非阈移噪声引起GABA/谷氨酸通路的改变导致中枢听觉处理功能障碍

Noise-induced hearing loss (NIHL) often results from prolonged exposure to high levels of noise. People are continuously bombarded by environmental noises with highly variable temporal patterns, intensities and exposure schedules in both modern workplace and living environments. As the intensity of noise and length of exposure increases, damage in the sensory organ and central auditory processing also increases and eventually becomes irreversible. As is known to us all, the impact of moderate-level environmental noises on the mature brain that do not cause noticeable peripheral deficits. Continuous non-damaging sounds (below about 85 dB SPL) always were ignored. In our recent study, exposing adult to chronic noise at a sound pressure level of 75 dB, which is markedly below the broadly accepted safety level standard, results in behavioural impairments and substantially impairs the function of the auditory cortex, as evidenced by the measurement of gap in noise, speech in noise, dichotic listening and competing sentence. Noise-exposed subjects had smaller P300 and mismatch negativity (MMN) amplitudes and longer latency than control subjects in event related potential (ERP). It indicated that the ERP is a relatively sensitive tool for the diagnosis of central auditory processing disorder (CAPD) in adult populations. As previously reported, NIHLinduced decreased expression of GABA Receptor in animal model. We used high-density electroencephalogram (EEG) source analysis and magnetic resonance spectroscopy to measure neurotransmitter concentrations in the region of interest in the adults exposed to chronic noise. Reduced GABA concentrations were measured in frontal lobe. Thus, we put forward the following hypothesis that the major excitatory and inhibitory neurotransmitters, glutamate and GABA, respectively, are associated with auditory processing. The aim of our study was to explore whether the changes of GABA/ glutamate pathway after the chronic noise exposure were directly related to central auditory processing disorders.

高强度噪声可引起耳蜗毛细胞的凋亡、坏死及中枢听觉处理功能障碍；中低强度（≤85dB SPL）噪声通常不会导致纯音听阈的变化因而称为非阈移噪声。我们研究发现，长期中低强度噪声暴露的工人，虽然纯音听阈正常，但已出现明确的言语识别率、时间分辨率下降等病征，表现为事件相关电位P300、MMN潜伏期的延长及振幅降低，其机制不明。我们应用256导高密度脑电溯源定位结合磁共振波谱分析技术发现，非阈移噪声暴露后人群脑内感兴趣脑区γ-氨基丁酸（GABA）递质浓度降低；既往动物实验结果也提示，噪声性耳蜗损伤引起的中枢听觉处理功能障碍与GABA及其受体的减少有关。为此我们提出如下假说，非阈移噪声通过影响听觉中枢GABA/谷氨酸通路导致抑制性及兴奋性递质失衡而引发中枢听觉处理功能障碍。本课题拟观察非阈移噪声对听觉中枢GABA/谷氨酸通路及中枢听觉处理功能的影响，旨在探索非阈移噪声暴露后中枢听觉处理功能障碍的机制。

本课题通过大规模的流行病学调查发现，噪声性聋的易感频率依次为4KHz、3KHz、6KHz、8KHz以及10KHz、12KHz，工龄15年以内，各频率听力损失呈线性进展，15年以后渐趋平缓；采用支持向量机(SVM)、随机森林（Random Forest）两种机器学习算法，纳入6个危险因子（年龄、性别、工龄、CNE、吸烟、饮酒）构建模型，并将年龄进行分层训练，预测噪声性聋的听力损失范围；对一部分个体随访追踪6年，探索噪声性聋的易感频率及发生、发展趋势，进一步验证模型的可靠性；对于机器学习算法误判个体进行分析，筛选出噪声性聋易感个体与非易感个体进一步追踪。结果发现，采用Random Forest分类器可建立可靠的噪声性聋预测模型，为尽早开展噪声性聋高危人群的筛查及遗传易感性的研究提供客观依据。在非阈移噪声暴露个体，85%的受试者存在不同程度的中枢听觉处理功能障碍，噪声暴露组噪声下言语测听、竞争语句测试、分听测试明显低于正常对照组，噪声中间隔测试结果较对照组延长，两组相比有显著统计学差异；噪声暴露组失匹配负波（MMN）的振幅降低，潜伏期明显延长，与对照组相比有显著的统计学差异；噪声暴露组P300的振幅显著降低，潜伏期明显延长，两组相比有显著的统计学差异。MMN差异波溯源分析后发现，正常对照组皮层兴奋区位于额叶Brodmann11脑区，噪声暴露组位于颞叶Brodmann20脑区。结合磁共振波谱分析技术发现，非阈移噪声暴露后人群脑内感兴趣脑区γ-氨基丁酸（GABA）递质浓度降低；建立非阈移噪声暴露未引起永久性阈移亦无毛细胞缺失的动物模型，非阈移噪声对豚鼠螺旋神经节和其纤维不造成永久性的损伤，非阈移噪声暴露后，听皮层、下丘GABA能受体减少，谷氨酸能受体表达数量增加。通过复合动作电位、前掩蔽恢复功能、掩蔽及非掩蔽条件下的近、远场振幅调制反应等测试，评估噪声性耳蜗突触损伤评估指标的敏感性,发现106 dB SPL噪声暴露2小时可引起噪声性突触损伤,高声强下近场记录的AM反应对噪声性耳蜗突触损伤的评估有更强的敏感性，对临床上早期发现噪声暴露导致的亚临床损伤具有指导意义。