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

Abstract

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.

Diffusible Tumor Necrosis Factor-Alpha (TNF-α) Promotes Noise-Induced Parvalbumin-Positive (PV+) Neuron Loss and Auditory Processing Impairments

“…The behavioral test and experimental procedures were the same as previously reported ( Wang et al, 2019 ). Briefly, a mouse was caged in a plastic container with a mesh lid.…”

“…A potential modulator of these synaptic and membrane properties is the neuroinflammatory process and the proinflammatory cytokine TNF-α ( Bellinger et al, 1993 ; Stellwagen et al, 2005 ; Stellwagen and Malenka, 2006 ; Di Filippo et al, 2008 ; Steinmetz and Turrigiano, 2010 ). Hearing loss causes inflammatory responses along the central auditory pathway, and an increase in the expression of several proinflammatory cytokines ( Fuentes-Santamaria et al, 2014 ; Baizer et al, 2015 ; Fuentes-Santamaria et al, 2017 ; Wang et al, 2019 ). Among them, TNF-α has been shown to play a central role in organizing the inflammatory response in the brain.…”

“…Among them, TNF-α has been shown to play a central role in organizing the inflammatory response in the brain. Its expression is rapidly upregulated following noise-induced hearing loss in mice, followed by microglial activation and increased expression of other proinflammatory cytokines ( Wang et al, 2019 ). Blocking noise-induced increase of TNF-α expression prevented both synaptic imbalance and behavioral impairment in gap detection in noise exposed mice ( Wang et al, 2019 ).…”

“…Its expression is rapidly upregulated following noise-induced hearing loss in mice, followed by microglial activation and increased expression of other proinflammatory cytokines ( Wang et al, 2019 ). Blocking noise-induced increase of TNF-α expression prevented both synaptic imbalance and behavioral impairment in gap detection in noise exposed mice ( Wang et al, 2019 ). In the same study, blocking TNF-α expression also prevented behavioral evidence of tinnitus assessed with an operant perceptual task ( Wang et al, 2019 ).…”

“…Blocking noise-induced increase of TNF-α expression prevented both synaptic imbalance and behavioral impairment in gap detection in noise exposed mice ( Wang et al, 2019 ). In the same study, blocking TNF-α expression also prevented behavioral evidence of tinnitus assessed with an operant perceptual task ( Wang et al, 2019 ). In humans, polymorphisms of several inflammatory cytokines, including TNF-α, are associated with the risk of noise-related tinnitus ( Doi et al, 2015 ; Marchiori et al, 2018 ; Marchiori et al, 2019 ), a central auditory disorder that is often comorbid with impairment in gap detection ( Fournier and Hebert, 2013 ; Mehdizade Gilani et al, 2013 ).…”