Glutamatergic somatosensory projections to the cochlear nucleus (CN) originate in trigeminal and dorsal column systems and terminate primarily in the CN granule cell domain (GCD). Stimulating these inputs alters spontaneous and sound-driven responses in principal neurons of the dorsal and ventral CN for extended periods of time. This long-term bimodal alteration is enhanced after unilateral deafness and could explain why patients are able to modulate their tinnitus by somatic maneuvers such as jaw clenching.
The aims of this proposal are to determine the physiological and molecular mechanisms underlying long-term suppression and enhancement of CN responses by somatosensory projection neurons and their implications for tinnitus generation and modulation.
Aim 1 a will examine long-term synaptic plasticity as a mechanism underlying bimodal enhancement and suppression in fusiform and bushy cells in normal and noise-damaged guinea pigs. We hypothesize that bimodal enhancement will predominate in noise-damaged animals with physiological correlates (increased spontaneous rates and synchrony) and behavioral evidence of tinnitus using the gap-detection tinnitus screening method (Aim 1b).
Aim 2 will examine the hypothesis that the predominance of bimodal enhancement in animals with tinnitus (preliminary data) is a result of up-regulation of specific Vglut2- positive somatosensory endings in the CN after deafness.
In Aim 2 a, tract-tracing and immunocytochemical studies will determine the precise origins and endings of the upregulated inputs in mouse.
Aim 2 b will utilize Vglut2-deficient mice to test the hypothesis that Vglut2+/- mice will be resistant to tinnitus induction. Mice will be tested for tinnitus using gap-detection before and after narrow-band noise overexposure. Preliminary data indicate that compared to matched wild-types, the Vglut2+/- mice show significantly less evidence of tinnitus, supporting this hypothesis.
Aim 2 c will then explore the involvement of the fibroblast growth factor, FGF22, as a postsynaptic signal for presynaptic upregulation of somatosensory mossy fibers to the CN after deafness. Our studies strongly implicate the somatosensory system, not only in the modulation, but also in the generation of tinnitus. Not surprisingly, more than half of tinnitus patients (~20 million) can modulate their tinnitus with somatic maneuvers, or attribute its onset to a somatosensory injury. Investigating underlying mechanisms in somatosensory-auditory integration after cochlear damage will allow us to elucidate the changes that contribute to tinnitus, and thus provide insights leading to successful interventions.

Public Health Relevance

The somatosensory (touch) system sends connections to the first auditory station in the brain, the cochlear nucleus. Since many patients can modulate the loudness and pitch of their tinnitus by touching their face or clenching their jaw, this implies tht these inputs may also produce the tinnitus in the first place. Here we examine the physiological and molecular mechanisms underlying somatosensory modulations of cochlear nucleus activity in animals with and without tinnitus, and examine how these mechanisms might lead to tinnitus. We hope that findings from these studies will lead to novel treatments and ultimately provide relief to millions of people across the world suffering from this often-debilitating disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
2R01DC004825-11A1
Application #
8297228
Study Section
Auditory System Study Section (AUD)
Program Officer
Miller, Roger
Project Start
2001-03-01
Project End
2017-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
11
Fiscal Year
2012
Total Cost
$515,767
Indirect Cost
$178,631
Name
University of Michigan Ann Arbor
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Koehler, Seth D; Shore, Susan E (2013) Stimulus-timing dependent multisensory plasticity in the guinea pig dorsal cochlear nucleus. PLoS One 8:e59828
Koehler, Seth D; Shore, Susan E (2013) Stimulus timing-dependent plasticity in dorsal cochlear nucleus is altered in tinnitus. J Neurosci 33:19647-56
Dehmel, Susanne; Pradhan, Shashwati; Koehler, Seth et al. (2012) Noise overexposure alters long-term somatosensory-auditory processing in the dorsal cochlear nucleus--possible basis for tinnitus-related hyperactivity? J Neurosci 32:1660-71
Turner, Jeremy; Larsen, Deb; Hughes, Larry et al. (2012) Time course of tinnitus development following noise exposure in mice. J Neurosci Res 90:1480-8
Koehler, Seth D; Pradhan, Shashwati; Manis, Paul B et al. (2011) Somatosensory inputs modify auditory spike timing in dorsal cochlear nucleus principal cells. Eur J Neurosci 33:409-20
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 176:142-51
Zhou, Jianxun; Zeng, Chunhua; Cui, Yilei et al. (2010) Vesicular glutamate transporter 2 is associated with the cochlear nucleus commissural pathway. J Assoc Res Otolaryngol 11:675-87
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Bledsoe Jr, Sanford C; Koehler, Seth; Tucci, Debara L et al. (2009) Ventral cochlear nucleus responses to contralateral sound are mediated by commissural and olivocochlear pathways. J Neurophysiol 102:886-900

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