Effects of cochlear synaptopathy on middle-ear muscle reflexes in unanesthetized mice

Abstract

Cochlear synaptopathy, i.e. the loss of auditory-nerve connections with cochlear hair cells, is seen in aging, noise damage, and other types of acquired sensorineural hearing loss. Because the subset of auditory-nerve fibers with high thresholds and low spontaneous rates (SRs) is disproportionately affected, audiometric thresholds are relatively insensitive to this primary neural degeneration. Although suprathreshold amplitudes of wave I of the auditory brainstem response (ABR) are attenuated in synaptopathic mice, there is not yet a robust diagnostic in humans. The middle-ear muscle reflex (MEMR) might be a sensitive metric (Valero et al., 2016), because low-SR fibers may be important drivers of the MEMR (Liberman and Kiang, 1984; Kobler et al., 1992). Here, to test the hypothesis that narrowband reflex elicitors can identify synaptopathic cochlear regions, we measured reflex growth functions in unanesthetized mice with varying degrees of noise-induced synaptopathy and in unexposed controls. To separate effects of the MEMR from those of the medial olivocochlear reflex, the other sound-evoked cochlear feedback loop, we used a mutant mouse strain with deletion of the acetylcholine receptor required for olivocochlear function. We demonstrate that the MEMR is normal when activated from non-synaptopathic cochlear regions, is greatly weakened in synaptopathic regions, and is a more sensitive indicator of moderate synaptopathy than the suprathreshold amplitude of ABR wave I.

Noise-induced cochlear synaptopathy in rhesus monkeys ( Macaca mulatta )

“…It is unlikely that this resilience is mediated by the middle-ear muscle reflex (MEMR) or medial olivocochlear reflex (MOCR), based on the observations that central anesthetics attenuate the strength of both reflexes ( MEMR : Borg et al, 1975; Valero et al, 2017; MOCR : Chambers et al, 2013; Aedo et al, 2015). Such resistance might arise from the mechanical strength of the reticular lamina and the tight junctions that also provide the diffusion barrier between endolymph and perilymphatic scalae.…”

“…In mice synaptopathy can be produced by a single 2-hr exposure to octave-band noise at 94-100 dB SPL (8-16 kHz; Fernandez et al, 2015; Valero and Liberman, 2017), while 106-dB SPL octave-band noise is required to produce synaptopathy in guinea pigs (4-8 kHz; Lin et al, 2011; Furman et al, 2013). Synaptopathy can be seen after exposures producing large TTSs ∼40-50 dB (24-hrs post-exposure; e.g., Lin et al, 2011; Hickox and Liberman, 2014; Fernandez et al, 2015).…”

Reliability and interrelations of seven proxy measures of cochlear synaptopathy

“…The present study elicited MEMRs using pure tones, based on the reasoning that synaptopathy might be most prevalent in the 3-6 kHz region, where early noise damage is often manifest (Coles et al, 2000), and that use of a broadband elicitor might dilute its effects. This reasoning is supported by MEMR findings in a mouse model (Valero et al, 2018), in which sensitivity to synaptopathy was far greater with a narrowband than a broadband elicitor. It is worth noting that our choice of probe (226 Hz tonal) differed from the wideband probe used by Valero and colleagues; however, when these two approaches have been compared in adult humans, they have been shown to yield similar 4 kHz thresholds (Feeney et al, 2004;Keefe et al, 2010).…”

“…We also assessed the reliability of a difference measure, comparing thresholds at 1 and 4 kHz. The mouse data of Valero et al (2018) suggest that such a measure might have value: synapse loss was highly correlated with MEMR threshold when elicitor frequency lay in a synaptopathic region (r = 0.89) and uncorrelated in a lower frequency region (r = 0.17). In the present data, the difference measure exhibited good reliability.…”

“…A more recent addition to the battery of potential measures of synaptopathy is the acoustic MEMR: the involuntary contraction of the stapedius muscle in response to high-level sound stimuli. The afferent portion of the reflex arc may be driven by medium-and low-SR fibers (Valero et al, 2018). Accordingly, Valero and colleagues showed that cochlear synaptopathy in mice was more readily detected by MEMR measures than by ABR wave I amplitude.…”