Show Summary Details

Page of

PRINTED FROM OXFORD HANDBOOKS ONLINE ( © Oxford University Press, 2018. All Rights Reserved. Under the terms of the licence agreement, an individual user may print out a PDF of a single chapter of a title in Oxford Handbooks Online for personal use (for details see Privacy Policy and Legal Notice).

date: 26 May 2019

Multimodal Inputs to the Cochlear Nucleus and Their Role in the Generation of Tinnitus

Abstract and Keywords

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.

Keywords: tinnitus, stimulus-timing-dependent plasticity, STDP, cochlear nucleus, multisensory integration, vesicular glutamate transporter, long-term potentiation/depression, synchrony, SFR

Multimodal Innervation of the Cochlear Nucleus

The cochlear nucleus (CN) is the obligatory central site in the brain for all cochlear-auditory nerve synapses. It is also the first central auditory site for multimodal integration, receiving projections from non-auditory brain areas, including the trigeminal ganglion (Shore, 2005; Shore, Vass, Wys, & Altschuler, 2000), spinal trigeminal nucleus (Sp5), cuneate (cu) and gracile nuclei (C. A. Haenggeli, Pongstaporn, Doucet, & Ryugo, 2005; H. Li & Mizuno, 1997; Wright & Ryugo, 1996; Zhou & Shore, 2004), cervical nerves (Zhan, Pongstaporn, & Ryugo, 2006), vestibular afferents and nuclei (Bukowska, 2002; Burian & Gstoettner, 1988), and the pontine nuclei (PN; Babalian, 2005; Ohlrogge, Doucet, & Ryugo, 2001). Synapses from these regions project to the granule cell domain (GCD) and are primarily located on CN granule cells in the marginal area of ventral CN (VCN) and the dorsal CN (DCN), but can also be found on the cell bodies and dendrites of large cells in the magnocellular VCN (Alibardi, 2004; C. Haenggeli, Doucet, & Ryugo, 2002; Ohlrogge et al., 2001; Wright & Ryugo, 1996) as well as Golgi cells and unipolar brush cells in the deep layers of DCN (Mugnaini et al., 1980b; Mugnaini et al., 1980a; Dino and Mugnaini, 2008. Projections from the somatosensory ganglia and brainstem nuclei have primarily been studied using tract tracing but were identified as glutamatergic using electron microscopy and by co-labeling with vesicular glutamate transporters (VGluTs; Zhou & Shore, 2004). In contrast to the cochlear auditory nerve fibers, whose synaptic terminals co-label with the isoform VGluT1, multimodal synaptic terminals in the CN co-label primarily with VGluT2 (Zeng, Shroff, & Shore, 2011; Zhou, Zeng, Cui, & Shore, 2010).

Electrically stimulating multimodal projections, such as somatosensory nuclei/dorsal column nuclei/or the PN, activates granule cells via VGluT2 positive terminals (Barker et al., 2012; Burian & Gstoettner, 1988; Zhou, Nannapaneni, & Shore, 2007). The parallel-fiber axons of granule cells, in turn, depolarize the principal output neurons of DCN, the fusiform cells, as well as inhibitory interneurons, the cartwheel cell (Golding & Oertel, 1997), via their apical dendrites. In contrast, sound activates the VGluT1 positive auditory nerve fibers, which contact the basal dendrites of fusiform cells (Voigt & Young, 1988). Both sound and multimodal inputs activate cartwheel cell via presumed descending projections (Parham & Kim, 1995; Portfors & Roberts, 2007) and parallel-fiber inputs, respectively, to cartwheel-cell apical dendrites. Cartwheel cells provide feed-forward or lateral inhibition to fusiform cells (Roberts & Trussell, 2010). The DCN, thus is similar to cerebellar circuits by virtue of granule cell activation of parallel fiber inputs to apical dendrites of fusiform cell and cartwheel-cell apical dendrites, and the feed forward inhibition of fusiform cells by cartwheel cells (Oertel & Young, 2004). See Figure 1 for a schematic of multimodal inputs to the CN circuit.

Multimodal Inputs to the Cochlear Nucleus and Their Role in the Generation of TinnitusClick to view larger

Figure 1. Multimodal integration in cochlear nucleus circuitry.

Stimulation of multimodal projections (spinal trigeminal (Sp5); dorsal column (DCoN); pontine (PN)) activates granule cells (gr) via VGluT2+ terminals (yellow). Gr-pf axons depolarize fusiform cells and cartwheel cells via apical dendrites (plastic synapse). Sound activates fusiform cells via VGluT 1+ (green) auditory nerve fiber (ANF) contacts on basal dendrites (non-plastic synapse). Bimodal plasticity of fusiform cell spontaneous or sound-driven firing rates is achieved by integration of ANF and multimodal inputs through StDP. Synapses on cartwheel cells (CWCs) in vitro demonstrate STDP. Sound and multimodal inputs activate CWCs via presumed descending and gr-pf inputs, respectively, to CWC apical dendrites. CWCs provide feed forward or lateral inhibition to fusiform cells. Bushy cells are excited by sound via ANF-VGluT 1+ somatic inputs and Sp5/Cu/PN-VGluT 2+ somatic and dendritic inputs.

Multimodal Inputs Induce Long-Term Plasticity in the DCN

Parallel-fiber axons of the CN granule cells thus transmit the bulk of multimodal information to DCN fusiform cells and their inhibitory interneurons, cartwheel cells (CWCs; Dino & Mugnaini, 2008; Mugnaini, Osen, Dahl, Friedrich, & Korte, 1980; Mugnaini, Warr, & Osen, 1980). Synapses from parallel fibers onto the apical dendrites of fusiform and cartwheel cells exhibit Ca2+-dependent long-term potentiation (LTP) and depression (LTD; Fujino & Oertel, 2003). But whether LTP or LTD occurs depends on spike timing (Tzounopoulos, Kim, Oertel, & Trussell, 2004) and can follow classical Hebbian or anti-Hebbian rules. In Hebbian plasticity, when presynaptic spikes are followed by postsynaptic spikes LTP occurs and conversely when postsynaptic spikes precede presynaptic spikes LTD occurs. In contrast, in anti-Hebbian plasticity, when presynaptic spikes precede postsynaptic spikes LTD occurs, and when postsynaptic spikes precede presynaptic spikes LTP follow. This process is termed spike-timing-dependent plasticity (STDP). Thus, STDP is a process whereby synapses are strengthened or weakened depending on the temporal pattern of pre- and postsynaptic events driving the cell (Bi & Poo, 1998; Tzounopoulos et al., 2004; Figure 2).

Multimodal Inputs to the Cochlear Nucleus and Their Role in the Generation of TinnitusClick to view larger

Figure 2. Fusiform cells exhibit spike-timing-dependent plasticity (STDP) at their apical dendrites.

A) In fusiform cells, apical-fiber synapses that repetitively elicit a post-synaptic spike can enhance the amplitude of the resulting EPSP (red), a process termed long-term potentiation (LTP). In contrast, spikes that precede apical fiber input EPSPs l reduce the amplitude of resultant ESPSs (blue), a process termed long-term depression (LTD). B) Timing rules, or the percentage change in EPSP amplitude over a repeated EPSP-spike pairing, quantify STDP. Positive x-axis values indicate EPSPs before spikes and negative values indicate spikes before EPSPs.

