Increasing evidence shows that hearing loss is a risk factor for tinnitus and hyperacusis. Although both often coincide, a causal relationship between tinnitus and hyperacusis has not been shown. Currently, tinnitus and hyperacusis are assumed to be caused by elevated responsiveness in subcortical circuits. We examined both the impact of different degrees of cochlear damage and the influence of stress priming on tinnitus induction. We used (1) a behavioral animal model for tinnitus designed to minimize stress, (2) ribbon synapses in inner hair cells (IHCs) as a measure for deafferentation, (3) the integrity of auditory brainstem responses (ABR) to detect differences in stimulus-evoked neuronal activity, (4) the expression of the activity-regulated cytoskeletal protein, Arc, to identify long-lasting changes in network activity within the basolateral amygdala (BLA), hippocampal CA1, and auditory cortex (AC), and (5) stress priming to investigate the influence of corticosteroid on trauma-induced brain responses. We observed that IHC ribbon loss (deafferentation) leads to tinnitus when ABR functions remain reduced and Arc is not mobilized in the hippocampal CA1 and AC. If, however, ABR waves are functionally restored and Arc is mobilized, tinnitus does not occur. Both central response patterns were found to be independent of a profound threshold loss and could be shifted by the corticosterone level at the time of trauma. We, therefore, discuss the findings in the context of a history of stress that can trigger either an adaptive or nonadaptive brain response following injury.

Tinnitus is proposed to be caused by decreased central input from the cochlea, followed by increased spontaneous and evoked subcortical activity that is interpreted as compensation for increased responsiveness of central auditory circuits. We compared equally noise exposed rats separated into groups with and without tinnitus for differences in brain responsiveness relative to the degree of deafferentation in the periphery. We analyzed (1) the number of CtBP2/RIBEYE-positive particles in ribbon synapses of the inner hair cell (IHC) as a measure for deafferentation; (2) the fine structure of the amplitudes of auditory brainstem responses (ABR) reflecting differences in sound responses following decreased auditory nerve activity and (3) the expression of the activity-regulated gene Arc in the auditory cortex (AC) to identify long-lasting central activity following sensory deprivation. Following moderate trauma, 30% of animals exhibited tinnitus, similar to the tinnitus prevalence among hearing impaired humans. Although both tinnitus and no-tinnitus animals exhibited a reduced ABR wave I amplitude (generated by primary auditory nerve fibers), IHCs ribbon loss and high-frequency hearing impairment was more severe in tinnitus animals, associated with significantly reduced amplitudes of the more centrally generated wave IV and V and less intense staining of Arc mRNA and protein in the AC. The observed severe IHCs ribbon loss, the minimal restoration of ABR wave size, and reduced cortical Arc expression suggest that tinnitus is linked to a failure to adapt central circuits to reduced cochlear input.

The precision of sound information transmitted to the brain depends on the transfer characteristics of the inner hair cell (IHC) ribbon synapse and its multiple contacting auditory fibers. We found that brain derived neurotrophic factor (BDNF) differentially influences IHC characteristics in the intact and injured cochlea. Using conditional knock-out mice (BDNF Pax2 KO) we found that resting membrane potentials, membrane capacitance and resting linear leak conductance of adult BDNF Pax2 KO IHCs showed a normal maturation. Likewise, in BDNF Pax2 KO membrane capacitance (⌬C m ) as a function of inward calcium current (I Ca ) follows the linear relationship typical for normal adult IHCs. In contrast the maximal ⌬C m , but not the maximal size of the calcium current, was significantly reduced by 45% in basal but not in apical cochlear turns in BDNF Pax2 KO IHCs. Maximal ⌬C m correlated with a loss of IHC ribbons in these cochlear turns and a reduced activity of the auditory nerve (auditory brainstem response wave I). Remarkably, a noise-induced loss of IHC ribbons, followed by reduced activity of the auditory nerve and reduced centrally generated wave II and III observed in control mice, was prevented in equally noise-exposed BDNF Pax2 KO mice. Data suggest that BDNF expressed in the cochlea is essential for maintenance of adult IHC transmitter release sites and that BDNF upholds opposing afferents in high-frequency turns and scales them down following noise exposure.

Subjective tinnitus is the conscious perception of sound in the absence of any acoustic source. The literature suggests various tinnitus mechanisms, most of which invoke changes in spontaneous firing rates of central auditory neurons resulting from modification of neural gain. Here, we present an alternative model based on evidence that tinnitus is: (1) rare in people who are congenitally deaf, (2) common in people with acquired deafness, and (3) potentially suppressed by active cochlear implants used for hearing restoration. We propose that tinnitus can only develop after fast auditory fiber activity has stimulated the synapse formation between fast-spiking parvalbumin positive (PV 1 ) interneurons and projecting neurons in the ascending auditory path and coactivated frontostriatal networks after hearing onset. Thereafter, fast auditory fiber activity promotes feedforward and feedback inhibition mediated by PV 1 interneuron activity in auditory-specific circuits. This inhibitory network enables enhanced stimulus resolution, attention-driven contrast improvement, and augmentation of auditory responses in central auditory pathways (neural gain) after damage of slow auditory fibers. When fast auditory fiber activity is lost, tonic PV 1 interneuron activity is diminished, resulting in the prolonged response latencies, sudden hyperexcitability, enhanced cortical synchrony, elevated spontaneous c oscillations, and impaired attention/stress-control that have been described in previous tinnitus models. Moreover, because fast processing is gained through sensory experience, tinnitus would not exist in congenital deafness. Electrical cochlear stimulation may have the potential to reestablish tonic inhibitory networks and thus suppress tinnitus. The proposed framework unites many ideas of tinnitus pathophysiology and may catalyze cooperative efforts to develop tinnitus therapies.

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