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date: 21 January 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.

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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).

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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.

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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.

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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.

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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).

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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.


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