Thesis: Measurement of very slow basilar membrane movements in vivo and outer hair cell auto-regulation
Human hearing requires the accurate and stable detection of near-atomic movement of the receptor cells within the cochlea. The maintenance of this stable detection must require some regulation (homeostasis), because the vibrating structure within the cochlea (the organ of Corti) is exposed to slow mechanical and electrical challenges minute-by-minute, and yet human hearing thresholds are maintained within 5dB over months and years.
The exquisite sensitivity and frequency selectivity of the mammalian cochlea comes largely from a specialised set of receptor cells in the organ of Corti, the outer hair cells (OHCs), that detect sound via specialised hair-like structures in their membrane ('stereocilia'). Their role is to enhance the sound-evoked vibration of the organ of Corti 1000-fold by actively 'kicking' in time with the vibration and cancelling friction, a mechanism known as 'the active process' which involves a specialised motor protein called prestin. The process by which the OHCs detect and enhance cochlear vibration are prone to significant changes in sensitivity if exposed to large, slow mechanical and electrical disturbances. For example, just a 10% change in efficiency of the active process results in a 10-fold loss of vibration.
In view of this, it seems inescapable that the cochlea has mechanisms to regulate itself and stabilise hearing thresholds. Furthermore, while some sensorineural hearing losses are due to loss of OHCs (e.g. noise exposure), others are likely to be a result of failure of these auto-regulatory systems (e.g. Meniere's syndrome).
There is debate about whether these OHC regulatory mechanisms involve changes of the stereocilia, or slow OHC length changes, which are mediated by the motor protein prestin, intracellular electrical potential and itnracellular calcium levels. Measurements of electrical signals from OHCs during experimental perturbations of OHC regulation suggest slow movements of the basilar membrane (BM) do take place. However, these electrical measurements cannot distinguish BM movements from active OHC length changes, which is crucial for determining the extent and nature of OHC auto-regulatory mechanisms.
Directi measurement of slow BM movements has not been done before. Because existing BM measurement techniques are insensitive to slow movements, we have developed a novel probe to measure slow BM movements in vivo with sub-micron resolution that will allow us to monitor movements of the order of 10 cell membrane widths. Direct measurement of BM displacements will help us to understand what slow movements of the organ of Corti take place in vivo, what auto-regulatory or compensatory processes exist in the normal cochlea, and may indicate the possible modes of failure of these auto-regulatory processes.
Why my research is important
Direct measurement of very slow BM movements in vivo will further our understanding of the regulatory processes in the cochlea that maintain hearing sensitivity, and may give insights into the generation of tinnitus, and the role of efferent neurones within the cochlea. Failure of these auto-regulatory processes is likely to be the cause of many forms of sensorineural hearing loss in humans, including Meniere's syndrome.
Meniere's syndrome affects an estimated 40,000 Australians. Sufferers experience repeated debilitating attacks of hearing loss, roaring tinnitus and vertigo that can last for days. The underlying causes of Meniere's syndrome are poorly understood. Meniere's is associated with abnormal OHC electrical responses and fluid and/or salt imbalances in the inner ear, but it is not known which of these observations are epiphenomena and which may be the causal event in the development of the disease.
This technique for measuring movements of cells and other biological structures will be applicable not only to further investigations of cochlear regulation, but may also be used for measuring similar compliant sensory membranes in the vestibular system (the balance organ in the inner ear) and for investigators studying contractile tissues such as airway, gut or cardiac muscle.