The Nose Knows Where Memories Go

Noses turn up in some odd phrases: “Put your nose to the grindstone,” says one timeworn adage, recommending that people work hard and keep their wits sharpened; another advises, “Keep your nose to the ground,” encouraging tenacity in chasing one’s goals and based on a literal example from humanity’s past.

“Humans were once pretty good at getting on their hands and knees to track prey with their noses from scents left on the ground,” says Michael Leon, UC Irvine professor emeritus of neurobiology and behavior. “But much of our ability to do that has degraded over evolutionary time.”

He and others at UC Irvine have been researching the sense of smell’s pathway into the brain and the surprisingly crucial role it plays in forming and strengthening memories. Leon recently led a study showing that a barrage of scents increases the short-term memory retention of seniors.

The study’s 43 participants ranged from 60 to 85 years of age, a span in which memory loss becomes an issue for many people. For four months, during two hours of their nightly sleep cycle, half of the subjects had seven different scents released in their bedrooms by a diffuser. Compared with the control group, their memory retention during standardized word tests improved by a remarkable 226 percent.

Leon and key collaborator Michael Yassa – UC Irvine professor of neurobiology and behavior and James L. McGaugh Chair in the Neurobiology of Learning and Memory – were surprised by the study participants’ level of advancement, though at least some was expected.

“The brain evolved at a time when there was plenty of olfactory stimulation. Nobody took a shower, ever, so everybody was redolent, and everything around them was odorous. In the world we’re in today, you can take a deep breath and not smell anything. There is a big downside to that.”

– Michael Leon, UC Irvine professor emeritus of neurology and behavior

“The sense of smell has a privileged status in the brain,” Yassa explains. “Unlike the other senses, it doesn’t have to filter through the brain’s gateways. It’s like a superhighway that directly accesses the memory parts of the brain: the hippocampus and its surrounding regions.”

Credit our smelly past for that. In our days as hunter-gatherers and rural agrarians, olfaction was more central to our lives and survival.

“The brain evolved at a time when there was plenty of olfactory stimulation,” Leon says. “Nobody took a shower, ever, so everybody was redolent, and everything around them was odorous. In the world we’re in today, you can take a deep breath and not smell anything.”

“There is a big downside to that,” he continues. “Your brain needs a lot of olfactory stimulation in order for the memory and emotional centers to be healthy, and we don’t get much of that in our modern world.”

Compounding matters, our sense of smell typically begins to diminish in our 60s, which is also when our ability to process memories lessens. With studies showing a causal connection, Leon and his colleagues began looking for a solution.

Stimulating Cognitive Reserve

“One of the things driving us is that there’s not really any treatment for memory loss in the elderly, and it gets worse in the context of Alzheimer’s disease,” Yassa says. “I’ve been working in this population for 20 years now, and trying to identify nonpharmacological strategies is important because the medications available for Alzheimer’s can have terrible side effects, and their efficacy is very limited.”

“For the study, Michael [Leon] provided the [scent diffuser], and my staff and I at the UCI Center for the Neurobiology of Learning and Memory tapped into our existing cohort of older adults in the community who participate in our studies,” he explains. “We did neuroimaging with them, which is what my lab specializes in, so we collected the brain imaging data, analyzed that and worked together with Michael interpreting the results and writing the paper.”

That 2023 study – titled “Overnight olfactory enrichment using an odorant diffuser improves memory and modifies the uncinate fasciculus in older adults” – caused something of a sensation when it was published in the Frontiers in Neuroscience journal, attracting coverage from over 200 media outlets.

Leon began researching the nose-brain connection not long after arriving on campus 44 years ago, when the neurobiology department bore a title that still amuses him: psychobiology.

He devoted himself to the study of brain function because, he says, “Why wouldn’t I be fascinated to see how the brain controls behavior and pretty much everything interesting that we do? You could study that forever, but in the last 10 or 15 years, I’ve switched from doing basic research to clinical research: I wanted to see if we could apply what we’ve learned in the lab to the real problems that people have.”

Leon’s Spartan office is a small former lab room, with little decoration aside from pipe fixtures jutting from one wall where a lab sink used to be. There is a complete absence of paper on his desk. “I like simplicity,” he says.

“I’ve been working in this population for 20 years now, and trying to identify non-pharmacological strategies is important because the medications available for Alzheimer’s can have terrible side effects, and their efficacy is very limited.”

– Michael Yassa, UC Irvine professor of neurobiology and behavior and James L. McGaugh Chair in the Neurobiology of Learning and Memory

“I’ve always been attracted to figuring out complex solutions to complex problems,” Leon elaborates. “When I moved into doing clinical research, it became immediately clear that even good complicated solutions can take billions of dollars and decades to do any good, so in my clinical work, I’m really attracted to simple answers to complex questions.”

