Cross section of the sensory epithelium of the developing inner ear in a mouse showing the calcium activated chloride channel TMEM16A (green) in the membranes of supporting cells that surround inner hair cells (red).
According to researchers at Johns Hopkins University School of Medicine, before the fluid of the middle ear drains and sound waves penetrate a developing ear for the first time, the inner ear cells of newborn rodents “practice” their ability to process sounds. The researchers, who describe their study in an article in the December 3, 2015 edition of the journal Cell, show how hair cells in the inner ear can be activated in the absence of sound.
“Cells in the inner ear exploit a system used for fluid secretion in other organs to simulate the effect of sound before hearing begins, preparing them for the real deal,” said Dwight Bergles, PhD, professor of neuroscience at Johns Hopkins Medicine.
Bergles explained in a Johns Hopkins announcement that normal hearing in most mammals is a multistep process that begins with sound waves hitting the ear drum, which transfers energy to the air-filled middle ear and its three tiny bones. Then the fluid in the inner ear vibrates at a corresponding electrical frequency, which bends the “hair cells,” causing them to release chemical messengers that tell nearby nerves to fire. That signal then travels to the brain, where it is interpreted as a particular sound.
Scientists already knew that hair cells and nearby supporting cells in the developing inner ear show synchronous bursts of activity that are triggered by release of the chemical ATP, which is also used as a potent communication signal. This activity is then conveyed to the brain in the same way that sound-evoked information is, leading to a burst of firing of neurons in different auditory centers of the brain.
What was unknown until this study was how ATP activates the hair cells in the inner ear. To find out, Bergles and his research team investigated biochemical elements of the system and found that chloride ion channels in the supporting cells seemed crucial to the process. They knew that ATP triggers a rise in calcium levels inside supporting cells, so they guessed that the calcium was the cue for a calcium-activated chloride channel to open.
An analysis of gene activity in the supporting cells pointed to involvement of the TMEM16A chloride channel, and they found high levels of this channel within supporting cells that surround inner hair cells. Experiments in mice revealed that when this channel was removed from supporting cells or blocked with drugs, the spontaneous excitation of the hair cells decreased.
The researchers conducted additional biochemical tests, combined with electrical recordings and imaging of calcium changes in the inner ears of mice, which allowed them to piece together a complete chain of events. First, supporting cells release ATP, leading to self-stimulation of their own ATP receptors, triggering an increase in calcium levels inside the cells. This rise in calcium opens the TMEM16A channels to let chloride out, which also drags potassium ions and water out. The potassium that is released during these events activates the hair cells, stimulating the nerve cells with which they have formed weak connections. The researchers report that it is this pairing that is thought to stabilize connections that help the brain make sense of sounds.
“This step happens during the first two weeks after birth in mice and rats, when the middle ear is still filled with fluid and outside sounds can’t reach the inner ear,” said Bergels. He explained that the hair cells are arranged in a line and respond to different frequencies based on their location, like keys on a piano. Their connection with nearby nerve cells is strengthened every time a hair cell is activated and causes its partner nerve cell to fire. When the brain receives a signal from hair cells near the entrance of the inner ear, it perceives a high-pitched sound; when the signal comes from farther in, it perceives a deeper sound.
“There’s a beauty to this seemingly overly complex process,” Bergles says. “It uses the capabilities of the cells in a novel way to trigger nerve cell activity. We think this helps establish and refine the connections between ear and brain so that the animals can properly hear sounds as soon as they are exposed to them.”
Bergles reports that these “sounds” that are produced might be perceived as single tones played in succession, something like tests of an emergency response system. The self-made sounds may be for the ear what a batting machine is for a baseball player. Although this self-stimulation process disappears after hearing begins, Bergles says that if this pathway were reactivated following injury, it could lead to tinnitus, or “ringing” in the ear. Further understanding of this early signaling, he says, may lead to new strategies for improving the integration and performance of cochlear implants and speeding recovery from sound-induced trauma.
Source: Johns Hopkins University
Photo credit: Han Chin Wang and Dwight E. Bergles, Johns Hopkins University Medical School
