Auditory information relayed by auditory nerve fibers and somatosensory information relayed by gr... more 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.
Dorsal cochlear nucleus fusiform cells receive spectrally relevant auditory input for sound local... more Dorsal cochlear nucleus fusiform cells receive spectrally relevant auditory input for sound localization. r Fusiform cells integrate auditory with other multisensory inputs. r 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. r These results suggests that multisensory cues interact early in an ascending sensory pathway to serve an essential function.
In addition to ascending auditory inputs, the external cortex of the inferior colliculus (ICX) re... more In addition to ascending auditory inputs, the external cortex of the inferior colliculus (ICX) receives prominent somatosensory inputs. To elucidate the extent of interaction between auditory and somatosensory representations at the level of IC, we explored the dual projections from the cochlear nucleus (CN) and the spinal trigeminal nucleus (Sp5) to the inferior colliculus (IC) in the guinea pig, using both retrograde and anterograde tracing techniques. Injections of retrograde tracers into ICX resulted in cell-labeling primarily in the contralateral DCN and pars interpolaris and caudalis of Sp5. Labeled cells in DCN were either fusiform or multipolar cells, whereas those in Sp5 varied in size and shape. Injections of anterograde tracers into either CN or Sp5 resulted in terminal labeling in ICX primarily on the contralateral side. Most projection fibers from Sp5 terminated in a laminar pattern from ventromedial to dorsolateral within the ventrolateral ICX, the ventral border of IC, and the ventromedial edge of IC (collectively termed "the ventrolateral border region of IC," ICXV). Less dense anterograde labeling was observed in lateral and rostral ICX. Injecting different tracers into both Sp5 and CN confirmed the overlapping areas of convergent projections from Sp5 and CN in IC: The most intense dual labeling was seen in the ICXV, and less intense dual labeling was also observed in the rostral part of ICX. This convergence of projection fibers from CN and Sp5 provides an anatomical substrate for multimodal integration in the IC.
Vesicular glutamate transporters 1 and 2 (VGLUT1 and VGLUT2) have distinct distributions in the c... more Vesicular glutamate transporters 1 and 2 (VGLUT1 and VGLUT2) have distinct distributions in the cochlear nucleus that correspond to the sources of the labeled terminals. VGLUT1 is mainly associated with terminals of auditory nerve fibers, whereas VGLUT2 is mainly associated with glutamatergic terminals deriving from other sources that project to the cochlear nucleus (CN), including somatosensory and vestibular terminals. Previous studies in guinea pig have shown that cochlear damage results in a decrease of VGLUT1-labeled puncta and an increase in VGLUT2labeled puncta. This indicates cross-modal compensation that is of potential importance in somatic tinnitus. To examine whether this effect is consistent across species and to provide a background for future studies, using transgenesis, the current study examines VGLUT expression profiles upon cochlear insult by intracochlear kanamycin injections in the mouse. Intracochlear kanamycin injections abolished ipsilateral ABR responses in all animals and reduced ipsilateral spiral ganglion neuron densities in animals that were sacrificed after four weeks, but not in animals that were sacrificed after three weeks. In all unilaterally deafened animals, VGLUT1 density was decreased in CN regions that receive auditory nerve fiber terminals, i.e. in the deep layer of the dorsal cochlear nucleus (DCN), in the interstitial region where the auditory nerve enters the CN, and in the magnocellular region of the antero-and posteroventral CN. In contrast, density of VGLUT2 expression was upregulated in the fusiform cell layer of the DCN and in the granule cell lamina, which are known to receive somatosensory and vestibular terminals. These results show that a cochlear insult induces cross-modal compensation in the cochlear nucleus of the mouse, confirming previous findings in guinea pig, and that these changes are not dependent on the occurrence of spiral ganglion neuron degeneration.
In addition to input from auditory centers, the cochlear nucleus (CN) receives inputs from nonaud... more In addition to input from auditory centers, the cochlear nucleus (CN) receives inputs from nonauditory centers, including the trigeminal sensory complex. The detailed anatomy, however, and the functional implications of the nonauditory innervation of the auditory system are not fully understood. We demonstrated previously that the trigeminal ganglion projects to CN, with terminal labeling most dense in the marginal cell area and secondarily in the magnocellular area of the ventral cochlear nucleus (VCN). We continue this line of study by investigating the projection from the spinal trigeminal nucleus to CN in guinea pig. After injections of the retrograde tracers Flu-oroGold or biotinylated dextran amine (BDA) in VCN, labeled cells were found in the spinal trigeminal nuclei, most densely in the pars interpolaris and pars caudalis with ipsilateral dominance. The anterograde tracers Fluoro-Ruby or BDA were stereotaxically injected into the spinal trigeminal nucleus. Most labeled puncta were found in the marginal area of VCN and the fusiform cell layer of dorsal cochlear nucleus (DCN). A smaller number of labeled puncta was located in the molecular and deep layers of DCN and the magnocellular area of VCN. The trigeminal projection to CN may provide somatosensory information necessary for pursuing a sound source or for vocal production. These projections may have a role in the generation and modulation of tinnitus.
