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Keeping the Noise Down

Credit: psdesign1/Adobe

Credit: psdesign1/Adobe

By Gary Housley

Transgenic mice have revealed how the cochlea protects itself from loud noise and why some people may be more susceptible to hearing loss than others.

Hearing loss is the most prevalent sensory disability in our society and the second leading cause of disability after depression, reflecting a larger non-fatal burden than alcohol-related health issues, osteoarthritis and schizophrenia ( Hearing loss is getting worse in our society because we are exposing our ears to more noise over our lifetime, and this stress exacerbates hearing loss with ageing.

It’s now possible to examine differences in the vulnerability of hearing to noise stress in the lab by measuring hearing in mice with particular gene mutations. Using this approach, we have identified new aspects of cochlear physiology that explain why some people may be more susceptible to hearing loss than others.

The Amazing Process of Hearing

The middle ear ossicles, which are the smallest bones in our body, transfer the sound vibrations collected by the ear drum to our cochlea, causing tiny bundles of hairs to flex. This flexing causes small ion channels at the tips of the hair bundles to open and let positive ions from the surrounding fluid enter for just long enough to trigger the release of glutamate neurotransmitter. Glutamate receptors on cochlear nerve fibres detect the neurotransmitter and trigger action potentials that travel along the cochlear nerve to the brainstem cochlear nucleus in 1/500th of a second.

The cochlea has two types of hair cells. There is a single row of about 3000 inner hair cells, each of which is specifically innervated by about a dozen type I sensory nerve fibres. However, our hearing is largely dependent upon three adjacent rows of outer hair cells that establish our “cochlear amplifier”. These cells have a piezo-electric protein in the cell wall that twists in response to hair bundle-mediated changes in voltage.

The outer hair cells literally dance to music, amplifying the sound vibration so that the inner hair cells are better able to detect the quietest sounds. The reason we can literally hear a “pin drop” when we are in bed in the quiet of night is because our outer hair cell-based cochlear amplifier has its volume control at maximum.

However, we don’t need our cochlear amplifier to hear loud sounds, where it could potentially damage the hair cells, so it is reassuring to know that there are at least two mechanisms the cochlea uses to suppress hearing sensitivity and extend the safe operational range for hearing.

The most well-understood system is efferent suppression via a neural feedback circuit from the brainstem to the cochlea. Brainstem processing of loud sound activates the cochlear efferent suppression pathway, triggering the release of the neurotransmitter acetylcholine at the outer hair cells to suppress the cochlear amplifier. This dynamic adaptation is switched on in milliseconds but runs down if high sound levels are sustained for long periods of time (tens of minutes). Only the outer hair cells that are amplifying the loudest sound frequencies are suppressed by the efferent fibres. This helps us to mask out background noise (like chatter in a noisy room) to better hear speech.

This efferent suppression also helps with sound localisation. Sound in one ear provides a signal that suppresses hearing in the opposite ear, so that hearing control is dynamic and balanced. Efferent suppression is also essential to cochlear self-preservation during exposure to loud sound.

A Matter of Self-Preservation

We have discovered that transgenic mice that don’t produce the neural protein peripherin failed to develop synapses between cochlear type II fibres and the outer hair cells. When we directed sound to one ear of these mice, their hearing sensitivity did not change in the opposite ear ( This meant that the origin of the sensory signal for efferent suppression of hearing is actually the cochlear amplifier itself.

While our work with this new model continues, it’s already evident that without efferent suppression, permanent hearing loss occurs at sound levels that would normally only cause a temporary loss of sensitivity. This supports evidence associating weaker cochlear efferent suppression with poorer hearing, and may help us understand why, as we age, we start to struggle to hold conversations in noisy places like restaurants.

Our transgenic approach has also enabled us to discover another cochlear self-preservation mechanism when we are exposed to sustained loud sound.

P2X2 receptors are adenosine triphosphate-activated ion channels found on cochlear sensory hair cells and adjacent cells facing the fluid space next to the hair bundles. When we “knocked out” the P2rX2 gene to produce mice without P2X2 receptors, and then exposed these mice to 85 dB noise for 30 minutes, we observed no reduction in their hearing sensitivity ( In contrast, wild-type mice that retained functioning P2X2 receptors experienced a hearing loss of about 18 dB, and this took more than 24 hours to recover.

We could measure this hearing loss by putting calibrated clicks and brief tones at various frequencies into the left ears of the mice and then measuring the auditory brainwaves on the skin around the ear. This revealed a novel slow hearing adaptation mechanism, with sustained loud sound causing the cochlear tissue to release adenosine triphosphate and activate the P2X2 receptors. This reduced the ability of the hair cells to transduce sound broadly throughout the cochlea for much longer periods than the efferent suppression pathway.

P2rX2 knockout mice experienced much greater permanent hearing loss than their wild-type littermates at sound levels greater than 95 dB. This showed that the temporary hearing loss evident in the wild-type mice after loud sound exposure reflected this underlying cochlear self-preservation mechanism, rather than reversible damage. Thus, this hearing adaptation mechanism, evident as sustained but recoverable hearing loss, extends the safe upper limit for hearing.

While the P2rX2 knockout mice were developed by a drug company in the USA for a range of studies, it’s now clear that there are naturally occurring mutations of this gene in human populations. These genetic differences cause increased susceptibility to hearing loss. In 2012 we reported that members of families with the P2rX2 mutation who moved from a quiet rural environment to noisy cities experienced more rapid progressive hearing loss than their relatives who had remained in a rural setting (

This serves to highlight the intimate balance between the lifelong management of noise exposure and age-related stress on the hearing organ. While temporary loss of hearing after exposure to sustained loud sound may reflect a natural adaptation to protect our hearing, it’s also a reminder that the cochlea is using all its intrinsic protective processes to save the sensory hair cells and nerve fibres from damage.

Gary Housley holds the Chair in Physiology at UNSW Australia and is Director of the Translational Neuroscience Facility in the School of Medical Sciences.