The neurotransmitter serotonin, best known for its role in regulating mood, may also influence the severity of tinnitus, new research has found.
According to a mouse study by scientists in the US and China, increasing serotonin signaling in a specific brain circuit increased behaviors associated with the neurological disorder.
Since serotonin is often targeted to alleviate symptoms of depression and anxiety, this finding could help guide the development of treatments that relieve these conditions without exacerbating tinnitus.
"We've suspected that serotonin was involved in tinnitus, but we didn't really understand how. Now, using mice, we've found a specific brain circuit involving serotonin that goes straight to the auditory system, and found that it can induce tinnitus-like effects," says neuroscientist Zheng-Quan Tang of Anhui University in China.
"When we turned that circuit off, we were able to ameliorate the tinnitus significantly. This gives us a much clearer picture of what's going on in the brain – and points toward new possibilities for treatment."
Tinnitus is usually defined as a 'phantom' noise heard only by the patient, often a high-pitched ringing, hissing, buzzing, or throbbing. Some of the underlying mechanisms are known, such as hearing loss or earwax buildup, but in many cases, it seems to be a neurological issue, generated not in the ears but in the brain's auditory system.
It's hard to describe the unrelenting anguish of an auditory system that just will not shut up, but many patients also report depression, anxiety, and suicidal ideation. The treatments for those mood disorders often involve a class of drugs called selective serotonin reuptake inhibitors (SSRIs), which block the reabsorption of serotonin in neurons, increasing serotonin signaling.
Several studies over the last few decades have implicated serotonin in tinnitus, but direct evidence of a link and a mechanism has been lacking. To investigate this mechanism, the researchers designed an experiment in mice.
First, they mapped the pathway from the dorsal raphe nucleus, a serotonin-producing region in the brainstem, to the dorsal cochlear nucleus, an auditory region. This pathway helps regulate how sound signals are processed in the brain.
Next, they genetically altered mice so that they could use either light or drugs to activate serotonin-releasing neurons in the dorsal raphe nucleus.
Mice with switched-on serotonin circuits and control mice were then tested using several paradigms to see whether they behaved in ways suggesting they were experiencing a subjective sound.
One of the most telling indicators was the inability to perceive silence gaps in a sound played to the mice – a widely used proxy for tinnitus in animal studies.
"When you stimulate these serotonergic neurons, we can see that it stimulates activity in the auditory region in the brain," says neuroscientist Laurence Trussell of Oregon Health & Science University.
"We also saw that animals then behaved as if they were hearing tinnitus. In other words, it's producing symptoms that we would expect to be experienced as tinnitus in humans."
When they used inhibitory tools to turn this serotonergic-to-auditory circuit off entirely, the tinnitus-like behavior in the mice decreased. And finally, when they used loud noise to induce tinnitus, the mice behaved the same way as they did when serotonin activity was turned up.
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The results suggest that the link between serotonin and tinnitus is real and that this brain circuit may play a direct role in generating the phantom sounds experienced by patients, warranting further investigation in human subjects.
It also suggests that the management of depression or anxiety that presents with tinnitus requires careful handling and treatment.
"Our study suggests a delicate balance," Trussell says.
"It may be possible to develop cell- or brain region-specific drugs that steer the elevation of serotonin in some brain regions but not others. In that way, it may be possible to separate the beneficial and important effects of the antidepressant from the potentially harmful effects on hearing."
The findings have been published in the Proceedings of the National Academy of Sciences.
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