Multisensory integration of auditory and tactile information occurs already at the level of the c... more Multisensory integration of auditory and tactile information occurs already at the level of the cochlear nucleus. Rodents use their whiskers for tactile perception to guide them in their exploration of the world. As nocturnal animals with relatively poor vision, audiotactile interactions are of great importance for this species. Here, the influence of whisker deflections on sound-evoked spiking in the cochlear nucleus was investigated in vivo in anesthetized mice. Multichannel, silicon-probe electrophysiological recordings were obtained from both the dorsal and ventral cochlear nucleus. Whisker deflections evoked an increased spiking activity in fusiform cells of the dorsal cochlear nucleus and t-stellate cells in ventral cochlear nucleus, whereas bushy cells in the ventral cochlear nucleus showed a more variable response. The response to broadband noise stimulation increased in fusiform cells and primary-like bushy cells when the sound stimulation was preceded (~ 20 ms) by whisker stimulation. Multi-sensory integration of auditory and whisker input can thus occur already in this early brainstem nucleus, emphasizing the importance of early integration of auditory and somatosensory information. In the auditory system, integration of information from the cochlea with information from other sensory modalities begins at the earliest processing stages in the cochlear nucleus . Anatomical studies demonstrate that several somatosensory structures in the brainstem provide inputs to the cochlear nucleus (CN). These regions include the dorsal column nuclei, consisting of the gracile 7 and cuneate nuclei that receive proprioceptive and somatosensory inputs from the lower and upper body, respectively. Projections to the cochlear nucleus also arise from the spinal trigeminal nucleus 10-14 that conveys touch sensation from the face. Projections from these regions form mossy fibre inputs that synapse onto granule cells in the cochlear nucleus granule-cell domain, as well as onto dendrites of ventral cochlear nucleus (VCN) bushy cells 15 and D-stellate cells . The D-stellate cells inhibit fusiform cells in dorsal cochlear nucleus (DCN) . The parallel fibre axons of granule cells in turn provide excitatory synaptic input to DCN cartwheel and fusiform cells. The presence of somatosensory inputs to a primary auditory nucleus such as the cochlear nucleus is intriguing in the context of the role of the pinnae and neck in generating sound localization cues 16 , as well as the suppression of self-generated signals . Correct interpretation of this information requires integration of auditory signals with somatosensory and proprioceptive signals conveying information about head and pinna position. Studies in cats and guinea pigs have demonstrated that direct electrical stimulation of brainstem somatosensory nuclei evokes neuronal responses in the DCN and VCN . These data suggest that activation of CN granule cells by these somatosensory inputs excites fusiform cells and provides feedforward inhibition to fusiform cells through the inhibitory interneurons, the cartwheel cells. The association between sound and whisker stimulation may be a consequence of similar encoding mechanisms: both senses process information that produces mechanical displacements of tissue (i.e., the basilar membrane for auditory and the skin for somatosensory) and are processed in frequency based codes in the cerebral cortex 25 . Rodents use a set of roughly 30 whiskers on each side of the snout, palpating surfaces through a 5-20 Hz forward-backward motion known as "whisking" . Whisker-mediated object identification can thus be used as a model to learn more about the mechanisms of multisensory processing and the transformation of this processing to a behavioural output. In the present in vivo electrophysiology study, spiking activity was measured in spike-sorted single units, and audiotactile interaction in the mouse cochlear nucleus was investigated using whisker stimulation in combination with sound. The results suggest that whisker stimulation can modify the sound-evoked spiking activity in the cochlear nucleus.
Temporal coding of auditory stimuli is critical for understanding communication signals. The bush... more 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.
A necessary requirement for multisensory integration is the convergence of pathways from differen... more A necessary requirement for multisensory integration is the convergence of pathways from different senses. The dorsal cochlear nucleus (DCN) receives auditory input directly via the VIIIth nerve and somatosensory input indirectly from the Vth nerve via granule cells. Multisensory integration may occur in DCN cells that receive both trigeminal and auditory nerve input, such as the fusiform cell. We investigated trigeminal system influences on guinea pig DCN cells by stimulating the trigeminal ganglion while recording spontaneous and sound-driven activity from DCN neurons. A bipolar stimulating electrode was placed into the trigeminal ganglion of anesthetized guinea pigs using stereotaxic co-ordinates. Electrical stimuli were applied as bipolar pulses (100 ls per phase) with amplitudes ranging from 10 to 100 lA. Responses from DCN units were obtained using a 16-channel, four-shank electrode. Current pulses were presented alone or preceding 100-or 200-ms broadband noise (BBN) bursts. Thirty percent of DCN units showed either excitatory, inhibitory or excitatory-inhibitory responses to trigeminal ganglion stimulation. When paired with BBN stimulation, trigeminal stimulation suppressed or facilitated the firing rate in response to BBN in 78% of units, reflecting multisensory integration. Pulses preceding the acoustic stimuli by as much as 95 ms were able to alter responses to BBN. Bimodal suppression may play a role in attenuating body-generated sounds, such as vocalization or respiration, whereas bimodal enhancement may serve to direct attention in low signal-to-noise environments.