In vivo the macroscopic equivalent of STDP—stimulus timing dependent plasticity (StDP; S. D. Koehler & S. E. Shore, 2013a) —is elicited by electrically stimulating multimodal inputs that depolarize the parallel fiber synapses onto fusiform-cell apical dendrites, (the presynaptic events), in temporal proximity to sound stimulation, which activates spikes in the postsynaptic fusiform cell. A plot of changes in fusiform-cell firing rate after bimodal stimulation in which change in firing rate is plotted as a function of bimodal interval reveals the “learning rule.” StDP manifests primarily as Hebbian plasticity across a population of fusiform cells (S. D. Koehler & S. E. Shore, 2013b). But it can also manifest as anti-Hebbian plasticity, either as “enhancing” (potentiating) plasticity, in which response rate is increased after bimodal stimulation at all bimodal intervals, or as “suppressing” (depressing) plasticity in which response rate is suppressed at all bimodal intervals (S. D. Koehler & S. E. Shore, 2013a), as shown in Figure 3. StDP can be achieved using deep brain stimulation of brainstem nuclei combined with auditory stimulation (Koehler & Shore, 2013), or trans-cutaneous stimulation of the cheek overlying the trigeminal ganglion, or on the neck region above the C2 cervical ganglion, combined with sound (Wu, Martel, & Shore, 2015a; Figure 4). Interestingly, in vivo, whether Hebbian or anti-Hebbian plasticity arises also depends on tone duration (e.g., compare Figure 3, using 50 ms tones to Figure 4, using either 10 or 50 ms tones combined with electrical stimulation) demonstrating that fusiform-cell circuit plasticity exhibits context-dependence which could enhance or diminish the salience of multimodal stimuli. However, the observation that stimulation of fusiform cells with auditory stimuli alone does not result in long-term effects (Figure 4E, F), whereas unimodal somatosensory stimulation (deep brain and transdermal) do result in LTP (S. D. Koehler & S. E. Shore, 2013b; Wu et al., 2015a), is consistent with in vitro findings of plasticity at apical but not basal fusiform-cell dendrites (Fujino & Oertel, 2003). This suggests that coding of unimodal auditory stimuli by the fusiform-cell circuit is not context-dependent.

Multimodal Inputs to the Cochlear Nucleus and Their Role in the Generation of TinnitusClick to view larger

Figure 3. Fusiform cells show variable individual timing rules in vivo.

Responses of fusiform cells to 50 ms BF tones before and 5, 15, or 25 min after bimodal stimulation (deep brain, Sp5+tone at BF). Change in firing rate (from before to after bimodal stimulation) is plotted for 4 different fusiform cells for 6 different bimodal intervals. Positive x-axis values indicate sound before somatosensory stimulation; negative values indicate somatosensory before sound stimulation. The bimodal interval (BI) was randomly varied from somatosensory preceding sound by 40 ms to somatosensory following the onset of sound by 40 ms. Examples show units with Hebbian-like or Anti-Hebbian-like stimulus-timing dependence, and enhancing-only or suppressing-only stimulus-timing dependence. Blue, red, and green lines indicate the change in firing rate 5, 15, and 25 minutes after bimodal stimulation, respectively. Figure reproduced with permission from Koehler and Shore, 2013a.

Multimodal Inputs to the Cochlear Nucleus and Their Role in the Generation of TinnitusClick to view larger

Figure 4. Transdermal stimulation elicits StDP with context-dependent learning rules.

Trigeminal (Tg) stimulation in guinea pigs via a transdermal cheek electrode elicits anti-Hebbian learning rules following A) 10 ms pairing tone (PT) stimulation, or Hebbian learning rules following B) 50 ms pairing tone. Dorsal column (DCo) stimulation produces similar tone-duration-dependent learning rules (C, D). Regardless of somatosensory stimulation location E) or pairing-tone duration F), unimodal somatosensory (red) and auditory (blue) stimulation did not produce significant changes in fusiform cell firing compared to baseline, but bimodal stimulation did (black). Figure reproduced with permission from Wu et al., 2015a.

Function of Multimodal Inputs to the Dorsal Cochlear Nucleus

As in other cerebellar-like circuits, the DCN is thought to adjust perception by incorporating predictive signals from the somatosensory system (Bell, Han, Sugawara, & Grant, 1997; Nelson, 2004). Internally generated sounds that arise from movement, as in head orientation, vocalization or chewing, recruit the somatosensory system, producing near-coincident auditory and somatosensory inputs to DCN. The circuit adaptively adjusts fusiform-cell output to amplify external (unpredicted) auditory cues while subtracting internally generated sounds. This process likely involves voluntary motor commands processed by the PN, which, in addition to relaying cortical motor efferent projections to the cerebellum, sends projections to the GCD (Babalian, 2005; Ohlrogge et al., 2001), thereby routing motor information to the DCN. Thus, the incorporation of motor as well as sensory information into this circuit may be fundamental for sound localization in the vertical plane (Davis, Ramachandran, & May, 2003; May, 2000) and for suppression of body-generated sounds, in addition to the acknowledged role of the trigeminal brainstem nucleus (Requarth & Sawtell, 2011; Singla, Dempsey, Warren, Enikolopov, & Sawtell, 2017).

Mechanisms Underlying StDP in DCN Fusiform Cells

StDP has been demonstrated in vivo in fusiform cells (S. D. Koehler & S. E. Shore, 2013a) using deep brain electrical-somatosensory stimulation combined with sound stimulation (Dehmel, Pradhan, Koehler, Bledsoe, & Shore, 2012; S. D. Koehler & S. E. Shore, 2013a), as well as transdermal electrical stimulation of the somatosensory system combined with sound stimulation (Wu et al., 2015a). In vitro, the development of STDP requires activation of NMDA and muscarinic cholinergic receptors as well as endocannabinoid receptors (Perez-Rosello et al., 2013; Sedlacek, Tipton, & Brenowitz, 2011; Zhao & Tzounopoulos, 2011). Likewise, in vivo studies show that blocking both AChRs and NMDARs (Stefanescu & Shore, 2015; Figure 5) results in significant alterations in the StDP “learning rules,” which mimic learning rule changes after tinnitus-induction (see next section; S. D. Koehler & S. E. Shore, 2013b; Stefanescu, Koehler, & Shore, 2015; Wu et al., 2015a). NMDARs may be involved in limiting plasticity in response to repeated unimodal stimulation because NMDAR antagonists unmask unimodal plasticity not previously observed in the normal animal (Stefanescu & Shore, 2015). While muscarinic AChR agonists might thus enhance bimodal plasticity, NMDAR antagonists could provide a way to induce plasticity with unimodal stimuli as well as bimodal stimuli.

Multimodal Inputs to the Cochlear Nucleus and Their Role in the Generation of TinnitusClick to view larger

Figure 5. Blocking NMDA and acetylcholine receptors alters StDP.

StDP timing rules were changed from Hebbian at baseline (black) to anti-Hebbian post-infusion (red) of A) CPP, an NMDA receptor antagonist, and B) atropine, an ACh receptor antagonist. Figure reproduced with permission from Stefanescu and Shore, 2015.

The Role of Feed Forward Inhibition and Retrograde Signaling in STDP

As shown in vitro, Hebbian plasticity increases synapse strength when presynaptic EPSPs are paired with post-synaptic spikes, while anti-Hebbian plasticity reduces synapse strength (Abbott & Nelson, 2000; Markram, Lubke, Frotscher, & Sakmann, 1997; Tzounopoulos et al., 2004). Both Hebbian and anti-Hebbian plasticity likely enable the fusiform cells to alter synapse strength to adaptively enhance fusiform-cell responses to external sounds while decreasing synaptic strength to decrease responses to self-generated sounds, similar to the electric eel’s electrosensory lobe (Bell, 1981; Bell et al., 1997; Singla et al., 2017).

Fusiform cells exhibiting Hebbian-like learning rules in vivo show predominantly excitatory receptive fields, while those with anti-Hebbian-like learning rules show more inhibition in their receptive fields (Koehler & Shore, 2013a; Koehler & Shore, 2013b). Computational models of cerebellar-like circuits, which are like the DCN fusiform-cell circuit, demonstrate that inhibition is essential for stabilizing network dynamics by preventing “run-away” excitation (Isaacson & Scanziani, 2011; Luz & Shamir, 2012; Moore, Carlen, Knoblich, & Cardin, 2010). The structural similarity of other cerebellar-like circuits to the DCN (Froemke, Letzkus, Kampa, Hang, & Stuart, 2010), including hippocampus (Magee & Johnston, 1997; Song, Miller, & Abbott, 2000), neocortex (Min & Nevian, 2012; Sarihi et al., 2008) and amygdala (Mahanty & Sah, 1998), suggests that inhibition could also influence STDP in these circuits.

