title: 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.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Shanghai Eye and ENT Hospital, Shanghai Medical College, Fudan University, 83 Fenyang Road, Xuhui District, Shanghai, 200031, China.|Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of WenZhou Medical University, Wenzhou, 325000, Zhejiang, China.
authors.forename: Lian
authors.initials: L
authors.lastname: Fang
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Shanghai Eye and ENT Hospital, Shanghai Medical College, Fudan University, 83 Fenyang Road, Xuhui District, Shanghai, 200031, China.
authors.forename: YaoYao
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Shanghai Eye and ENT Hospital, Shanghai Medical College, Fudan University, 83 Fenyang Road, Xuhui District, Shanghai, 200031, China. doczhangtianyu@163.com.
authors.forename: Tian-Yu
authors.initials: TY
authors.lastname: Zhang
mesh_terms: D000161:Acoustic Stimulation / Q000379:methods; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity; D017626:Cochlear Nucleus / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure*; D025461:Feedback, Physiological / Q000187:drug effects / Q000502:physiology; D034381:Hearing Loss / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009415:Nerve Net / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D012459:Salicylates / Q000633:toxicity*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D012459:Salicylates
keywords: Auditory system; Growth associated protein-43; Synapses; Tinnitus; Ventral cochlear nucleus