In experimental animal models of auditory hair cell (HC) loss, insults such as noise or ototoxic ... more 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. 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 cochlear nucleus 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.
This article covers the convergence of auditory and somatosensory information at various levels o... more This article covers the convergence of auditory and somatosensory information at various levels of the auditory nervous system, from the brain stem and midbrain to the cortex. In the auditory cortex, multisensory neurons are found in the border regions surrounding the auditory cortex, and are capable of integrating information from each modality. Similarly, the external nucleus of the inferior colliculus plays a predominant role in integrating somatosensory and auditory inputs, as do the shell regions of the cochlear nucleus (CN) that surround the core regions. Examples of anatomical convergence to each of these areas from somatosensory nuclei are provided as well as physiological descriptions of how this information is integrated.
ur es: and interpolar regions of the spinal trigeminal nucleus (Sp5I and Sp5C). These projections... more ur es: and interpolar regions of the spinal trigeminal nucleus (Sp5I and Sp5C). These projections terminate primarily in the granule cell domain, but also in magnocellular regions of the ventral and dorsal CN. Additionally, new evidence is presented demonstrating that cells in the colliculus (IC), superior colliculus (SC) and auditory cor- ple, the trigeminal ganglion (TG), dorsal column nuclei and interpolar and caudal spinal trigeminal nuclei send Shore, 2004; Shore, 2005) suggest that these projections may be involved in mechanisms related to suppression of self-generated sounds such as respiration, chewing or self-vocalizations. Sp5C, pars caudalis of spinal trigeminal nucleus; Sp5I, pars interpolaris of spinal trigeminal nucleus; Sp5O, pars oralis of spinal trigeminal nucleus; TG, trigeminal ganglion; VCN, ventral cochlear nucleus
The Oxford Handbook of the Auditory Brainstem, 2018
As the first brain station in the auditory neuraxis, the cochlear nucleus integrates information ... more As the first brain station in the auditory neuraxis, the cochlear nucleus integrates information from the cochlea with multimodal information from somatosensory ganglia and brainstem nuclei, as well as motor systems. Fusiform cells in the dorsal division of the cochlear nucleus receive auditory nerve fiber synapses on their basal dendrites and multimodal synapses on their apical dendrites via granule-cell axons. Multimodal integration in fusiform cells is modified by inhibitory interneurons in a cerebellar-like arrangement. Like other cerebellar-like brain circuits, fusiform cells exhibit spike-timing-dependent plasticity, or STDP, which is reflected in vivo as stimulus-timing-dependent plasticity or StDP. This chapter describes how fusiform-cell circuitry uses STDP to process multisensory information. StDP disruption results in tinnitus, or phantom sound perception, which can be alleviated through circuit modulation to restore normal plasticity.
Jaro-journal of The Association for Research in Otolaryngology, Jun 24, 2010
The cochlear nucleus (CN) is the first auditory structure to receive binaural information via CN-... more The cochlear nucleus (CN) is the first auditory structure to receive binaural information via CN-commissural connections. In spite of an abundance of evidence that CN-commissural neurons are glycinergic and thus inhibitory, physiological, and anatomical evidence suggests that a small group of CN-commissural neurons are excitatory. In this study, we examined the excitatory portion of the CN-commissural pathway by combining anterograde tract tracing with immunohistochemistry of vesicular glutamate transporters (VGLUTs) and retrograde tract tracing with immunohistochemistry of glycine and GABA. VGLUTs accumulate glutamate in synaptic vesicles and are prime markers for glutamatergic neurons. The terminal endings of CN-commissural projections were typically en passant or small terminal boutons, but large, irregular swellings were also observed, confined to the granule cell domain (GCD). Both small and large terminal endings in the GCD colabeled with VGLUT2, but not VGLUT1. In addition, some CN-commissural cells themselves received VGLUT2-positive puncta on their somata. After large injections into the CN, 37% of the total number of retrogradely labeled commissural neurons was immunonegative to glycine or GABA. Retrograde labeling after a restricted GCD injection revealed a majority of putative excitatory CN-commissural neurons as multipolar, in the marginal regions of the ventral CN, medially as well as in the small cell cap region and deep dorsal CN. These results provide direct anatomical evidence that an excitatory commissural projection is present, and VGLUT2 is associated with this pathway both as its source and as a recipient.
