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

The major aim of this research is to understand the complex electromechanical functional relationships between cellular elements of the organ of Corti, and between these elements and the major extracellular matrices, in the healthy impaired cochlea.

A focus of this objective is to discover the bases for apparent differences in sensory processing between the apical low frequency and basal high frequency regions of the cochlea. To achieve our research goal, we will use methodology that is largely in place in our labs and is published, except where specifically mentioned in the case for support.

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).

Hair cells 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. Hair cells in the Organ of Corti are not replaced when they die. Subsequent hearing depends on remaining, usually low frequency, sensory hair cells. Why hair cells 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 hair cells are tuned to acoustic frequencies.

Our prime objective is to study interaction between outer hair cells (OHCs) and the supporting cells (SCs) that comprise a restraining, complex, flexible, fluid filled cage that is proposed to optimise exchange and control of energy between OHCs and the cochlear partition, including the basilar membrane (BM). Cochlear HCs die and are not replaced when damaged by exposure to intense sounds, disease, age, and genetic disorders.

Recently, however, we have shown that supporting cells can be converted into hair cells at various postnatal stages, but remain immature. Hair cell immaturity is likely due to lack of interaction with surrounding supporting cells, which is why it is essential to understand this interaction for restoration of hearing.

To this end, we will systematically modify and delete the motor protein, prestin, in outer hair cells and cytoskeletal proteins in supporting cells in mice and produce mouse models of age-related and congenital hearing loss. With mice that express channel rhodopsins in outer hair cells and supporting cells, 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 outer hair cells and their supporting cell cages can be developed and tested, leading to the detailed understanding necessary to fully exploit the regenerative possibilities now becoming available.

Outcomes of our research will be of immediate relevance to those who investigate and model the workings of the cochlea and explore ways of repairing and replenishing the sensory epithelium of the organ of Corti.

We provide fundamental information about sensory processing in the cochlea that should contribute to the training and knowledge base of neuroscientists, medical practitioners and bioengineers.

Techniques and approaches that will be employed in the proposed research programme have potential utility in research fields outside neuroscience. Hearing research at £1.34 per person affected is massively underfunded compared with cardiovascular and vision research at £49.74 and £14.50 respectively (Action on Hearing Loss, 2013). One outcome of underfunding is lack of basic understanding of the peripheral auditory system that is necessary to produce effective and radical new treatments.

A main objective of our proposed research is to contribute towards filling this knowledge gap. A potential outcome of immediate to medium-term application in public health is a validated model of hearing impairment that could be used to investigate the behaviour of different types of cochlear implant and prostheses in terms of their action at the cochr level.

This might inspire novel strategies for signal processing or implant stimulation, which exploit particular features of the impaired cochlea. A better model of the hearing-impaired cochlea would drive the development of hearing loss simulation algorithms and hence enable better and more reliable testing of new signal processing strategies for hearing prostheses.