In vitro, parallel-fiber inputs that trigger Ca2+ influx into the fusiform cell after post-synaptic NMDA-receptor activation elicit Hebbian plasticity in fusiform cells, but anti-Hebbian plasticity in cartwheel cells (Tzounopoulos et al., 2004; Tzounopoulos, Rubio, Keen, & Trussell, 2007). Differential expression of presynaptic neuromodulator receptors in cartwheel and fusiform cells can help explain these learning-rule differences. For example, endocannabinoid receptors that hyperpolarize pre-synaptic terminals are more numerous in parallel fiber terminals on cartwheel-cell dendrites than on fusiform-cell dendrites (Zhao, Rubio, & Tzounopoulos, 2011). Sustained parallel-fiber EPSPs, leading to post-synaptic Ca2+ release in fusiform cells, would tend to elicit Hebbian plasticity. However, in the cartwheel cell, sustained Ca2+ release coupled with muscarinic AChR activation retrogradely activates pre-synaptic endocannabinoid receptors on parallel fibers, thereby suppressing glutamate release from their synaptic terminals (Sedlacek et al., 2011) thus converting Hebbian plasticity into anti-Hebbian plasticity (Zhao & Tzounopoulos, 2011). By altering STDP timing rules through differential activation of these receptors, the fusiform-cell circuit exhibits input-selective gain-control. This gain-control process allows single fusiform cells to learn new stimulus representations through Hebbian plasticity, while anti-Hebbian plasticity attenuates circuit responses when external contexts change (S. D. Koehler & S. E. Shore, 2013a).

In vivo, fusiform cells exhibit a complex mixture of Hebbian and anti-Hebbian plasticity compared to in vitro preparations of isolated neural circuits (Figure 3; . Koehler & Shore, 2013a; Wu, Martel, & Shore, 2015). In normal hearing animals, fusiform cells show predominantly Hebbian timing rules, although a sizeable fraction also undergoes anti-Hebbian rules. However, the proportions of learning-rule types can change depending on the environmental context, which influences differential activation of inhibition. For instance, tone duration can modulate whether a given fusiform cell exhibits Hebbian or anti-Hebbian plasticity. Short-duration tones elicit opposite learning rules to those elicited by long-duration tones (Wu, Martel & Shore, 2015). By activating feed-forward inhibition by cartwheel cells for a longer time, longer tones can result in delayed firing in fusiform cells. A similar firing delay occurs through inactivation of A-type potassium channels (Kanold & Manis, 1999; Manis, 1990). This in turn alters the timing of post-synaptic spikes relative to the presynaptic, parallel-fiber events. In visual cortex, feed forward inhibition of pyramidal neurons can also change plasticity from LTP to LTD, and vice-versa (Vogels et al., 2013; L. Wang, Fontanini, & Maffei, 2012). Switches between LTP and LTD require Ca2+ influx via NMDAR activation (Kurotani, Yamada, Yoshimura, Crair, & Komatsu, 2008), which then triggers retrograde co-activation of endocannabinoid receptors (Maejima, Hashimoto, Yoshida, Aiba, & Kano, 2001; Nevian & Sakmann, 2006; Rodriguez-Moreno & Paulsen, 2008; Sjostrom, Turrigiano, & Nelson, 2003), as in the fusiform-cell circuit.

Computational studies have shown that StDP-like learning rules can regulate responses of parallel arrays of neurons, through a process similar to classical lateral inhibition (Masquelier, Guyonneau, & Thorpe, 2009). Inputs that consistently trigger spikes from a specific neuron in an array strengthen that neuron’s response (Hebbian plasticity). With lateral inhibition, the neuron’s response becomes stronger compared to that of neighboring neurons. Thus, individual neurons in the array can tune their outputs to sharpen the output of the entire array in response to specific inputs. Repeating this process over the elements of the array allows the array to enhance the salience of many different stimuli, even in the presence of a noisy signal. By enhancing firing of information-conveying neurons and reducing activity of neighboring neurons, StDP-mediated lateral inhibition provides a mechanism for eliciting array responses tuned to specific stimuli (Cohen & Mizrahi, 2015). In the DCN, StDP-mediated lateral inhibition could sharpen responses of fusiform cell arrays to aid in the computation of spectral-notch information for sound localization, particularly during head motion relative to a sound source (Hofman, Van Riswick, & Van Opstal, 1998; Populin & Yin, 1998),

The fusiform-cell circuit also uses StDP in the suppression of self-generated sounds. To demonstrate this effect, Singla et al. (2017) recorded the activity of DCN fusiform cells and VCN cells while mice were licking from a water spout. When the mice were actively licking, DCN responses were dampened, while VCN responses remained robust. However, when the recorded “licking sound” was played back to the mice in the absence of licking behavior, responses in VCN and DCN responses to the sound both remained robust. Furthermore, blocking spinal trigeminal inputs to the CN with Lidocaine resulted in significant increases in fusiform cell firing that correlated with lick-generated sounds. These findings demonstrate how the fusiform cells use multisensory information to adaptively cancel out self-generated sounds.

Alterations to the DCN Circuit in Tinnitus

Neural signatures of tinnitus include increased spontaneous firing rate (SFR), increased synchrony across fusiform cell pairs and increased bursting from individual fusiform cells with BFs in tinnitus frequency regions (Figure 6A–C). Furthermore, fusiform cells from noise-exposed animals with behavioral signs of tinnitus exhibit broader StDP timing rules with more LTP-eliciting bimodal intervals (Koehler & Shore, 2013b; (Figure 6D). In contrast, fusiform cells in noise-exposed animals that do not develop signs of tinnitus show more bimodal intervals eliciting LTD (Koehler & Shore, 2013b; Marks et al., 2018; Wu, Martel, & Shore, 2016). This pattern reflects a hyperexcitable CN circuit in animals with tinnitus compared to those in animals without tinnitus and normal hearing animals, a finding which has also been described by other studies (Dehmel et al., 2012; Li, Choi, & Tzounopoulos, 2013; Li, Kalappa, & Tzounopoulos, 2015; Middleton et al., 2011; Pilati, Large, Forsythe, & Hamann, 2012). When the fusiform cell circuit is in a hyperexcitable and hypersynchronous state, spontaneous activity is theoretically “bound” into an auditory object that the brain interprets as a phantom sound (Singer, 1999). Tinnitus-related alterations in fusiform-cell multisensory integration predict a somatosensory element in tinnitus, consistent with observations that over two thirds of tinnitus sufferers can modulate the pitch and/or intensity of their tinnitus through muscular contractions (R. A. Levine, 1999; Levine, Nam, Oron, & Melcher, 2007; Wu, Stefanescu, Martel, & Shore, 2014). Interestingly, some humans without tinnitus can induce transient tinnitus through somatic manipulations of the head and neck (Abel & Levine, 2004). These findings suggest a fundamental role for the DCN fusiform-cell circuit role in the generation and ultimately treatment of tinnitus (Marks et al., 2018).

Multimodal Inputs to the Cochlear Nucleus and Their Role in the Generation of TinnitusClick to view larger

Figure 6. Neural signatures of tinnitus in fusiform cells.

Compared to non-exposed controls (NE, black) and noise-overexposed no-tinnitus (ENT, blue) animals, noise-overexposed animals that develop tinnitus (ET, red) show increased tinnitus indices (TI) that correlate with A) spontaneous firing rates (SFR), B) pairwise-unit synchrony, and C) single-unit bursting. D) Percent change in fusiform-cell firing rate to a BF tone 15 min. after auditory-somatosensory bimodal stimulation as a function of bimodal interval. Negative intervals indicate auditory (sound) before somatosensory; positive intervals indicate somatosensory before auditory (sound) stimulation. Somatosensory stimulation was transdermal (200 µsec) with electrodes overlying the C2–4 vertebrae. Non-exposed control animals (N) had anti-Hebbian rules; exposed, tinnitus animals (ET) had Hebbian or enhancing rules (indicating a strengthened circuit). Exposed, no-tinnitus animals (ENT) had suppressing timing rules. Figures reproduced with permission from Wu et al., 2016, and Koehler and Shore, 2013b.

