tag:theconversation.com,2011:/us/topics/olfactory-system-81692/articlesOlfactory system – The Conversation2023-01-18T13:38:45Ztag:theconversation.com,2011:article/1970092023-01-18T13:38:45Z2023-01-18T13:38:45ZVaccination to prevent dementia? New research suggests one way viral infections can accelerate neurodegeneration<figure><img src="https://images.theconversation.com/files/503691/original/file-20230109-7992-tpch1g.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2190%2C1369&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Many viruses interact with the olfactory system, and can damage other areas of the brain through it.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/brain-viral-infection-on-science-background-royalty-free-image/1352255856">Mohammed Haneefa Nizamudeen/iStock via Getty Images Plus</a></span></figcaption></figure><p>One in nine Americans ages 65 and over had <a href="https://www.alz.org/alzheimers-dementia/facts-figures">Alzheimer’s disease</a> in 2022, and countless others were indirectly affected as caregivers, health care providers and taxpayers. There is currently no cure – available treatments primarily focus on prevention by encouraging protective factors, such as exercise and healthy diet, and reducing <a href="https://doi.org/10.1186/s12929-019-0524-y">aggravating factors</a>, such as diabetes and high blood pressure.</p>
<p>One of these aggravating factors is viral infections. Researchers have identified that certain viruses such as <a href="https://doi.org/10.3389/fnagi.2018.00324">herpes simplex virus type 1</a> (HSV-1, which causes cold sores), <a href="https://doi.org/10.1371/journal.pone.0188490">varicella zoster virus</a> (VZV, which causes chickenpox and shingles) and <a href="https://doi.org/10.3233/JAD-220717">SARS-CoV-2</a> (which causes COVID-19) can lead to a higher risk of Alzheimer’s disease and dementia following infection.</p>
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<iframe width="440" height="260" src="https://www.youtube.com/embed/rTAOX4ahMK0?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">There is increasing evidence supporting the potential role viruses play in Alzheimer’s disease.</span></figcaption>
</figure>
<p>Figuring out how and when these viruses contribute to disease could help scientists develop new therapies to prevent dementia. However, researchers have been <a href="https://doi.org/10.1371/journal.ppat.1008575">unable to consistently detect</a> suspect viruses in brains of people who died of Alzheimer’s. Because the Alzheimer’s disease process can start decades before symptoms, some researchers have proposed that viruses act early in a “<a href="https://doi.org/10.1016/j.neurobiolaging.2003.12.021">hit-and-run</a>” manner; they trigger a cascade of events that lead to dementia but have already taken off. In other words, by the time researchers analyze patient brains, any detectable viral components are gone and causation is difficult to establish.</p>
<p>We are a <a href="https://scholar.google.com/citations?user=rH1ZZcwAAAAJ&hl=en">neurovirologist</a>, <a href="https://scholar.google.com/citations?user=hp81rCYAAAAJ&hl=en">neurologist</a> and <a href="https://scholar.google.com/citations?user=LEcQAR0AAAAJ&hl=en">neuroscientist</a> team interested in the role viruses play in neurodegenerative diseases. In our <a href="https://doi.org/10.1016/j.neurobiolaging.2022.12.004">recently published research</a>, we use new technology to search for the tire tracks of these viruses in Alzheimer’s patients. By focusing on the most vulnerable entry point to the brain, the nose, we discovered a genetic network that provides evidence of a robust viral response.</p>
<h2>Focusing on the olfactory system</h2>
<p>Many of the viruses implicated in dementia, including <a href="https://doi.org/10.1038/ncpneuro0401">herpesviruses</a> and the <a href="https://doi.org/10.1126/sciadv.abc5801">virus that causes COVID-19</a>, enter the nose and interact with the olfactory system.</p>
<p>The <a href="https://www.britannica.com/science/olfactory-system">olfactory system</a> is constantly bombarded with odors, pollutants and pathogens. Particles inhaled through the nostrils bind to specific olfactory receptor cells in the tissue lining the nasal cavity. These receptors send messages to other cells in what’s called the olfactory bulb, which acts like a relay station that transmits these messages down the long nerves of the olfactory tract. These messages are then transferred to the area of the brain responsible for learning and memory, the hippocampus.</p>
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<figcaption><span class="caption">Sensory cells translate information from your environment into electrical signals your brain can interpret.</span></figcaption>
</figure>
<p>The hippocampus plays a critical role assigning contextual information to odors, such as danger from the foul smell of propane or comfort from the smell of lavender. This area of the brain is also dramatically damaged in Alzheimer’s disease, causing devastating learning and memory deficits. For as many as 85% to 90% of Alzheimer’s patients, <a href="https://doi.org/10.1016/B978-0-12-819973-2.00030-7">loss of smell</a> is an early sign of disease.</p>
<p>The mechanism leading to smell loss in Alzheimer’s disease is relatively unknown. Like muscles that atrophy from lack of use, <a href="https://doi.org/10.1002/cne.901780310">sensory deprivation</a> is thought to lead to atrophy of the brain regions that specialize in interpreting sensory information. Strong sensory input to these regions is critical to maintain general brain health.</p>
<h2>Olfactory inflammation and Alzheimer’s disease</h2>
<p>We hypothesize that viral infections throughout life are both contributors to and potential drug targets in Alzheimers’s disease. To test this idea, <a href="https://doi.org/10.1016/j.neurobiolaging.2022.12.004">we used emerging, state-of-the-art technology to investigate</a> the mRNA and protein networks of the olfactory system of Alzheimer’s disease patients. </p>
<p>The body uses <a href="https://theconversation.com/what-is-mrna-the-messenger-molecule-thats-been-in-every-living-cell-for-billions-of-years-is-the-key-ingredient-in-some-covid-19-vaccines-158511">mRNA</a>, which is transcribed from DNA, to translate genetic material into proteins. The body uses specific mRNA sequences to produce a network of proteins that are used to fight against certain viruses. In some cases, the body continues to <a href="https://doi.org/10.1038/sj.cr.7310019">activate these pathways</a> even after the the virus is cleared, leading to chronic inflammation and tissue damage. Identifying which mRNA sequences and protein networks are present can allow us to infer, to a degree, whether the body is or was responding to a viral pathogen at some point.</p>
<p>Previously, sequencing mRNA in tissue samples was difficult because the molecules degrade very quickly. However, <a href="https://doi.org/10.1371/journal.pone.0212031">new technology</a> specifically addresses that issue by measuring small subsections of mRNA at a time instead of trying to reconstruct the whole mRNA sequence at once.</p>
<p>We leveraged this technology to sequence the mRNA of olfactory bulb and olfactory tract samples from six people with familial Alzheimer’s, an inherited form of the disease, and six people without Alzheimer’s. We focused on familial Alzheimer’s because there is less variability in disease than in the sporadic, or nonfamilial, form of the disease, which can result from a number of different individual and environmental factors.</p>
