Glutamatergic Projections to the Cochlear Nucleus are Redistributed in Tinnitus

Heeringa, Amarins N.; Wu, Calvin; Chung, Christopher; West, Mary Jane; Martel, David T.; Liberman, Leslie D.; Shore, Susan E.

doi:10.1016/j.neuroscience.2018.09.008

Cited by 33 publications

(47 citation statements)

References 62 publications

(127 reference statements)

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“…In the present study, the right ear of each rat was protected, and the ABR recording confirmed that hearing loss was not apparent on the right side. The present study employed TTS to induce cochlear insults and found reductions in VGLUT1 levels after noise exposure, which is consistent with previous findings (15,21,32,33). In addition, comparisons of the tinnitus and non-tinnitus groups revealed that the tinnitus group exhibited a greater decrease in VGLUT1 expression levels; this occurred earlier (i.e., in the first week after noise exposure) compared with the non-tinnitus group, which showed a decrease in VGLUT1 level at 2 weeks.…”

Section: Discussionsupporting

confidence: 92%

“…Thus, changes in neural input can be observed by assessing changes in VGLUT expression. A number of studies have demonstrated that cross-modal compensation occurs in the ipsilateral DCN after cochlear insults, as evidenced by decreases in VGLUT1, which reflects auditory inputs, and increases in VGUT2, which reflects non-auditory inputs (15,16,21,34).…”

Section: Discussionmentioning

confidence: 99%

“…This was consistent with a previous study that used a unilateral deaf model and reported that reductions in VGLUT1 levels do not persist at 3 and 6 weeks after noise exposure (16); it was proposed that this change may be due to a temporary shift in parallel fiber intrinsic connections (16,23). A recent study that investigated VGLUT expression in the cochlear nucleus of guinea pigs after TTS reported that the VGLUT1 expression levels in the deep layer of the DCN (DCN3), the granule cell domain and the ventral cochlear nucleus of the tinnitus group did not differ from those of sham-exposed controls at 12 weeks following noise exposure (21). Even in the molecular layer of the DCN (DCN1), all noise-exposed animals in both the tinnitus and non-tinnitus groups exhibited significant increases in VGLUT1 expression (21).…”

Section: Discussionmentioning

confidence: 99%

“…To date, several studies have provided evidence that a disruption in the balance of auditory and somatosensory inputs to the DCN might induce tinnitus; many of these studies use animal models of hearing loss in which the hearing is insulted in various ways, such as noise, ototoxic drugs or cochlear ablation surgery (15-18,20). However, few studies have demonstrated this phenomenon using animal models of tinnitus (21,22). Heeringa et al demonstrated redistribution of glutamatergic projections to the cochlear nucleus (21), and Kraus et al examined synaptic plasticity in the ventral cochlear nucleus by measuring growth associated protein 43 (GAP43) in behavioral model of tinnitus (22).…”

Section: Introductionmentioning

confidence: 99%

“…However, few studies have demonstrated this phenomenon using animal models of tinnitus (21,22). Heeringa et al demonstrated redistribution of glutamatergic projections to the cochlear nucleus (21), and Kraus et al examined synaptic plasticity in the ventral cochlear nucleus by measuring growth associated protein 43 (GAP43) in behavioral model of tinnitus (22).…”

Section: Introductionmentioning

confidence: 99%

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Axonal sprouting in the dorsal cochlear nucleus affects gap‑prepulse inhibition following noise exposure

et al. 2019

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One of the primary theories of the pathogenesis of tinnitus involves maladaptive auditory-somatosensory plasticity in the dorsal cochlear nucleus (DCN), which is assumed to be due to axonal sprouting. Although a disrupted balance between auditory and somatosensory inputs may occur following hearing damage and may induce tinnitus, examination of this phenomenon employed a model of hearing damage that does not account for the causal relationship between these changes and tinnitus. The present study aimed to investigate changes in auditory-somatosensory innervation and the role that axonal sprouting serves in this process by comparing results between animals with and without tinnitus. Rats were exposed to a noise-inducing temporary threshold shift and were subsequently divided into tinnitus and non-tinnitus groups based on the results of gap prepulse inhibition of the acoustic startle reflex. DCNs were collected from rats divided into three sub-groups according to the number of weeks (1, 2 or 3) following noise exposure, and the protein levels of vesicular glutamate transporter 1 (VGLUT1), which is associated with auditory input to the DCN, and VGLUT2, which is in turn primarily associated with somatosensory inputs, were assessed. In addition, factors related to axonal sprouting, including growth-associated protein 43 (GAP43), postsynaptic density protein 95, synaptophysin, α-thalassemia/mental retardation syndrome X-linked homolog (ATRX), growth differentiation factor 10 (GDF10), and leucine-rich repeat and immunoglobulin domain-containing 1, were measured by western blot analyses. Compared to the non-tinnitus group, the tinnitus group exhibited a significant decrease in VGLUT1 at 1 week and a significant increase in VGLUT2 at 3 weeks post-exposure. In addition, rats in the tinnitus group exhibited significant increases in GAP43 and GDF10 protein expression levels in their DCN at 3 weeks following noise exposure. Results from the present study provided further evidence that changes in the neural input distribution to the DCN may cause tinnitus and that axonal sprouting underlies these alterations.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Axonal sprouting in the dorsal cochlear nucleus affects gap‑prepulse inhibition following noise exposure

