Deciphering the molecular heterogeneity of spiral ganglion neurons by single-cell gene expression profiling.

The human ear is an extraordinary sensory organ, in which sensory cells and their nerve connections are able to analyse an impressive range of sound frequencies and intensities. The role of the sensory hair cells is to convert sound information from the outside world into electrical signals that are sent to the brain via specialized nerve fibres, allowing us hear speech and music. The development of the auditory organ, the cochlea, is an extremely ordered process, which allows to build sensory cells and nerve connections that, for example, respond preferencially to either low- or high-frequency sound depending on their location along the sensory organ. Age-related hearing impairment (ARHI) is a complex disorder caused by a combination of genetic and environmental factors. Noise exposure is the major environmental factor that causes ARHI. It is clinically very difficult to distinguish between these two most common forms of hearing impairment: noise-induced and age-related hearing impairments (NIHI and ARHI respectively). The large impact of NIHI and ARHI on human health is caused by the continuous increase in the average lifespan of the population, and by the fact that our ears are not well adapted to cope with long-lasting exposure of loud sounds characteristic of modern society. Currently, the only option available to ameliorate hearing loss is using hearing aids and cochlear implants, which are beneficial but they are far from restoring normal hearing. The problem is that we still know very little about the biological mechanisms causing NIHI and ARHI to be able to develop effective alternative treatments to either prevent or cure this disease. Until very recently the sensory cells have been considered the most vulnerable elements to aging and noise exposure but recent finding have shown that their nerve connections are more easily damaged during insults. In the adult auditory system, each sensory cell in the ear (inner hair cell) is contacted by multiple nerve connections that are anatomically and physiologically diverse, and as such able to carry a different sound intensity and frequencies to the brain. In particular, it has been suggested that the nerve connections having the highest detectable sound intensities seem more vulnerable to noise and aging, resulting in their specific damage. However, there is no direct evidence as to why these specific nerve connections are predominantly affected by aging and/or noise exposure as compared to those responding to lowest detectable intensity sound. Therefore, the ability to identifying genetic factors and molecules that render these nerve connections more susceptible to aging and/or noise trauma is essential for devising early diagnostic, intervention and/or treatments for both ARHI & NIHI. Identifying the genetic factors and molecules in humans has been hampered by many inherent difficulties: 1) not all individuals with the same genetic defects have the same clinical presentations, probably depending on the intensity and the duration of the noise exposed to; 2) similar environmental exposures sometimes have different effects on individuals, probably because of differences in their underlying genetic makeup. For these reasons we will address this important aspect of human biology by studying gene-noise interaction in mice where both factors can be controlled and we know that the structure and physiology of the ear is similar to that of humans. In the proposed project, we will combine expertise in genetic and physiology to evaluate gene expression and function in the nerve connections. Our approach will generate new mouse models to address why a specific population of nerve connections is selectively damaged to noise and aging. These steps are important towards understanding the etiology of human noise-induced and age related hearing impairment (long-term goal), and will take us closer to the goal of developing a suitable therapeutic intervention to treat patients.