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<a href="https://images.theconversation.com/files/503694/original/file-20230109-15603-tfjiny.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Microscopy image of neurons in mouse olfactory bulb" src="https://images.theconversation.com/files/503694/original/file-20230109-15603-tfjiny.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/503694/original/file-20230109-15603-tfjiny.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=600&fit=crop&dpr=1 600w, https://images.theconversation.com/files/503694/original/file-20230109-15603-tfjiny.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=600&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/503694/original/file-20230109-15603-tfjiny.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=600&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/503694/original/file-20230109-15603-tfjiny.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=754&fit=crop&dpr=1 754w, https://images.theconversation.com/files/503694/original/file-20230109-15603-tfjiny.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=754&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/503694/original/file-20230109-15603-tfjiny.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=754&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">This image shows neurons in a small cross section of a mouse’s olfactory bulb.</span>
<span class="attribution"><a class="source" href="https://directorsblog.nih.gov/2017/11/16/snapshots-of-life-making-sense-of-smell/">Jeremy McIntyre/University of Florida College of Medicine via National Institutes of Health</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc/4.0/">CC BY-NC</a></span>
</figcaption>
</figure>
<p>In the familial Alzheimer’s samples, we found altered gene expression indicating signs of a past viral infection in the olfactory bulb, as well as inflammatory immune responses in the olfactory tract. We also found higher levels of proteins involved in demyelination in the olfactory tract of familial Alzheimer’s samples than in the controls. Myelin is a protective fatty layer around nerves that allows electrical impulses to move quickly and smoothly from one area of the brain to another. Damage to myelin stalls signal transduction, resulting in impaired neural communication and, by extension, neurodegeneration.</p>
<p>Based on these findings, we hypothesize that viral infections, and the resulting inflammation and demyelination within the olfactory system, may disrupt the function of the hippocampus by impairing communication from the olfactory bulb. This scenario could contribute to the accelerated neurodegeneration seen in Alzheimer’s disease.</p>
<h2>Implications for patient health</h2>
<p>Epidemiological data supports the role of viral infections in the development of Alzheimer’s disease. For example, the <a href="https://doi.org/10.1371/journal.pone.0188490">varicella zoster virus</a> is linked to a nearly threefold risk of developing dementia within five years of infection for patients with a shingles rash on their face. A recent report also found a <a href="https://doi.org/10.3233/JAD-220717">nearly 70% increased risk</a> of getting diagnosed with Alzheimer’s within a year of a COVID-19 diagnosis for people over 65.</p>
<p>These studies suggest that vaccination may be a potential measure to prevent dementia. For example, vaccination against the <a href="https://doi.org/10.1016/j.arr.2021.101534">seasonal flu virus</a> and <a href="https://doi.org/10.1371/journal.pone.0257405">herpes zoster</a> is associated with an up to 29% and 30% reduced risk of developing dementia, respectively.</p>
<p>Further research investigating how viral infections can trigger neurodegeneration could aid in the development of antiviral drugs and vaccines against the viruses implicated in Alzheimer’s disease.</p><img src="https://counter.theconversation.com/content/197009/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Andrew Bubak receives funding from the National Institute on Aging. </span></em></p><p class="fine-print"><em><span>Diego Restrepo receives funding from the National Institute of Health and the National Science Foundation </span></em></p><p class="fine-print"><em><span>Maria Nagel receives funding from the National Institutes of Health.</span></em></p>Inflammation and damage to the olfactory system from shingles, COVID-19 and herpes infections may contribute to Alzheimer’s disease.Andrew Bubak, Assistant Research Professor of Neurology, University of Colorado Anschutz Medical CampusDiego Restrepo, Professor of Cell and Developmental Biology, University of Colorado Anschutz Medical CampusMaria Nagel, Professor of Neurology and Ophthalmology, University of Colorado Anschutz Medical CampusLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1738112022-01-25T13:27:01Z2022-01-25T13:27:01ZFrom odor to action – how smells are processed in the brain and influence behavior<figure><img src="https://images.theconversation.com/files/441580/original/file-20220119-23-1y38fqx.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2734%2C1342&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">The compact olfactory system provides a more accessible way to study the brain as a whole.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/close-up-of-a-dogs-nose-royalty-free-image/603137803">Esther Kok/EyeEm via Getty Images</a></span></figcaption></figure><p>A dog raises its nose in the air before chasing after a scent. A mosquito zigzags back and forth before it lands on your arm for its next meal. What these behaviors have in common is that they help these animals “see” their world through their noses.</p>
<p>While humans primarily use their vision to navigate their environment, the vast majority of organisms on Earth communicate and experience the world through <a href="https://doi.org/10.1016/j.neuron.2005.10.022">olfaction</a> – their sense of smell.</p>
<p><a href="https://scholar.google.com/citations?user=wn_f7y0AAAAJ&hl=en">We</a> <a href="https://scholar.google.com/citations?user=JEi-fdoAAAAJ&hl=en">are</a> <a href="https://www.bbe.caltech.edu/people/elizabeth-j-hong">members</a> <a href="https://scholar.google.com/citations?user=GpkJjVUAAAAJ&hl=en">of</a> <a href="https://www.odor2action.org">Odor2Action</a>, an international network of over 50 scientists and students using olfaction to study brain function in animals. Our goal is to understand a fundamental question in neuroscience: How do animal brains translate information from their environments to changes in their behaviors?</p>
<p>Here, we trace the interconnections between smells and behaviors – looking at how behavior influences odor detection, how the brain processes sensory information from smells and how this information triggers new behaviors.</p>
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<iframe width="440" height="260" src="https://www.youtube.com/embed/58U52lDTuvk?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Visualizing what smells look like helps researchers design technologies that detect odors as well as a dog can.</span></figcaption>
</figure>
<h2>Detecting odors in the environment</h2>
