Lisa Goodrich, AB ’91, PhD
Professor of Neurobiology
We are equipped with the extraordinary ability to detect a wide range of sounds, from the whizz of a honeybee flying by to the sound of an airplane’s engine. This amazing range of hearing ability often deteriorates with age, and specifically, our ability to detect softer sounds can decline as we grow older. This is often most noticeable in very noisy environments, such as while on a train platform trying to get directions or keeping up with the conversation around the Thanksgiving dinner table.
We hear sounds thanks to specialized sensory cells in the inner ear. Hair cells deep inside the ear respond to sound vibrations and convert that information into electrical signals that can be understood by the brain. It is the job of spiral ganglion neurons (SGNs) to relay the electrical information from hair cells to the brain. Indeed, these neurons are the highway from the ear to the brain.
Decades of work have shown that SGNs come in different “flavors” based on their electrical properties and the way they receive information from hair cells. Different types of SGNs have specific electrical properties that provide a type of neural code of auditory signals to the brain, and the repertoire of sounds we can detect is because the repertoire of SGNs enables the wide range of sounds we can hear.
We know that in aging and after noise damage, humans can lose a particular type of SGN that fires electrical signals at a low rate and is less sensitive to sound. The selective vulnerability of this type of SGN is not well understood, mainly because we have not had the tools to properly identify these cells so that we can understand what happens to their biology as we age. Moreover, the differences in electrical properties traditionally used to classify SGNs are difficult to assess and arise during a mouse’s adolescence, precluding investigations into the early stages of their diversification. A type of “parts list” with tools that enable visualization of each SGN type has been needed to enable us to better understand how SGN diversity arises and what molecular and cellular features confer cellular vulnerability in age-related hearing loss.
My lab has recently made progress toward generating tools to identify different types of SGNs by cataloguing their gene activity. We used a new technology called single cell-RNA sequencing that captures the gene expression changes of individual cells. We manually dissected 186 single SGNs and assessed their molecular content. By clustering our cell types into groups based on similarity in genetic profiles, we found that these SGNs fell into four distinct groups. Remarkably, this is much like the groups of SGNs defined over 40 years ago classified using electrical and synaptic properties.
We took advantage of this dataset to identify genes that are mainly active in one class of SGNs versus the others, so as to use this gene as way of “marking” and visualizing each type. This approach allowed us to monitor distinct types of cells following various manipulations, such as during development and in a mouse model of congenital deafness. These are experiments that would not have been possible without this analysis.
We also used our molecular tools to confirm the longstanding observation that a particular class of SGNs is selectively lost in aging mice, and for the first time we have a lead with the ability to determine whether certain interventions could slow down this degeneration. Moreover, we can compare gene sets across “vulnerable” and “resilient” cell types for insights into the basis for this selectivity. With the discovery both of reliable markers and of the cohorts of genes expressed by each subtype, we and the rest of the field of auditory processing have new ways to study how SGNs confer our ability to hear distinct sounds.
This work is a great example of how fundamental insights into the development and biology of neurons can inform therapeutic treatments for age-related hearing loss. This molecular toolbox will be of immense importance as we continue to test interventions that will help those suffering from hearing disorders ranging from congenital deafness to age-related hearing loss.