Hearing loss often results in tinnitus and auditory cortical map changes, leading to the prevailing view that the phantom perception is associated with cortical reorganization. However, we show here that tinnitus is mediated by a cortical area lacking map reorganization. High-frequency hearing loss results in two distinct cortical regions: a sensory-deprived region characterized by a decrease in inhibitory synaptic transmission and a normal hearing region showing increases in inhibitory and excitatory transmission and map reorganization. Hearing-lesioned animals displayed tinnitus with a pitch in the hearing loss range. Furthermore, drugs that enhance inhibition, but not those that reduce excitation, reversibly eliminated the tinnitus behavior. These results suggest that sensory deprivation-induced homeostatic down-regulation of inhibitory synapses may contribute to tinnitus perception. Enhancing sensory input through map reorganization may plausibly alleviate phantom sensation.innitus, the perception of sounds in the absence of acoustic stimuli, often occurs as the result of hearing loss. Despite its simple origins, the mechanisms underlying the phantom perception remain elusive (1-5). Although often arising from peripheral hearing loss, tinnitus persists after auditory nerve transection or lesions of the cochlear nucleus, suggesting the involvement of more central mechanisms (6, 7). Recent studies revealed that abnormal auditory cortex activation and cortical map reorganization are correlated with the occurrence and severity of tinnitus in patients and model animals (8-12). Hearing loss normally associated with tinnitus leads to altered spontaneous activity and map reorganization, both of which are prevented if the trauma is followed by enriched acoustic experience (13-16). These findings suggest that cortical map reorganization may cause abnormal cortical activity and tinnitus, and prevention and reversal of such reorganization could alleviate tinnitus symptoms (5,16,17).Although Hebbian plasticity is believed to be the primary mediator of long-term map reorganization, non-Hebbian homeostatic plasticity may also be activated by altered sensory input (18,19). Cochlear ablation, for example, weakens inhibitory synapses and strengthens excitatory synapses, resulting in enhanced neuronal excitability in auditory cortex (20). These effects could potentially lead to elevated spontaneous cortical activity and tinnitus (21,22). Because map reorganization generally increases sensory-driven activity in the previously sensorydeprived neurons, it may attenuate or reverse homeostatic up-regulation of neuronal excitability, thereby reducing or eliminating tinnitus.In this study, we investigated hearing loss-induced cortical map reorganization, synaptic plasticity and tinnitus behaviors. We found that high-frequency hearing loss differentially alters synaptic transmissions in two zones of primary auditory cortex (AI) that represent the hearing-loss vs. normal-hearing frequency ranges. In the low-characteristic frequency (CF...

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.

Early experience shapes sensory representations in a critical period of heightened plasticity. This adaptive process is thought to involve both Hebbian and homeostatic synaptic plasticity. Although Hebbian plasticity has been investigated as a mechanism for cortical map reorganization, less is known about the contribution of homeostatic plasticity. We investigated the role of homeostatic synaptic plasticity in the development and refinement of frequency representations in the primary auditory cortex using the tumor necrosis factor-α (TNF-α) knockout (KO), a mutant mouse with impaired homeostatic but normal Hebbian plasticity. Our results indicate that these mice develop weaker tonal responses and incomplete frequency representations. Rearing in a single-frequency revealed a normal expansion of cortical representations in KO mice. However, TNF-α KOs lacked homeostatic adjustments of cortical responses following exposure to multiple frequencies. Specifically, while this sensory over-stimulation resulted in competitive refinement of frequency tuning in wild-type controls, it broadened frequency tuning in TNF-α KOs. Our results suggest that homeostatic plasticity plays an important role in gain control and competitive interaction in sensory cortical development.

Exposure to loud noises not only leads to trauma and loss of output from the ear but also alters downstream central auditory circuits. A perceptual consequence of noise-induced central auditory disruption is impairment in gap-induced prepulse inhibition, also known as gap detection. Recent studies have implicated cortical parvalbumin (PV)-positive inhibitory interneurons in gap detection and prepulse inhibition. Here, we show that exposure to loud noises specifically reduces the density of cortical PV but not somatostatin (SOM)-positive interneurons in the primary auditory cortex in mice (C57BL/6) of both sexes. Optogenetic activation of PV neurons produced less cortical inhibition in noise-exposed than sham-exposed animals, indicative of reduced PV neuron function. Activation of SOM neurons resulted in similar levels of cortical inhibition in noise-and sham-exposed groups. Furthermore, chemogenetic activation of PV neurons with the hM3-based designer receptor exclusively activated by designer drugs completely reversed the impairments in gap detection for noise-exposed animals. These results support the notions that cortical PV neurons encode gap in sound and that PV neuron dysfunction contributes to noiseinduced impairment in gap detection.