Smells Can Become Hardwired to Trigger Brain-Wide Anxiety

A new brain imaging study of awake behaving mice offers fresh clues about how experiencing life-threatening fear that is associated with a "scary" smell can evolve into a lifetime of anxiety. These findings (Uselman et al., 2020) were published online May 28 in the journal NeuroImage.

For this study, researchers used a neuroimaging technique called manganese-enhanced MRI (MEMRI) to monitor brain-wide neural activity in laboratory mice as they were exposed to acute fear triggered by the scent of a deadly predator. Observing the brain-wide activity in awake mice as their fear transitioned to anxiety gave researchers new insights into the neural correlates that accompany one exposure to life-or-death fear evolving into chronic anxiety over time.

Manganese is a non-toxic substance that lights up active neurons in an MRI. Quantitative computational analysis of how manganese lit up different brain regions as fear transformed into anxiety in laboratory mice was captured in statistical parametric mapping (SPM) of brain-wide activity.

Through a series of MEMRI experiments that were staggered over time, the researchers mapped how fear-based neural activity evolved in 45 cortical and sub-cortical regions throughout the entire brain. Some brain regions were immediately activated by a life-threatening smell associated with a predator, while other brain regions became more active over time.

In one cohort of mice, the researchers deleted a serotonin transporter (SERT) gene to create "knockout mice" (SERT-KO) that were more vulnerable to anxiety. SERT-KO mice helped the researchers identify the brain mechanisms that accompany one life-threatening experience morphing into long-term anxiety.

"Until now, psychiatrists had little information about what goes on in the brain after a fearful experience, and why some people don't easily recover and remain anxious, for even as long as the rest of their lives," senior author Elaine Bearer said in a July 9 news release. "Life-threatening fear frequently leads to post-traumatic stress syndrome (PTSD). The goal is to shed light on the brain's response to fear and why, in some cases, it can lead to prolonged anxiety states like PTSD."

In most animals, a broad range of predator odors can trigger hardwired fight-flight-or-freeze fear responses that are key to each animal's individual survival and the survival of the species. Mice can detect chemosignals associated with a predator's scent that warn a mouse of life-threatening danger. Because of this, mice tend to display innate fear-like behavior in response to diverse predator odors such as cat saliva, major urine proteins (MUPs) from a rat, or the smell of snakeskin. The vomeronasal organ mediates these specialized odor cues via the detection of protein pheromone homologs (Papes, Logan & Stowers, 2010).

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Interestingly, humans don't seem to have nearly as many (if any) evolutionarily conserved odor cues that elicit an unconditioned fear response in all humans, all the time. That said, humans are highly sensitive to irritants or stinging odors (e.g., ammonia, paint thinner) that activate the trigeminal pathway (Doty, 1975). Most odorants stimulate the trigeminal nerve to some degree; however, the threshold for trigeminal chemoreception is typically higher than for regular olfaction.

Notably, a study of odor sensitivity in combat veterans with PTSD (Cortese, Leslie, & Uhde, 2015) found that for warriors in combat zones, odorants with strong trigeminal properties are much more likely than other smells to become associated with life-threatening fear. As the authors explain:

"To the extent our PTSD veterans had the same levels of self-perceived alarm to burnt hair, fuel, gunpowder, and blood odors (i.e., odors signaling true danger) during deployment as they did at the time of our assessment, we would expect these individuals to have been especially skilled in identifying and responding to true threat odors during combat."

For some veterans, many of these trauma-related odors become resistant to extinction and can trigger vivid flashbacks to life-threatening situations after they return to civilian life. As an example, for combat veterans with PTSD, the auditory and olfactory cues associated with Fourth of July festivities in the U.S. can trigger trauma-related flashbacks. Many of the smells associated with Independence Day (e.g., fireworks with gunpowder, charcoal lighter fluid with kerosene) activate the trigeminal pathway.

In his book, The Smell of Kerosene: A Test Pilot's Odyssey, Donald Mallick recalls how the particular trigeminal smell found in jet fuel reminds him of "thrilling" life-or-death situations he experienced in the cockpit of over 125 different prototype aircraft and as the chief project pilot for NASA's lunar landing vehicle. For Mallick, who didn't have PTSD, the smell of kerosene is associated with adrenaline rush and adventure. However, for a combat veteran with PTSD who associates the smell of kerosene with a life-threatening experience in the theater of war, this trigeminal odor can become hardwired as a "scary" smell that triggers crippling anxiety and panic attacks.

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Hopefully, the latest mouse research on how acute exposure to a "scary" smell triggers brain-wide fear that can evolve into a lifetime of anxiety will help humans with odor-related PTSD someday. "We now know that brain activity in anxiety is not the same as in an acute fear response," Bearer noted. "With anxiety, neural activity is elevated across many specific regions of the brain, and normal coordination between regions is lost."

The latest (2020) brain-wide activity mapping by Bearer and colleagues at the University of New Mexico unearths how a smell that is associated with life-threatening danger can trigger a complex dynamic between multiple brain regions as an acute fear experience evolves into chronic anxiety. "These results have the potential for translation to human fMRI results to inform future clinical research in drug targeting of sub-cortical and deeper brain structures," the UNM authors conclude.