Salicylate-Induced Hearing Loss Trigger Structural Synaptic Modifications in the Ventral Cochlear Nucleus of Rats via Medial Olivocochlear (MOC) Feedback Circuit

Abstract

Lesion-induced cochlear damage can result in synaptic outgrowth in the ventral cochlear nucleus (VCN). Tinnitus may be associated with the synaptic outgrowth and hyperactivity in the VCN. However, it remains unclear how hearing loss triggers structural synaptic modifications in the VCN of rats subjected to salicylate-induced tinnitus. To address this issue, we evaluated tinnitus-like behavior in rats after salicylate treatment and compared the amplitude of the distortion product evoked otoacoustic emission (DPOAE) and auditory brainstem response (ABR) between control and treated rats. Moreover, we observed the changes in the synaptic ultrastructure and in the expression levels of growth-associated protein (GAP-43), brain-derived neurotrophic factor (BDNF), the microglial marker Iba-1 and glial fibrillary acidic protein (GFAP) in the VCN. After salicylate treatment (300 mg/kg/day for 4 and 8 days), analysis of the gap prepulse inhibition of the acoustic startle showed that the rats were experiencing tinnitus. The changes in the DPOAE and ABR amplitude indicated an improvement in cochlear sensitivity and a reduction in auditory input following salicylate treatment. The treated rats displayed more synaptic vesicles and longer postsynaptic density in the VCN than the control rats. We observed that the GAP-43 expression, predominantly from medial olivocochlear (MOC) neurons, was significantly up-regulated, and that BDNF- and Iba-1-immunoreactive cells were persistently decreased after salicylate administration. Furthermore, GFAP-immunoreactive astrocytes, which is associated with synaptic regrowth, was significantly increased in the treated groups. Our study revealed that reduced auditory nerve activity triggers synaptic outgrowth and hyperactivity in the VCN via a MOC neural feedback circuit. Structural synaptic modifications may be a reflexive process that compensates for the reduced auditory input after salicylate administration. However, massive increases in excitatory synapses in the VCN may represent a detrimental process that causes central hyperactivity, leading to tinnitus.

Reductions in cortical alpha activity, enhancements in neural responses and impaired gap detection caused by sodium salicylate in awake guinea pigs

“…These were present despite a reduction in the amplitude of wave I brainstem responses to 20 kHz tones and no change in the cerebellar ABR to clicks, indicating that high frequency auditory nerve activity was reduced, likely due to the ototoxic effects of salicylate (see Cazals, 2000 for a review). These results are consistent with the effects of salicylate shown previously (Sun et al, 2009;Fang et al, 2016) and could suggest a compensatory mechanism in line with the central gain theory of tinnitus (Schaette & Kempter, 2006;Schaette & McAlpine, 2011), in which a reduction in peripheral sensitivity initiates homeostatic mechanisms that increase central auditory activity. Furthermore, increased evoked activity could be an indication of hyperacusis, an oversensitivity to sound that is commonly comorbid with tinnitus (Baguley, 2003).…”

Axonal sprouting in the dorsal cochlear nucleus affects gap‑prepulse inhibition following noise exposure

“…Several previous studies have reported that auditory damage after noise or salicylate exposure increases the expression of various synaptic markers, including GAP43 and synaptophysin, in the cochlear nucleus (22,35,41-44). GAP43 is a neuronal growth cone marker that denotes synaptogenesis and axonal outgrowth (25).…”

Glutamatergic Projections to the Cochlear Nucleus are Redistributed in Tinnitus

“…Electron microscopic analysis shows that these newly-grown axons are qualitatively different from auditory nerve synapses and are likely derived centrally (Kim et al, 2004b). Furthermore, several markers for axonal outgrowth and synaptic sprouting, including GAP-43 (Benowitz and Routtenberg, 1997), glial fibrillary acidic protein (GFAP) (Brenner, 2014), and synaptophysin (Leclerc et al, 1989), have been shown to be increased following acoustic trauma or salicylate treatment (Muly et al, 2002; Kraus et al, 2011; Fang et al, 2016). Previous research showed that the number of somatosensory terminals from the spinal trigeminal nucleus and cuneate nucleus to the CN increases following cochlear damage, and that these projections are VGLUT2-positive (Zeng et al, 2012).…”