Deterioration of the Medial Olivocochlear Efferent System Accelerates Age-Related Hearing Loss in Pax2-Isl1 Transgenic Mice

Abstract

The development, maturation, and maintenance of the inner ear are governed by temporal and spatial expression cascades of transcription factors that form a gene regulatory network. ISLET1 (ISL1) may be one of the major players in this cascade, and in order to study its role in the regulation of inner ear development, we produced a transgenic mouse overexpressing Isl1 under the Pax2 promoter. Pax2-regulated ISL1 overexpression increases the embryonic ISL1(+) domain and induces accelerated nerve fiber extension and branching in E12.5 embryos. Despite these gains in early development, the overexpression of ISL1 impairs the maintenance and function of hair cells of the organ of Corti. Mutant mice exhibit hyperactivity, circling behavior, and progressive age-related decline in hearing functions, which is reflected in reduced otoacoustic emissions (DPOAEs) followed by elevated hearing thresholds. The reduction of the amplitude of DPOAEs in transgenic mice was first detected at 1 month of age. By 6-9 months of age, DPOAEs completely disappeared, suggesting a functional inefficiency of outer hair cells (OHCs). The timing of DPOAE reduction coincides with the onset of the deterioration of cochlear efferent terminals. In contrast to these effects on efferents, we only found a moderate loss of OHCs and spiral ganglion neurons. For the first time, our results show that the genetic alteration of the medial olivocochlear (MOC) efferent system induces an early onset of age-related hearing loss. Thus, the neurodegeneration of the MOC system could be a contributing factor to the pathology of age-related hearing loss.

Minimal Effects of Age and Exposure to a Noisy Environment on Hearing in Alpha9 Nicotinic Receptor Knockout Mice

“…At this age, these mice show hearing loss of about 30–45 dB at all frequencies compared to 2 month old mice of the same strain, with only scattered outer hair cell loss. Heterozygous mice with an IsL1 transgene also show accelerated age-related hearing loss, partial outer hair cell loss, and partial MOC terminal loss (Chumak et al, 2016). These mice exhibit a number of other abnormalities, including hyperactivity, circling behavior, and a reduced complement of spiral ganglion neurons, so it is difficult to tease apart the various central and peripheral factors contributing to loss of MOC terminals and hearing loss in this strain.…”

Incomplete and delayed Sox2 deletion defines residual ear neurosensory development and maintenance

“…All tests were carried out on anaesthetized mice as previously described52. Briefly, hearing thresholds were determined at 2, 4, 8, 16, 32 and 40 kHz and DPOAEs were recorded at individual frequencies over the frequency range 4–38 kHz with a resolution of four points per octave.…”

Olivocochlear efferents: Their action, effects, measurement and uses, and the impact of the new conception of cochlear mechanical responses

“…MOC inhibition decreases with age (Yilmaz et al, 2007; Abdala et al, 2014). This may be a contributing factor to age-related hearing loss and synaptopathy (Chumak et al, 2015).…”