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Morphological and Molecular Development of Efferent Innervation of the Cochlea

耳蜗传出神经支配的形态和分子发育

基本信息

批准号：
10409742
负责人：
Austen Anne Sitko
金额：
$ 7.39万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10409742
关键词：
Acoustic Trauma Acoustics Address Affect Afferent Neurons Auditory Auditory system Axon Binding Bioinformatics Brain Stem Candidate Disease Gene Cell Communication Cell Nucleus Cells Cochlea Cochlear nucleus Communities Complex Data Data Analyses Development Developmental Process Embryo Ensure Environment Ephrin-A5 Ephrins Feedback Fiber Gene Expression Profile Genetic Genetic Recombination Genetic Transcription Group Meetings Hearing Image Analysis Inner Hair Cells Knowledge Label Labyrinth Lateral Light Medial Mediating Molecular Molecular Genetics Morphology Motor Neurons Mus Mutant Strains Mice Neurobiology Neurons Noise Outer Hair Cells Pattern Peripheral Peripheral Nervous System Play Positioning Attribute Process Research Research Training Rodent Role Series Shapes Synapses Testing Time Training axon growth axon guidance axonal pathfinding base career cell type cholinergic cochlear development conditional knockout differential expression genetic approach insight lateral superior olive mutant nerve supply neurodevelopment neuron development neuronal cell body postnatal quantitative imaging single-cell RNA sequencing skills spiral ganglion student mentoring symposium tool trapezoid body

项目摘要

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.

项目总结