<p>When the odor of a flower is released into the air, it takes the shape of a wind-borne <a href="https://doi.org/10.1007/s003480000263">cloud of molecules called a plume</a>. It encounters physical obstacles and temperature differences as it flows through space. These interactions create turbulence that splits the odor plume into thin threads that spread out as the scent moves away from its source. These filaments eventually reach an animal’s nose or an insect’s antenna.</p>
<p>Odors that are broken up into filaments present a challenge to animals using them to find food or mates or avoid threats. It becomes difficult to predict precisely where the odor is coming from. Is the source directly ahead, to the left or right, above or below?</p>
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<figcaption><span class="caption">This video by the Crimaldi Laboratory of the University of Colorado Boulder shows an odor plume developing behind a moving source over time. The source moves up and down from the left side, and the odor flows from left to right.</span></figcaption>
</figure>
<p>To work around this, animals have evolved what are called <a href="https://doi.org/10.1007/s10827-021-00798-1">active sensing</a> behaviors that improve their ability to detect and find odors in the environment.</p>
<p>When a fly detects the smell of fruit or a mosquito detects carbon dioxide from a possible host, for example, both insects first move upwind to get closer to the odor of the food source. They then move in a meandering, back-and-forth motion called casting to find more odor threads before surging upwind again. If they lose the scent, they’ll start casting again until they find the scent. Larger animals, such as mice and dogs, also alternate between more directed movements and more exploratory searching actions. </p>
<p>Animals also move their noses and antennae to improve the chances that they’ll encounter an odor. This is why dogs raise their noses in the air to increase the amount of odor they can sniff, and why insects move their antennae to stir up and penetrate the air to make better contact with odor molecules. </p>
<p>Once information from odors tell the animal that they’re close to the source, visual searching then comes into play.</p>
<h2>Making sense of odors</h2>
<p>When an animal comes into contact with an odor plume, it detects the presence of these odor molecules through tiny proteins called <a href="https://www.nobelprize.org/prizes/medicine/2004/summary/">odorant receptors</a>. These receptors are embedded in the sensory neurons lining its nasal cavity or antennae.</p>
<p>Each sensory neuron contains only one type of odorant receptor. And each type of odorant receptor has a different shape and set of chemical properties that determine which odors can bind to and activate it. Most of these receptors recognize multiple odors, and most odors can bind to multiple different receptors. What encodes the identity of a specific odor in the brain is determined by which combination of receptors are activated, and their relative strength of activation.</p>
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<figcaption><span class="caption">This video from the Wachowiak Lab at the University of Utah shows the activity of the olfactory bulb in a mouse brain as the mouse is exposed to different odors. Different odors make different combinations of neurons in the olfactory bulb light up.</span></figcaption>
</figure>
<p>An animal like a mouse has about a <a href="https://doi.org/10.1016/j.neuron.2005.10.022">thousand types</a> of odorant receptors. Having a large number of these receptors with diverse shapes allows the system to detect and distinguish between a very large number of chemically unique odors, including ones the animal has never encountered before. Most odors in the environment are often a mix of many different types of molecules. The smell of some <a href="https://doi.org/10.1146/annurev.ecolsys.38.091206.095601">flowers</a> can be a blend of over 100 different chemical compounds.</p>
<p>Once an odor molecule binds to a receptor, sensory neurons send specific <a href="https://nba.uth.tmc.edu/neuroscience/m/s2/chapter09.html">electrical signals</a> into compartments of the brain called <a href="https://doi.org/10.3389/fncir.2014.00098">olfactory glomeruli</a>. Different odors elicit distinct patterns of electrical activity across these regions, and this generates a specific neural representation of the odor in the brain.</p>
<p>An important step toward understanding olfaction is figuring out how different classes of odors map to different patterns of electrical signals in the brain.</p>
<p>Neuroscientists hypothesize that as these signals undergo successive stages of processing deep in the brain, sensory representations of odor are <a href="https://doi.org/10.1146/annurev-neuro-071013-013941">reformatted</a> in ways that extract information most useful to survival. This could be whether the smell is coming from something nutritious, indicating a potential source of food, or it could help the animal identify whether the smell is coming from a potential competitor or predator.</p>
<p>These reformatted sensory representations form the basis for how animals perceive smell and determine what actions they take in response to this information.</p>
<h2>From odor to action</h2>
<p>Once information about a particular odor reaches the brain, it often elicits both instinctual and learned <a href="https://doi.org/10.1523/JNEUROSCI.1668-18.2018">behaviors</a>. Odors that signal danger may trigger the animal to freeze or run away, while odors from a member of the same species may trigger the animal to mark its territory or initiate courtship. </p>
<p>In many cases, animals perform these tasks with incredible <a href="https://www.pbs.org/wgbh/nova/article/dogs-sense-of-smell/">precision and effectiveness</a>. It’s still common to use search dogs to find lost people and pigs to find truffles because available technologies aren’t capable of performing as well.</p>
<p>Animals achieve this level of performance not just because they’re able to detect and identify an odor. They’re also able to integrate odor features, like how intense the odor smells, with environmental clues, like wind direction, and internal cues, like hunger. All this information comes together to generate specific sequences of behaviors such as “face into the wind and then walk forward.”</p>
<figure>
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<figcaption><span class="caption">Dogs rely on smells to provide long-distance information. Humans, on the other hand, use smells for short distances.</span></figcaption>
</figure>
<p>To understand how odor guides these behaviors, scientists measure or manipulate an animal’s brain activity as they perform specific actions. This is done using imaging, electrophysiology or <a href="https://doi.org/10.1038/nn.4091">optogenetics</a>, which selectively activates specific neurons by shining a light on them. These approaches allow researchers to understand how patterns of brain activity shift when an animal changes its behavior to chase after an odor, or how environmental and internal cues combine to produce a best guess on the location of its next meal. </p>
<h2>Leading science and technology by the nose</h2>
<p>The olfactory system offers a unique opportunity to understand how the brain processes environmental information and translates it to behavior. Compared to other areas of the brain, the olfactory circuit is simpler in structure and uses fewer stages of processing. Its relative simplicity is what allows scientists like us to study it from end to end and learn how the brain works as a whole.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/441622/original/file-20220119-15-1atg4u1.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="A rescue worker with a service dog goes through the ruins of a residential house to search for survivors" src="https://images.theconversation.com/files/441622/original/file-20220119-15-1atg4u1.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/441622/original/file-20220119-15-1atg4u1.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=415&fit=crop&dpr=1 600w, https://images.theconversation.com/files/441622/original/file-20220119-15-1atg4u1.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=415&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/441622/original/file-20220119-15-1atg4u1.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=415&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/441622/original/file-20220119-15-1atg4u1.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=521&fit=crop&dpr=1 754w, https://images.theconversation.com/files/441622/original/file-20220119-15-1atg4u1.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=521&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/441622/original/file-20220119-15-1atg4u1.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=521&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Robots may one day be able to replace dogs in search and rescue situations.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/news-photo/rescue-worker-with-a-service-dog-goes-through-the-ruins-of-news-photo/1229115883">Valery Sharifulin/TASS via Getty Images</a></span>
</figcaption>
</figure>
<p>Understanding brain function through the lens of olfaction could also pave the way for transformative developments in engineering, neuroscience and public health. Our research should accelerate the development of robots with <a href="https://doi.org/10.1177%2F0278364908095118">electronic noses</a> that can use odors to search for <a href="https://doi.org/10.1016/j.sbsr.2019.100305">chemical weapons</a>,
<a href="https://www.reuters.com/world/us/divers-try-locate-source-reported-oil-spill-gulf-coast-guard-2021-09-05/">underwater oil spills</a>
and <a href="https://doi.org/10.3390/inventions5030028">natural gas</a> leaking from pipelines in environments where it may be tedious or dangerous for humans or animals to go. Robots might also be able to search for missing people or disaster victims, something typically done with <a href="https://www.popsci.com/scientists-want-to-build-robotic-sniffer-that-outperforms-search-dogs/">trained dogs</a>.</p>
<p>An exciting future in scientific and medical development, we believe, is right under our noses.</p>
<p>[<em>Over 140,000 readers rely on The Conversation’s newsletters to understand the world.</em> <a href="https://memberservices.theconversation.com/newsletters/?source=inline-140ksignup">Sign up today</a>.]</p><img src="https://counter.theconversation.com/content/173811/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>John Crimaldi receives funding from the National Science Foundation, the National Institutes of Health, and the Department of Defense.</span></em></p><p class="fine-print"><em><span>Brian H Smith receives funding from the National Science Foundation.</span></em></p><p class="fine-print"><em><span>Elizabeth Hong receives funding from the National Science Foundation, the National Institutes of Health, the Curci Research Foundation, and the Luce Foundation</span></em></p><p class="fine-print"><em><span>Nathan Urban receives funding from the National Science Foundation and the National Institutes of Health. </span></em></p>Understanding how the brain translates smells into behavior change can help advance search and rescue technology and treatments for neurological conditions.John Crimaldi, Professor of Civil, Environmental and Architectural Engineering, University of Colorado BoulderBrian H. Smith, Trustees of ASU Professor, Arizona State UniversityElizabeth Hong, Assistant Professor of Neuroscience, California Institute of TechnologyNathan Urban, Provost and Senior Vice President, Lehigh University Licensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1414372020-07-08T12:13:26Z2020-07-08T12:13:26ZSynthetic odors created by activating brain cells help neuroscientists understand how smell works<figure><img src="https://images.theconversation.com/files/346129/original/file-20200707-194405-awzgsl.jpg?ixlib=rb-1.1.0&rect=767%2C8%2C4838%2C3242&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">When you sniff a particular scent, your brain cells fire in a recognizable pattern.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/young-woman-smelling-perfume-from-bottle-at-royalty-free-image/953961844">Maskot via Getty Images</a></span></figcaption></figure><p>When you experience something with your senses, it evokes complex patterns of activity in your brain. One important goal in neuroscience is to decipher how these neural patterns drive the sensory experience.</p>
<p>For example, can the smell of chocolate be represented by a single brain cell, groups of cells firing all at the same time or cells firing in some precise symphony? The answers to these questions will lead to a broader understanding of how our brains represent the external world. They also have implications for treating disorders where the brain fails in representing the external world: for example, in the loss of sight of smell.</p>
<p>To understand how the brain drives sensory experience, <a href="https://rinberglab.com">my colleagues and I</a> focus on the sense of smell in mice. We directly control a mouse’s neural activity, <a href="https://doi.org/10.1126/science.aba2357">generating “synthetic smells”</a> in the olfactory part of its brain in order to learn more about how the sense of smell works.</p>
<p>Our latest experiments discovered that scents are represented by very specific patterns of activity in the brain. Like the notes of a melody, the cells fire in a unique sequence with particular timing to represent the sensation of smelling a unique odor.</p>
<h2>Scents produced by light projections</h2>
<p>Using mice to study smell is appealing to researchers because the <a href="https://doi.org/10.1016/j.conb.2018.04.008">relevant brain circuits have been mapped out</a>, and modern tools allow us to directly manipulate these brain connections.</p>
<p>The mice we use are genetically engineered so we can activate individual brain cells simply by shining light of specific wavelengths onto them – <a href="https://doi.org/10.1038/nn1525">a technique known as optogenetics</a>. Early uses of optogenetics involved light delivered through implanted optical fibers, letting researchers control coarse patches of brain cells. More recent uses of optogenetics allow <a href="https://doi.org/10.1126/science.aaw5202">more sophisticated control</a> of <a href="https://doi.org/10.1016/j.cell.2019.05.045">precise patterns of brain activity</a>.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/346080/original/file-20200707-22-1rfavl2.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/346080/original/file-20200707-22-1rfavl2.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/346080/original/file-20200707-22-1rfavl2.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=393&fit=crop&dpr=1 600w, https://images.theconversation.com/files/346080/original/file-20200707-22-1rfavl2.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=393&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/346080/original/file-20200707-22-1rfavl2.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=393&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/346080/original/file-20200707-22-1rfavl2.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=494&fit=crop&dpr=1 754w, https://images.theconversation.com/files/346080/original/file-20200707-22-1rfavl2.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=494&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/346080/original/file-20200707-22-1rfavl2.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=494&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">A simplified image of a mouse brain, looking down from the top. The olfactory bulb (left) is at the front of the brain and receives connections from receptor cells in the nose.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:Mouse_brain_top_view.png">Database Center for Life Science/Wikimedia Commons</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>For our study, we projected light patterns onto the surface of the brain, targeting a region known as the olfactory bulb. Previous research has found that when mice sniff different scents, cells in the olfactory bulb appear to fire in a sort of patterned symphony, with a <a href="https://doi.org/10.1152/jn.90902.2008">unique pattern formed in response to each distinct smell</a>.</p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/346101/original/file-20200707-194405-1ojhb4o.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/346101/original/file-20200707-194405-1ojhb4o.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/346101/original/file-20200707-194405-1ojhb4o.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=617&fit=crop&dpr=1 600w, https://images.theconversation.com/files/346101/original/file-20200707-194405-1ojhb4o.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=617&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/346101/original/file-20200707-194405-1ojhb4o.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=617&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/346101/original/file-20200707-194405-1ojhb4o.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=776&fit=crop&dpr=1 754w, https://images.theconversation.com/files/346101/original/file-20200707-194405-1ojhb4o.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=776&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/346101/original/file-20200707-194405-1ojhb4o.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=776&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Rather than receiving sensory signals from the nose, the olfactory bulb was activated by light projections.</span>
<span class="attribution"><span class="source">Edmund Chong</span>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span>
</figcaption>
</figure>
<p>When we shined light patterns onto a mouse’s olfactory bulb, it generated corresponding patterns of cellular activity. We called these patterns “synthetic smells.” As opposed to a pattern of activity triggered by a mouse sniffing a real odor, we directly triggered the neural activity of a “synthetic smell” with our light projections.</p>
<p>Next we trained each individual mouse to recognize a randomly generated synthetic smell. Since they can’t describe to us in words what they’re perceiving, we rewarded each mouse with water if it licked a water spout whenever it detected its assigned smell. Over weeks of training, mice learned to lick when their assigned smell was activated, and not to lick for other randomly generated synthetic smells. </p>
<p>[<em><a href="https://theconversation.com/us/newsletters/the-daily-3?utm_source=TCUS&utm_medium=inline-link&utm_campaign=newsletter-text&utm_content=experts">Expertise in your inbox. Sign up for The Conversation’s newsletter and get expert takes on today’s news, every day.</a></em>]</p>
<p>We cannot say for sure that these synthetic smells correspond to any known odor in the world, nor do we know what they smell like to the mouse. But we did calibrate our synthetic patterns to broadly resemble olfactory bulb patterns observed when actual scents are present. Furthermore, mice learn to discriminate synthetic smells about as quickly as they did real smells.</p>
<h2>Tweaking the pattern of a synthetic smell</h2>
<p>Once each mouse learned to recognize its assigned synthetic smell, we measured how much they still licked when we modified the assigned smell. Within each synthetic pattern, we altered which cells were activated or when they activated.</p>
<p>Imagine taking a familiar song, changing individual notes in the song, and asking whether you still recognized the song after each change. By testing many different changes, one can eventually understand which precise composition of notes is essential to the song’s identity and which tweaks are extreme enough to make the song unrecognizable.</p>
<p>Likewise, by measuring how mice changed their licking as we modified their projected light patterns, we were able to understand which combinations of cells within the pattern were important for identifying the synthetic smell.</p>
<p>The precise combination of cells activated was crucial. But just as important was when they are activated in an ordered sequence, akin to timed notes in a melody. For example, changing the order of cells in the sequence would render the smell unrecognizable.</p>
<p>It turned out that the cells activated earlier in the sequence were more important for recognition – changing the sequences later in the pattern seemed to have negligible effects.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/lJ2bof_fWgM?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Watch an animation of how these sequences in the brain work.</span></figcaption>
</figure>
<p>Changes in recognition were graded, and not drastic: When we changed small parts of the pattern, the smell did not become completely unrecognizable. In fact, the degree to which the smell was recognized was proportional to the degree of change in the pattern. This implies that if I slightly modify the brain activity that represents an orange, you would still smell something similar – maybe recognizing it as citrus, or fruity.</p>
<p>So while the brain has huge capacity to store many different smells in unique timed sequences of cell activity, you can still recognize similar smells by the similarity in their patterns: The smell of coffee is still distinctly recognizable even with a splash of vanilla added to it. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/346134/original/file-20200707-194418-1oc455r.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/346134/original/file-20200707-194418-1oc455r.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/346134/original/file-20200707-194418-1oc455r.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=402&fit=crop&dpr=1 600w, https://images.theconversation.com/files/346134/original/file-20200707-194418-1oc455r.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=402&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/346134/original/file-20200707-194418-1oc455r.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=402&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/346134/original/file-20200707-194418-1oc455r.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=506&fit=crop&dpr=1 754w, https://images.theconversation.com/files/346134/original/file-20200707-194418-1oc455r.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=506&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/346134/original/file-20200707-194418-1oc455r.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=506&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">You know the smell of coffee even if it’s served with a dash of fragrant vanilla.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/hot-espresso-royalty-free-image/981402468">Roland Beerli/500px Prime via Getty Images</a></span>
</figcaption>
</figure>
<p>The next step in this research is to bring the synthetic approach to real smells. To do so, we would need to record brain activity in response to a real smell, then reactivate the very same cells using optogenetics. The synthetic re-creation of real objects in the brain is the current focus of research in <a href="https://doi.org/10.1126/science.aaw5202">multiple</a> <a href="https://doi.org/10.1016/j.cell.2019.05.045">labs</a> <a href="https://doi.org/10.1364/BRAIN.2019.BM3A.2">including ours</a>.</p>
<p>Addressing this issue is exciting because it opens up possibilities not just for understanding how the brain works, but also for developing brain implants that may one day restore the loss of sensory experiences.</p><img src="https://counter.theconversation.com/content/141437/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Edmund Chong does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Brains recognize a smell based on which cells fire, in what order – the same way you recognize a song based on its pattern of notes. How much can you change the ‘tune’ and still know the smell?Edmund Chong, Ph.D. Student in Neuroscience, New York UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1369292020-06-01T12:16:54Z2020-06-01T12:16:54ZWhat makes something smell good or bad?<figure><img src="https://images.theconversation.com/files/334484/original/file-20200512-82403-1wqng6q.jpg?ixlib=rb-1.1.0&rect=184%2C1062%2C1956%2C1423&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Cookies taste so good. Smell tells us that before we even take a bite. How?</span> <span class="attribution"><a class="source" href="https://unsplash.com/photos/OfdDiqx8Cz8">Jennifer Pallian/Unsplash</a></span></figcaption></figure><hr>
<figure class="align-left ">
<img alt="" src="https://images.theconversation.com/files/281719/original/file-20190628-76743-26slbc.png?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/281719/original/file-20190628-76743-26slbc.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=293&fit=crop&dpr=1 600w, https://images.theconversation.com/files/281719/original/file-20190628-76743-26slbc.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=293&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/281719/original/file-20190628-76743-26slbc.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=293&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/281719/original/file-20190628-76743-26slbc.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=368&fit=crop&dpr=1 754w, https://images.theconversation.com/files/281719/original/file-20190628-76743-26slbc.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=368&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/281719/original/file-20190628-76743-26slbc.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=368&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<p><em><a href="https://theconversation.com/us/topics/curious-kids-us-74795">Curious Kids</a> is a series for children of all ages. If you have a question you’d like an expert to answer, send it to <a href="mailto:curiouskidsus@theconversation.com">curiouskidsus@theconversation.com</a>.</em></p>
<hr>
<blockquote>
<p><strong>What makes something smell bad or good? – Taylor, Atlanta, Georgia</strong></p>
</blockquote>
<hr>
<p>Pee-yew! Your old socks <a href="https://theconversation.com/why-do-feet-stink-by-the-end-of-the-day-125037">smell soooo bad</a>.</p>
<p>But why?</p>
<p>Maybe you’ve learned to dislike the smell. Maybe your socks are full of gross bacteria. Or maybe, it’s both. Our team studies the brain and sense of smell – it’s one of our favorite topics. But first, how do you smell?</p>
<h2>What is that smell?</h2>
<p>The air is filled with many small odor molecules which are released from “smelly” things like perfume or food. Your nose has the astonishing ability to smell thousands of different scents because in your nose are millions of <a href="https://youtu.be/snJnO6OpjCs">smell receptors</a> – cells that can recognize odor molecules. When you sniff the air, these special cells are alerted. </p>
<p>These receptor cells then send a signal to your brain. Your brain recognizes many scents when different types of odors enter your nose. The smell of baking cookies, for instance, is composed of <a href="https://www.brainfacts.org/thinking-sensing-and-behaving/smell/2015/making-sense-of-scents-smell-and-the-brain">many odor molecules</a>. Your brain can piece together all this information and let you know there are cookies baking in the oven.</p>
<h2>Smells that make memories</h2>
<p>Your brain is very good at memorizing good and bad experiences and associating particular smells with them. Scientists call these “<a href="https://www.livescience.com/why-smells-trigger-memories.html">olfaction-associated memories</a>.”</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/BjBOel3A6n4?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">What’s that smell? Now I remember.</span></figcaption>
</figure>
<p>One example of this is when you smell a favorite meal. It might remind you of someone who makes it for you, which triggers your brain to release chemicals that make you feel good and comforted.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/334495/original/file-20200512-82375-1bvdibn.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/334495/original/file-20200512-82375-1bvdibn.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/334495/original/file-20200512-82375-1bvdibn.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/334495/original/file-20200512-82375-1bvdibn.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/334495/original/file-20200512-82375-1bvdibn.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/334495/original/file-20200512-82375-1bvdibn.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/334495/original/file-20200512-82375-1bvdibn.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/334495/original/file-20200512-82375-1bvdibn.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Memory can signal a smell tied to happiness.</span>
<span class="attribution"><a class="source" href="http://www.apimages.com/metadata/Index/China-Food/92f09e881a5849fdae1ea71b95735ee4/15/0">AP Photo/Ng Han Guan</a></span>
</figcaption>
</figure>
<p>Of course, smell can also be associated with unpleasant experiences. You have probably eaten some food that went bad, and you might find that you hate that food now. This is your brain associating getting sick with a certain smell, which stops you from eating something that could be bad for you. Memories linked to smells can form because of good and bad feelings. </p>
<h2>Smells to warn you</h2>
<p>But what about things that you know smell good or bad even if you’ve never experienced them? Scientists have found that although a lot of the smells people like come from past experiences, <a href="https://www.fredhutch.org/en/news/center-news/2015/04/instinctive-reactions-to-smells-linked-to-olfactory-neurons.html">instincts</a> play a big role.</p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/334491/original/file-20200512-82379-1vnpyql.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/334491/original/file-20200512-82379-1vnpyql.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/334491/original/file-20200512-82379-1vnpyql.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=800&fit=crop&dpr=1 600w, https://images.theconversation.com/files/334491/original/file-20200512-82379-1vnpyql.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=800&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/334491/original/file-20200512-82379-1vnpyql.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=800&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/334491/original/file-20200512-82379-1vnpyql.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1005&fit=crop&dpr=1 754w, https://images.theconversation.com/files/334491/original/file-20200512-82379-1vnpyql.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1005&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/334491/original/file-20200512-82379-1vnpyql.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1005&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Skunks are cute, but wow, that smell!</span>
<span class="attribution"><a class="source" href="https://unsplash.com/photos/jG8eaA5Iq3A">Bryan Padron/Unsplash</a></span>
</figcaption>
</figure>
<p>Scent tells you a lot about your environment, and your instincts help to decide what is safe or dangerous. For example, <a href="https://www.livescience.com/60827-blood-molecule-attracts-and-repels.html">blood</a> has been shown to repel humans and many prey species, like deer, but attract predators, like wolves. This guides people away from predators that might want to eat us, but lets the predator get its meal. </p>
<p>Smell can warn you when something could make you sick. When eggs rot, bacteria multiply like crazy inside them, <a href="https://www.thedailymeal.com/eat/why-do-rotten-eggs-smell-sulfur">breaking down proteins</a> that release a toxic chemical called hydrogen sulfide. This produces a stench that makes you want to stay far away, stopping you from eating the egg and becoming ill.</p>
<p>As for your socks… if they smell bad now, don’t wait. Wash them with soap and water! The bacteria growing on your socks will be <a href="https://youtu.be/RZc09wD5wYQ">killed</a>, which will stop that nasty smell. </p>
<hr>
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<p class="fine-print"><em><span>Weihong Lin receives research funding from NIH. </span></em></p><p class="fine-print"><em><span>Kayla Lemons and Rakaia Kenney do not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and have disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Mmmmmmm. That smells delicious. Wait, how do you know that?Rakaia Kenney, Research Assistant, University of Maryland, Baltimore CountyKayla Lemons, Research Associate, Ph.D., University of Maryland, Baltimore CountyWeihong Lin, Professor of Biological Sciences, University of Maryland, Baltimore CountyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1293182020-01-29T13:20:28Z2020-01-29T13:20:28ZE-cig flavors may be more than alluring; they could cause damage themselves<figure><img src="https://images.theconversation.com/files/312168/original/file-20200128-81336-phd8ra.jpg?ixlib=rb-1.1.0&rect=63%2C120%2C4669%2C2963&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">A vape shop in New York City shows a line of flavorings on Jan. 2, 2020.</span> <span class="attribution"><a class="source" href="https://theconversation.com/drafts/129424/edit">Mary Altaffer/AP Photo</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span></figcaption></figure><p><a href="https://news.gallup.com/poll/267413/percentage-americans-vape.aspx">Millions of Americans</a> are vaping, and some are getting sick. Since June 2019, <a href="https://www.cdc.gov/tobacco/basic_information/e-cigarettes/severe-lung-disease.html">2,711 have been hospitalized and 60 have died</a> due to <a href="https://www.cdc.gov/tobacco/basic_information/e-cigarettes/severe-lung-disease.html">EVALI</a> (e-cigarette-associated lung injury), the devastating lung disease linked to e-cigarettes.</p>
<p><a href="https://www.ncbi.nlm.nih.gov/pubmed/31688912">Five million</a> users are middle and high school students. Some are as young as 11, although it’s illegal to sell vaping products to anyone under 21. </p>
<p>Especially for kids, much of the lure is <a href="https://doi.org/10.1371/journal.pone.0194145">flavor</a>. E-cigarettes offer attractive smells and tastes. Fruit, mint, candy and dessert flavors are the favorites, and <a href="https://doi.org/10.1001/jama.2019.18387">studies suggest</a> they ignite the desire to vape. That’s why the Trump administration <a href="https://www.fda.gov/consumers/consumer-updates/facts-fdas-new-tobacco-rule">just banned</a> the sale of those sweet flavors from cartridge-based e-cigs, the delivery method most popular with teens. </p>
<p>One of us (<a href="https://biology.umbc.edu/directory/faculty/person/SA20601/">Weihong</a>) is a chemosensory neurobiologist, and the other (Rakaia) is a research assistant in <a href="https://linlab.umbc.edu/">my lab</a>. Put simply, we study how the sensory systems and brain react to chemical stimulation. With e-cigarettes, we are focusing on how the enticing flavors ensnare our children. </p>
<p>But our studies have shown that the effect of flavor goes beyond the pleasure they may bring – the flavorings themselves may actually harm tissue. </p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/uyCl3BdlICY?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">These ads extol the virtues of flavored cigarettes.</span></figcaption>
</figure>
<h2>Flavors enhance e-cig appeal</h2>
<p>The tobacco industry <a href="http://dx.doi.org/10.1136/tobaccocontrol-2014-051830">has long been using</a> flavorings make their products more palatable; it <a href="https://www.ncbi.nlm.nih.gov/pubmed/14507484">added menthol</a> to cigarettes nearly a century ago. </p>
<p>Today, the allure of flavors in e-cigarettes bring potential health consequences, and kids are particularly vulnerable. E-cigarettes can put adolescents at risk for respiratory, cardiopulmonary diseases, brain disorders and cancers.</p>
<p>About <a href="http://dx.doi.org/10.1136/tobaccocontrol-2019-055303">20,000 flavored e-liquids</a> are on the market – countless combinations of hundreds of flavoring molecules extracted from natural ingredients or artificially made. The vast majority are volatile odor chemicals, perceived not by taste, but by smell.</p>
<p>Your olfactory system, with far more sensitivity than your taste buds, can distinguish more than 10,000 smells. During vaping, a flavoring enters our nose, and like any agreeable scent, immediately evokes the <a href="https://doi.org/10.3758/BF03193837">fond memories</a> and <a href="https://www.livescience.com/why-smells-trigger-memories.html">pleasant emotions</a> associated with the aroma. Vanillin, a popular e-cigarette flavoring, smells like dessert; <a href="https://pubchem.ncbi.nlm.nih.gov/compound/Ethyl-maltol">ethyl maltol</a>, a flavoring used in many foods, has a candy-like odor. The user, comforted and calmed, savors the moment – then goes back for more. </p>
