Elsevier

Hearing Research

Volume 353, September 2017, Pages 213-223
Hearing Research

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

https://doi.org/10.1016/j.heares.2017.07.003Get rights and content

Highlights

  • Cochlear synaptopathy is an important component of sensorineural hearing loss.

  • Cochlear synaptopathy is a primary event following acoustic trauma in primates.

  • Primates are resilient to noise-induced hair cell loss and threshold shifts.

  • Primates do not appear to be more resilient to synaptopathy than non-primates.

Abstract

Cochlear synaptopathy can result from various insults, including acoustic trauma, aging, ototoxicity, or chronic conductive hearing loss. For example, moderate noise exposure in mice can destroy up to ∼50% of synapses between auditory nerve fibers (ANFs) and inner hair cells (IHCs) without affecting outer hair cells (OHCs) or thresholds, because the synaptopathy occurs first in high-threshold ANFs. However, the fiber loss likely impairs temporal processing and hearing-in-noise, a classic complaint of those with sensorineural hearing loss. Non-human primates appear to be less vulnerable to noise-induced hair-cell loss than rodents, but their susceptibility to synaptopathy has not been studied. Because establishing a non-human primate model may be important in the development of diagnostics and therapeutics, we examined cochlear innervation and the damaging effects of acoustic overexposure in young adult rhesus macaques. Anesthetized animals were exposed bilaterally to narrow-band noise centered at 2 kHz at various sound-pressure levels for 4 h. Cochlear function was assayed for up to 8 weeks following exposure via auditory brainstem responses (ABRs) and otoacoustic emissions (OAEs). A moderate loss of synaptic connections (mean of 12–27% in the basal half of the cochlea) followed temporary threshold shifts (TTS), despite minimal hair-cell loss. A dramatic loss of synapses (mean of 50–75% in the basal half of the cochlea) was seen on IHCs surviving noise exposures that produced permanent threshold shifts (PTS) and widespread hair-cell loss. Higher noise levels were required to produce PTS in macaques compared to rodents, suggesting that primates are less vulnerable to hair-cell loss. However, the phenomenon of noise-induced cochlear synaptopathy in primates is similar to that seen in rodents.

Introduction

Acoustic overexposure is a significant health concern in the industrialized world. Vulnerable populations include military personnel, professional musicians, miners, and construction workers (McBride, 2004, Humes et al., 2005, Gordon et al., 2016, Schink et al., 2014), but everyday noise-exposure from leisure activities may also threaten cochlear integrity (e.g., Portnuff et al., 2011, Flamme et al., 2012, Le Prell et al., 2012, Liberman et al., 2016). Noise-related damage to the cochlea scales with the intensity, duration, and number of acoustic overexposures (Harris, 1950, Eldredge et al., 1973, Hawkins et al., 1976, Bohne and Clark, 1982), and the perceptual consequences can range from degradations in temporal processing and speech perception (Plack et al., 2014, Bharadwaj et al., 2014, Bharadwaj et al., 2015) to significant impairments in sound detection.

An acoustic overexposure sufficiently intense to damage or destroy outer hair cells (OHCs) and/or their stereocilia will induce permanent threshold shifts (PTS) that are detectable by behavioral audiograms, auditory brainstem responses (ABRs), or distortion-product otoacoustic emissions (DPOAEs) (Wang et al., 2002, Liberman and Dodds, 1984). Exposures that were once thought to be benign, because hair cells were spared and threshold shifts were temporary, are now known to produce primary neuronal degeneration (Kujawa and Liberman, 2009). This degeneration begins immediately as an atrophy of the afferent cochlear synapses between IHCs and auditory nerve fiber (ANFs), and it is followed by a slow retraction of the myelinated distal axons of ANFs that finalizes after months or years with the death of the ANF cell bodies (the spiral ganglion cells) and their central axons projecting to the cochlear nucleus (Johnsson, 1974, Liberman and Kiang, 1978, Felix et al., 2002, Kujawa and Liberman, 2009, Lin et al., 2011). Cochlear synaptopathy may be a key contributor to the differences in speech-in-noise performance among listeners with similar threshold audiograms, a.k.a. hidden hearing loss (Liberman, 2015, Schaette and McAlpine, 2011).

