Sensory Neuron Diversity in the Inner Ear Is Shaped by Activity

Abstract

In the auditory system, type I spiral ganglion neurons (SGNs) convey complex acoustic information from inner hair cells (IHCs) to the brainstem. Although SGNs exhibit variation in physiological and anatomical properties, it is unclear which features are endogenous and which reflect input from synaptic partners. Using single-cell RNA sequencing, we derived a molecular classification of mouse type I SGNs comprising three subtypes that express unique combinations of Ca binding proteins, ion channel regulators, guidance molecules, and transcription factors. Based on connectivity and susceptibility to age-related loss, these subtypes correspond to those defined physiologically. Additional intrinsic differences among subtypes and across the tonotopic axis highlight an unexpectedly active role for SGNs in auditory processing. SGN identities emerge postnatally and are disrupted in a mouse model of deafness that lacks IHC-driven activity. These results elucidate the range, nature, and origins of SGN diversity, with implications for treatment of congenital deafness.

In vivo ectopic Ngn1 and Neurod1 convert neonatal cochlear glial cells into spiral ganglion neurons

“…It demonstrated that new SGNs were present in all the samples of experimental groups. In addition, we checked other SGN genes such as Calb2, Pou4f1, Lypd1, Slc17a6, Slc17a7, and Pvalb , which have recently been reported in different SGN single‐cell RNA‐Seq studies . Samples #4 and #9 showed enhanced expression of all of these SGN genes compared to other samples (red arrows in Figure D).…”

“…This data were also generated by manual picking making it potentially comparable to our data. We re‐analyzed the data and divided cells into four clusters based on results of t‐SNE: Type I‐A, Type I‐B, Type I‐C, and Type II (Figure ), consistent with the original report of SGN subtypes . We chose four samples, which were #372, #373, #365, and #452, to represent Type I‐A, Type I‐B, Type I‐C, and Type II, respectively.…”

“…We next specifically explored whether new SGNs from samples #4 and #9 resembled type I or type II SGNs. We downloaded a single‐cell RNA‐Seq dataset from a previous wild‐type SGN single‐cell study covering both type I and II SGNs, which was also performed via manual picking approach, and could serve as reference to score our new SGNs . We were also able to divide the SGN single cells into four clusters (or cell types): Type I‐A, Type I‐B, Type I‐C, and Type II (Figure A).…”

“…Besides our control wild‐type glial cells (ID: #1, #2, and #3), new SGNs (ID: #4, #5, and #6) from experimental group‐1 and new SGNs (ID: #7, #8, and #9) from experimental group‐2, we also downloaded data from one previous SGN single‐cell RNA‐sequencing data . This data were also generated by manual picking making it potentially comparable to our data.…”

A dual‐AAV approach restores fast exocytosis and partially rescues auditory function in deaf otoferlin knock‐out mice

“…In rodents, SGNs diversify in the first four postnatal weeks into low, medium, and high spontaneous rate fibers to encode different sound intensities (Liberman & Liberman, 2016). In mature Vglut3 À/À mice lacking~40% of SGNs (Seal et al, 2008), almost all low spontaneous rate fibers and half of the medium rate fibers are missing (Shrestha et al, 2018). Similarly, aging or mild noise trauma result in the selective loss of low spontaneous rate fibers, which does not affect auditory thresholds, but likely impairs speech comprehension (Furman et al, 2013;Wu et al, 2018).…”