Interaction between sensory and supporting cells in the organ of Corti: basis for sensitivity and frequency selectivity of mammalian cochlea.

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Our prime objective is to study interaction between individual cells and other elements of the complex sensory epithelium of the organ of Corti (OC) of the cochlea that determines the exquisite sensitivity and frequency selectivity of mammalian audition. Understanding this interaction is essential for future development of successful treatments for hearing loss, especially those involving recovery of damaged, or replacement of dead, sensory hair cells (HCs). HCs die when damaged by exposure to intense sounds, ototoxicity, disease, age, and genetic disorders. According to WHO, 5% of the world population suffer from irrecoverable hearing loss. HCs in the OC are not replaced when they die. Subsequent hearing depends on remaining, usually low frequency, HCs. Why HCs of non-mammalian vertebrates are replaced, but not those in the mammalian cochlea, is not known. We suggest it is a consequence of the mechanism, by which HCs are tuned to acoustic frequencies. HC frequency tuning of non-mammalian vertebrates is due usually to intrinsic electrical and mechanical resonances and each HC is surrounded by a ring of supporting cells (SC)s that provide a source of replacement HCs. HCs in the mammalian cochlea rely on an extrinsic source of mechanical tuning: the basilar membrane (BM), which constitutes a spiralling acellular ribbon with graded stiffness increasing from apex to the base of the cochlea and is intimately attached to the OC. BM vibrations deflect the HC sensory hair bundles. For the three rows of sensory-motor outer HCs (OHCs) extending the length of the OC, the resultant receptor potentials drive motile forces that feedback energy to the BM. The forces boost BM vibrations close to the frequency place of the OHC, which are transmitted to the row of sensory inner hair cells (IHCs). Resultant deflections of IHC hair bundles generate voltages that control transmitter release and flow of afferent signals in the auditory nerve.To interact with the BM, each OHC is restrained in a complex, flexible, fluid filled cage of specialized, interconnected, SCs comprising pillar cells (PCs) and Deiter's cells (DCs). The cage is proposed to optimize exchange and control of energy between OHCs and other elements of the cochlear partition, including the BM. It has been suggested that their complexity renders mammalian SCs unavailable as sources for HC replacement. Recently, however, we have shown that SCs can be converted into HCs at various postnatal stages, but remain immature, possibly due to lack of interaction with surrounding SCs, which is why it is essential to understand this interaction for restoration of hearing. To this end, we will systematically modify and delete specific proteins in OHCs, PCs, DCs and BM in mice and produce mouse models of age-related and congenital hearing loss. With mice that express channel rhodopsins in OHCs and SCs, we can excite and reversibly change the mechanical properties of the cochlea with light flashes. Through modelling, based on in vivo and in vitro acoustical, mechanical, and electrical measurements, our understanding of the functional significance of interaction between OHCs and their SC cages can be developed and tested, leading to the detailed understanding necessary to fully exploit the exciting regenerative possibilities now becoming available.SCs, but not HCs, are interconnected by gap junctions that are thought to play a role in fluid homeostasis in the cochlea and/or intercellular signalling. Gap junctions are mediated by special proteins (connexins). The majority of hereditary hearing disorders, including age-related hearing-loss (ARHL) are associated with defects in, or lack of expression of, connexions 26 (Cx26) and Cx30. Cx26 and Cx30, which interconnect DCs and PCs, have been recently implicated in the transmission of forces within the OC. We wish to discover how they might do this and how a specific Cx30 mutation can rescue hearing loss in a mouse strain with severe ARHL.