TY - JOUR
T1 - Neuroinflammation mediates noise-induced synaptic imbalance and tinnitus in rodent models
AU - Wang, Weihua
AU - Zhang, Li S.
AU - Zinsmaier, Alexander K.
AU - Patterson, Genevieve
AU - Leptich, Emily Jean
AU - Shoemaker, Savannah L.
AU - Yatskievych, Tatiana A.
AU - Gibboni, Robert
AU - Pace, Edward
AU - Luo, Hao
AU - Zhang, Jinsheng
AU - Yang, Sungchil
AU - Bao, Shaowen
N1 - Funding Information:
This work was partially supported by National Institute of Health (DC009259 for SB, DC014335 for JZ), Department of Defense (W81XWH-15-1-0028 and W81XWH-15-1-0356 for SB, W81XWH-15-1-0357 for JZ) and the Food and Health Bureau of Hong Kong Special Administrative Region Government (04150076 for SY). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2019 Wang et al.
PY - 2019/6
Y1 - 2019/6
N2 - Hearing loss is a major risk factor for tinnitus, hyperacusis, and central auditory processing disorder. Although recent studies indicate that hearing loss causes neuroinflammation in the auditory pathway, the mechanisms underlying hearing loss–related pathologies are still poorly understood. We examined neuroinflammation in the auditory cortex following noise-induced hearing loss (NIHL) and its role in tinnitus in rodent models. Our results indicate that NIHL is associated with elevated expression of proinflammatory cytokines and microglial activation—two defining features of neuroinflammatory responses—in the primary auditory cortex (AI). Genetic knockout of tumor necrosis factor alpha (TNF-α) or pharmacologically blocking TNF-α expression prevented neuroinflammation and ameliorated the behavioral phenotype associated with tinnitus in mice with NIHL. Conversely, infusion of TNF-α into AI resulted in behavioral signs of tinnitus in both wild-type and TNF-α knockout mice with normal hearing. Pharmacological depletion of microglia also prevented tinnitus in mice with NIHL. At the synaptic level, the frequency of miniature excitatory synaptic currents (mEPSCs) increased and that of miniature inhibitory synaptic currents (mIPSCs) decreased in AI pyramidal neurons in animals with NIHL. This excitatory-to-inhibitory synaptic imbalance was completely prevented by pharmacological blockade of TNF-α expression. These results implicate neuroinflammation as a therapeutic target for treating tinnitus and other hearing loss–related disorders.
AB - Hearing loss is a major risk factor for tinnitus, hyperacusis, and central auditory processing disorder. Although recent studies indicate that hearing loss causes neuroinflammation in the auditory pathway, the mechanisms underlying hearing loss–related pathologies are still poorly understood. We examined neuroinflammation in the auditory cortex following noise-induced hearing loss (NIHL) and its role in tinnitus in rodent models. Our results indicate that NIHL is associated with elevated expression of proinflammatory cytokines and microglial activation—two defining features of neuroinflammatory responses—in the primary auditory cortex (AI). Genetic knockout of tumor necrosis factor alpha (TNF-α) or pharmacologically blocking TNF-α expression prevented neuroinflammation and ameliorated the behavioral phenotype associated with tinnitus in mice with NIHL. Conversely, infusion of TNF-α into AI resulted in behavioral signs of tinnitus in both wild-type and TNF-α knockout mice with normal hearing. Pharmacological depletion of microglia also prevented tinnitus in mice with NIHL. At the synaptic level, the frequency of miniature excitatory synaptic currents (mEPSCs) increased and that of miniature inhibitory synaptic currents (mIPSCs) decreased in AI pyramidal neurons in animals with NIHL. This excitatory-to-inhibitory synaptic imbalance was completely prevented by pharmacological blockade of TNF-α expression. These results implicate neuroinflammation as a therapeutic target for treating tinnitus and other hearing loss–related disorders.
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U2 - 10.1371/journal.pbio.3000307
DO - 10.1371/journal.pbio.3000307
M3 - Article
C2 - 31211773
AN - SCOPUS:85068441705
VL - 17
JO - PLoS Biology
JF - PLoS Biology
SN - 1544-9173
IS - 6
M1 - e3000307
ER -