Tinnitus is the perception of sound in the absence of a physical sound stimulus. It is thought to... more 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), 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 Sp5tone pairing intervals (10, 20, & 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.
The dorsal cochlear nucleus (DCN) is the first neural site of bimodal auditory-somatosensory inte... more The dorsal cochlear nucleus (DCN) is the first neural site of bimodal auditory-somatosensory integration. Previous studies have shown that stimulation of somatosensory pathways results in immediate suppression or enhancement of subsequent acoustically evoked discharges. In the unimpaired auditory system suppression predominates. However, damage to the auditory input pathway leads to enhancement of excitatory somatosensory inputs to the cochlear nucleus, changing their effects on DCN neurons (Shore et al., 2008; Zeng et al., 2009). Given the well described connection between the somatosensory system and tinnitus in patients we sought to determine whether plastic changes in long-lasting bimodal somatosensory-auditory processing accompany tinnitus. Here we demonstrate for the first time in vivo long-term effects of somatosensory inputs on acoustically evoked discharges of DCN neurons in guinea pigs. The effects of trigeminal nucleus stimulation are compared between normal-hearing animals and animals overexposed with narrow band noise and behaviorally tested for tinnitus. The noise exposure resulted in a temporary threshold shift in auditory brainstem responses but a persistent increase in spontaneous and sound-evoked DCN unit firing rates and increased steepness of rate-level functions. Rate increases were especially prominent in buildup units. The long-term somatosensory enhancement of sound-evoked responses was strengthened while suppressive effects diminished in noise-exposed animals, especially those that developed tinnitus. Damage to the auditory nerve is postulated to trigger compensatory long-term synaptic plasticity of somatosensory inputs that might be an important underlying mechanism for tinnitus generation.
The cochlear nucleus (CN) receives innervation from auditory and somatosensory structures, which ... more The cochlear nucleus (CN) receives innervation from auditory and somatosensory structures, which can be identified using vesicular glutamate transporters, VGLUT1 and VGLUT2. VGLUT1 is highly expressed in the magnocellular ventral CN (VCN), which receives auditory nerve inputs. VGLUT2 is predominantly expressed in the granule cell domain (GCD), which receives nonauditory inputs from somatosensory nuclei, including spinal trigeminal nucleus (Sp5) and cuneate nucleus (Cu). Two weeks after unilateral deafening VGLUT1 is significantly decreased in ipsilateral VCN while VGLUT2 is significantly increased in the ipsilateral GCD (Zeng et al., 2009), putatively reflecting decreased inputs from auditory nerve and increased inputs from nonauditory structures in guinea pigs. Here, we wished to determine whether the upregulation of VGLUT2 represents increases in the number of somatosensory projections to the CN that are maintained for longer periods of time. Thus, we examined concurrent changes in VGLUT levels and somatosensory projections in the CN using immunohistochemistry combined with anterograde tract tracing three and six weeks following unilateral deafening. The data reveal that unilateral deafness leads to increased numbers of VGLUT2-colabeled Sp5 and Cu projections to the ventral and dorsal CN. These findings suggest that Sp5 and Cu play significant and unique roles in cross-modal compensation and that, unlike after shorter term deafness, neurons in the magnocellular regions also participate in the compensation. The enhanced glutamatergic somatosensory projections to the CN may play a role in neural spontaneous hyperactivity associated with tinnitus.
Integration of multimodal information is essential for understanding complex environments. In the... more Integration of multimodal information is essential for understanding complex environments. In the auditory system, multisensory integration first occurs in the cochlear nucleus (CN), where auditory nerve and somatosensory pathways converge (Shore, 2005). A unique feature of multisensory neurons is their propensity to receive cross-modal compensation after deafening. Based on our findings that the vesicular glutamate transporters, VGLUT1 and VGLUT2, are differentially associated with auditory nerve and somatosensory inputs to the CN, respectively (Zhou et al., 2007), we examined their relative distributions after unilateral deafening. After unilateral intracochlear injections of kanamycin (1 and 2 weeks), VGLUT1 immunoreactivity (ir) in the magnocellular CN ipsilateral to the cochlear damage was significantly decreased, whereas VGLUT2-ir in regions that receive nonauditory input was significantly increased 2 weeks after deafening. The pathway-specific amplification of VGLUT2 expression in the CN suggests that, in compensatory response to deafening, the nonauditory influence on CN is significantly enhanced. One undesirable consequence of enhanced glutamatergic inputs could be the increased spontaneous rates in CN neurons that occur after hearing loss and that have been proposed as correlates of the phantom auditory sensations commonly called tinnitus.
Tinnitus has been associated with enhanced central gain manifested by increased spontaneous activ... more 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.
