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Cellular and Molecular Mechanisms Underlying Vulnerability and Resilience to Noise-Induced Tinnitus.

Li, Shuang (2015) Cellular and Molecular Mechanisms Underlying Vulnerability and Resilience to Noise-Induced Tinnitus. Doctoral Dissertation, University of Pittsburgh.

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Abstract

Tinnitus, the perception of phantom sound, is often a debilitating condition that affects many millions of people. Little is known, however, about the molecule that underlies vulnerability and resilience to tinnitus. We investigated these mechanisms in the dorsal cochlear nucleus (DCN), an auditory brainstem nucleus that is essential for the induction of tinnitus. In DCN principal neurons (fusiform cells), we reveal a tinnitus-specific increase in the spontaneous firing rate (hyperactivity). We show that a reduction in Kv7.2/3 (KCNQ2/3) channel activity is essential for tinnitus induction and for the tinnitus-specific hyperactivity. This reduction is due to a shift in the voltage-dependence of KCNQ channel activation to more positive voltages. Importantly, in vivo pharmacological manipulation that shifts the voltage-dependence of KCNQ channels to more negative voltages prevents the development of tinnitus and provides an important link between the biophysical properties of the KCNQ channel and the vulnerability to tinnitus. Fusiform cells from noise-exposed mice that show resilience to tinnitus (non-tinnitus mice) display normal levels of spontaneous firing, but have more hyperpolarized subthreshold dynamics and more hyperpolarized resting membrane potential. These differences are due to a reduction in hyperpolarization-activated cyclic nucleotide-gated (HCN) channel activity. Longitudinal study reveals that 4 days after noise exposure, noise-exposed mice display non-tinnitus behavior, no fusiform cell hyperactivity, but reduced KCNQ2/3 currents. Importantly, while the preservation of reduced KCNQ2/3 currents 7 days after noise exposure gives rise to tinnitus behavior, the recovery of KCNQ2/3 currents to pre-exposed control levels is associated with non-tinnitus behavior, and is accompanied by a decrease in HCN channel activity. In vivo pharmacological opening of KCNQ2/3 channels prevented the development of tinnitus and decreased HCN currents, suggesting that KCNQ2/3 plasticity determines vulnerability and resilience to tinnitus and drives the reduction in HCN channel activity. Reduced HCN channel activity in non-tinnitus mice, by hyperpolarizing the resting membrane potential, may further prevent fusiform cell hyperactivity and contribute to tinnitus resilience. Together, our results highlight KCNQ2/3 and HCN channels as potential targets for designing therapeutics that may reduce vulnerability and promote resilience to tinnitus.


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Item Type: University of Pittsburgh ETD
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Li, Shuangshl61@pitt.eduSHL61
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairKandler, Karlkkarl@pitt.eduKKARL
Thesis AdvisorTzounopoulos, Thanosthanos@pitt.eduTHANOS
Committee MemberDoiron, Brentbdoiron@pitt.eduBDOIRON
Committee MemberAizenman, Eliasredox@pitt.eduREDOX
Committee MemberBarth, Alisonbarth@cmu.edu
Committee MemberHuguenard, Johnjohn@huguenardlab.stanford.edu
Date: 8 April 2015
Date Type: Publication
Defense Date: 16 December 2014
Approval Date: 8 April 2015
Submission Date: 7 April 2015
Release Date: 8 April 2015
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 145
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Neurobiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Tinnitus, hyperactivity, dorsal cochlear nucleus, potassium channel, pathogenic plasticity
Date Deposited: 08 Apr 2015 11:47
Last Modified: 08 Apr 2017 05:15
URI: http://d-scholarship.pitt.edu/id/eprint/24584

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