Abstract
Tinnitus, the phantom perception of sound, often occurs as a clinical sequela of auditory traumas. In an effort to develop an objective test and therapeutic approach for tinnitus, the present study was performed in blast-exposed rats and focused on measurements of auditory brainstem responses (ABRs), prepulse inhibition of the acoustic startle response, and presynaptic ribbon densities on cochlear inner hair cells (IHCs). Although the exact mechanism is unknown, the “central gain theory” posits that tinnitus is a perceptual indicator of abnormal increases in the gain (or neural amplification) of the central auditory system to compensate for peripheral loss of sensory input from the cochlea. Our data from vehicle-treated rats supports this rationale; namely, blast-induced cochlear synaptopathy correlated with imbalanced elevations in the ratio of centrally-derived ABR wave V amplitudes to peripherally-derived wave I amplitudes, resulting in behavioral evidence of tinnitus. Logistic regression modeling demonstrated that the ABR wave V/I amplitude ratio served as a reliable metric for objectively identifying tinnitus. Furthermore, histopathological examinations in blast-exposed rats revealed tinnitus-related changes in the expression patterns of key plasticity factors in the central auditory pathway, including chronic loss of Arc/Arg3.1 mobilization. Using a formulation of N-acetylcysteine (NAC) and disodium 2,4-disulfophenyl-N-tert-butylnitrone (HPN-07) as a therapeutic for addressing blast-induced neurodegeneration, we measured a significant treatment effect on preservation or restoration of IHC ribbon synapses, normalization of ABR wave V/I amplitude ratios, and reduced behavioral evidence of tinnitus in blast-exposed rats, all of which accorded with mitigated histopathological evidence of tinnitus-related neuropathy and maladaptive neuroplasticity.
Highlights
Tinnitus has been linked to common sequelae of acoustic overexposures [1,2,3]
In our prior studies with an open field blast model, we demonstrated that a combinatorial treatment of NAC/HPN-07, administered shortly after blast, was capable of addressing both peripheral and central manifestations of neuropathy but had not extended these studies to examine whether this treatment was capable of addressing chronic neuroplastic reorganization in the central auditory pathway and potential tinnitus-related dysfunction [39,40,41]
To examine whether we could detect objective molecular evidence of chronic blast-induced neuroplastic changes and whether these putative response patterns were addressable by NAC/ HPN-07 treatment, we exposed rats to a single shock tube blast of 10 psi (~190 dB peak SPL), which consistently induced minor to moderate permanent Auditory brainstem responses (ABRs) threshold shifts in untreated controls of 8.7±1.1, 8.0±1.4, 15.8±1.4, and 42.0±2.7 dB at 4, 8, 16, and 24 kHz, respectively, at eight weeks post-blast in our electrophysiological evaluation studies
Summary
Tinnitus has been linked to common sequelae of acoustic overexposures [1,2,3]. Tinnitus occurs in 14–20% of the population and is one of the most prevalent service-related disabilities in the U.S military [4, 5]. The study of the underlying mechanisms that drive tinnitus has increased exponentially over the past several decades, and the prevailing view has shifted to a belief that tinnitus, even when triggered by peripheral cochlear damage, originates within the central auditory system [6,7,8,9,10,11,12]. This unifying “central gain” model proposes that tinnitus results from compensatory increases in gain (or sensitivity) at virtually all levels in the central auditory system due to loss of cochlear sensory input [10, 13, 14]. Animal studies have revealed that acoustic traumas, causing only transient threshold elevations can, cause immediate and permanent loss of cochlear ribbon synapses, which is consistent with clinical observations in which people with normal audiograms report tinnitus [20,21,22,23,24]
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