Introduction
Tinnitus – the perception of a sound without external physical source – is commonly believed to be the result of an interaction of a damage to the peripheral auditory system and central neuroplastic adaptations to the new, changed auditory input (Nelson & Chen, 2004). We already put forward a bottom-up model for tinnitus development in which these neuroplastic adaptations – after a mild hearing loss – start in the dorsal cochlear nuclei (DCN) after losing a part of the neuronal information not transmitted from the damaged cochlea anymore (Krausset al. , 2016; Krauss et al. , 2017; Schilling et al. , 2021). In a nutshell, this Erlangen model of tinnitus development (Schulze et al. , 2023) assumes that a neurophysiological mechanism detects a drop in information after a hearing loss by computing the autocorrelation of the signal of the cochlear nerve (Schulze & Tziridis, 2023), as less temporally structured spike trains reach the DCN neurons (Schulze & Tziridis, 2023). By disinhibition of neuronal noise, most probably coming from the somatosensory system (Schilling et al. , 2021), a reduced – but still information containing – input signal plus that noise can reach the threshold and activate the DCN neurons, a mechanism known as stochastic resonance. As a consequence, otherwise sub-threshold activity from the cochlea can now be further transmitted along the auditory pathway, thereby optimizing information transmission within the auditory system. This comes at the cost of co-propagation of the noise up to the auditory cortex, where the activity is then perceived as a sound, namely tinnitus. based on that model we were able to predict and explain several tinnitus related effects on hearing loss, e.g., that the hearing thresholds in patients with mild to moderate hearing loss and tinnitus are better than in matched patients without tinnitus (Gollnast et al. , 2017). Furthermore, we were able to develop a new therapeutic approach based on that model which allows a causative reduction of tinnitus loudness in tinnitus patients (Schilling et al. , 2020; Tziridis et al. , 2022). However, the original model failed to describe the effects of chronic manifestation of tinnitus and made no predictions on tinnitus related plasticity in the auditory cortex. To overcome these drawbacks, in a previous paper, the stochastic resonance model was unified with the predictive coding model of auditory phantom perception (Sedley et al. , 2016; Schilling et al. , 2023b). in this view, tinnitus might be induced and chronically manifested through an interplay of two feedback loops – the stochastic resonance loop in the brainstem and the predictive coding circuit in the cortex (Sedley et al. , 2016; Schilling et al. , 2023b).
In the present study we aim to investigate tinnitus related adaptations in the auditory cortex (AC) after an assumed chronic manifestation of the phantom percept. Based on electrophysiological recordings in animals (Engineer et al. , 2011; Tziridis et al. , 2015) and e.g., imaging methods or EEG recordings in humans (Haab et al. , 2009; Schoisswohl et al. , 2021), it is already known that tinnitus before and after chronification has different neurophysiological manifestations within the AC of mammals. While before chronification the neurophysiology of the AC seems to undergo profound changes in, e.g., tonotopy (e.g., Eggermont, 2006), the normal processing in the AC seems to be recovered after the new percept is developed, with the addition of the phantom sound activity in the affected frequency range (Ahlfet al. , 2012; Langers et al. , 2012).
Neuronal plasticity in the cortex can be assessed using several different methods (Ohl & Scheich, 2005; Peters et al. , 2017; Irvine, 2018). One of them is the investigation of the density of the extracellular matrix (ECM) by using immunofluorescence luminance of Wisteria floribunda lectin-fluoresceine-5-isothiocyanate (WFA-FITC) on histological slices (e.g., Happel et al. , 2014). The higher the density (WFA-FITC luminance) of the ECM, the more stable are the synapses connecting the neurons and therefore the less likely it is that a once formed pattern can be changed by new information (Dityatevet al. , 2010; Gundelfinger et al. , 2010). With that in mind, we asked, how the ECM density of the primary AC – and indirectly the potential for neuroplasticity of that area – is affected by tinnitus after its chronification in our animal model, the Mongolian gerbil (Meriones unguiculatus ).