Noise-Induced Inner Hair Cell Ribbon Loss Disturbs Central Arc Mobilization: A Novel Molecular Paradigm for Understanding Tinnitus

Abstract

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.

Bimodal stimulus timing-dependent plasticity in primary auditory cortex is altered after noise exposure with and without tinnitus

“…This cytoskeletal protein is mobilized after LTP activity and has been proposed to influence postsynaptic AMPA receptor expression that is required for LTP (reviewed by Knipper et al 2013). Interestingly, A1 Arc/Arg3.1 following noise exposure was only mobilized in animals without tinnitus and was not changed in those with tinnitus Singer et al 2013). This suggested that increased cortical firing following moderate deafferentation following noise may be the result of enhanced glutamate sensitivity.…”

Cochlear NMDA Receptors as a Therapeutic Target of Noise-Induced Tinnitus

“…Following the treatment protocols of Kaltenbach et al [42], the rats were exposed for 2 h and sacrificed 10-15 d following noise exposure (acoustic trauma, AT). This exposure paradigm has been reported to induce tinnitus in more than 90% of rats (29 out of 31 rats with tinnitus; [11]). Sham-exposed animals were anesthetized and placed in the reverberating chamber, but not exposed to acoustic stimulus (i.e., the speaker remained turned off).…”

“…Ribbon synapses of IHCs (Fig. 1) were counted as previously described [11,47]. Briefly, cross sections of the cochleae containing all three cochlear turns (apical/medial, midbasal and basal) were used for immunhistochemistry.…”

“…Thus, clinically normal auditory thresholds (i.e. less than 20 dB (decibel) hearing threshold loss for frequencies up to 8 kHz [5]) can be found in tinnitus patients (for review see [6,7]) in spite of IHC deafferentation, which has been proposed to be causally involved in tinnitus generation [8,9,10,11]. …”

Changes in the Numbers of Ribbon Synapses and Expression of RIBEYE in Salicylate-Induced Tinnitus

“…Effective IHC synaptic ribbons are essential for normal auditory signaling and hearing [26]. Significant losses of IHC ribbon synapses accompanied by hearing impairment can be observed in noise-induced tinnitus [27,28]. Nevertheless, the mechanisms by which ototoxicity causes damage to synaptic ribbons are still unknown.…”