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

Subject Area Otolaryngology, Phoniatrics and Audiology
Clinical Neurology; Neurosurgery and Neuroradiology
Term from 2019 to 2024
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 428869206
 
Final Report Year 2025

Final Report Abstract

Noise-induced hearing loss (NIHL) leads to significant changes in the auditory structures of the central nervous system (CNS). This project investigated how cell density, axonal density, and glutamatergic and GABAergic neurotransmission are affected at different time points after acute noise exposure in the central inferior colliculus (CIC) and the ventral medial geniculate body of the thalamus (MGV). The study also explored the development of imaging-based biomarkers using magnetic resonance imaging (MRI). The project was pre-registered on open science framework (osf.io). Mice were exposed to high (115 dB) or moderate (90 dB) broadband white noise (5-20 kHz) for 3 hours, with unexposed mice as controls. Investigations occurred 1, 7, 56, and 84 days post-exposure. Frequency-specific auditory brainstem responses (ABR) were recorded at 4, 8, 16, and 32 kHz to assess shifts in hearing thresholds, confirming NIHL through increased thresholds in exposed groups. Following ABR, in vivo MRI was conducted. T2-weighted MRI and voxel-based morphometry (VBM) served as biomarkers for neurodegeneration by calculating gray matter density (GMD). Diffusion MRI (dMRI) and classical diffusion tensor analysis captured microstructural changes through fractional anisotropy (FA), an established neurodegeneration biomarker. Connectome analysis of dMRI data examined changes in axonal connections between CIC and MGV. Proton (^1H) single voxel MR spectroscopy (MRS) quantified GABA and glutamate in the target regions. All techniques were made publicly available on GitHub. Changes in dMRI connectivity were observed in the MGV 7 days after moderate NIHL, and alterations in GABA and glutamate concentrations were found 84 days post-NIHL. After MRI scans, animals were sacrificed and perfused for histological examinations, including fluorescence immunohistochemical staining (FIHC) against NeuN, DAPI, neurofilaments, VGAT, and VGLUT1/2. Automated Fiji macros were developed for quantitative cell counting and fluorescence intensity analysis. Results indicated that ABR thresholds were significantly higher 7, 56, and 84 days after exposure in animals exposed to 115 dB compared to those exposed to 90 dB or controls, indicating an NIHL phenotype. Significant increases in neurofilament density in the CIC and MGV were observed 1 day after exposure, but not at later time points. This suggests early excitatory and/or compensatory neuroplastic changes in the auditory CNS due to acoustic overstimulation. However, no significant changes in NeuN, DAPI, or VGLUT1/2 and VGAT expression were noted post-exposure. Our data reveal complex adaptive mechanisms in the auditory CNS due to noise trauma, potentially representing neural correlates for changes in auditory processing and perception in patients with noise- or age-related hearing loss, and may relate to psychoacoustic phenomena such as tinnitus, hyperacusis, or reduced speech understanding.

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