Most people who lose their sense of smell recover within a few weeks. They catch a cold, can’t taste their favorite meal for a little while and then everything returns to normal.
But for thousands of people, especially those who had COVID-19, that loss can persist. They are left disconnected from the world of scent.
Dr. Cuihong Jia, a professor in the Department of Biomedical Sciences at East Tennessee State University’s Quillen College of Medicine, spends her days trying to understand how to fix that problem. But fixing a damaged sense of smell is just one of three puzzles she has been investigating, and all three involve research into proteins and cellular processes in the brain and nervous system.
“The paradox is what excites me most,” Jia said. “We think we understand something. Then we test it in a different situation, and the story completely changes.”
Inside the tissue lining the nose are specialized cells called olfactory sensory neurons that detect odorants and send signals to the brain. These neurons continually die and are replaced by new ones produced from stem cells through a process called neurogenesis.
When someone becomes sick with COVID-19 or a severe cold, inflammation can affect that tissue. The immune system responds to fight the infection, and the tissue typically recovers within a few weeks. Sometimes, however, the neurons do not return.
Jia’s lab has been investigating the problem through a project led by Ph.D. graduate student Derek Cox and supported by a grant from the National Institute on Deafness and Other Communication Disorders.
Researchers discovered that blocking a protein called focal adhesion kinase, or FAK, in stem cells increases the production of ciliary neurotrophic factor, or CNTF. When CNTF increases, researchers have observed the development of new neurons and improved smell recovery.
“We don’t have to give patients CNTF directly,” Jia said. “We use something to promote CNTF expression, which can benefit patients with smell loss.”
The work, published in the journal “Stem Cells” last year, could eventually have implications for people experiencing persistent smell loss.
The research has also identified sex differences in how chronic nasal inflammation or smell loss affects learning and memory. In studies involving mice with chronic nasal inflammation, inflammation impaired learning and memory in both sexes, but female mice recovered their learning ability more quickly after the inflammation cleared. Male mice did not recover as quickly.
Jia said researchers have also observed differences in reports of cognitive symptoms associated with long COVID. Women report brain fog more frequently than men, but Jia suspects differences in reporting behavior could contribute to that disparity.
“I don’t think women have more cognitive effects,” she said. “I think most men just don’t report it.”
Jia’s collaboration with Dr. Justin Gass revealed another finding involving CNTF.
In the amygdala, a region of the brain involved in processing fear and other emotions, CNTF can strengthen memories and help form new connections between neurons. While those effects can be beneficial in some situations, Jia said they could present a different challenge when studying post-traumatic stress disorder.
“PTSD patients need to forget their fear experiences,” Jia said. “But if you have high CNTF in the amygdala, it can help the patient remember the fear. They have a hard time forgetting.”
The same protein that may help in one context could have different effects in another. Supported by a grant from the National Institute of Mental Health, Jia’s team, led by Dr. Bailey Adams, is studying how that process might be controlled.
Another part of Jia’s research, led by senior Ph.D. graduate student Joshua Bullen, focuses on multiple sclerosis, or MS.
While much MS research focuses on immune responses, Jia’s team studied support cells called astrocytes. Researchers found that blocking FAK in these cells reduced MS lesions in their model, an effect Jia said was unrelated to CNTF. However, the effect occurred only in female mice.
Her lab continues to investigate those differences and identify potential therapeutic targets.
Jia did not always study the sense of smell. During her doctoral studies, she focused on depression and why antidepressants can take weeks to work. When she moved to Michigan for postdoctoral research, she encountered a toxicology center studying olfaction.
She was skeptical at first, but that skepticism eventually turned into a passion for the research.
“Those are the puzzles that get me excited about coming to work,” Jia said.
Key terms
Neurogenesis: The process through which new neurons are produced from stem cells.
CNTF (ciliary neurotrophic factor): A protein involved in the growth, survival and development of nerve cells.
FAK (focal adhesion kinase): A protein involved in cellular processes including adhesion and movement. Jia’s research examines how blocking FAK can affect CNTF production.
Astrocytes: Support cells found in the central nervous system that perform several functions related to maintaining and regulating neural activity.
Amygdala: A region of the brain involved in processing emotions, including fear.
