Early functional alterations in membrane properties and neuronal degeneration are hallmarks of progressive hearing loss in NOD mice

Abstract

Presbycusis or age-related hearing loss (ARHL) is the most common sensory deficit in the human population. A substantial component of the etiology stems from pathological changes in sensory and non-sensory cells in the cochlea. Using a non-obese diabetic (NOD) mouse model, we have characterized changes in both hair cells and spiral ganglion neurons that may be relevant for early signs of age-related hearing loss (ARHL). We demonstrate that hair cell loss is preceded by, or in parallel with altered primary auditory neuron functions, and latent neurite retraction at the hair cell-auditory neuron synapse. The results were observed first in afferent inner hair cell synapse of type I neurites, followed by type II neuronal cell-body degeneration. Reduced membrane excitability and loss of postsynaptic densities were some of the inaugural events before any outward manifestation of hair bundle disarray and hair cell loss. We have identified profound alterations in type I neuronal membrane properties, including a reduction in membrane input resistance, prolonged action potential latency, and a decrease in membrane excitability. The resting membrane potential of aging type I neurons in the NOD, ARHL model, was significantly hyperpolarized, and analyses of the underlying membrane conductance showed a significant increase in K + currents. We propose that attempts to alleviate some forms of ARHL should include early targeted primary latent neural degeneration for effective positive outcomes.

Beneficial effects of time‐restricted feeding on gentamicin cytotoxicity in mouse cochlea and vestibular organs

“…Also, we counted only the hair cells in both the cochlea and vestibular organs. Although the HCs in the basal turn were histologically normal in the NS + TRF group, the ABR thresholds were higher than other reports 16 . The ICR mice used in our study may have had some abnormalities in cochlear tissues other than the HCs.…”

“…Although the HCs in the basal turn were histologically normal in the NS + TRF group, the ABR thresholds were higher than other reports. 16 The ICR mice used in our study may have had some abnormalities in cochlear tissues other than the HCs. A detailed histological analysis of other tissues, such as nerve fibers, spiral ganglion cells, and the stria vascularis, may also be necessary.…”

“…In addition, the experiments in hearing research are predominantly performed on male animals because of the possibility of variances in hearing levels due to the reproductive cycle 14 . The hearing thresholds in ICR mice match well with those in other mouse stains 15 and do not deteriorate at least until the age of 12 weeks 16 . ICR mice are less likely to exhibit congenital hearing loss and are considered to be suitable for studying hearing function 17…”

“…14 The hearing thresholds in ICR mice match well with those in other mouse stains 15 and do not deteriorate at least until the age of 12 weeks. 16 ICR mice are less likely to exhibit congenital hearing loss and are considered to be suitable for studying hearing function. 17 Mice were divided into three groups and were assigned to different feeding regimens randomly, as described in Figure 1A-C.…”