Noise exposures that cause both permanent threshold shift (with accompanying hair cell loss) and temporary threshold shifts (no evident hair cell loss) also result in rapid and permanent loss of synaptic elements and cochlear nerve terminals. Such injury also leads to degeneration of spiral ganglion (SG) cell bodies, but this occurs over a period of months to years. Neuronal survival is a key determinant of the success of cochlear implants, so it is of great interest to understand the mechanisms that promote neuronal survival after cochlear insults. We have recently discovered that hair cell loss is sufficient to recruit macrophages into the spiral ganglion, and that disruption of signaling between macrophages and afferent neurons (by genetic deletion of fractalkine receptor CX3CR1), leads to reduced macrophage recruitment into the spiral ganglion, and also results in diminished survival of afferent neurons. Here we propose to investigate the role of fractalkine signaling after noise induced hearing loss. We hypothesize that: 1) fractalkine regulates macrophage recruitment into the noise-damaged cochlea, and 2) fractalkine promotes the survival of afferent synapses and neurons after noise injury.
Aim 1 will examine the role of fractalkine signaling in neuropathy caused by permanent threshold shift. Specific experiments will assess the effects of genetic disruption of fractalkine signaling on macrophage infiltration, spiral ganglion cell pathology, and auditory function over short (weeks) and long (months) survival periods.
Aim 2 will test the hypothesis that macrophages also serve a critical role after noise exposure that causes temporary threshold shift (TTS). We will characterize any migration of macrophages towards inner hair cell-afferent nerve fiber synapse, and determine whether disruption of fractalkine signaling can influence the severity of, or recovery from, noise-induced cochlear synaptopathy and neuropathy. For both aims, we will monitor changes in cochlear function via ABRs, and cochleae will be collected for histological analysis of macrophages, hair cells and afferent neurons, as well as inner hair cell- cochlear nerve terminal synapse number and morphology.
Noise exposure results in inner ear degeneration and infiltration of inflammatory cells into the cochlea, where they are in close proximity with neurons that carry sound information to the brain. The proposed studies will examine whether cochlear inflammation plays an important role in noise-induced synaptopathy and neuropathy. Such knowledge will be essential for the development of therapeutic strategies for successful cochlear implantation and hair cell synapse restoration approaches in humans.
| Ohlemiller, Kevin K; Kaur, Tejbeer; Warchol, Mark E et al. (2018) The endocochlear potential as an indicator of reticular lamina integrity after noise exposure in mice. Hear Res 361:138-151 |
| Kaur, Tejbeer; Ohlemiller, Kevin K; Warchol, Mark E (2018) Genetic disruption of fractalkine signaling leads to enhanced loss of cochlear afferents following ototoxic or acoustic injury. J Comp Neurol 526:824-835 |
