receptors can alter StDP timing rules and decrease synchrony in DCN fusiform cells. Thus, systemic activation of NMDA receptors with sodium salicylate should elicit pathological changes to StDP, thereby increasing SFR and synchrony and induce tinnitus. Herein, we examined the action of salicylate in tinnitus generation in guinea pigs in vivo by measuring tinnitus using two behavioral measures and recording single-unit responses from DCN fusiform cells pre- and post-salicylate administration in the same animals. First, we show that animals administered salicylate show evidence of tinnitus using both behavioral paradigms, cross-validating the tests. Second, fusiform cells in animals with tinnitus showed increased SFR, synchrony and altered StDP timing rules, like animals with noise-induced tinnitus. These findings suggest that alterations to fusiform-cell plasticity are an essential component of tinnitus, regardless of induction technique. [ABSTRACT FROM AUTHOR]

Cochlear microphonic recordings from 10 guinea pig cochleas were used to infer cochlear partition displacement patterns to frequency varying signals. Rate-dependent differences between rising and falling sweeps were predicted on the basis of delay-line characteristics of the cochlear partition. The frequency responses of three basal turn locations were assessed using puretones of different frequencies. Tone sweeps with different frequency change rates (i.e., frequency endpoints were kept constant and duration was varied) were generated near the 'best-frequencies' of these regions. Responses to sweeps obtained from each electrode location were summed and the time of occurrence of cochlear microphonic maxima and minima from each location was measured relative to the other locations. The results indicate that inferred cochlear partition displacements to falling frequency sweeps occur sequentially at different points along the partition. Corresponding rising-frequency sweeps cause displacements more closely spaced in time. Displacement pattern differences occurred only at high rates of change. At low rates, cochlear partition displacements for the rising sweep disperse in time, showing the sequential pattern obtained with falling sweeps. [Work supported by NIH.] [ABSTRACT FROM AUTHOR]

Abstract: Tinnitus is the perception of sound in the absence of a physical sound stimulus. It is thought to arise from aberrant neural activity within central auditory pathways that may be influenced by multiple brain centers, including the somatosensory system. Auditory–somatosensory (bimodal) integration occurs in the dorsal cochlear nucleus (DCN), where electrical activation of somatosensory regions alters pyramidal cell spike timing and rates of sound stimuli. Moreover, in conditions of tinnitus, bimodal integration in DCN is enhanced, producing greater spontaneous and sound-driven neural activity, which are neural correlates of tinnitus. In primary auditory cortex (A1), a similar auditory–somatosensory integration has been described in the normal system (Lakatos et al., 2007), where sub-threshold multisensory modulation may be a direct reflection of subcortical multisensory responses (Tyll et al., 2011). The present work utilized simultaneous recordings from both DCN and A1 to directly compare bimodal integration across these separate brain stations of the intact auditory pathway. Four-shank, 32-channel electrodes were placed in DCN and A1 to simultaneously record tone-evoked unit activity in the presence and absence of spinal trigeminal nucleus (Sp5) electrical activation. Bimodal stimulation led to long-lasting facilitation or suppression of single and multi-unit responses to subsequent sound in both DCN and A1. Immediate (bimodal response) and long-lasting (bimodal plasticity) effects of Sp5-tone stimulation were facilitation or suppression of tone-evoked firing rates in DCN and A1 at all Sp5-tone pairing intervals (10, 20, and 40ms), and greater suppression at 20ms pairing-intervals for single unit responses. Understanding the complex relationships between DCN and A1 bimodal processing in the normal animal provides the basis for studying its disruption in hearing loss and tinnitus models. This article is part of a Special Issue entitled: Tinnitus Neuroscience. [Copyright &y& Elsevier]

