Morphological and Molecular Development of Efferent Innervation of the Cochlea

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Project Summary Olivocochlear neurons (OCNs) reside in the auditory brainstem and project to the cochlea, providing efferent innervation in addition to the afferent circuitry of the spiral ganglion neurons (SGNs), housed within the cochlea. OCNs protect the cochlea from noise damage and modulate acoustic input, and alignment between the afferent and efferent components of auditory circuitry is crucial for proper auditory functioning. OCNs are composed of medial olivocochlear neurons (MOCs) and lateral olivocochlear neurons (LOCs), which innervate the outer hair cells (OHCs) and SGNs, respectively. MOC axons arrive in the cochlea before LOCs and transiently innervate inner hair cells (IHCs) during an important period of development of the SGN afferent circuitry. MOCs are therefore in a prime position to influence both the development of SGNs and later-arriving OCN axons. A lack of genetic access to MOCs and LOCs has so far hindered progress in identifying the cell-cell interactions between OCNs and SGNs during early cochlear development, leaving many open questions about how central and peripheral components of the auditory system align. This research training plan will use newly identified genetic tools to selectively label and perturb OCNs in order to address the hypothesis that early arriving OCN axons interact with SGNs and IHCs to shape the development of cochlear circuitry. Aim 1 will use early induction of recombination in RetCreER mice to sparsely and selectively label the first MOC axons to enter the cochlea. Labeled OCN fibers and synapses will be analyzed to provide a detailed account of key interactions between MOC axons and SGNs and IHCs. Aim 2 will first transcriptionally profile embryonic MOCs and LOCs using single-cell RNA-sequencing to identify Ephs, ephrins, and other molecules that may guide OCN development. Finally, efferent/afferent wiring will be assessed in EphA4 and ephrin-A5 mutants to shed light on efferent pathfinding mechanisms and how EphA4/ephrin-A5 interactions mediate multiple aspects of cochlear circuitry. Results from these studies will reveal important morphological and molecular interactions between OCN axons and other cells in the cochlea that establish a functioning auditory circuit. The research training plan will provide extensive training in the auditory system, molecular genetics approaches, quantitative image analysis, and basic bioinformatics. Additionally, the training plan will offer professional development opportunities, including mentoring students and presenting research at small group meetings, departmental talks, and conferences. The skills developed under this plan will pave the way for an independent research career in the field of auditory neurobiology, studying the role of axon-axon interactions in the development of auditory circuitry.