et al. 2019

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Reversing Synchronized Brain Circuits Using Targeted Auditory-Somatosensory Stimulation to Treat Phantom Percepts

et al. 2023

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ImportanceAnimal models have shown altered dorsal cochlear nucleus circuitry in animals that develop tinnitus; however, precise treatment using bisensory (auditory and somatosensory) stimuli can reverse altered neural patterns and lessen tinnitus.ObjectiveTo confirm and extend the findings of a pilot study, which suggested an increased efficacy of bisensory stimulation, to a clinical trial with a greater duration and greater number of participants.Design, Setting, and ParticipantsThis double-blind, crossover, single-center randomized clinical trial was conducted from March 2019, with a 3-month follow-up per participant ending in July 2022. Eligible adults were recruited from the University of Michigan Health System in Ann Arbor, Michigan. Eligibility criteria included bothersome tinnitus (Tinnitus Functional Index [TFI] score, ≥17 points), somatic tinnitus, normal to moderate hearing loss, and no other tinnitus treatments in the 6 months prior to the trial. Included participants were randomized to either treatment group 1, which received active (bisensory) treatment, or group 2, which received the control (auditory-only) treatment. Results were analyzed using intent-to-treat (ITT) and per protocol (PP) populations.InterventionPrecisely timed bisensory (combined auditory and somatosensory) treatment was delivered through a portable, custom, take-home device that was provided to each participant for daily, at-home treatments. Group 1 participants received 30 minutes per day of the bisensory treatment for 6 weeks, followed by a 6-week washout phase, and then 30 minutes per day of the auditory-only treatment followed by a second 6-week washout phase. Group 2 participants received the auditory-only treatment first, followed by a washout phase, and then the bisensory treatment followed by a second washout phase.Main Outcomes and MeasuresPrimary end points were changes in TFI score and tinnitus loudness level from baseline through week 6 and week 12.ResultsOf 337 screened individuals, 99 (mean [SD] age, 47 [12.7] years; 59 males [60%]; 85 with non-Hispanic White [86%] race and ethnicity) were enrolled into the study and randomized to treatment group 1 (n = 49) or group 2 (n = 50). The active but not the control treatment resulted in clinically significant decreases in TFI scores at week 6 of phase 1 (ITT population: –12.0 [95% CI, –16.9 to –7.9] points; P &lt; .001; PP population: –13.2 [95% CI, –16.0 to –10.5] points; P &lt; .001). Decreases in tinnitus loudness level were greater than 6 dB sensation level (SL; &gt;half as loud) at week 6 for the bisensory treatment group, with little effect for the auditory-only treatment control group at week 6 of phase 1 (ITT population: –5.8 [95% CI, –9.5 to –2.2] dB; P = .08; PP population: –7.2 [95% CI, –11.4 to –3.1] dB; P = .03), and up to 11 dB SL at week 12 of phase 2 (ITT population: –10.9 [95% CI, –15.2 to –6.5] dB; P = .001; PP population: –14.1 [95% CI, –18.4 to –9.8] dB; P &lt; .001). Decreased tinnitus loudness level and TFI scores extended into the washout phase, indicating a prolonged treatment effect.Conclusions and RelevanceThis trial found that precisely timed bisensory treatment using stimuli and timing developed in a validated animal model was effective for adults with somatic tinnitus. Prolonged reduction in tinnitus symptoms can result from using an extended treatment duration.Trial RegistrationClinicalTrials.gov Identifier: NCT03621735

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Bimodal Auditory Electrical Stimulation for the Treatment of Tinnitus: Preclinical and Clinical Studies

Riffle

Martel

Jones

et al. 2020

The Behavioral Neuroscience of Tinnitus

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Glutamatergic Projections to the Cochlear Nucleus are Redistributed in Tinnitus

Cited by 33 publications

References 62 publications

Axonal sprouting in the dorsal cochlear nucleus affects gap‑prepulse inhibition following noise exposure

Axonal sprouting in the dorsal cochlear nucleus affects gap‑prepulse inhibition following noise exposure

Reversing Synchronized Brain Circuits Using Targeted Auditory-Somatosensory Stimulation to Treat Phantom Percepts

Bimodal Auditory Electrical Stimulation for the Treatment of Tinnitus: Preclinical and Clinical Studies

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