As the first obligatory central nucleus in the auditory pathway, increased and synchronous spontaneous activity in the fusiform cell circuit propagates up the ascending auditory pathway. Indeed, DCN ablation has been suggested to prevent noise-overexposure induced tinnitus (Brozoski, Wisner, Sybert, & Bauer, 2012). Thus, it would be expected that target nuclei in the auditory neuraxis would also show tinnitus-related increases in SFR and synchrony. This prediction is consistent with studies in the medial geniculate body (MGB; Kalappa, Brozoski, Turner, & Caspary, 2014) and auditory cortex (Engineer et al., 2011), which show that increased SFR, synchrony and behavioral measures of tinnitus are correlated. However, studies in the inferior colliculus (IC) complicate this picture. Several studies have shown that enhanced spontaneous activity does not appear to be directly related to noise- induced tinnitus (Berger, Coomber, Wells, Wallace, & Palmer, 2014; Mulders & Robertson, 2009; Ropp, Tiedemann, Young, & May, 2014). Other studies of IC neurons suggest that increased synchrony correlates with tinnitus only in the external nucleus (Bauer, Turner, Caspary, Myers, & Brozoski, 2008). Sturm, Zhang-Hooks, Roos, Nguyen, and Kandler (2017) showed that in tinnitus animals, changes in excitatory as well as inhibitory synaptic strength do occur in the central nucleus and that these magnitude and direction of these changes depend on whether the postsynaptic neuron is excitatory or inhibitory, leading to an overall increase in net excitation of the IC. Mere increased SFR in IC might reflect generalized hyperactivity that is a consequence of noise exposure (Ma, Hidaka, & May, 2006; Manzoor, Gao, Licari, & Kaltenbach, 2013), while tinnitus arises from pathological enhancement of spontaneous synchrony. These findings suggest that both increased SFR and synchrony across a population of neurons are necessary for tinnitus, and that the CN is a likely candidate for its generation.

Disinhibition-Mediated Synchrony

Other studies have shown that fusiform cells show altered glycine-receptor expression in animals with evidence of tinnitus (Wang et al., 2009), perhaps driving the circuit to produce more spikes. Increased fusiform-cell spiking increases the probability that a pre-synaptic event will correlate with a spike, thereby biasing the circuit toward LTP. This process is termed disinhibition-mediated LTP (Ormond & Woodin, 2009, 2011). Disinhibition-mediated LTP in the DCN circuit could strengthen LTP across groups of fusiform cells, producing the enhanced synchrony observed in tinnitus (Shore, Roberts, & Langguth, 2016; Wu et al., 2016). Similarly, in the hippocampus, a cerebellar-like circuit, disinhibition mediates LTP by rapidly activating NMDA receptors and upregulating pyramidal-cell firing before inhibition prevents EPSP generation (Ormond & Woodin, 2009, 2011). This process requires circuitry with coordinated regulation of excitatory/inhibitory plasticity. Like the hippocampus, the fusiform-cell-circuit parallel fibers concurrently activate fusiform cells and their inhibitory interneuron cartwheel cells (Oertel & Young, 2004; Tzounopoulos et al., 2004).

Multimodal Influences on Tinnitus Generation by CN Neurons

Following acoustic insult, auditory nerve input to CN is reduced by deafferentation (Zeng, Nannapaneni, Zhou, Hughes, & Shore, 2009), but central changes that result in physiological correlates of tinnitus—increased spontaneous activity (SA), synchrony and bursting—develop over time (Kaltenbach, Zhang, & Finlayson, 2005; Salvi, Wang, & Ding, 2000; Wu et al., 2016). The somatosensory system compensates for the reduced auditory nerve input to the cochlear nucleus by upregulating its excitatory input and altering StDP-mediated auditory- somatosensory plasticity in the DCN (Dehmel et al., 2012; S. D. Koehler & S. E. Shore, 2013b; Shore, Koehler, Oldakowski, Hughes, & Syed, 2008; Zeng, Yang, Shreve, Bledsoe, & Shore, 2012a), providing a physiological basis for “somatic” (Abel & Levine, 2004; R. Levine, 1999) and perhaps most forms of tinnitus. The upregulation of somatosensory projections from Sp5 and Cu to the CN (Shore & Zhou, 2006; Zeng et al., 2012a) as well as alterations in NMDA and ACh receptors (Sefanescu & Shore, 2015; Stefanescu & Shore, 2017) likely contribute to tinnitus development by altering fusiform cell StDP in the somatosensory –parallel-fiber circuits (Figure 2 Figure 5; Dehmel et al., 2012; S. D. Koehler & S. E. Shore, 2013b; Zeng et al., 2009; Zeng et al., 2012a). Clinical reports of additional tinnitus modulators such as eye gaze or balance (Said, Izita, Gonzalez, & Tovar, 2006; Wall, Rosenberg, & Richardson, 1987) also implicate the motor system, consistent with brain-imaging studies demonstrating motor system deficits in tinnitus subjects (Benninger et al., 2011). These cases suggest that the motor system may play a previously unappreciated role in mediating tinnitus, as a major recipient of PN output, the cerebellum, has been proposed as a putative tinnitus generation site (Bauer, Kurt, Sybert, & Brozoski, 2013).

What Happens to Fusiform Cells in an Animal Model of Tinnitus?

Terminal endings from Sp5 and Cu are increased in number after cochlear damage (Zeng, Yang, Shreve, Bledsoe, & Shore, 2012b). Vesicular glutamate transporter1 (Vglut1), which co-labels with AN terminals (Zhou et al., 2007), was decreased following cochlear damage, while Vglut2, which co-labels with somatosensory inputs (Zhou et al., 2010), was significantly increased in regions receiving somatosensory inputs in guinea pigs (Zeng et al., 2012a) and mice (Heeringa, Stefanescu, Raphael, & Shore, 2016). Four sources of Vglut2-positive inputs to the CN have been identified: Sp5 (Zhou et al., 2007); contralateral CN (Zhou et al., 2010), cu (Zeng et al., 2011) and PN (preliminary data). The increased number of somatosensory inputs to the granule-PF-fusiform cell circuit likely contributes to the alterations in StDP observed after noise induced tinnitus (Dehmel et al., 2012; S. Koehler & S. Shore, 2013) by differentially driving up EPSPs in fusiform-cell apical dendrites compared to cartwheel cell apical dendrites.

Reversing StDP, Synchrony and Spontaneous Rates to Treat Tinnitus

StDP inversions associated with tinnitus can be reversed by repeated daily stimulation with a bimodal stimulus shown to induce LTD in guinea pigs (Marks et al., 2018). In the study by Marks et al. (2018), the bimodal auditory-somatosensory stimulus was presented to guinea pigs with behavioral evidence of tinnitus under the assumption that repeated induction of LTD in the fusiform-cell circuit would reduce spontaneous rates and synchrony and lead to tinnitus reduction. The prediction was borne out and demonstrated that just 4 weeks of this specialized stimulation was sufficient to reduce tinnitus in all the animals. As predicted by the circuitry, unimodal auditory stimulation that activates the non-plastic basal dendrites of fusiform cells had no effect on spontaneous rates or tinnitus. Unimodal somatosensory stimulation predictably enhanced spontaneous rates and worsened tinnitus. Given the significant results of bimodal stimulation in the animal model, 20 human subjects with somatic tinnitus were treated with the same bimodal stimulus for 4 weeks with the same result: The bimodal stimulus resulted in significant and cumulative reductions in tinnitus loudness and discomfort in the human subjects, whereas the unimodal auditory stimulation had no effect. The unimodal somatosensory stimulation was not employed in the human study as it had been shown to have a deleterious effect in animals (Marks et al., 2018). This study demonstrates that systematic study of circuitry involved in generating tinnitus can lead to potential treatments for tinnitus in humans by reversing circuit plasticity through bimodal stimulation.