<p>But e-cigarette vapor also contains nicotine, heavy metals and formaldehyde, as pungent as they are <a href="https://www.ncbi.nlm.nih.gov/books/NBK507184/">harmful</a>. Mixing in delectable flavorings disguises their unpleasantness, much like the cherry additive that camouflages the otherwise medicinal taste of children’s cough syrup. </p>
<p>Yet perceptions of irritation and pain in the nose, mouth, and throat serve as warning signals, the body’s cautionary bells and whistles evolved over millions of years. A <a href="https://scholarblogs.emory.edu/evolutionshorts/2014/05/01/the-evolution-of-bitter-taste/">bitter taste</a> might originate from a toxic plant; irritation in the nose or respiratory tract indicates the inhaled substance is potentially harmful. </p>
<p>But now that flavorings in e-cigarette mask the warning signals, many consumers have been lulled into believing vaping is benign. They rate <a href="https://doi.org/10.18001/TRS.5.6.4:10.18001/">mint flavors as safer</a>, though they are not. And instead of irritation from the e-cigarette prompting a cough – an action that removes harmful stimuli from the airway – the flavorings instead dampen the user’s sensory alarms and protective reactions. The risk of chemically induced injury, along with nicotine abuse, is increased.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/312349/original/file-20200128-81362-i84vlg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/312349/original/file-20200128-81362-i84vlg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=485&fit=crop&dpr=1 600w, https://images.theconversation.com/files/312349/original/file-20200128-81362-i84vlg.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=485&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/312349/original/file-20200128-81362-i84vlg.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=485&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/312349/original/file-20200128-81362-i84vlg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=609&fit=crop&dpr=1 754w, https://images.theconversation.com/files/312349/original/file-20200128-81362-i84vlg.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=609&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/312349/original/file-20200128-81362-i84vlg.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=609&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Flavorings themselves, and not just e-cigarettes, could lead to chronic coughing.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/coughing-senior-man-sitting-on-sofa-615311849">Africa Studios/Shutterstock.com</a></span>
</figcaption>
</figure>
<h2>How flavors themselves may be toxic</h2>
<p>Although the U.S. Food and Drug Administration has acknowledged some flavorings as “safe for consumption,” its label dodges a critical distinction. Safe for consumption does not mean safe for inhalation. While scientists still haven’t confirmed the <a href="https://doi.org/10.1016/j.jaci.2019.11.001">inhalation toxicity</a> for all flavorings, the latest research reveals some disturbing evidence.</p>
<p>Many of the most common flavorings when present at high levels can cause <a href="https://doi.org/10.1016/j.toxlet.2018.02.025">inflammation</a>, cell death, <a href="https://doi.org/10.1016/j.toxlet.2018.02.025">free radical formation</a> and DNA damage. One class of compounds, known as furfurals, trigger <a href="https://doi.org/10.1016/j.toxlet.2018.02.025">tumor growth in mice</a>. </p>
<p>Flavor molecules, reacting <a href="https://doi.org/10.1093/ntr/nty192">with the propylene glycol</a> in the e-liquid, can produce <a href="https://www.news-medical.net/life-sciences/What-are-Metabolites.aspx">metabolites</a>, or intermediate substances that are part of metabolic reactions, that are irritating to the respiratory system. Long-term exposure to irritants can lead to chronic cough; inflammation; hyper-reactive airway (wheezing, shortness of breath); edema (swelling in the arms, hands, legs or feet); and acute lung damage.</p>
<p>Some flavorings, inhaled chronically or at high levels, are already known to cause serious and sometimes deadly respiratory illnesses. Diacetyl, a buttery flavor used in processed foods – notably some popcorn products – causes “<a href="https://www.lung.org/about-us/blog/2016/07/popcorn-lung-risk-ecigs.html">popcorn lung,</a>” an irreversible disease that affects factory workers exposed daily to the compound. </p>
<p>Many e-liquids contain diacetyl; <a href="https://www.ncbi.nlm.nih.gov/pubmed/26642857#">an analysis</a> found the substance in 39 out of 51 tested e-cigarette samples. In about half the samples, the estimated daily consumption was above safety limits. </p>
<p>Patients with EVALI exhibit a significant number of these symptoms, and all were attributed to vaping. <a href="https://doi.org/10.1016/j.drugalcdep.2018.11.030">In one survey</a>, users reported cough (40.0%); dry or irritated mouth or throat (31.0%); dizziness or lightheadedness (27.1%); headache or migraine (21.9%); or shortness of breath (18.1%). </p>
<p>Similar health problems have been reported by patients with chemically induced <a href="https://doi.org/10.1016/0378-4274(96)03673-9">sick building syndrome</a>. This implies that e-cigarette users share common health problems with those suffering from chemical exposure.</p>
<h2>What about long-term vaping?</h2>
<p>Ongoing chemical exposure, especially at high doses, can cause olfactory dysfunction, including a reduced sense of smell. This encourages chronic e-cigarette users to choose stronger-flavored e-liquids to receive a sufficient buzz. In turn, more potent e-liquids generate more irritation and damage to the nose, lungs and lower airway. </p>
<p>The health effects of e-cigarette exposure go beyond the sensory and respiratory systems. Mint and candy flavors are more than chemical accessories that enhance a harmless experience. They shape our behavior, perhaps for a lifetime. </p>
<p>Our government is making progress towards keeping teens away from e-cigarettes. Now, long-term research is needed to fully comprehend the adverse health effects and toxicity of flavorings and other chemical substances in the e-cigarette vapor to prevent the potentially catastrophic effects of vaping.</p>
<p>[ <em>Deep knowledge, daily.</em> <a href="https://theconversation.com/us/newsletters?utm_source=TCUS&utm_medium=inline-link&utm_campaign=newsletter-text&utm_content=deepknowledge">Sign up for The Conversation’s newsletter</a>. ]</p><img src="https://counter.theconversation.com/content/129318/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Weihong Lin receives research funding from NIH NIDA/TRSP.</span></em></p><p class="fine-print"><em><span>Rakaia Kenney does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>The FDA has banned flavored e-cigarettes that appeal to kids. But new research shows that the danger of flavors could go beyond their appeal to kids. The flavorings themselves could cause damage.Weihong Lin, Professor of Biological Sciences, University of Maryland, Baltimore CountyRakaia Kenney, Research assistant, University of Maryland, Baltimore CountyLicensed as Creative Commons – attribution, no derivatives.