Molecular Characterization of the Olivocochlear Efferent System

Abstract

Our sense of hearing relies on connections between diverse cell types to process acoustic information and guide behaviors. Incoming sounds are transduced by hair cells in the cochlea and transmitted into the brain by spiral ganglion neurons (SGNs). In turn, feedback circuits modulate this auditory information at every level of sensory processing, including the sensory periphery. In particular, the olivocochlear neurons (OCNs) send projections from the auditory brainstem into the ear, synapsing onto both hair cells and SGNs. These enigmatic cells have been implicated in numerous aspects of auditory processing, including attentional modulation, separating speech sounds from background noise, and protecting the cochlea from damage. Mammalian OCNs are typically classified into medial (MOC) and lateral (LOC) components, with MOCs projecting to hair cells and LOCs targeting SGNs. However, a robust understanding of the development and function of these cells has long been hampered by a lack of genetic access and poorly understood heterogeneity among OCNs.

We used high-throughput, single-nucleus sequencing to profile the transcriptomes of individual brainstem neurons from neonatal and mature animals. There are two main clusters of OCNs at each timepoint, corresponding to MOC and LOC neurons. OCN subtypes differ in their expression of guidance and adhesion molecules, ion channels, and neurotransmitters, providing insights into the distinct ways that MOCs and LOCs are integrated into auditory circuitry. Although many of these differences are present neonatally and persist into adulthood, other OCN attributes emerge during the course of postnatal development, as the expression of ion channels, receptors, and neurotransmitters all vary between neonatal and mature cells. In addition, I identified a subset of LOCs that express the neuropeptides Npy, CGRP-II, and Ucn. Peptidergic and non-peptidergic LOCs also differ in their expression of the cell adhesion factor Tenm3, suggesting that they may have distinct targets. In order to investigate OCNs in even greater detail, I generated Gata3-FlpO and Ucn-Cre mouse lines, which together provide an intersectional strategy for manipulating LOC neurons without affecting MOCs. Collectively, this work addresses longstanding questions about how coordinated networks of feedforward and feedback cells develop and interact to influence sensory processing.