Summary: For millions of people, Selective Serotonin Reuptake Inhibitors (SSRIs) are a lifeline for managing depression and anxiety. However, a new study reveals a hidden cost: elevated serotonin can directly exacerbate or even induce tinnitus (ringing in the ears).
By mapping a specific “straight-line” neural circuit from serotonin-producing neurons to the auditory system, researchers have finally explained why some patients report their tinnitus flares up after starting medication.
Key Findings
- Circuit Specificity: For the first time, scientists have identified a specific brain circuit that links serotonin directly to auditory symptoms.
- Reversibility: When researchers “turned off” this specific serotonergic circuit in mice, the tinnitus symptoms were significantly reduced (ameliorated), pointing to a potential target for future drugs.
- The “Delicate Balance”: The goal isn’t to stop using SSRIs, but to find a “drug regimen balance” that treats psychiatric symptoms without overloading the auditory system.
Source: Oregon Health and Science University
The same neurotransmitter commonly leveraged to relieve symptoms of depression and anxiety also may exacerbate a vexing condition known as tinnitus, according to new research published in the Proceedings of the National Academy of Sciences.
Tinnitus is a constant sensation of ringing or buzzing in the ears, creating a continual irritation for some and severe anxiety for others. Global prevalence is estimated as high as 14%, with many severely affected.
Researchers with Oregon Health & Science University and Anhui University in China found in a mouse model that elevated levels of the neurotransmitter serotonin in the brain also resulted in elevated behavioral symptoms of tinnitus.
The findings should be especially meaningful for millions of people around the world who suffer from tinnitus, said co-senior author Laurence Trussell, Ph.D., professor of otolaryngology in the OHSU School of Medicine and a scientist in the OHSU Vollum Institute and Oregon Hearing Research Center.
“People with tinnitus should work with their prescribing physician to find a drug regimen that gives them a balance between relief of psychiatric symptoms like depression and anxiety, while minimizing the experience of tinnitus,” Trussell said. “This study highlights the importance of clinicians recognizing and validating patient reports of medication-associated increases in tinnitus.”
Those medications include a common class of antidepressants known as selective serotonin reuptake inhibitors, or SSRIs. They alleviate symptoms of moderate to severe depression and anxiety by increasing the level of serotonin in the brain.
“We’ve suspected that serotonin was involved in tinnitus, but we didn’t really understand how,” said co-author Zheng-Quan Tang, Ph.D., of Anhui University in China. “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. 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.”
Tang started the research as a postdoctoral scholar in Trussell’s lab.
‘A delicate balance’
Researchers made significant advances from a previous study published in 2017.
In the new study, researchers used optogenetics via fiber optics to precisely aim light into the brain such that it triggered electrical activity of neurons that produce serotonin. They then tested the behavioral response of the mice through a modified type of auditory startle response.
“When you stimulate these serotonergic neurons, we can see that it stimulates activity in the auditory region in the brain,” Trussell said. “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.”
The findings are consistent with the experience of people who report worsening effects of tinnitus with serotonin-elevating drugs like SSRIs, Trussell said.
“Our study suggests a delicate balance,” he said. “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.”
Funding: Trussell’s work was supported by the National Institutes of Health, award RO1DC004450. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Key Questions Answered:
A: No. Never stop medication without a doctor’s guidance. Tinnitus is frustrating, but depression and anxiety are serious conditions. The researchers suggest working with your physician to find a “delicate balance” or perhaps a different class of medication that doesn’t trigger your specific auditory circuits.
A: No. Tinnitus is a complex condition influenced by many factors, including past loud noise exposure and genetics. This study explains the mechanism for why it happens to some, but it doesn’t mean it will happen to everyone.
A: This study is a major step forward. By identifying the exact circuit involved, researchers can now move toward developing “precision” drugs that turn off the ringing without affecting your mood or other brain functions.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this psychopharmacology and auditory neuroscience research news
Author: Erik Robinson
Source: Oregon Health & Science University
Contact: Erik Robinson – Oregon Health & Science University
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“A discrete serotonergic circuit involved in the generation of tinnitus behavior” by Meng-Ting Yu, Zhen-Yu Dai, Si-Xin Wang, Ke-Jian Wang, Chun-Hui Qin, Yi-Mei Zhou, Xiao-Tao Guo, Chun-Chen Pan, Jia-Qiang Sun, Jing-Wu Sun, Wei-Heng Chen, Yan Jin, Qin-Wei Wu, Laurence O. Trussell, and Zheng-Quan Tang. PNAS
DOI:10.1073/pnas.2509692123
Abstract
A discrete serotonergic circuit involved in the generation of tinnitus behavior
Although dysregulated serotonergic neurotransmission has been implicated in the pathophysiology of tinnitus, the precise neural circuit mechanisms underlying this complex sensory neurological disorder remain elusive.
In the current study, we investigated whether a serotonergic input from the dorsal raphe nucleus (DRN) to the dorsal cochlear nucleus (DCN), a key auditory brain region whose hyperactivity is associated with tinnitus, modulates behaviors in mice consistent with the presence of tinnitus. Using neural tracing and viral-genetic methods, we identified an anatomically and functionally defined serotonergic subpopulation in the DRN that projects to the DCN (5-HTDRN→DCN neurons).
Optogenetic activation of 5-HTDRN→DCN circuit increased spike activity in DCN fusiform cells, exhibiting characteristics consistent with tinnitus-like electrical hyperactivity. Chemogenetic activation of 5-HTDRN→DCN circuit induced tinnitus-related behaviors in mice, which was largely reversed by blocking 5-HT2A receptors.
Additionally, we found that noise exposure increased 5-HT levels in the DCN and the activity of 5-HTDRN→DCN neurons in mice with noise-induced tinnitus-related behaviors.
Importantly, chemogenetic inhibition of 5-HTDRN→DCN circuit ameliorated significantly noise-induced tinnitus–related behavior in mice. These results reveal that activation of 5-HTDRN→DCN circuit induces hyperactivity in the DCN sufficient for the perceptual generation and modulation of tinnitus.
These findings provide direct evidence that 5-HT neurons in the DRN play an important role in tinnitus and facilitate our understanding of the circuit mechanisms of pathophysiology in sensory neurological disorders.