Auditory information relayed by auditory nerve fibers and somatosensory information relayed by gr... more 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.
Dorsal cochlear nucleus fusiform cells receive spectrally relevant auditory input for sound local... more Dorsal cochlear nucleus fusiform cells receive spectrally relevant auditory input for sound localization. r Fusiform cells integrate auditory with other multisensory inputs. r 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. r These results suggests that multisensory cues interact early in an ascending sensory pathway to serve an essential function.
In addition to ascending auditory inputs, the external cortex of the inferior colliculus (ICX) re... more In addition to ascending auditory inputs, the external cortex of the inferior colliculus (ICX) receives prominent somatosensory inputs. To elucidate the extent of interaction between auditory and somatosensory representations at the level of IC, we explored the dual projections from the cochlear nucleus (CN) and the spinal trigeminal nucleus (Sp5) to the inferior colliculus (IC) in the guinea pig, using both retrograde and anterograde tracing techniques. Injections of retrograde tracers into ICX resulted in cell-labeling primarily in the contralateral DCN and pars interpolaris and caudalis of Sp5. Labeled cells in DCN were either fusiform or multipolar cells, whereas those in Sp5 varied in size and shape. Injections of anterograde tracers into either CN or Sp5 resulted in terminal labeling in ICX primarily on the contralateral side. Most projection fibers from Sp5 terminated in a laminar pattern from ventromedial to dorsolateral within the ventrolateral ICX, the ventral border of IC, and the ventromedial edge of IC (collectively termed "the ventrolateral border region of IC," ICXV). Less dense anterograde labeling was observed in lateral and rostral ICX. Injecting different tracers into both Sp5 and CN confirmed the overlapping areas of convergent projections from Sp5 and CN in IC: The most intense dual labeling was seen in the ICXV, and less intense dual labeling was also observed in the rostral part of ICX. This convergence of projection fibers from CN and Sp5 provides an anatomical substrate for multimodal integration in the IC.
Vesicular glutamate transporters 1 and 2 (VGLUT1 and VGLUT2) have distinct distributions in the c... more Vesicular glutamate transporters 1 and 2 (VGLUT1 and VGLUT2) have distinct distributions in the cochlear nucleus that correspond to the sources of the labeled terminals. VGLUT1 is mainly associated with terminals of auditory nerve fibers, whereas VGLUT2 is mainly associated with glutamatergic terminals deriving from other sources that project to the cochlear nucleus (CN), including somatosensory and vestibular terminals. Previous studies in guinea pig have shown that cochlear damage results in a decrease of VGLUT1-labeled puncta and an increase in VGLUT2labeled puncta. This indicates cross-modal compensation that is of potential importance in somatic tinnitus. To examine whether this effect is consistent across species and to provide a background for future studies, using transgenesis, the current study examines VGLUT expression profiles upon cochlear insult by intracochlear kanamycin injections in the mouse. Intracochlear kanamycin injections abolished ipsilateral ABR responses in all animals and reduced ipsilateral spiral ganglion neuron densities in animals that were sacrificed after four weeks, but not in animals that were sacrificed after three weeks. In all unilaterally deafened animals, VGLUT1 density was decreased in CN regions that receive auditory nerve fiber terminals, i.e. in the deep layer of the dorsal cochlear nucleus (DCN), in the interstitial region where the auditory nerve enters the CN, and in the magnocellular region of the antero-and posteroventral CN. In contrast, density of VGLUT2 expression was upregulated in the fusiform cell layer of the DCN and in the granule cell lamina, which are known to receive somatosensory and vestibular terminals. These results show that a cochlear insult induces cross-modal compensation in the cochlear nucleus of the mouse, confirming previous findings in guinea pig, and that these changes are not dependent on the occurrence of spiral ganglion neuron degeneration.
In addition to input from auditory centers, the cochlear nucleus (CN) receives inputs from nonaud... more In addition to input from auditory centers, the cochlear nucleus (CN) receives inputs from nonauditory centers, including the trigeminal sensory complex. The detailed anatomy, however, and the functional implications of the nonauditory innervation of the auditory system are not fully understood. We demonstrated previously that the trigeminal ganglion projects to CN, with terminal labeling most dense in the marginal cell area and secondarily in the magnocellular area of the ventral cochlear nucleus (VCN). We continue this line of study by investigating the projection from the spinal trigeminal nucleus to CN in guinea pig. After injections of the retrograde tracers Flu-oroGold or biotinylated dextran amine (BDA) in VCN, labeled cells were found in the spinal trigeminal nuclei, most densely in the pars interpolaris and pars caudalis with ipsilateral dominance. The anterograde tracers Fluoro-Ruby or BDA were stereotaxically injected into the spinal trigeminal nucleus. Most labeled puncta were found in the marginal area of VCN and the fusiform cell layer of dorsal cochlear nucleus (DCN). A smaller number of labeled puncta was located in the molecular and deep layers of DCN and the magnocellular area of VCN. The trigeminal projection to CN may provide somatosensory information necessary for pursuing a sound source or for vocal production. These projections may have a role in the generation and modulation of tinnitus.