Highlights • VGLUT2 puncta density is upregulated in the cochlear nucleus ipsilateral to acoustic trauma. • VGLUT1 puncta density is downregulated in the cochlear nucleus contralateral to acoustic trauma. • Tinnitus does not correlate with measures of cochlear dysfunction or histopathology. • VGLUT asymmetries are abolished upon auditory–somatosensory bimodal stimulation treatment that reversed behavioral tinnitus. • Tinnitus-associated glutamatergic redistribution is likely the result of maladaptive somatosensory compensation. Abstract Tinnitus alters auditory–somatosensory plasticity in the cochlear nucleus (CN). Correspondingly, bimodal auditory–somatosensory stimulation treatment attenuates tinnitus, both in animals and humans (Marks et al., 2018). Therefore, we hypothesized that tinnitus is associated with altered somatosensory innervation of the CN. Here, we studied the expression of vesicular glutamate transporters 1 and 2 (VGLUT1 and VGLUT2) in the CN, which reveals glutamatergic projections from the cochlea as well as somatosensory systems to this brainstem auditory center. Guinea pigs were unilaterally exposed to narrowband noise and behaviorally tested for tinnitus using gap-prepulse inhibition of the acoustic startle. Following physiological and behavioral measures, brain sections were immunohistochemically stained for VGLUT1 or VGLUT2. Puncta density was determined for each region of the ipsilateral and contralateral CN. Tinnitus was associated with an ipsilateral upregulation of VGLUT2 puncta density in the granule cell domain (GCD) and anteroventral CN (AVCN). Furthermore, there was a tinnitus-associated interaural asymmetry for VGLUT1 expression in the AVCN and deep layer of the dorsal CN (DCN3), due to contralateral downregulation of VGLUT1 expression. These tinnitus-related glutamatergic imbalances were reversed upon bimodal stimulation treatment. Tinnitus-associated ipsilateral upregulation of VGLUT2-positive projections likely derives from somatosensory projections to the GCD and AVCN. This upregulation may underlie the neurophysiological hallmarks of tinnitus in the CN. Reversing the increased ipsilateral glutamatergic innervation in the CN is likely a key mechanism in treating tinnitus. [ABSTRACT FROM AUTHOR]

In experimental animal models of auditory hair cell (HC) loss, insults such as noise or ototoxic drugs often lead to secondary changes or degeneration in non-sensory cells and neural components, including reduced density of spiral ganglion neurons, demyelination of auditory nerve fibers and altered cell numbers and innervation patterns in the cochlear nucleus (CN). However, it is not clear whether loss of HCs alone leads to secondary degeneration in these neural components of the auditory pathway. To elucidate this issue, we investigated changes of central components after cochlear insults specific to HCs using diphtheria toxin receptor (DTR) mice expressing DTR only in HCs and exhibiting complete HC loss when injected with diphtheria toxin (DT). We showed that DT-induced HC ablation has no significant impacts on the survival of auditory neurons, central synaptic terminals, and myelin, despite complete HC loss and profound deafness. In contrast, noise exposure induced significant changes in synapses, myelin and CN organization even without loss of inner HCs. We observed a decrease of neuronal size in the auditory pathway, including peripheral axons, spiral ganglion neurons, and CN neurons, likely due to loss of input from the cochlea. Taken together, selective HC ablation and noise exposure showed different patterns of pathology in the auditory pathway and the presence of HCs is not essential for the maintenance of central synaptic connectivity and myelination. [ABSTRACT FROM AUTHOR]

Neurons of the lateral olivocochlear (LOC) system project from the auditory brainstem to the cochlea, where they synapse on radial dendrites of auditory nerve fibers. Selective LOC disruption depresses sound-evoked auditory nerve activity in the guinea pig, but enhances it in the mouse. Here, LOC disruption depressed spontaneous auditory nerve activity in the guinea pig. Recordings from single auditory nerve fibers revealed a significantly reduced proportion of fibers with the highest spontaneous firing rates (SRs) and an increased proportion of neurons with lower SRs. Ensemble activity, estimated using round window noise, also decreased after LOC disruption. Decreased spontaneous activity after LOC disruption may be a consequence of reduced tonic release of excitatory transmitters from the LOC terminals in guinea pigs. [ABSTRACT FROM AUTHOR]

Tinnitus, or the phantom perception of sound, arises from pathological neural activity. Neurophysiological research has shown increased spontaneous firing rates and synchronization along the auditory pathway correlate strongly with behavioral measures of tinnitus. Auditory neurons are plastic, enabling external stimuli to be utilized to elicit long-term changes to spontaneous firing and synchrony. Pathological plasticity can thus be reversed using bimodal auditory plus nonauditory stimulation to reduce tinnitus. This chapter discusses preclinical and clinical evidence for efficacy of bimodal stimulation treatments of tinnitus, with highlights on sham-controlled, double-blinded clinical trials. The results from these studies have shown some efficacy in reducing the severity of tinnitus, based on subjective and objective outcome measures including tinnitus questionnaires and psychophysical tinnitus measurements. While results of some studies have been positive, the degree of benefit and the populations that respond to treatment vary across the studies. Directions and implications of future studies are discussed., (© 2020. Springer Nature Switzerland AG.)

