Biased auditory nerve central synaptopathy is associated with age‐related hearing loss

Abstract

Key points Sound information is transmitted by different subtypes of spiral ganglion neurons (SGN) from the ear to the brain. Selective damage of SGN peripheral synapses (cochlear synaptopathy) is widely recognized as one of the primary mechanisms of hearing loss, whereas the mechanisms at the SGN central synapses remain unclear. We report that different subtypes of SGN central synapses converge at different ratios onto individual target cochlear nucleus neurons with distinct physiological properties, and show biased morphological and physiological changes during age‐related hearing loss (ARHL). The results reveal a new dimension in cochlear nucleus neural circuitry that systematically reassembles and processes auditory information from different SGN subtypes, which is altered during ageing and probably contributes to the development of ARHL. In addition to known cochlear synaptopathy, the present study shows that SGN central synapses are also pathologically changed during ageing, which collectively helps us better understand the structure and function of SGNs during ARHL. Abstract Sound information is transmitted from the cochlea to the brain by different subtypes of spiral ganglion neurons (SGN), which show varying degrees of vulnerability under pathological conditions. Selective cochlear synaptopathy, the preferential damage of certain subtypes of SGN peripheral synapses, has been recognized as one of the main mechanisms of hearing loss. The organization and function of the auditory nerve (AN) central synapses from different subtypes of SGNs remain unclear, including how different AN synapses reassemble onto individual neurons in the cochlear nucleus, as well as how they differentially change during hearing loss. Combining immunohistochemistry with electrophysiology, we investigated the convergence pattern and subtype‐specific synaptopathy of AN synapses at the endbulb of Held, as well as the response properties of their postsynaptic bushy neurons in CBA/CaJ mice of either sex under normal hearing and age‐related hearing loss (ARHL). We found that calretinin‐expressing (type Ia) and non‐calretinin‐expressing (type Ib/Ic) endbulbs converged along a continuum of different ratios onto individual bushy neurons with varying physiological properties. Endbulbs degenerated during ageing in parallel with ARHL. Furthermore, the degeneration was more severe in non‐calretinin‐expressing synapses, which correlated with a gradual decrease in bushy neuron subpopulation predominantly innervated by these inputs. These synaptic and cellular changes were profound in middle‐aged mice when their hearing thresholds were still relatively normal and prior to severe ARHL. Our findings suggest that biased AN central synaptopathy and the correlated shift in cochlear nucleus neuronal composition play significant roles in weakened auditory input and altered central auditory processing during ARHL.

Robustness of neuronal tuning to binaural sound localization cues against age-related loss of inhibitory synaptic inputs

“…In gerbils, age-related loss of high-threshold, low-spontaneous rate auditory nerve fibers was also observed [ 79 ]. Recent evidence in aged mice suggests that changes of low- and medium-spontaneous rate fibers may impact bushy cells’ function [ 80 ]. Furthermore, spiking activity of a bushy cell is modulated by inhibitory inputs [ 81 , 82 ] from several sources including D-stellate cells in the anteroventral cochlear nucleus [ 83 ], whose synaptic inputs were found to degrade with aging [ 84 ].…”

Age-Related Hearing Loss: Sensory and Neural Etiology and Their Interdependence

“…The cochlear nuclei have defined numerous cell types based on morphological and physiological criteria (Oertel and Cao, 2020 ). Synapses from type I SGNs onto bushy cells in the AVCN have structural adaptations that receive the endbulbs of Held; the endbulb of Held permits highly secure signaling between the auditory periphery of SGN and bushy cells (Manis et al, 2012 ; Caspary and Llano, 2018 ; Syka, 2020 ; Wang et al, 2021 ). Losing proper auditory innervation that leads to a simplification of the endbulb termination (Muniak et al, 2016 ).…”

“…This activity will reflect the loss of inhibition (Caspary et al, 2006 ; Caspary and Llano, 2018 ). Physiologically, numerous studies show the temporal fidelity that breaks down at the synapse between cochlear nerve fibers and bushy cells in old mice (Xie, 2016 ; Xie and Manis, 2017 ; Wang et al, 2021 ). These data suggest multiple instruments may be responsible for the aging-related temporal spreading of cochlear nucleus neuronal responses from temporally patterned sounds.…”

“…An interesting size of MNTB differs between 1 year-old mice: more significant more lateral neurons are becoming more smaller in the medial MNTB ( Figures 4C,C”” ). Individual neurons can be traced by calretinin to form a calyx of Held ( Figure 4C” ) that resembles the endbulb of Held of bushy cells (Wang et al, 2021 ). While all calyx receives innervation from the contralateral cochlea, the size of innervation suggests that smaller MNTB neurons have fewer calyces ( Figures 4C”’,C”” ).…”

The Conspicuous Link between Ear, Brain and Heart–Could Neurotrophin-Treatment of Age-Related Hearing Loss Help Prevent Alzheimer’s Disease and Associated Amyloid Cardiomyopathy?

“…Sensorineural hearing loss (SNHL) is generally caused by the loss of hair cells, the sound transducing sensory cells of the cochlea, or by loss of peripheral and central parts of spiral ganglion neurons (SGNs) [ 118 ], which connect the hair cells to the nucleus cochlearis in the brainstem. Age-related loss of peripheral and central SGN synapses (neural ARHL) is consistently observed in humans and animals and is one of the main contributing factors to the development of ARHL [ 119 , 120 ].…”