Multisensory integration of auditory and tactile information occurs already at the level of the c... more Multisensory integration of auditory and tactile information occurs already at the level of the cochlear nucleus. Rodents use their whiskers for tactile perception to guide them in their exploration of the world. As nocturnal animals with relatively poor vision, audiotactile interactions are of great importance for this species. Here, the influence of whisker deflections on sound-evoked spiking in the cochlear nucleus was investigated in vivo in anesthetized mice. Multichannel, silicon-probe electrophysiological recordings were obtained from both the dorsal and ventral cochlear nucleus. Whisker deflections evoked an increased spiking activity in fusiform cells of the dorsal cochlear nucleus and t-stellate cells in ventral cochlear nucleus, whereas bushy cells in the ventral cochlear nucleus showed a more variable response. The response to broadband noise stimulation increased in fusiform cells and primary-like bushy cells when the sound stimulation was preceded (~ 20 ms) by whisker stimulation. Multi-sensory integration of auditory and whisker input can thus occur already in this early brainstem nucleus, emphasizing the importance of early integration of auditory and somatosensory information. In the auditory system, integration of information from the cochlea with information from other sensory modalities begins at the earliest processing stages in the cochlear nucleus . Anatomical studies demonstrate that several somatosensory structures in the brainstem provide inputs to the cochlear nucleus (CN). These regions include the dorsal column nuclei, consisting of the gracile 7 and cuneate nuclei that receive proprioceptive and somatosensory inputs from the lower and upper body, respectively. Projections to the cochlear nucleus also arise from the spinal trigeminal nucleus 10-14 that conveys touch sensation from the face. Projections from these regions form mossy fibre inputs that synapse onto granule cells in the cochlear nucleus granule-cell domain, as well as onto dendrites of ventral cochlear nucleus (VCN) bushy cells 15 and D-stellate cells . The D-stellate cells inhibit fusiform cells in dorsal cochlear nucleus (DCN) . The parallel fibre axons of granule cells in turn provide excitatory synaptic input to DCN cartwheel and fusiform cells. The presence of somatosensory inputs to a primary auditory nucleus such as the cochlear nucleus is intriguing in the context of the role of the pinnae and neck in generating sound localization cues 16 , as well as the suppression of self-generated signals . Correct interpretation of this information requires integration of auditory signals with somatosensory and proprioceptive signals conveying information about head and pinna position. Studies in cats and guinea pigs have demonstrated that direct electrical stimulation of brainstem somatosensory nuclei evokes neuronal responses in the DCN and VCN . These data suggest that activation of CN granule cells by these somatosensory inputs excites fusiform cells and provides feedforward inhibition to fusiform cells through the inhibitory interneurons, the cartwheel cells. The association between sound and whisker stimulation may be a consequence of similar encoding mechanisms: both senses process information that produces mechanical displacements of tissue (i.e., the basilar membrane for auditory and the skin for somatosensory) and are processed in frequency based codes in the cerebral cortex 25 . Rodents use a set of roughly 30 whiskers on each side of the snout, palpating surfaces through a 5-20 Hz forward-backward motion known as "whisking" . Whisker-mediated object identification can thus be used as a model to learn more about the mechanisms of multisensory processing and the transformation of this processing to a behavioural output. In the present in vivo electrophysiology study, spiking activity was measured in spike-sorted single units, and audiotactile interaction in the mouse cochlear nucleus was investigated using whisker stimulation in combination with sound. The results suggest that whisker stimulation can modify the sound-evoked spiking activity in the cochlear nucleus.
Temporal coding of auditory stimuli is critical for understanding communication signals. The bush... more 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.
A necessary requirement for multisensory integration is the convergence of pathways from differen... more A necessary requirement for multisensory integration is the convergence of pathways from different senses. The dorsal cochlear nucleus (DCN) receives auditory input directly via the VIIIth nerve and somatosensory input indirectly from the Vth nerve via granule cells. Multisensory integration may occur in DCN cells that receive both trigeminal and auditory nerve input, such as the fusiform cell. We investigated trigeminal system influences on guinea pig DCN cells by stimulating the trigeminal ganglion while recording spontaneous and sound-driven activity from DCN neurons. A bipolar stimulating electrode was placed into the trigeminal ganglion of anesthetized guinea pigs using stereotaxic co-ordinates. Electrical stimuli were applied as bipolar pulses (100 ls per phase) with amplitudes ranging from 10 to 100 lA. Responses from DCN units were obtained using a 16-channel, four-shank electrode. Current pulses were presented alone or preceding 100-or 200-ms broadband noise (BBN) bursts. Thirty percent of DCN units showed either excitatory, inhibitory or excitatory-inhibitory responses to trigeminal ganglion stimulation. When paired with BBN stimulation, trigeminal stimulation suppressed or facilitated the firing rate in response to BBN in 78% of units, reflecting multisensory integration. Pulses preceding the acoustic stimuli by as much as 95 ms were able to alter responses to BBN. Bimodal suppression may play a role in attenuating body-generated sounds, such as vocalization or respiration, whereas bimodal enhancement may serve to direct attention in low signal-to-noise environments.
