Neuroinflammation mediates noise-induced synaptic imbalance and tinnitus in rodent models

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 exa...

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Bibliographic Details
Published in:	PLoS biology 2019-06, Vol.17 (6), p.e3000307
Main Authors:	Wang, Weihua, Zhang, Li S, Zinsmaier, Alexander K, Patterson, Genevieve, Leptich, Emily Jean, Shoemaker, Savannah L, Yatskievych, Tatiana A, Gibboni, Robert, Pace, Edward, Luo, Hao, Zhang, Jinsheng, Yang, Sungchil, Bao, Shaowen
Format:	Article
Language:	eng
Subjects:	Acoustic Stimulation Acoustics Animal models Animals Apoptosis Auditory Cortex - physiopathology Auditory Pathways - physiopathology Auditory processing disorder Biology and Life Sciences Brain Cortex (auditory) Cytokines Cytokines - metabolism Depletion Dyslexia Engineering and Technology Funding Hearing loss Hearing Loss - physiopathology Hearing Loss, Noise-Induced - physiopathology Inflammation Information processing Male Medicine and Health Sciences Mice Mice, Inbred C57BL Mice, Knockout Microglia Nervous system Neuroimmunomodulation - immunology Neurons Neurosciences Noise Noise - adverse effects Otolaryngology Pathogens Pharmacology Phenotypes Physiology Pyramidal cells Rats Rats, Sprague-Dawley Research and Analysis Methods Risk analysis Risk factors Therapeutic applications Tinnitus Tinnitus - physiopathology Tumor Necrosis Factor-alpha - genetics Tumor Necrosis Factor-alpha - metabolism Tumor necrosis factor-TNF Tumor necrosis factor-α
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Summary:	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.
ISSN:	1545-7885 1544-9173 1545-7885