Immediate and Delayed Cochlear Neuropathy after Noise Exposure in Pubescent Mice

Abstract

Moderate acoustic overexposure in adult rodents is known to cause acute loss of synapses on sensory inner hair cells (IHCs) and delayed degeneration of the auditory nerve, despite the completely reversible temporary threshold shift (TTS) and morphologically intact hair cells. Our objective was to determine whether a cochlear synaptopathy followed by neuropathy occurs after noise exposure in pubescence, and to define neuropathic versus non-neuropathic noise levels for pubescent mice. While exposing 6 week old CBA/CaJ mice to 8-16 kHz bandpass noise for 2 hrs, we defined 97 dB sound pressure level (SPL) as the threshold for this particular type of neuropathic exposure associated with TTS, and 94 dB SPL as the highest non-neuropathic noise level associated with TTS. Exposure to 100 dB SPL caused permanent threshold shift although exposure of 16 week old mice to the same noise is reported to cause only TTS. Amplitude of wave I of the auditory brainstem response, which reflects the summed activity of the cochlear nerve, was complemented by synaptic ribbon counts in IHCs using confocal microscopy, and by stereological counts of peripheral axons and cell bodies of the cochlear nerve from 24 hours to 16 months post exposure. Mice exposed to neuropathic noise demonstrated immediate cochlear synaptopathy by 24 hours post exposure, and delayed neurodegeneration characterized by axonal retraction at 8 months, and spiral ganglion cell loss at 8-16 months post exposure. Although the damage was initially limited to the cochlear base, it progressed to also involve the cochlear apex by 8 months post exposure. Our data demonstrate a fine line between neuropathic and non-neuropathic noise levels associated with TTS in the pubescent cochlea.

Intracochlear Perfusion of Tumor Necrosis Factor-Alpha Induces Sensorineural Hearing Loss and Synaptic Degeneration in Guinea Pigs

“…In summary, although we did not observe any direct effects of TNF-α on CAP or DPOAE thresholds or on hair cell counts, our experiments did reveal that TNF-α specifically caused a decrease in CAP amplitudes accompanied by an increase in the number of unpaired or orphaned ribbon synapses within 6 h of exposure. This finding suggests a pathologic profile that is similar to what is observed in primary cochlear neuropathyin the latter disease, reductions in ABR Wave I amplitudes and synaptic degeneration are observed with minimal changes in ABR Wave I and DPOAE thresholds and minimal loss of inner and outer hair cells in mice (34,40) and guinea pigs (29). These synaptic changes occur rapidly, within hours of noise exposure.…”

“…Histologic sections of the organ of Corti were prepared as previously described (34). In brief, following decalcification, the otic capsule was removed from the cochlea and the spiraling cochlea was microdissected into 10 pieces.…”

Dietary Supplement Comprised of β-Carotene, Vitamin C, Vitamin E, and Magnesium: Failure to Prevent Music-Induced Temporary Threshold Shift

“…It is essential to disclose unknown risks, as the boundary at which synaptopathy emerges in animals and humans is unknown [Le Prell et al, 2012; Spankovich et al, 2014]. Since this study was completed, it has become clear that smaller TTS insults are not always accompanied by synaptic loss and decreased auditory brainstem response amplitude [Fernandez et al, 2015; Hickox and Liberman, 2014; Jensen et al, 2015]. Ethically, these unknown boundaries must be transparent to all participants in any study expected to produce TTS.…”

Translational issues in cochlear synaptopathy

“…Animal models of noise-induced cochlear synaptopathy typically use exposure stimuli targeting mid- to basal cochlear regions, reliably leading to acute basal synaptopathy, although with time, more apical synaptopathy can be observed (Fernandez et al, 2015; Jensen et al, 2015). However, in many of these models, some degree of sensory cell damage is reported in the extreme cochlear base, whether by slight OHC loss or small but significant threshold shifts for the highest frequencies tested (Kujawa and Liberman, 2009; Hickox and Liberman, 2014; Jensen et al, 2015; Liberman and Liberman, 2015; Shaheen et al, 2015; Suzuki et al, 2016; Valero et al, 2016).…”

“…However, in many of these models, some degree of sensory cell damage is reported in the extreme cochlear base, whether by slight OHC loss or small but significant threshold shifts for the highest frequencies tested (Kujawa and Liberman, 2009; Hickox and Liberman, 2014; Jensen et al, 2015; Liberman and Liberman, 2015; Shaheen et al, 2015; Suzuki et al, 2016; Valero et al, 2016). The vulnerability of hair cells in the extreme base has been known for some time (Johnsson and Hawkins, 1972).…”