Concluding Remarks

This chapter has outlined how a complex cerebellar-like circuit, the fusiform-cell circuit in the DCN, is involved in fundamental processes for localizing sounds in space and suppression of self-generated signals, and how disruption of the circuit hampers function essential for survival. Through processes of multisensory integration and long-term plasticity, the circuit dampens internally generated sounds, thereby enhancing the salience of sounds. When normal auditory processing is disrupted by deafferentation, the fusiform-cell circuit undergoes homeostatic plasticity that interacts with underlies timing-dependent plasticity to render the circuit hyperexcitable and leads to the development of tinnitus. Remarkably, the same plastic mechanisms that drive tinnitus can be reversed to treat this debilitating condition.


Abbott, L. F., & Nelson, S. B. (2000). Synaptic plasticity: Taming the beast. Nature Neuroscience, 3 Suppl, 1178–1183. doi:10.1038/81453Find this resource:

Abel, M. D., & Levine, R. A. (2004). Muscle contractions and auditory perception in tinnitus patients and nonclinical subjects. Cranio, 22(3), 181–191.Find this resource:

Alibardi, L. (2004). Mossy fibers in granule cell areas of the rat dorsal cochlear nucleus from intrinsic and extrinsic origin innervate unipolar brush cell glomeruli. Journal of Submicroscopic Cytology and Pathology, 36(2), 193–210.Find this resource:

Babalian, A. L. (2005). Synaptic influences of pontine nuclei on cochlear nucleus cells. Experimental Brain Research, 167(3), 451–457. doi:10.1007/s00221-005-0178-8Find this resource:

Barker, M., Solinski, H. J., Hashimoto, H., Tagoe, T., Pilati, N., & Hamann, M. (2012). Acoustic overexposure increases the expression of VGLUT-2 mediated projections from the lateral vestibular nucleus to the dorsal cochlear nucleus. PLoS One, 7(5), e35955. doi:10.1371/journal.pone.0035955 PONE-D-11-18058 [pii]Find this resource:

Bauer, C. A., Kurt, W., Sybert, L. T., & Brozoski, T. J. (2013). The cerebellum as a novel tinnitus generator. Hearing Research, 295, 130–139.Find this resource:

Bauer, C. A., Turner, J. G., Caspary, D. M., Myers, K. S., & Brozoski, T. J. (2008). Tinnitus and inferior colliculus activity in chinchillas related to three distinct patterns of cochlear trauma. Journal of Neuroscience Research, 86(11), 2564–2578. doi:10.1002/jnr.21699Find this resource:

Bell, C. C. (1981). An efference copy which is modified by reafferent input. Science, 214(4519), 450–453.Find this resource:

Bell, C. C., Han, V. Z., Sugawara, Y., & Grant, K. (1997). Synaptic plasticity in a cerebellum-like structure depends on temporal order. Nature, 387(6630), 278–281. doi:10.1038/387278a0Find this resource:

Benninger, D. H., Berman, B. D., Houdayer, E., Pal, N., Luckenbaugh, D. A., Schneider, L., … Hallett, M. (2011). Intermittent theta-burst transcranial magnetic stimulation for treatment of Parkinson disease. Neurology, 76(7), 601–609. doi:10.1212/WNL.0b013e31820ce6bb 76/7/601 [pii]Find this resource:

Berger, J. I., Coomber, B., Wells, T. T., Wallace, M. N., & Palmer, A. R. (2014). Changes in the response properties of inferior colliculus neurons relating to tinnitus. Frontiers in Neurology, 5, 203. doi:10.3389/fneur.2014.00203Find this resource:

Bi, G. Q., & Poo, M. M. (1998). Synaptic modifications in cultured hippocampal neurons: Dependence on spike timing, synaptic strength, and postsynaptic cell type. Journal of Neuroscience, 18(24), 10464–10472.Find this resource:

Brozoski, T. J., Wisner, K. W., Sybert, L. T., & Bauer, C. A. (2012). Bilateral dorsal cochlear nucleus lesions prevent acoustic-trauma induced tinnitus in an animal model. Journal of the Association for Research in Otolaryngology, 13(1), 55–66. doi:10.1007/s10162-011-0290-3Find this resource:

Bukowska, D. (2002). Morphological evidence for secondary vestibular afferent connections to the dorsal cochlear nucleus in the rabbit. Cells, Tissues, Organs, 170(1), 61–68. doi:47921 [pii] 47921Find this resource:

Burian, M., & Gstoettner, W. (1988). Projection of primary vestibular afferent fibres to the cochlear nucleus in the guinea pig. Neuroscience Letters, 84(1), 13–17. doi:0304-3940(88)90329-1 [pii]Find this resource:

Cohen, L., & Mizrahi, A. (2015). Plasticity during motherhood: Changes in excitatory and inhibitory layer 2/3 neurons in auditory cortex. Journal of Neuroscience, 35(4), 1806–1815. doi:10.1523/JNEUROSCI.1786-14.2015Find this resource:

Davis, K. A., Ramachandran, R., & May, B. J. (2003). Auditory processing of spectral cues for sound localization in the inferior colliculus. Journal of the Association for Research Otolaryngologists, 4(2), 148–163. doi:10.1007/s10162-002-2002-5Find this resource:

Dehmel, S., Pradhan, S., Koehler, S., Bledsoe, S., & Shore, S. (2012). Noise overexposure alters long-term somatosensory-auditory processing in the dorsal cochlear nucleus—possible basis for tinnitus-related hyperactivity? Journal of Neuroscience, 32(5), 1660–1671. doi:10.1523/JNEUROSCI.4608-11.2012Find this resource:

Dino, M. R., & Mugnaini, E. (2008). Distribution and phenotypes of unipolar brush cells in relation to the granule cell system of the rat cochlear nucleus. Neuroscience. doi:S0306-4522(08)00108-5 [pii] 10.1016/j.neuroscience.2008.01.035Find this resource:

Engineer, N. D., Riley, J. R., Seale, J. D., Vrana, W. A., Shetake, J. A., Sudanagunta, S. P., … Kilgard, M. P. (2011). Reversing pathological neural activity using targeted plasticity. Nature, 470(7332), 101–104. doi:nature09656 [pii] 10.1038/nature09656Find this resource:

Froemke, R. C., Letzkus, J. J., Kampa, B. M., Hang, G. B., & Stuart, G. J. (2010). Dendritic synapse location and neocortical spike-timing-dependent plasticity. Frontiers in Synaptic Neuroscience, 2, 29. doi:10.3389/fnsyn.2010.00029Find this resource:

Fujino, K., & Oertel, D. (2003). Bidirectional synaptic plasticity in the cerebellum-like mammalian dorsal cochlear nucleus. Proceedings of the National Academy of Sciences of the United States of America, 100(1), 265–270.Find this resource:

Golding, N. L., & Oertel, D. (1997). Physiological identification of the targets of cartwheel cells in the dorsal cochlear nucleus. Journal of Neurophysiology, 78(1), 248–260.Find this resource:

Haenggeli, C., Doucet, J., & Ryugo, D. (2002). Trigeminal projections to the cochlear nucleus in rats. Abstracts for the Association for Research in Otolaryngology, 25, 7.Find this resource:

Haenggeli, C. A., Pongstaporn, T., Doucet, J. R., & Ryugo, D. K. (2005). Projections from the spinal trigeminal nucleus to the cochlear nucleus in the rat. Journal of Comparative Neurology, 484(2), 191–205. doi:10.1002/cne.20466Find this resource:

Heeringa, A., Stefanescu, R. A., Raphael, Y., & Shore, S. (2016). Altered vesicular glutamate transporter distributions in the mouse cochlear nucleus following cochlear insult. Neuroscience,325, 119.Find this resource:

Hofman, P. M., Van Riswick, J. G., & Van Opstal, A. J. (1998). Relearning sound localization with new ears. Nature Neuroscience, 1(5), 417–421. doi:10.1038/1633Find this resource:

Isaacson, J. S., & Scanziani, M. (2011). How inhibition shapes cortical activity. Neuron, 72(2), 231–243. doi:10.1016/j.neuron.2011.09.027Find this resource:

Kalappa, B. I., Brozoski, T. J., Turner, J. G., & Caspary, D. M. (2014). Single unit hyperactivity and bursting in the auditory thalamus of awake rats directly correlates with behavioural evidence of tinnitus. Journal of Physiology, 592(Pt 22), 5065–5078. doi:10.1113/jphysiol.2014.278572Find this resource:

Kaltenbach, J. A., Zhang, J., & Finlayson, P. (2005). Tinnitus as a plastic phenomenon and its possible neural underpinnings in the dorsal cochlear nucleus. Hearing Research, 206(1–2), 200–226. doi:S0378-5955(05)00078-X [pii] 10.1016/j.heares.2005.02.013Find this resource:

Kanold, P. O., & Manis, P. B. (1999). Transient potassium currents regulate the discharge patterns of dorsal cochlear nucleus pyramidal cells. Journal of Neuroscience, 19(6), 2195–2208.Find this resource:

Koehler, S., & Shore, S. (2013). Stimulus timing-dependent plasticity in dorsal cochlear nucleus is altered in tinnitus. Journal of Neuroscience, 33(50), 19647–19656.Find this resource:

Koehler, S. D., & Shore, S. E. (2013a). Stimulus-timing dependent multisensory plasticity in the guinea pig dorsal cochlear nucleus. PLoS One, 8(3), e59828. doi:10.1371/journal.pone.0059828Find this resource:

Koehler, S. D., & Shore, S. E. (2013b). Stimulus timing-dependent plasticity in dorsal cochlear nucleus is altered in tinnitus. Journal of Neuroscience, 33(50), 19647–19656. doi:10.1523/JNEUROSCI.2788-13.2013 33/50/19647 [pii]Find this resource:

Kurotani, T., Yamada, K., Yoshimura, Y., Crair, M. C., & Komatsu, Y. (2008). State-dependent bidirectional modification of somatic inhibition in neocortical pyramidal cells. Neuron, 57(6), 905–916. doi:10.1016/j.neuron.2008.01.030Find this resource:

Levine, R. (1999). Somatic modulation of tinnitus appears to be a fundamental attribute of tinnitus. Proceedings of the 6th International Tinnitus Seminar, Cambridge England, 1, 93–197.Find this resource:

Levine, R. A. (1999). Somatic (craniocervical) tinnitus and the dorsal cochlear nucleus hypothesis. American Journal of Otolaryngology, 20(6), 351–362.Find this resource:

Levine, R. A., Nam, E. C., Oron, Y., & Melcher, J. R. (2007). Evidence for a tinnitus subgroup responsive to somatosensory based treatment modalities. Progress in Brain Research, 166, 195–207. doi:S0079-6123(07)66017-8 [pii] 10.1016/S0079-6123(07)66017-8Find this resource:

Li, H., & Mizuno, N. (1997). Single neurons in the spinal trigeminal and dorsal column nuclei project to both the cochlear nucleus and the inferior colliculus by way of axon collaterals: A fluorescent retrograde double-labeling study in the rat. Neuroscience Research, 29, 135–142.Find this resource:

Li, S., Choi, V., & Tzounopoulos, T. (2013). Pathogenic plasticity of Kv7.2/3 channel activity is essential for the induction of tinnitus. Proceedings of the National Academy of Sciences of the United States, 110(24), 9980–9985. doi:10.1073/pnas.1302770110 1302770110 [pii]Find this resource:

Li, S., Kalappa, B. I., & Tzounopoulos, T. (2015). Noise-induced plasticity of KCNQ2/3 and HCN channels underlies vulnerability and resilience to tinnitus. Elife, 4. doi:10.7554/eLife.07242Find this resource:

Luz, Y., & Shamir, M. (2012). Balancing feed-forward excitation and inhibition via Hebbian inhibitory synaptic plasticity. PLoS Computational Biology, 8(1), e1002334. doi:10.1371/journal.pcbi.1002334Find this resource:

Ma, W. L., Hidaka, H., & May, B. J. (2006). Spontaneous activity in the inferior colliculus of CBA/J mice after manipulations that induce tinnitus. Hearing Research, 212(1–2), 9–21. doi:S0378-5955(05)00303-5 [pii] 10.1016/j.heares.2005.10.003Find this resource:

Maejima, T., Hashimoto, K., Yoshida, T., Aiba, A., & Kano, M. (2001). Presynaptic inhibition caused by retrograde signal from metabotropic glutamate to cannabinoid receptors. Neuron, 31(3), 463–475.Find this resource:

Magee, J. C., & Johnston, D. (1997). A synaptically controlled, associative signal for Hebbian plasticity in hippocampal neurons. Science, 275(5297), 209–213.Find this resource:

Mahanty, N. K., & Sah, P. (1998). Calcium-permeable AMPA receptors mediate long-term potentiation in interneurons in the amygdala. Nature, 394(6694), 683–687. doi:10.1038/29312Find this resource:

Manis, P. B. (1990). Membrane properties and discharge characteristics of guinea pig dorsal cochlear nucleus neurons studied in vitro. Journal of Neuroscience, 10(7), 2338–2351.Find this resource:

Manzoor, N. F., Gao, Y., Licari, F., & Kaltenbach, J. A. (2013). Comparison and contrast of noise-induced hyperactivity in the dorsal cochlear nucleus and inferior colliculus. Hearing Research, 295, 114–123. doi:10.1016/j.heares.2012.04.003 S0378-5955(12)00089-5 [pii]Find this resource:

Markram, H., Lubke, J., Frotscher, M., & Sakmann, B. (1997). Regulation of synaptic efficacy by coincidence of postsynaptic APs and EPSPs. Science, 275(5297), 213–215.Find this resource:

Marks, K. L., Martel, D. T., Wu, C., Basura, G. J., Roberts, L. E., Schvartz-Leyzac, K. C., & Shore, S. E. (2018). Auditory-somatosensory bimodal stimulation desynchronizes brain circuitry to reduce tinnitus in guinea pigs and humans. Science Translational Medicine, 10(422). doi:10.1126/scitranslmed.aal3175Find this resource:

Masquelier, T., Guyonneau, R., & Thorpe, S. J. (2009). Competitive STDP-based spike pattern learning. Neural Computation, 21(5), 1259–1276. doi:10.1162/neco.2008.06-08-804Find this resource:

May, B. J. (2000). Role of the dorsal cochlear nucleus in the sound localization behavior of cats. Hearing Research, 148(1–2), 74–87.Find this resource:

Middleton, J. W., Kiritani, T., Pedersen, C., Turner, J. G., Shepherd, G. M., & Tzounopoulos, T. (2011). Mice with behavioral evidence of tinnitus exhibit dorsal cochlear nucleus hyperactivity because of decreased GABAergic inhibition. Proceedings of the National Academy of Sciences of the United States of America, 108(18), 7601–7606. doi:10.1073/pnas.1100223108 1100223108 [pii]Find this resource:

Min, R., & Nevian, T. (2012). Astrocyte signaling controls spike timing-dependent depression at neocortical synapses. Nature Neuroscience, 15(5), 746–753. doi:10.1038/nn.3075Find this resource:

Moore, C. I., Carlen, M., Knoblich, U., & Cardin, J. A. (2010). Neocortical interneurons: from diversity, strength. Cell, 142(2), 189–193. doi:10.1016/j.cell.2010.07.005Find this resource:

Mugnaini, E., Osen, K. K., Dahl, A. L., Friedrich, V. L., Jr., & Korte, G. (1980a). Fine structure of granule cells and related interneurons (termed Golgi cells) in the cochlear nuclear complex of cat, rat and mouse. Journal of Neurocytology, 9(4), 537–570.Find this resource:

Mugnaini, E., Warr, W. B., & Osen, K. K. (1980b). Distribution and light microscopic features of granule cells in the cochlear nuclei of cat, rat, and mouse. Journal of Comparative Neurology, 191(4), 581–606.Find this resource:

Mulders, W. H., & Robertson, D. (2009). Hyperactivity in the auditory midbrain after acoustic trauma: Dependence on cochlear activity. Neuroscience, 164(2), 733–746. doi:S0306-4522(09)01395-5 [pii] 10.1016/j.neuroscience.2009.08.036Find this resource:

Nelson, S. B. (2004). Hebb and anti-Hebb meet in the brainstem. Nature Neuroscience, 7(7), 687–688. doi:10.1038/nn0704-687 nn0704-687 [pii]Find this resource:

Nevian, T., & Sakmann, B. (2006). Spine Ca2+ signaling in spike-timing-dependent plasticity. Journal of Neuroscience, 26(43), 11001–11013. doi:10.1523/JNEUROSCI.1749-06.2006Find this resource:

Oertel, D., & Young, E. D. (2004). What's a cerebellar circuit doing in the auditory system? Trends in Neuroscience, 27(2), 104–110. doi:10.1016/j.tins.2003.12.001Find this resource:

Ohlrogge, M., Doucet, J. R., & Ryugo, D. K. (2001). Projections of the pontine nuclei to the cochlear nucleus in rats. Journal of Comparative Neurology, 436(3), 290–303.Find this resource:

Ormond, J., & Woodin, M. A. (2009). Disinhibition mediates a form of hippocampal long-term potentiation in area CA1. PLoS One, 4(9), e7224. doi:10.1371/journal.pone.0007224Find this resource:

Ormond, J., & Woodin, M. A. (2011). Disinhibition-mediated LTP in the hippocampus is synapse specific. Frontiers in Cellular Neuroscience, 5, 17. doi:10.3389/fncel.2011.00017Find this resource:

Parham, K., & Kim, D. O. (1995). Spontaneous and sound-evoked discharge characteristics of complex-spiking neurons in the dorsal cochlear nucleus of the unanesthetized decerebrate cat. Journal of Neurophysiology, 73(2), 550–561.Find this resource:

Perez-Rosello, T., Anderson, C. T., Schopfer, F. J., Zhao, Y., Gilad, D., Salvatore, S. R., … Tzounopoulos, T. (2013). Synaptic Zn2+ inhibits neurotransmitter release by promoting endocannabinoid synthesis. Journal of Neuroscience, 33(22), 9259–9272. doi:10.1523/JNEUROSCI.0237-13.2013 33/22/9259 [pii]Find this resource:

Pilati, N., Large, C., Forsythe, I. D., & Hamann, M. (2012). Acoustic over-exposure triggers burst firing in dorsal cochlear nucleus fusiform cells. Hearing Research, 283(1–2), 98–106. doi:10.1016/j.heares.2011.10.008 S0378-5955(11)00262-0 [pii]Find this resource:

Populin, L. C., & Yin, T. C. (1998). Pinna movements of the cat during sound localization. Journal of Neuroscience, 18(11), 4233–4243.Find this resource:

Portfors, C. V., & Roberts, P. D. (2007). Temporal and frequency characteristics of cartwheel cells in the dorsal cochlear nucleus of the awake mouse. Journal of Neurophysiology, 98(2), 744–756.Find this resource:

Requarth, T., & Sawtell, N. B. (2011). Neural mechanisms for filtering self-generated sensory signals in cerebellum-like circuits. Current Opinion in Neurobiology, 21(4), 602–608. doi:S0959-4388(11)00099-7 [pii] 10.1016/j.conb.2011.05.031Find this resource:

Roberts, M. T., & Trussell, L. O. (2010). Molecular layer inhibitory interneurons provide feedforward and lateral inhibition in the dorsal cochlear nucleus. Journal of Neurophysiology, 104(5), 2462–2473. doi:jn.00312.2010 [pii] 10.1152/jn.00312.2010Find this resource:

Rodriguez-Moreno, A., & Paulsen, O. (2008). Spike timing-dependent long-term depression requires presynaptic NMDA receptors. Nature Neuroscience, 11(7), 744–745. doi:10.1038/nn.2125Find this resource:

Ropp, T. J., Tiedemann, K. L., Young, E. D., & May, B. J. (2014). Effects of unilateral acoustic trauma on tinnitus-related spontaneous activity in the inferior colliculus. Journal of the Association for Research Otolaryngology, 15(6), 1007–1022. doi:10.1007/s10162-014-0488-2Find this resource:

Said, J., Izita, A., Gonzalez, A. L., & Tovar, E. (2006). Comparative results of craniocorpography and the test of balance in tinnitus and vertigo patients. International Tinnitus Journal, 12(2), 179–183.Find this resource:

Salvi, R. J., Wang, J., & Ding, D. (2000). Auditory plasticity and hyperactivity following cochlear damage. Hearing Research, 147(1–2), 261–274. doi:S0378-5955(00)00136-2 [pii]Find this resource:

Sarihi, A., Jiang, B., Komaki, A., Sohya, K., Yanagawa, Y., & Tsumoto, T. (2008). Metabotropic glutamate receptor type 5-dependent long-term potentiation of excitatory synapses on fast-spiking GABAergic neurons in mouse visual cortex. Journal of Neuroscience, 28(5), 1224–1235. doi:10.1523/JNEUROSCI.4928-07.2008Find this resource:

Sedlacek, M., Tipton, P. W., & Brenowitz, S. D. (2011). Sustained firing of cartwheel cells in the dorsal cochlear nucleus evokes endocannabinoid release and retrograde suppression of parallel fiber synapses. Journal of Neuroscience, 31(44), 15807–15817. doi:10.1523/JNEUROSCI.4088-11.2011 31/44/15807 [pii]Find this resource:

Sefanescu, R., & Shore, S. (2015). NMDA receptors mediate stimulus timing dependent plasticity and neural synchrony in dorsal cochlear nucleus. Frontiers in Neural Circuits 9:75. doi: 10.3389/fncir.2015.00075Find this resource:

Shore, S. E. (2005). Multisensory integration in the dorsal cochlear nucleus: Unit responses to acoustic and trigeminal ganglion stimulation. European Journal of Neuroscience, 21(12), 3334–3348. doi:EJN4142 [pii] 10.1111/j.1460-9568.2005.04142.xFind this resource:

Shore, S. E., Koehler, S., Oldakowski, M., Hughes, L. F., & Syed, S. (2008). Dorsal cochlear nucleus responses to somatosensory stimulation are enhanced after noise-induced hearing loss. European Journal of Neuroscience, 27(1), 155–168. doi:10.1111/j.1460-9568.2007.05983.xFind this resource:

Shore, S. E., Roberts, L. E., & Langguth, B. (2016). Maladaptive plasticity in tinnitus: Triggers, mechanisms and treatment. Nature Review Neurology, 12(3), 150–160. doi:10.1038/nrneurol.2016.12Find this resource:

Shore, S. E., Vass, Z., Wys, N. L., & Altschuler, R. A. (2000). Trigeminal ganglion innervates the auditory brainstem. Journal of Comparative Neurology, 419(3), 271–285. doi:10.1002/(SICI)1096-9861(20000410)419:3<271::AID-CNE1>3.0.CO;2-M [pii]Find this resource:

Shore, S. E., & Zhou, J. (2006). Somatosensory influence on the cochlear nucleus and beyond. Hearing Research, 216217, 90–99. doi:S0378-5955(06)00009-8 [pii] 10.1016/j.heares.2006.01.006Find this resource:

Singer, W. (1999). Neuronal synchrony: A versatile code for the definition of relations? Neuron, 24(1), 49–65, 111–125.Find this resource:

Singla, S., Dempsey, C., Warren, R., Enikolopov, A. G., & Sawtell, N. B. (2017). A cerebellum-like circuit in the auditory system cancels responses to self-generated sounds. Nature Neuroscience, 20(7), 943–950. doi:10.1038/nn.4567Find this resource:

Sjostrom, P. J., Turrigiano, G. G., & Nelson, S. B. (2003). Neocortical LTD via coincident activation of presynaptic NMDA and cannabinoid receptors. Neuron, 39(4), 641–654.Find this resource:

Song, S., Miller, K. D., & Abbott, L. F. (2000). Competitive Hebbian learning through spike-timing-dependent synaptic plasticity. Nature Neuroscience, 3(9), 919–926. doi:10.1038/78829Find this resource:

Stefanescu, R. A., Koehler, S. D., & Shore, S. E. (2015). Stimulus-timing-dependent modifications of rate-level functions in animals with and without tinnitus. Journal of Neurophysiology, 113(3), 956–970. doi:10.1152/jn.00457.2014Find this resource:

Stefanescu, R. A., & Shore, S. E. (2017). Muscarinic acetylcholine receptors control baseline activity and Hebbian stimulus timing-dependent plasticity in fusiform cells of the dorsal cochlear nucleus. Journal of Neurophysiology, 117, 1229–1238.Find this resource:

Stefanescu, R. A., & Shore, S. E. (2015). NMDA receptors mediate stimulus-timing-dependent plasticity and neural synchrony in the dorsal cochlear nucleus. Frontiers in Neural Circuits, 9, 75. doi:10.3389/fncir.2015.00075Find this resource:

Sturm, J. J., Zhang-Hooks, Y. X., Roos, H., Nguyen, T., & Kandler, K. (2017). Noise trauma-induced behavioral gap detection deficits correlate with reorganization of excitatory and inhibitory local circuits in the inferior colliculus and are prevented by acoustic enrichment. Journal of Neuroscience, 37(26), 6314–6330. doi:10.1523/JNEUROSCI.0602-17.2017Find this resource:

Tzounopoulos, T., Kim, Y., Oertel, D., & Trussell, L. O. (2004). Cell-specific, spike timing-dependent plasticities in the dorsal cochlear nucleus. Nature Neuroscience, 7(7), 719–725. doi:10.1038/nn1272 nn1272 [pii]Find this resource:

Tzounopoulos, T., Rubio, M. E., Keen, J. E., & Trussell, L. O. (2007). Coactivation of pre- and postsynaptic signaling mechanisms determines cell-specific spike-timing-dependent plasticity. Neuron, 54(2), 291–301. doi:S0896-6273(07)00249-8 [pii] 10.1016/j.neuron.2007.03.026Find this resource:

Vogels, T. P., Froemke, R. C., Doyon, N., Gilson, M., Haas, J. S., Liu, R., … Sprekeler, H. (2013). Inhibitory synaptic plasticity: spike timing-dependence and putative network function. Front Neural Circuits, 7, 119. doi:10.3389/fncir.2013.00119Find this resource:

Voigt, H. F., & Young, E. D. (1988). Neural correlations in the dorsal cochlear nucleus: Pairs of units with similar response properties. Journal of Neurophysiology, 59(3), 1014–1032.Find this resource:

Wall, M., Rosenberg, M., & Richardson, D. (1987). Gaze-evoked tinnitus. Neurology, 37(6), 1034–1036.Find this resource:

Wang, H., Brozoski, T. J., Turner, J. G., Ling, L., Parrish, J. L., Hughes, L. F., & Caspary, D. M. (2009). Plasticity at glycinergic synapses in dorsal cochlear nucleus of rats with behavioral evidence of tinnitus. Neuroscience, 164(2), 747–759. doi:10.1016/j.neuroscience.2009.08.026 S0306-4522(09)01383-9 [pii]Find this resource:

Wang, L., Fontanini, A., & Maffei, A. (2012). Experience-dependent switch in sign and mechanisms for plasticity in layer 4 of primary visual cortex. Journal of Neuroscience, 32(31), 10562–10573. doi:10.1523/JNEUROSCI.0622-12.2012Find this resource:

Wright, D. D., & Ryugo, D. K. (1996). Mossy fiber projections from the cuneate nucleus to the cochlear nucleus in the rat. Journal of Comparative Neurology, 365(1), 159–172. doi:10.1002/(SICI)1096-9861(19960129)365:1<159::AID-CNE12>3.0.CO;2-L [pii] 10.1002/(SICI)1096-9861(19960129)365:1&lt;159::AID-CNE12&gt;3.0.CO;2-LFind this resource:

Wu, C., Martel, D. T., & Shore, S. E. (2015a). Transcutaneous induction of stimulus-timing-dependent plasticity in dorsal cochlear nucleus. Frontiers in Systems Neuroscience, 9, 116. doi:10.3389/fnsys.2015.00116Find this resource:

Wu, C., Martel, D. T., & Shore, S. E. (2015b). Transcutaneous induction of stimulus-timing-dependent plasticity in dorsal cochlear nucleus. Frontiers in Systems Neuroscience. doi:10.3389/fnsys.2015.00116Find this resource:

Wu, C., Martel, D. T., & Shore, S. E. (2016). Increased synchrony and bursting of dorsal cochlear nucleus fusiform cells correlate with tinnitus. Journal of Neuroscience, 36(6), 2068–2073. doi:10.1523/JNEUROSCI.3960-15.2016Find this resource:

Wu, C., Stefanescu, R. A., Martel, D. T., & Shore, S. E. (2014). Listening to another sense: Somatosensory integration in the auditory system. Cell and Tissue Res. doi:10.1007/s00441-014-2074-7Find this resource:

Zeng, C., Nannapaneni, N., Zhou, J., Hughes, L. F., & Shore, S. (2009). Cochlear damage changes the distribution of vesicular glutamate transporters associated with auditory and nonauditory inputs to the cochlear nucleus. Journal of Neuroscience, 29(13), 4210–4217. doi:29/13/4210 [pii] 10.1523/JNEUROSCI.0208-09.2009Find this resource:

Zeng, C., Shroff, H., & Shore, S. E. (2011). Cuneate and spinal trigeminal nucleus projections to the cochlear nucleus are differentially associated with vesicular glutamate transporter-2. Neuroscience, 176, 142–151. doi:10.1016/j.neuroscience.2010.12.010Find this resource:

Zeng, C., Yang, Z., Shreve, L., Bledsoe, S., & Shore, S. (2012a). Somatosensory projections to cochlear nucleus are upregulated after unilateral deafness. Journal of Neuroscience, 32(45), 15791–15801. doi:10.1523/JNEUROSCI.2598-12.2012Find this resource:

Zeng, C., Yang, Z., Shreve, L., Bledsoe, S., & Shore, S. (2012b). Somatosensory projections to cochlear nucleus are upregulated after unilateral deafness. Journal of Neuroscience, 32(45), 15791–15801. doi:10.1523/JNEUROSCI.2598-12.2012Find this resource:

Zhan, X., Pongstaporn, T., & Ryugo, D. K. (2006). Projections of the second cervical dorsal root ganglion to the cochlear nucleus in rats. Journal of Comparative Neurology, 496(3), 335–348.Find this resource:

Zhao, Y., Rubio, M., & Tzounopoulos, T. (2011). Mechanisms underlying input-specific expression of endocannabinoid-mediated synaptic plasticity in the dorsal cochlear nucleus. Hearing Research, 279(1–2), 67–73. doi:10.1016/j.heares.2011.03.007 S0378-5955(11)00078-5 [pii]Find this resource:

Zhao, Y., & Tzounopoulos, T. (2011). Physiological activation of cholinergic inputs controls associative synaptic plasticity via modulation of endocannabinoid signaling. Journal of Neuroscience, 31(9), 3158–3168. doi:10.1523/JNEUROSCI.5303-10.2011 31/9/3158 [pii]Find this resource:

Zhou, J., Nannapaneni, N., & Shore, S. (2007). Vessicular glutamate transporters 1 and 2 are differentially associated with auditory nerve and spinal trigeminal inputs to the cochlear nucleus. Journal of Comparative Neurology, 500(4), 777–787. doi:10.1002/cne.21208Find this resource:

Zhou, J., & Shore, S. (2004). Projections from the trigeminal nuclear complex to the cochlear nuclei: A retrograde and anterograde tracing study in the guinea pig. Journal of Neuroscience Research, 78(6), 901–907. doi:10.1002/jnr.20343Find this resource:

Zhou, J., Zeng, C., Cui, Y., & Shore, S. (2010). Vesicular glutamate transporter 2 is associated with the cochlear nucleus commissural pathway. Journal of the Association for Research Otolaryngology, 11(4), 675–687. doi:10.1007/s10162-010-0224-5Find this resource: