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Abstract: Interactions between somatosensory and auditory systems occur at peripheral levels in the central nervous system. The cochlear nucleus (CN) receives innervation from trigeminal sensory structures: the ophthalmic division of the trigeminal ganglion and the caudal 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 lateral paragiganticular regions of the reticular formation (RF) also project to the CN. Not unlike the responses obtained from electrically stimulating the trigeminal system, stimulating RF regions can also result in excitation/inhibition of dorsal CN neurons. The origins and central connections of these projection neurons are associated with systems controlling vocalization and respiration. Electrical stimulation of trigeminal and RF projection neurons can suppress acoustically driven activity of not only CN neurons, but also neurons in the inferior colliculus. Together with the anatomical observations, these physiological observations suggest that one function of somatosensory input to the auditory system is to suppress responses to “expected” body-generated sounds such as vocalization or respiration. This would serve to enhance responses to “unexpected” externally-generated sounds, such as the vocalizations of other animals. [Copyright &y& Elsevier]

A projection from the trigeminal ganglion to the ventral cochlear nucleus (VCN) of the guinea pig was recently described. The synaptic terminals of this projection terminate in the granule and magnocellular regions of the VCN. Stimulation of this projection has been shown to result in activation of neurons of the ventral cochlear nucleus. We investigated the effect of electrically stimulating the trigeminal ganglion on the central auditory system activity using 2-deoxyglucose (2-DG) autoradiographic techniques. Electrical stimuli were applied to the left trigeminal ganglion as bipolar pulses, 100 μs per phase, at intervals of 200 ms and an amplitude of 100 μA. Negative control animals were not stimulated. A positive control animal was stimulated in the left ear using a 1 kHz tone burst with 200 ms duration and an amplitude of 80 dB SPL. 2-DG was administered by intramuscular injection. Following a 1 h incorporation period, animals were sacrificed, the brains rapidly harvested, and prepared for autoradiography using standard techniques. Autoradiographs were analyzed using computer-assisted video densitometry to determine film optical density in the central auditory regions of interest. The cerebellum was also sampled as a gray matter indifferent intra-brain control region. Results showed systematic and significant differences between 2-DG uptake in the cochlear nucleus and higher auditory centers between control and stimulated animals. Trigeminally stimulated animals showed significantly higher uptake than unstimulated animals in all auditory centers examined, especially ipsilateral to the stimulation site. The activation pattern differs qualitatively from that seen with sound stimulation in that mainly contralateral pathways are activated with sound stimulation. These results demonstrate that a projection from the predominantly somatosensory trigeminal ganglion can influence the activity of central auditory neurons in a manner distinct from acoustic stimulation, suggesting activation of non-classical auditory pathways. [Copyright &y& Elsevier]

• 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]

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]

Tinnitus, the phantom perception of sound, is physiologically characterized by an increase in spontaneous neural activity in the central auditory system. However, as tinnitus is often associated with hearing impairment, it is unclear how a decrease of afferent drive can result in central hyperactivity. In this review, we first assess methods for tinnitus induction and objective measures of the tinnitus percept in animal models. From animal studies, we discuss evidence that tinnitus originates in the cochlear nucleus (CN), and hypothesize mechanisms whereby hyperactivity may develop in the CN after peripheral auditory nerve damage. We elaborate how this process is likely mediated by plasticity of auditory–somatosensory integration in the CN: the circuitry in normal circumstances maintains a balance of auditory and somatosensory activities, and loss of auditory inputs alters the balance of auditory somatosensory integration in a stimulus timing dependent manner, which propels the circuit towards hyperactivity. Understanding the mechanisms underlying tinnitus generation is essential for its prevention and treatment. This article is part of a Special Issue entitled . [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]