MR biomarkers of noise-induced hearing loss - studies of neurodegeneration, connectivity and neurotransmitter metabolism in the central auditory system of the mouse

部分或完全听力损失常伴有各种心理声学现象，如耳鸣、听觉亢进、对噪音的辨别能力受损或言语理解能力下降。因此，详细研究导致进行性听力损失的潜在机制至关重要。近年来，越来越多的研究表明，噪声创伤不仅对耳蜗外周结构产生影响，而且对大脑听觉加工结构的生理解剖也产生了显著的影响。该项目的总体目标是利用噪音创伤性听力损失作为模型疾病，开发和组织学验证神经退行性和神经可塑性过程的无创成像生物标志物。将开发基于磁共振成像（MRI）的神经病理变化推导和相应功能测量的实验和临床适用的预测模型。该项目的设计方式可以将结果转移到其他神经退行性过程中，例如脑血管疾病或痴呆症。使用非侵入性MRI连续多次记录小鼠中央听觉系统中噪声诱导的病理生理过程。为此，神经退行性过程将使用基于体素的形态测量（VBM）进行研究，结构连接的变化将通过扩散张量成像（DTI）绘制，突触可塑性在抑制性和兴奋性传递中的调节将通过听觉中脑和丘脑的质子磁共振波谱（1H-MRS）进行分析。对于每次MR检查，这些脑结构的组织将被处理用于神经退行性变（细胞和神经元染色）、轴突投影（神经丝染色）和突触活性（抑制性和兴奋性囊泡性神经递质转运的表征）的免疫组织化学研究。采用线性模型，定性和定量分析无创MRI在噪声创伤后组织学和功能预后方面的价值。这项计划的研究结果将作为发展新型核磁共振诊断工具的基础，用于诊断病人的噪音创伤。

Partial or complete hearing loss is often accompanied by various psychoacoustic phenomena such as tinnitus, hyperacusis, impaired discrimination in noise, or a reduced speech comprehension. Therefore, detailed investigations of the underlying mechanisms leading to progressive hearing loss are of utmost importance. In recent years, it has become increasingly evident that noise trauma not only has an impact on peripheral cochlear structures but also causes prominent effects on the physiology and anatomy of auditory processing structures in the brain. The overarching goal of the proposed project is to develop and histologically validate noninvasive imaging biomarkers of neurodegenerative and neuroplastic processes using noise trauma-induced hearing loss as a model disease. Experimentally and clinically applicable prediction models for the derivation of neuropathological changes and corresponding functional measures based on Magnetic Resonance Imaging (MRI) will be developed. The project will be designed in a way that results can be transferred to other neurodegenerative processes, e.g. in cerebrovascular diseases or dementia. Noise-induced pathophysiological processes in the central auditory system of the mouse will be recorded at several consecutive times using non-invasive MRI. To this end, neurodegenerative processes will be investigated using voxel-based morphometric measurements (VBM), changes in structural connectivity will be mapped by diffusion tensor imaging (DTI) and modulation of synaptic plasticity in inhibitory and excitatory transmission will be analyzed by proton magnetic resonance spectroscopy (1H-MRS) in the auditory midbrain and thalamus. For each MR examination, tissue of these brain structures will be processed for immunohistochemical studies of neurodegeneration (cell and neuronal staining), axonal projections (staining of neurofilaments) and synaptic activity (representation of inhibitory and excitatory vesicular neurotransmitter transporter). Using linear models, the value of non-invasive MRI in terms of histological and functional outcome after noise trauma will be both qualitatively and quantitatively analyzed. The findings of the proposed project will serve as a basis for the development of novel MR-based diagnostic tools of noise-induced trauma in patients.