Synaptopathy in the noise-exposed and aging cochlea: Primary neural degeneration in acquired sensorineural hearing loss

Abstract

The classic view of sensorineural hearing loss (SNHL) is that the “primary” targets are hair cells, and that cochlear-nerve loss is “secondary” to hair cell degeneration. Our recent work in mouse and guinea pig has challenged that view. In noise-induced hearing loss, exposures causing only reversible threshold shifts (and no hair cell loss) nevertheless cause permanent loss of >50% of cochlear-nerve / hair-cell synapses. Similarly, in age-related hearing loss, degeneration of cochlear synapses precedes both hair cell loss and threshold elevation. This primary neural degeneration has remained hidden for three reasons: 1) the spiral ganglion cells, the cochlear neural elements commonly assessed in studies of SNHL, survive for years despite loss of synaptic connection with hair cells, 2) the synaptic terminals of cochlear nerve fibers are unmyelinated and difficult to see in the light microscope, and 3) the degeneration is selective for cochlear-nerve fibers with high thresholds. Although not required for threshold detection in quiet (e.g. threshold audiometry or auditory brainstem response threshold), these high-threshold fibers are critical for hearing in noisy environments. Our research suggests that 1) primary neural degeneration is an important contributor to the perceptual handicap in SNHL, and 2) in cases where the hair cells survive, neurotrophin therapies can elicit neurite outgrowth from spiral ganglion neurons and re-establishment of their peripheral synapses.

Cortical and Sensory Causes of Individual Differences in Selective Attention Ability Among Listeners With Normal Hearing Thresholds

“…A growing number of animal studies show that noise exposure can cause a loss of auditory nerve fibers (ANFs) without elevating hearing detection thresholds or affecting the audiogram (Kujawa & Liberman, 2015;Liberman, 2015;Liberman, Liberman, & Maison, 2015). Noise exposure that leaves cochlear mechanical responses intact can produce a rapid loss of as many as 40%-60% of the ANF synapses driven by cochlear inner hair cells (cochlear synaptopathy), which carry the ascending signal up the auditory pathway (Kujawa & Liberman, 2006.…”

Auditory neuropathy — neural and synaptic mechanisms

“…Indeed, certain noise exposure protocols can cause a temporary threshold shift with full recovery of otoacoustic emissions (OAEs) and ABR thresholds, but a persistent substantial reduction of SGN compound action potential (CAP) amplitudes. Glutamate excitotoxicity that eventually leads to damage or loss of the postsynaptic terminal of SGNs is likely to underlie the synaptic loss in both disorders 118 (FIG. 6).…”

“…Lack of synapse regeneration after noise might reflect impaired neurotrophic signalling in the organ of Corti 123 ; indeed, synaptic loss (deafferentia tion) could be mitigated by virally mediated expression of neurotrophic factors in the mouse cochlea 123 . Synaptic loss also takes place in the cochlea as a result of ageing in mice 115,117,118 and is accelerated if animals were previously subjected to 'nondamaging' noise exposure 118 . Currently, the role of excitotoxic damage to synapses in hearing impairment has only been studied in animal models; hence, we do not yet know with certainty how relevant excitotoxic synaptic loss is to noiseinduced and agerelated hearing impairment in humans.…”

A review of the perceptual effects of hearing loss for frequencies above 3 kHz

“…Following the loss of synapses, the neurons in the auditory nerve degenerate, but this can take a considerable time, up to several years (Kujawa & Liberman, 2015). The degeneration tends to be greatest in neurons tuned to high frequencies (Kujawa & Liberman, 2009).…”