Defining population-specific macrophage functions in noise-induced cochlear injury

About This Grant

Abstract: Noise exposure causes permanent damage to the cochlea. A moderate level of noise causes temporary threshold shifts (TTS), synapse loss, and subsequent repair, whereas a severe level of noise causes permanent threshold shifts (PTS), and loss of hair cells and synapses. Noise also induces inflammation in the cochlea by increasing the macrophage populations and upregulating inflammatory genes among them. Broad ablation of macrophages prevents synapse repair after TTS, suggesting that they mediate this recovery mechanism. However, several knowledge gaps exist and prevent us from identifying precise therapeutic targets to treat noise-induced hearing loss: whether macrophages are heterogenous and whether subsets of macrophages serve different functions in the cochlea during homeostasis and post-damage are not known. To bridge these gaps, we have in preliminary experiments found and characterized 3 subtypes of macrophages with distinct transcriptomes and spatial distributions in the mature mouse cochlea. In this proposal, we have designed two independent aims to interrogate the roles of these macrophage subtypes in mice exposed to noise-induced TTS or PTS. In Aim 1, we will selectively ablate individual macrophage subtypes and determine whether this approach confers protection or increases susceptibility to TTS-induced synapse loss/recovery, spiral ganglion neuron loss, and wave 1 amplitude decrease. Moreover, we will assess the spatiotemporal changes of macrophages, spiral ganglion neurons, and other sensory and non-sensory cochlear cell types using single-cell RNA sequencing on the cochlea after noise exposure. In Aim 2, we will ablate macrophage subtypes and assess their effects on PTS-associated damage at both the histologic, physiologic, and transcriptomic levels. In summary, we will apply state-of-the-art technologies (single-cell RNA-sequencing, novel transgenic mouse models, bioinformatic strategies) to study the roles of macrophage subtypes in noise- induced TTS and PTS. We have assembled a team of experts experienced in macrophage and cochlear biology and physiology. At the end of this 5-year proposal, we will have 1) revealed whether ablating macrophage subtypes affects the cochlea during homeostasis and post-noise, 2) revealed the transcriptome of macrophage subtypes post-noise and identified putative therapeutic targets, 3) revealed the transcriptomes of noise-susceptible sensory and non-sensory cell types post-noise and after ablation of macrophage subtypes.