Beyond Amygdala: Researchers Unearth a New Pathway to Fear

"I am often said to have identified the amygdala as the brain's 'fear' center. But the fact is, I have not done this, nor has anyone else." —Joseph LeDoux (2015)

3D illustration of both amygdala. Humans have two almond-shaped amygdalae, which are located within the brain's left and right medial temporal lobes.

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In 2015, Joseph LeDoux wrote a Psychology Today blog post, "The Amygdala Is Not the Brain's Fear Center." In this article, he says, "The idea that the amygdala is the home of fear in the brain is just that—an idea. It is not a scientific finding but instead a conclusion based on an interpretation of a finding."

According to LeDoux, when he started research on this brain region in the 1980s, it was a "lonely field of inquiry" because, at that time, the hippocampus "was all the rage." However, by the aughts, our amygdala had gone from obscurity to practically being a household word, synonymous with fear (LeDoux, 2007).

Move Over Amygdala—The Human Sensory Cortex Takes Center Stage as a Pathway to Fear

Flash forward to 2022. Groundbreaking fMRI-based research from Florida State University gives credence to the notion that our amygdala is not the brain's fear center.

Researchers from FSU's Cognitive Affective Neuroscience Lab, led by senior author Wen Li have unearthed a new fear pathway in the human brain routed through the primary olfactory (piriform) cortex. These findings (You et al., 2022) were published on March 23 in the open-access, peer-reviewed journal Current Biology.

A colorful illustration of different functional brain regions, including olfactory areas of the human sensory cortex

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The most recent Current Biology paper by Li and her FSU team is a follow-up to another study, "Human Sensory Cortex Contributes to the Long-Term Storage of Aversive Conditioning" (You, Brown, & Li, 2021), published in the Journal of Neuroscience last year. FSU's ongoing research in humans (not mice) gives us fresh insights into how fear-based threat memories are stored in our sensory cortex.

"We were hoping to find neural evidence supporting long-term threat memory in the olfactory cortex at the outset of this research," first author Yuqi You said in a news release. "What surprised me was that long-term threat memory in the olfactory cortex could take many forms, and these different neural mechanisms were all consistently hyperfunctioning in anxiety."

In a March 2022 comment on Disqus about her team's recent findings—which disrupt the status quo and rock the boat—Li quipped, "Unpopular finding @CurrentBiology—Sorry, Amygdala!"

She added that her team's research favors "a distributed threat circuitry" (over a fear center) rooted in the human sensory cortex. Li highlights two noteworthy aspects of this previously underexplored fear pathway:

1. Long-term fear memories show pattern differentiation and tuning shifts in the human sensory (olfactory) cortex but not in amygdalae or the orbitofrontal cortex (OFC).

2. This evolutionarily conserved sensory-based memory system is hyperactive in people with anxiety disorders.

"This work fills a critical gap in the literature by revealing a new pathway to fear and fear memory," Li noted. "The findings can lead to a critical paradigm shift in how we conceive and end up treating fear disorders, such as post-traumatic stress disorder and anxiety."

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The Primary Olfactory (Piriform) Cortex May Be a New Therapeutic Target for Treating Fear Disorders

Accumulating evidence suggests that people with generalized anxiety disorder (GAD) or post-traumatic stress disorder (PTSD) may have more intense fear-based memories due to pattern differentiation and tuning shifts in their sensory cortex. Identifying a sensory-based fear pathway beyond the amygdala opens the door for helping people with fear disorders using a novel therapeutic approach.

Knowing that a sensory-based threat memory pathway rooted in the primary olfactory (piriform) cortex is hyperactive in anxious individuals brings us a step closer to helping people with crippling anxiety change maladaptive responses to fear in ways that go beyond the amygdala.