Grosh, K. | bioRxiv Science

bioRxiv2020

Contrasting mechanisms for hidden hearing loss: synaptopathy vs myelin defects

Hidden hearing loss (HHL) is an auditory neuropathy characterized by normal hearing thresholds but reduced amplitude of the sound-evoked auditory nerve compound action potential (CAP). It has been proposed that in humans HHL leads to speech discrimination and intelligibility deficits, particularly in noisy environments. Animal models originally indicated that HHL can be caused by moderate noise exposures or aging, and that loss of inner hair cell (IHC) synapses could be its cause. A recent study provided evidence that transient loss of cochlear Schwann cells also causes permanent auditory deficits in mice which have characteristics of HHL. Histological analysis of the cochlea after auditory nerve remyelination showed a permanent disruption of the myelination patterns at the heminode of type I spiral ganglion neuron (SGN) peripheral terminals, suggesting that this defect could be contributing to HHL. To shed light on the mechanisms of different HHL scenarios and to test their impact on type I SGN activity, we constructed a reduced biophysical model for a population of SGN peripheral axons. We found that the amplitudes of simulated sound-evoked SGN CAPs are lower and have greater latencies when the heminodes are disorganized, i.e. they are placed at different distances from the hair cell rather than at the same distance as seen in the normal cochlea. Thus, our model confirms that disruption of the position of the heminode causes desynchronization of SGN spikes leading to a loss of temporal resolution and reduction of the sound-evoked SGN CAP. We also simulated synaptopathy by removing high threshold IHC-SGN synapses and found that the amplitude of simulated sound-evoked SGN CAPs decreases while latencies remain unchanged, corresponding to what has been observed in noise exposed animals. This model can be used to further study the effects of synaptopathy or demyelination on auditory function. Author summaryHidden hearing loss is an auditory disorder caused by noise exposure, aging or peripheral neuropathy which is estimated to affect 12-15% of the worlds population. It is a hidden disorder because subjects have normal hearing thresholds, i.e., the condition cannot be revealed by standard audiological tests, but they report difficulties in understanding speech in noisy environments. Studies on animal models suggest two possible pathogenic mechanisms for hidden hearing loss: (1) loss of synapses between inner hair cells and auditory nerve fibers, and (2) disruption of auditory-nerve myelin. In this study, we constructed a computational model of sound-evoked auditory neuron fiber activity and auditory nerve compound action potential to understand how each one of these mechanisms affects nerve transmission. We show that disruption of auditory-nerve myelin desynchronizes sound-evoked auditory neuron spiking, decreasing the amplitude and increasing the latency of the compound action potential. In addition, elongation of the initial axon segment may cause spike generation failure leading to decreased spiking probability. In contrast, the effect of synapse loss is only to decrease the probability of firing, thus reducing the compound action potential amplitude without disturbing its latency. This model, which accurately represents the in vivo findings, could be useful to make further predictions on the consequences of HHL and extend it to explore the impact of synaptopathy and myelinopathy on hearing.

neuroscience↗

bioRxiv2020

A role for tectorial membrane mechanics in activating the cochlear amplifier

The mechanical and electrical responses of the mammalian cochlea to acoustic stimuli are nonlinear and highly tuned in frequency. This is due to the electromechanical properties of cochlear outer hair cells (OHCs). At each location along the cochlear spiral, the OHCs mediate an active process in which the sensory tissue motion is enhanced at frequencies close to the most sensitive frequency (called the characteristic frequency CF). Previous experimental results showing an approximate 0.3 cycle phase shift in the OHC-generated extracellular voltage relative the basilar membrane displacement that is initiated at a frequency approximately one-half octave lower than the CF are repeated in the present paper with similar findings. This shift is significant because it brings the phase of the OHC-derived electromotile force near to that of the basilar membrane velocity at frequencies above the shift, thereby enabling the transfer of electrical to mechanical power at the basilar membrane. In order to seek a candidate physical mechanism for this phenomenon, we used a comprehensive electromechanical mathematical model of the cochlear response to sound. The model predicts the phase shift in the extracellular voltage referenced to the basilar membrane at a frequency approximately one-half octave below CF, in accordance with the experimental data. In the model, this feature arises from a minimum in the radial impedance of the tectorial membrane and its limbal attachment. These experimental and theoretical results are consistent with the hypothesis that a tectorial membrane resonance introduces the correct phasing between mechanical and electrical responses for power generation, effectively turning on the cochlear amplifier. SIGNIFICANCEThe mechanical and electrical responses of the mammalian cochlea are nonlinear exhibiting up to a thousand-fold difference in gain depending on the frequency and level of sound stimulus. Cochlear outer hair cells (OHC) are broadband electro-mechanical energy converters that mediate this nonlinear active process. However, the mechanism by which the OHC electromotile force acquires the appropriate phase to power this nonlinearity remains unknown. By analyzing new and existing experimental data and using a mathematical model, we address this open issue. We present evidence which suggests that a relatively simple feature, the frequency dependence of the radial impedance of the tectorial membrane, provides requisite mechanics to turn on the frequency-specific nonlinear process essential for healthy hearing.

systems biology↗