依维莫司减轻水杨酸盐诱导的耳鸣样行为及听觉皮层过度兴奋。

文献信息

中文摘要

目的： 耳鸣是在无外部刺激情况下的听觉感知，由适应不良的神经可塑性驱动。本研究使用水杨酸钠（SS）诱导的急性耳鸣大鼠模型，探讨以依维莫司（EVE）靶向mTOR通路是否能够改善初级听觉皮层（A1）中的病理性突触标志物改变、神经化学失衡和神经超同步。
方法： 将成年大鼠分为对照组、耳鸣组和耳鸣+EVE组。使用声惊跳的前脉冲抑制（GPIAS）测试评估行为表型。采用在体多通道电生理记录测量A1中的自发放电率（SFR）和局部场电位（LFP），重点关注γ波段功率和θ-γ相位-振幅耦合（PAC）。通过Western blotting、免疫荧光、免疫组织化学和靶向LC-MS/MS神经递质谱分析定量分子变化。
结果： 全身给予EVE可减轻水杨酸盐诱导的耳鸣样间隙检测缺陷。具有耳鸣样行为的大鼠表现出A1过度兴奋，反映为自发放电率升高和c-Fos表达增强。其网络活动受到破坏，表现为γ波段功率增加以及θ-γ相位-振幅耦合显著增强。在分子水平上，mTOR通路被激活，突触蛋白BDNF和PSD95上调。在神经化学方面，兴奋性神经递质谷氨酸显著蓄积。给予依维莫司可抑制这些异常，减轻异常放电率、病理性θ-γ耦合以及过高的突触蛋白和谷氨酸水平。
结论： 靶向抑制mTOR可通过调节适应不良的突触可塑性标志物并减轻A1中的病理性网络超同步，从而减轻水杨酸盐诱导的耳鸣样行为。这些发现提示，mTOR级联可作为听觉幻听感知模型中调节皮层振荡和突触稳态的潜在靶点。

英文摘要

OBJECTIVE: Tinnitus is an auditory perception without external stimuli, driven by maladaptive neuroplasticity. This study investigated whether targeting the mTOR pathway with everolimus (EVE) could ameliorate pathological synaptic marker alterations, neurochemical imbalance, and neural hypersynchrony in the primary auditory cortex (A1) using a sodium salicylate (SS)-induced acute tinnitus rat model.
METHODS: Adult rats were divided into Control, Tinnitus, and Tinnitus+EVE groups. Behavioral phenotypes were assessed using gap prepulse inhibition of the acoustic startle (GPIAS) test. In vivo multi-channel electrophysiology was used to measure spontaneous firing rates (SFR) and local field potentials (LFPs), focusing on gamma-band power and theta-gamma phase-amplitude coupling (PAC) in A1. Molecular changes were quantified via Western blotting, immunofluorescence, immunohistochemistry, and targeted LC-MS/MS neurotransmitter profiling.
RESULTS: Salicylate-induced tinnitus-like gap-detection deficits were mitigated by systemic EVE administration. Rats with tinnitus-like behavior displayed A1 hyperexcitability, reflected by elevated spontaneous firing rates and heightened c-Fos expression. Their network activity was disrupted, showing increased gamma-band power and significantly strengthened theta-gamma phase-amplitude coupling. At the molecular level, the mTOR pathway was activated, and the synaptic proteins BDNF and PSD95 were upregulated. Neurochemically, the excitatory neurotransmitter glutamate accumulated significantly. Everolimus administration suppressed these abnormalities, attenuating the aberrant firing rates, pathological theta-gamma coupling, and the excessive synaptic protein and glutamate levels.
CONCLUSION: Targeted mTOR inhibition attenuates salicylate-induced tinnitus-like behavior by modulating maladaptive synaptic plasticity markers and mitigating pathological network hypersynchrony in A1. These findings suggest the mTOR cascade as a potential target for regulating cortical oscillatory and synaptic homeostasis in auditory phantom perception models.