Cholinergic efferent re-wiring of hair cells in the aging cochlea: understanding mechanisms and functional significance

Age-related hearing loss (ARHL) is the most common health condition in the elderly. Approximately half of adults in their 70's exhibit ARHL severe enough to affect communication. It is expected that approximately 14.5 million people in the UK will be affected by hearing loss by 2030, with ARHL being the single biggest cause. ARHL is a progressive disorder decreasing the ability to understand speech, especially in a noisy environment. ARHL is also associated with social isolation, depression, and an increased risk for neurodegenerative diseases. Although hearing aids and cochlear implants are beneficial, they cannot restore hearing especially if the cells in the ear are missing or do not function, which are both characteristic features in ARHL. The major obstacle preventing the development of new treatments for ARHL is a lack of understanding about why we progressively lose our sense of hearing with age, making it impossible to prevent, slowdown or even reverse ARHL.

Sound is detected by extremely sensitive sensory cells named hair cells that are located inside a bony structure called the cochlea in the inner ear. Their name derives from the hair-like elements (stereocilia) that project from their apical surface. When sound enters the ear canal it produces minute vibrations of the stereocilia. These vibrations initiate the conversion of sound waves into an electrical current generated by the movement of charged ions through the opening of mechanically gated channels present in the hair cell stereocilia; a process known as mechano-electrical transduction. These electrical currents are a billion times smaller than those used to charge, for example, a mobile phone. Nevertheless, these tiny currents produced by the hair cells are sent to the brain via specialized sensory nerve fibres, allowing us to perceive sound such as speech and music.

Crucial for normal hearing is the presence of motor nerve fibres, which are used by the brain to send instructions to hair cells and sensory nerve fibres (see above) in order to make a change in how they are functioning. For example, in the presence of a very loud noise, the motor nerve fibres reduce the activity of hair cells to avoid damage. Therefore, these motor neurons normally serve a protective role and generally help to keep the hair cells and sensory nerve fibres healthy. However, a recently discovered feature of ARHL is a change in the connections between the motor nerve fibres and hair cells, reverting back to an organization that is only present during pre-hearing stages of cochlear development. This change is peculiar since the motor nerve fibres in the immature cochlea do not serve a protective role, but instead influence the formation of the auditory pathway during early development. Currently, we do not know why the motor nerve fibres are changing in the aging cochlea. The hypothesis we plan to test in this grant is that the changes in the motor nerve fibre is an attempt to repair the faulty aged cochlea by "recapitulating" early development.

In this project we will use aged mice showing signs of ARHL. However, working with aged mice is challenging and extremely costly because changes in the cochlea occur over long periods of time. Therefore, we will also use a few genetically modified mice that show the same changes in the motor nerve fibres as seen in aged mice, but within a much shorter time window. We will not only investigate when, how and why these changes in the organization of the motor nerve fibre occur, but also provide evidence about their functional role and whether the faulty cochlea has the potential to revert back to its normal mature structure following repair. This project will provide a better understanding of a crucial biological aspect associated with ARHL, which will contribute, in the future, to the identification of targetable genes allowing the development of diagnostic and therapeutic interventions in humans.

Age-related hearing loss (ARHL), which causes the progressive loss of hearing sensitivity, is the most common sensory deficit in elderly, leading to their social isolation and depression. The major obstacle that hampers the development of treatments for ARHL is that we know almost nothing about the disease.

Recent findings have shown that a distinctive feature of ARHL is that the efferent system descending from the brainstem undergoes major re-wiring in the aging cochlea, reverting to a configuration normally present during immature pre-hearing stages. Our overarching hypothesis is that the efferent re-wiring is an attempt to repair damage in the aged cochlea by "recapitulating" early development. Understanding whether the efferent re-wiring has a positive or negative effect on the aging cochlea is of fundamental biological importance. As we begin to think about therapeutic strategies to combat ARHL, should we be trying to prevent, or promote, the efferent re-wiring?

Therefore, the aim of this project is to understand the mechanisms triggering the re-organization of the efferent projections within the cochlea, the functional implication of these changes, and whether the process is reversible following hair cell recovery. We also aim to understand whether efferent re-wiring within the aged or damaged cochlea is a signature of early hair cell dysfunction.

To address the above aims we will: 1) determine the temporal progression and mechanisms leading to efferent re-wiring during cochlear aging; 2) determine whether the re-organization of efferent innervation is directly influenced by the dysfunction of hair cells; 3) determine the physiological relevance of efferent re-wiring on IHCs and SGNs; 4) determine the degree of plasticity of the efferent system in the mature mouse cochlea.

Addressing the above objectives will be done with the complementary expertise present at Sheffield and the support of world-expert colleagues (collaborators).

Academic Impact
The proposed work will provide an in depth understanding of the mechanisms underlying the re-wiring hair cells during aging, and more generally under conditions impacting on hair cell function. This project will be of great interest, not only to auditory scientists interested in cochlear function and hearing loss, but also to a large proportion of colleagues interested in aging, morphogenesis, mechanobiology, cellular physiology and plasticity. We will continue to disseminate our results in high-impact peer-reviewed publications and conference presentations. We also expect that the results produced will lead to invitations to give talks and seminars at international institutions, which will be undertaken by the PI, Co-PIs and PDRA. In addition we are proposing to organize a small international symposium at the University of Sheffield that will bring together PIs from key groups interested in gene-related hearing loss and gene therapy.

Societal and economic Impact
ARHL is not only the most common sensory deficit in the elderly, but also one of the most prevalent chronic medical conditions associated with aging in humans. People affected by ARHL are excluded from basic day-to-day communication, which ultimately leads to their social isolation and cognitive impairment. The proposed project will provide an understanding of some of the mechanisms associated with ARHL, which will lead in the future to the development of therapies to prevent or ameliorate the progression of the disease. Therefore, we will inform the general public via several routes: we organize, together with Action on Hearing Loss, open meetings to discuss our scientific work with the elderly community. We also present our findings to the public during the MRC Festival at Sheffield and the Science Week and on Discovery Night held at the University of Sheffield.

Post-doctoral scientist
The proposed work combines a wide-range of physiological, morphological and imaging techniques using in vitro and in vivo models, providing excellent training for a young PDRA. The postdoc will receive training in not only the wide range of expertise already established at Sheffield, but will also benefit from training in mouse-genetics available at Harwell (course provided: see Pathways to Impact). The PI and Co-Is work very closely with joint projects, and we expect this to lead to considerable interaction and exchange of expertise for the PDRA employed under the grant.

Undergraduates
The number of hearing research PIs in the UK has been steadily decreasing in recent years, resulting in the UK falling behind compared to other European countries. The PI at the University of Sheffield runs a 3rd year research-driven module in Sensory Neuroscience, which attracts high-level students (3 have started a PhD in hearing research group). The proposed work will underpin the continued interest and recruitment of undergraduates onto graduate study programmes with the aim of building capacity and UK leadership in this critical area of neuroscience research.