Tinnitus, sound perception in the absence of physical stimuli, occurs in 15% of the population and is the top-reported disability for soldiers after combat. Noise overexposure is a major factor associated with tinnitus but does not always lead to tinnitus. Furthermore, people with normal audiograms can get tinnitus. In animal models, equivalent cochlear damage occurs in animals with and without behavioral evidence of tinnitus. But cochlear-nerve-recipient neurons in the brainstem demonstrate distinct, synchronized spontaneous firing patterns only in animals that develop tinnitus, driving activity in central brain regions and ultimately giving rise to phantom perception. Examining tinnitus-specific changes in single-cell populations enables us to begin to distinguish neural changes due to tinnitus from those that are due to hearing loss., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Tinnitus, the perception of phantom sounds, is thought to arise from increased neural synchrony, which facilitates perceptual binding and creates salient sensory features in the absence of physical stimuli. In the auditory cortex, increased spontaneous cross-unit synchrony and single-unit bursting are de facto physiological correlates of tinnitus. However, it is unknown whether neurons in the dorsal cochlear nucleus (DCN), the putative tinnitus-induction site, exhibit increased synchrony. Using a temporary-threshold shift model and gap-prepulse inhibition of the acoustic startle to assess tinnitus, we recorded spontaneous activity from fusiform cells, the principle neurons of the DCN, in normal hearing, tinnitus, and non-tinnitus guinea pigs. Synchrony and bursting, as well as spontaneous firing rate (SFR), correlated with behavioral evidence of tinnitus, and increased synchrony and bursting were associated with SFR elevation. The presence of increased synchrony and bursting in DCN fusiform cells suggests that a neural code for phantom sounds emerges in this brainstem location and likely contributes to the formation of the tinnitus percept., Significance Statement: Tinnitus, a phantom auditory percept, is encoded by pathological changes in the neural synchrony code of perceptual processing. Increased cross-unit synchrony and bursting have been linked to tinnitus in several higher auditory stations but not in fusiform cells of the dorsal cochlear nucleus (DCN), key brainstem neurons in tinnitus generation. Here, we demonstrate increased synchrony and bursting of fusiform cell spontaneous firing, which correlate with frequency-specific behavioral measures of tinnitus. Thus, the neural representation of tinnitus emerges early in auditory processing and likely drives its pathophysiology in higher structures., (Copyright © 2016 the authors 0270-6474/16/362068-06$15.00/0.)

In the normal guinea pig, contralateral sound inhibits more than a third of ventral cochlear nucleus (VCN) neurons but excites <4% of these neurons. However, unilateral conductive hearing loss (CHL) and cochlear ablation (CA) result in a major enhancement of contralateral excitation. The response properties of the contralateral excitation produced by CHL and CA are similar, suggesting similar pathways are involved for both types of hearing loss. Here we used the neurotoxin melittin to test the hypothesis that this "compensatory" contralateral excitation is mediated either by direct glutamatergic CN-commissural projections or by cholinergic neurons of the olivocochlear bundle (OCB) that send collaterals to the VCN. Unit responses were recorded from the left VCN of anesthetized, unilaterally deafened guinea pigs (CHL via ossicular disruption, or CA via mechanical destruction). Neural responses were obtained with 16-channel electrodes to enable simultaneous data collection from a large number of single- and multiunits in response to ipsi- and contralateral tone burst and noise stimuli. Lesions of each pathway had differential effects on the contralateral excitation. We conclude that contralateral excitation has a fast and a slow component. The fast excitation is likely mediated by glutamatergic neurons located in medial regions of VCN that send their commissural axons to the other CN via the dorsal/intermediate acoustic striae. The slow component is likely mediated by the OCB collateral projections to the CN. Commissural neurons that leave the CN via the trapezoid body are an additional source of fast, contralateral excitation.

Conductive hearing loss (CHL) is an attenuation of signals stimulating the cochlea, without damage to the auditory end organ. It can cause central auditory processing deficits that outlast the CHL itself. Measures of oxidative metabolism show a decrease in activity of nuclei receiving input originating at the affected ear but, surprisingly, an increase in the activity of second-order neurons of the opposite ear. In normal hearing animals, contralateral sound produces an inhibitory response to broadband noise in approximately one third of ventral cochlear nucleus (VCN) neurons. Excitatory responses also occur but are very rare. We looked for changes in the binaural properties of neurons in the VCN of guinea pigs at intervals immediately, 1 day, 1 wk, and 2 wk after the induction of a unilateral CHL by ossicular disruption. CHL was always induced in the ear ipsilateral to the VCN from which recordings were made. The main observations were as follows: 1) ipsilateral excitatory thresholds were raised by at least 40 dB; 2) contralateral inhibitory responses showed a small but statistically significant immediate decrease followed by an increase, returning to normal by 14 days; and 3) there was a large increase in the proportion of units with excitatory responses to contralateral BBN. The increase was immediate and lasting. The latencies of the excitatory responses were at least 6 ms, consistent with activation by a path involving several synapses and inconsistent with cross talk. The latencies and rate-level functions of contralateral excitation were similar to those seen occasionally in normal hearing animals, suggesting an upregulation of an existing pathway. In conclusion, contralateral excitatory inputs to the VCN exist, which are not normally effective, and can compensate rapidly for large changes in afferent input.