In experimental animal models of auditory hair cell (HC) loss, insults such as noise or ototoxic ... more 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. 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 cochlear nucleus 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.
This article covers the convergence of auditory and somatosensory information at various levels o... more This article covers the convergence of auditory and somatosensory information at various levels of the auditory nervous system, from the brain stem and midbrain to the cortex. In the auditory cortex, multisensory neurons are found in the border regions surrounding the auditory cortex, and are capable of integrating information from each modality. Similarly, the external nucleus of the inferior colliculus plays a predominant role in integrating somatosensory and auditory inputs, as do the shell regions of the cochlear nucleus (CN) that surround the core regions. Examples of anatomical convergence to each of these areas from somatosensory nuclei are provided as well as physiological descriptions of how this information is integrated.
ur es: and interpolar regions of the spinal trigeminal nucleus (Sp5I and Sp5C). These projections... more ur es: and interpolar regions of the spinal trigeminal nucleus (Sp5I and Sp5C). These projections terminate primarily in the granule cell domain, but also in magnocellular regions of the ventral and dorsal CN. Additionally, new evidence is presented demonstrating that cells in the colliculus (IC), superior colliculus (SC) and auditory cor- ple, the trigeminal ganglion (TG), dorsal column nuclei and interpolar and caudal spinal trigeminal nuclei send Shore, 2004; Shore, 2005) suggest that these projections may be involved in mechanisms related to suppression of self-generated sounds such as respiration, chewing or self-vocalizations. Sp5C, pars caudalis of spinal trigeminal nucleus; Sp5I, pars interpolaris of spinal trigeminal nucleus; Sp5O, pars oralis of spinal trigeminal nucleus; TG, trigeminal ganglion; VCN, ventral cochlear nucleus
The Oxford Handbook of the Auditory Brainstem, 2018
As the first brain station in the auditory neuraxis, the cochlear nucleus integrates information ... more As the first brain station in the auditory neuraxis, the cochlear nucleus integrates information from the cochlea with multimodal information from somatosensory ganglia and brainstem nuclei, as well as motor systems. Fusiform cells in the dorsal division of the cochlear nucleus receive auditory nerve fiber synapses on their basal dendrites and multimodal synapses on their apical dendrites via granule-cell axons. Multimodal integration in fusiform cells is modified by inhibitory interneurons in a cerebellar-like arrangement. Like other cerebellar-like brain circuits, fusiform cells exhibit spike-timing-dependent plasticity, or STDP, which is reflected in vivo as stimulus-timing-dependent plasticity or StDP. This chapter describes how fusiform-cell circuitry uses STDP to process multisensory information. StDP disruption results in tinnitus, or phantom sound perception, which can be alleviated through circuit modulation to restore normal plasticity.
Jaro-journal of The Association for Research in Otolaryngology, Jun 24, 2010
The cochlear nucleus (CN) is the first auditory structure to receive binaural information via CN-... more The cochlear nucleus (CN) is the first auditory structure to receive binaural information via CN-commissural connections. In spite of an abundance of evidence that CN-commissural neurons are glycinergic and thus inhibitory, physiological, and anatomical evidence suggests that a small group of CN-commissural neurons are excitatory. In this study, we examined the excitatory portion of the CN-commissural pathway by combining anterograde tract tracing with immunohistochemistry of vesicular glutamate transporters (VGLUTs) and retrograde tract tracing with immunohistochemistry of glycine and GABA. VGLUTs accumulate glutamate in synaptic vesicles and are prime markers for glutamatergic neurons. The terminal endings of CN-commissural projections were typically en passant or small terminal boutons, but large, irregular swellings were also observed, confined to the granule cell domain (GCD). Both small and large terminal endings in the GCD colabeled with VGLUT2, but not VGLUT1. In addition, some CN-commissural cells themselves received VGLUT2-positive puncta on their somata. After large injections into the CN, 37% of the total number of retrogradely labeled commissural neurons was immunonegative to glycine or GABA. Retrograde labeling after a restricted GCD injection revealed a majority of putative excitatory CN-commissural neurons as multipolar, in the marginal regions of the ventral CN, medially as well as in the small cell cap region and deep dorsal CN. These results provide direct anatomical evidence that an excitatory commissural projection is present, and VGLUT2 is associated with this pathway both as its source and as a recipient.