Leon sees promise in a therapy that can be simply delivered through the air while a patient sleeps, as it’s non-invasive and doesn’t expect the person to adhere to a regimen of medications or self-testing.*

One thing that should be more complex, he says, is the array of smells used in memory treatment. While the seven scents in the study had a surprisingly positive result, Leon says 40 is better because, along with needing olfactory stimulation, the brain thrives on novelty.

Leon says: “There’s a phenomenon in Alzheimer’s disease called cognitive reserve, where some people have Alzheimer’s neuropathology and brain damage, but they don’t have memory loss. These people tend to be ones with a high level of education, a cognitively challenging career and a high level of social interaction – adding up to an enriched-environment life filled with novel experiences.

“We’re hopeful we may be able to mimic that phenomenon with olfactory enrichment, where instead of needing 60 years to develop what an enriched life does, we can do it very rapidly because the stimulation of the olfactory system goes directly to the memory centers of the brain.”

The Science of Memory

Yassa is enthusiastic about the work of Kei Igarashi, UC Irvine Chancellor’s Fellow and associate professor of anatomy and neurobiology, detailing olfaction’s interaction with brain function.

“I helped recruit Kei to UCI in 2016, and he’s fantastic,” Yassa says. “We’re both very interested in the internal cortex, one of those regions that has olfactory information piping directly into it. Each of our labs published work years ago on how the lateral entorhinal cortex processes information, and in 2021, Kei had a paper published in Nature showing that the lateral entorhinal cortex has beautiful memory mechanisms and also very specialized mechanisms to process information using the neurotransmitter dopamine. It’s absolutely fantastic work.”

It’s also a whole lot of work, judging by the activity in Igarashi’s sizable lab. In one room, a team member requires a microscope to hand-affix 16 minute fibers containing 64 electrodes to a connecting board, for recording a mouse’s brain activity. In another room, team members train mice to associate certain scents with rewards, while off-work mice hang out in an enclosure, the electrode devices on their heads protected by gauze caps that look like little chef’s hats.

“My grandmother has Alzheimer’s, and it is my regret that, for all the years I and others have tried to find a cure, there isn’t one yet. So I really want to contribute as much as I can to help.

– Kei Igarashi, UC Irvine Chancellor’s Fellow and associate professor of anatomy and neurobiology

“In our research here, we’ve found we have to be engineers and neurosurgeons,” says Igarashi, who has studied olfaction and the brain since his days at the University of Tokyo, where he earned a Ph.D. in 2007. “I started off thinking scents weren’t any more special than other remembered objects. As I studied how we build olfactory memory, it looked more and more like the sense of smell is quite connected to the memory areas of the brain and has a large influence on it.”

The 2021 paper in Nature, “Dopamine facilitates associative memory encoding in the entorhinal cortex,” of which Igarashi was lead author, addresses how the brain forms memories of delicious smells. That innocuous subject matter belies the study’s groundbreaking discoveries, including the previously unknown role that fan cells in the lateral entorhinal cortex play as memory receptors and that dopamine performs an important role in the fan cells’ function.

Igarashi and his colleagues are now anxious to see if fan cell health and dopamine deficiency might be factors in Alzheimer’s disease.

It’s also a personal mission for Igarashi. “My grandmother has Alzheimer’s, and it is my regret that, for all the years I and others have tried to find a cure, there isn’t one yet,” he says. “So I really want to contribute as much as I can to help. I’m not a clinician, so I can’t really do any direct tests, but we can at least share what findings we have to add to the basic understanding of Alzheimer’s.”

Yassa and Leon also hope that their work might ultimately treat or prevent that devastating disease. They anticipate conducting further studies, ideally with funding from the National Institutes of Health, to test their olfactory findings with a larger group of senior subjects with normal memory loss, then with those suffering significant loss. As the science accrues, they believe, it will reveal strategies for dealing with Alzheimer’s and other forms of dementia.

Leon says that, in addition, they’re interested to see if increased olfaction can be of service at the other end of life. “We’re looking to do a study with young children based on preliminary evidence suggesting that we can improve their executive function, meaning flexible intelligence, focused attention and ability to inhibit inappropriate behaviors – all things they need to do well in school,” he says.

“We’re also concerned about the high rate of depression among undergraduates on campuses. Along with memory, olfaction influences our emotional health. There are reasons to think we might be able to decrease depression symptoms in as little as a month with only 12 odors. Olfactory enrichment isn’t a panacea, but we’ve already found that it’s a remarkable tool, without downsides, for helping people.”