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J.-H. Nam et al., “Underestimated sensitivity of mammalian cochlear hair cells due to splay between stereociliary columns,” Biophys J, 108:2633-47, 2015.
A sound wave that hits your ear can only be perceived after it has been converted from mechanical to electrical energy through a process called mechanotransduction, which is carried out by hair cells within the cochlea, the snail shell–shape canal of the inner ear. To study hair cells, researchers typically excise a portion of the cochlea and use a tiny probe to stimulate bundles of stereocilia that protrude from the tops of the hair cells into the central duct of the cochlea. Stereocilia movement opens up potassium ion channels on the hair cell membrane, resulting in a change in membrane voltage, which in turn allows an influx of calcium ions that scientists can measure with electrodes.
Although these methods have yielded much information about how stereocilia work, in vitro techniques often give results that suggest stereocilia are much less sensitive than researchers know them to be from early in vivo and whole-cochlear explant studies. “[It’s] kind of a paradox that the movement of the bundle that you need to open up the channels [in vitro] is larger than the needed movement to open them up in vivo,” says Anthony Ricci, who studies the molecular mechanisms of hearing at Stanford University. He says that in vivo, the stereocilia bundles need only move a few nanometers to transduce a signal, but in studies using a microprobe, that measurement is “off by several orders of magnitude.”
Ricci’s team has now figured out why that discrepancy exists. The researchers used known parameters of rat hair cells to create a computer simulation of what happens to individual stereocilia when the bundle is stimulated by probes of different shapes. They found that because stereocilia are arranged into stadium seating–like rows, the probes could not contact all of them uniformly, causing them to splay out.
“You can imagine the mismatch between the shape of the hair bundle and this big glass blob,” says Peter Barr-Gillespie, a mechanotransduction researcher at Oregon Health and Science University who was not involved in the study.
The researchers confirmed the model’s predictions of splaying using real rat hair cells, microprobes, and a fluorescent calcium dye to watch individual hair cells light up as their stereocilia were activated. Indeed, when the team lightly poked a bundle on just one side, mechanotransduction only occurred there and not evenly across the stereocilia. Greater force was needed to mimic in vivo activation of the bundle.
The probes, Gillespie says, cannot fully stand in for the tectorial membrane, a thin flap of gel-like material that rests above stereocilia along the length of the cochlea and stimulates them uniformly when it moves. “I don’t think there is an ideal model system yet, and this paper just shows that we have to work harder on that,” he says.
“We’re developing a lot of technology to get back to in vivo,” says Ricci. “Once we know how that movement happens, we’ll be able to better design a probe...that matches the natural stimulus better.”