Most of what we know about cochlear synaptopathy is based on studies in mice and guinea pigs (reviewed by Kujawa and Liberman, 2015), but several lines of evidence suggest that humans are less vulnerable to noise damage than smaller mammals (see Dobie and Humes, 2017). Nonetheless, emerging data in humans also suggest that, as in mice and guinea pigs, cochlear neurons are more vulnerable than hair cells. Because the inner ear cannot be biopsied, direct evaluation of cochlear synaptopathy in humans must rely on accrual of post-mortem specimens, and such material is slowly accumulating: normal-aging human ears show minimal hair-cell loss but a progressive primary neural degeneration, i.e. a steady age-related loss of spiral ganglion cells (Makary et al., 2011). Based on a small sample of cases, there appears to be a much more dramatic loss of cochlear synapses in the normal-aging human than can be seen in counts of ganglion cells (Viana et al., 2015), as has been more exhaustively documented in mice (Fernandez et al., 2015). No data are yet available on noise-induced cochlear synaptopathy in humans.

Here, we chose to study noise-induced cochlear synaptopathy in a non-human primate. Given that the physiological processes and biomarkers of human ailments are often closely mirrored in monkeys (e.g., Wendler and Wehling, 2010), these data may be useful in inferring the patterns of human synaptopathy, and a primate model of noise-induced synaptopathy could be key in assessing emerging therapies to reconnect surviving ANFs to IHCs (Wan et al., 2014, Suzuki et al., 2016). We show that rhesus ears are less vulnerable to hair-cell loss and permanent threshold shifts than other well-studied small mammals (cats, guinea pigs, mice, and chinchillas). However, as seen in rodent models (Kujawa and Liberman, 2009, Lin et al., 2011), primate cochlear synapses are more vulnerable than hair cells to acoustic trauma, and many of the IHCs remaining in acoustically traumatized ears are partially or largely de-afferented.

Section snippets

Animals and groups

Ten rhesus monkeys (Macaca mulatta) 6.5–11 yrs of age were included in this study. Seven (5 male, 2 female) were housed at Vanderbilt University, and three (males) at Boston University. At both institutions, animals were on a 12 h light/dark cycle with access to food and water ad libitum, except for 12 h prior to physiological testing, noise-overexposure, and euthanasia. Four macaques (3 from Boston University, 1 from Vanderbilt) served as histological controls. The remaining six (from

Cochlear pathophysiology - titrating noise levels to produce TTS vs. PTS

Four monkeys were exposed for 4 h to a narrow-band noise (50 Hz bandwidth, centered at 2 kHz) at 108 dB SPL. Although this exposure would likely produce significant permanent threshold shift (PTS) and hair cell damage in guinea pigs (Lin et al., 2011), chinchillas (Hickox et al., 2016), and cats (Miller et al., 1963, Miller et al., 1997), it caused only a temporary threshold shift (TTS) in these monkeys. The immediate, ∼20 dB reduction in DPOAE magnitudes (Fig. 1C, black vs. teal) recovered

Discussion

A longstanding dogma in noise-exposure studies was that hair cells are most vulnerable to damage, and ANFs degenerate only if they lose their peripheral targets (Bohne and Harding, 2000, Johnsson, 1974). Recent animal studies showed that acoustic overexposures can induce primary neural degeneration, i.e. loss of synapses between ANFs and IHCs, without damaging OHCs or elevating cochlear thresholds (Kujawa and Liberman, 2009, Furman et al., 2013, Hickox et al., 2016). This cochlear synaptopathy

Conflict of interest

The authors declare no conflict of interest.

Acknowledgements

We are grateful to Drs. Tara Moore and Farzad Mortazavi at Boston University for assistance in tissue acquisition, and we remain ever grateful to Leslie Liberman for expert advice in cochlear immunohistochemistry. Mary Feurtado provided assistance with anesthetic procedures at Vanderbilt. In addition, we thank Dr. Lavinia Sheets for helpful input. Funded in part by NIH R01 DC 00188, NIH P30 DC 005209 (MCL), NIH F32 DC 014405 (MDV), and the Intramural Hobbs Discovery Grant from the Vanderbilt

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    Ramachandran, R. and Liberman, M.C. are co-senior authors and contributed equally to this work.

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