Tinnitus is the perception of sound in the absence of a physical sound stimulus. It is thought to... more 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), 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 Sp5tone pairing intervals (10, 20, & 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.
The dorsal cochlear nucleus (DCN) is the first neural site of bimodal auditory-somatosensory inte... more The dorsal cochlear nucleus (DCN) is the first neural site of bimodal auditory-somatosensory integration. Previous studies have shown that stimulation of somatosensory pathways results in immediate suppression or enhancement of subsequent acoustically evoked discharges. In the unimpaired auditory system suppression predominates. However, damage to the auditory input pathway leads to enhancement of excitatory somatosensory inputs to the cochlear nucleus, changing their effects on DCN neurons (Shore et al., 2008; Zeng et al., 2009). Given the well described connection between the somatosensory system and tinnitus in patients we sought to determine whether plastic changes in long-lasting bimodal somatosensory-auditory processing accompany tinnitus. Here we demonstrate for the first time in vivo long-term effects of somatosensory inputs on acoustically evoked discharges of DCN neurons in guinea pigs. The effects of trigeminal nucleus stimulation are compared between normal-hearing animals and animals overexposed with narrow band noise and behaviorally tested for tinnitus. The noise exposure resulted in a temporary threshold shift in auditory brainstem responses but a persistent increase in spontaneous and sound-evoked DCN unit firing rates and increased steepness of rate-level functions. Rate increases were especially prominent in buildup units. The long-term somatosensory enhancement of sound-evoked responses was strengthened while suppressive effects diminished in noise-exposed animals, especially those that developed tinnitus. Damage to the auditory nerve is postulated to trigger compensatory long-term synaptic plasticity of somatosensory inputs that might be an important underlying mechanism for tinnitus generation.
The cochlear nucleus (CN) receives innervation from auditory and somatosensory structures, which ... more The cochlear nucleus (CN) receives innervation from auditory and somatosensory structures, which can be identified using vesicular glutamate transporters, VGLUT1 and VGLUT2. VGLUT1 is highly expressed in the magnocellular ventral CN (VCN), which receives auditory nerve inputs. VGLUT2 is predominantly expressed in the granule cell domain (GCD), which receives nonauditory inputs from somatosensory nuclei, including spinal trigeminal nucleus (Sp5) and cuneate nucleus (Cu). Two weeks after unilateral deafening VGLUT1 is significantly decreased in ipsilateral VCN while VGLUT2 is significantly increased in the ipsilateral GCD (Zeng et al., 2009), putatively reflecting decreased inputs from auditory nerve and increased inputs from nonauditory structures in guinea pigs. Here, we wished to determine whether the upregulation of VGLUT2 represents increases in the number of somatosensory projections to the CN that are maintained for longer periods of time. Thus, we examined concurrent changes in VGLUT levels and somatosensory projections in the CN using immunohistochemistry combined with anterograde tract tracing three and six weeks following unilateral deafening. The data reveal that unilateral deafness leads to increased numbers of VGLUT2-colabeled Sp5 and Cu projections to the ventral and dorsal CN. These findings suggest that Sp5 and Cu play significant and unique roles in cross-modal compensation and that, unlike after shorter term deafness, neurons in the magnocellular regions also participate in the compensation. The enhanced glutamatergic somatosensory projections to the CN may play a role in neural spontaneous hyperactivity associated with tinnitus.
Integration of multimodal information is essential for understanding complex environments. In the... more Integration of multimodal information is essential for understanding complex environments. In the auditory system, multisensory integration first occurs in the cochlear nucleus (CN), where auditory nerve and somatosensory pathways converge (Shore, 2005). A unique feature of multisensory neurons is their propensity to receive cross-modal compensation after deafening. Based on our findings that the vesicular glutamate transporters, VGLUT1 and VGLUT2, are differentially associated with auditory nerve and somatosensory inputs to the CN, respectively (Zhou et al., 2007), we examined their relative distributions after unilateral deafening. After unilateral intracochlear injections of kanamycin (1 and 2 weeks), VGLUT1 immunoreactivity (ir) in the magnocellular CN ipsilateral to the cochlear damage was significantly decreased, whereas VGLUT2-ir in regions that receive nonauditory input was significantly increased 2 weeks after deafening. The pathway-specific amplification of VGLUT2 expression in the CN suggests that, in compensatory response to deafening, the nonauditory influence on CN is significantly enhanced. One undesirable consequence of enhanced glutamatergic inputs could be the increased spontaneous rates in CN neurons that occur after hearing loss and that have been proposed as correlates of the phantom auditory sensations commonly called tinnitus.
Tinnitus has been associated with enhanced central gain manifested by increased spontaneous activ... more 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.
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Papers by Susan Shore