Researchers have identified a new pathway in the brain that plays an important role in our response to fear

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Florida State University researchers have identified a new pathway in the brain that plays an important role in our response to fear.

Scientists have long considered the amygdala, an almond-shaped structure in the center of the brain, to be the “center of fear” and believed it to be largely responsible for how an individual responds to frightening circumstances or perceives threats. That belief has served as the foundation for many scientific models explaining various psychiatric illnesses, but these models often fell short of fully explaining these conditions.

Professor of Psychology and Neuroscience Wen Li, along with members of her Cognitive Affective Neuroscience Lab (FSU doctoral alumni Yuqi You and Kevin Clancy, and lab mate Lucas Novak), were able to identify a different tract in the brain, routed through the human sensory cortex, where information from our environment is first analyzed.

The team published their findings this week in the journal Current Biology.

“This work fills a critical gap in the literature by revealing a new pathway to fear and fear memory,” Li said. “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.”

The research was conducted at FSU’s functional magnetic resonance imaging (fMRI) facility, where the team utilized an aversive conditioning method pairing neutral smells with disgusting images and sounds. The team also assessed long-term threat memory, occurring over the course of several days.

“We were hoping to find neural evidence supporting long-term threat memory in the olfactory cortex at the outset of this research,” You said. “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.”

The team ultimately found that the human sensory cortex, not the amygdala, is responsible for storing our memories of frightening events from the past.

The findings among individuals with anxiety highlight how those diagnosed with the disorder may perceive threats differently and be impacted by fear longer than other individuals.

“This research reveals mechanistic insight into how threat memory forms and is stored in our sensory cortex,” You said. “Knowing that this sensory-based threat memory is hyperactive in anxiety takes us a step closer to helping people with anxiety disorders change their maladaptive threat perception and memory.”

The team’s findings have the potential to drastically shift our understanding of how fear and fear disorders emerge and persist. This novel discovery further points to new therapeutic targets, which could present new options for treating fear disorders.

This study comes on the heels of another research discovery from Li’s lab, published in the Proceedings of the National Academy of Sciences of the United States of America, which identifies a link between two key parts of the brain that play significant roles in conditions such as Alzheimer’s disease, post-traumatic stress disorder, schizophrenia and depression.


Discussion
We demonstrated affective and perceptual learning and long-term memory, accompanied by immediate and lasting pattern differentiation as well as late-onset, lasting tuning shift in the human olfactory cortex, especially among anxious individuals.

These findings highlight the role of the human sensory cortex in threat memory and advance the extant (human and non-human) literature of anxiety modulation of the sensory cortical system of threat memory. Together, they illuminate hitherto underexplored human sensory mechanisms of threat processing and their contribution to the pathophysiology of anxiety.

Differential conditioning is known to promote divergent conditioned responses to (threat and safety) CS, minimizing conditioning generalization and facilitating CS discrimination (especially from similar stimuli).17,29,43,44 Our risk ratings over a parametrically morphed odor continuum confirmed differential affective learning and memory for CSt and CSs and minimal generalization to the nCS. Our ODT further demonstrated perceptual (discrimination) learning and memory for CS (versus neighboring nCS).

Together, differential conditioning warped both affective and perceptual spaces over the continuum, expanding the distance between the CS and their neighboring nCS and compressing the distance among the nCS. Such paralleled reorganization of affective and perceptual spaces reiterates that acquisition and generalization/specification of threat response tracks the perceptual distance between the CS and nCS.45, 46, 47

Neurally, the olfactory (APC and PPC) cortex exhibited immediate and lasting pattern differentiation between the CS and neighboring nCS, especially in anxious individuals. This pattern differentiation resembles conditioning-induced pattern separation in nonhuman sensory cortex, underpinning CS memory representation10,11 as a “perceptual-mnemonic” mechanism.48 It is yet unclear whether this process directly relates to hippocampal pattern separation characterized by sparse orthogonalized representation.49,50

The human PPC is a critical site for olfactory sensory representation and underpins odor object encoding.51,52 The immediate effect in PPC replicates our previous finding, reflecting adapted sensory representation of CS.29 The lasting effect in PPC suggests that this plasticity would persist to support enduring sensory cortical representation of CS as part of the long-term memory of acquired threat/safety. The APC exhibited a comparable effect, replicating decorrelation of APC responses to CS and similar nCS in rodents.10,17 Given human APC’s role in olfactory attention and arousal,52 this APC pattern differentiation could reflect heightened sensory vigilance to CS.

The other mnemonic mechanism—tuning shift that underpins associative representational plasticity—is also confirmed here in humans, particularly in the PPC. Interestingly, this plastic process was observed on day 9 only. This temporal profile accords with nonhuman findings: sensory cortical tuning shift is relatively weak in magnitude and specificity immediately after conditioning but becomes stronger over time (days and weeks).19

It also coincides with our recent finding of delayed (day 16, but not immediate) plasticity in human primary visual cortex (V1/V2).14 Therefore, this tuning shift, particularly in the PPC that is critical for olfactory sensory representation, underscores time-dependent associative representational plasticity in human olfactory cortex to support enduring CS representation as part of long-term memory of acquired threat/safety.7,19

In comparison, the amygdala and OFC exhibited no clear evidence of pattern differentiation or tuning shift by conditioning. The null findings here highlight the human sensory cortex (outside the canonical threat circuit) as an independent neural substrate for threat memory. That said, we analyzed these processes expressly along a physical dimension (i.e., odor-morphing continuum) to elucidate neural representation of CS sensory input, which does not rule out amygdala/OFC associative plasticity in other, abstract dimensions (e.g., valence or value).

In fact, previous research comparing (immediate, appetitive) conditioning effects in the rodent piriform cortex and OFC has revealed sensory-based plasticity in the former and value/rule-based plasticity in the latter (e.g., 53). Similarly, human research of (both appetitive and aversive) conditioning has underscored value-based (versus sensory-based) pattern differentiation in the OFC and amygdala.29,54,55 In sum, the contrast here highlights a sensory-bound representation system of threat memory (“S-memory”) 56,57 in the sensory cortex.

Finally, leveraging self-report from human participants, we demonstrated that anxiety amplified these threat mnemonic processes in the sensory cortex. Similar to our recent finding in the visual cortex,14 anxiety particularly heightened piriform plasticity on day 9. This anxiety effect helps to reconcile the seeming temporal dissociation between group-level (average) effects of pattern differentiation (present on day 1) and tuning shift (present on day 9), that is, in anxious individuals, the two forms of plasticity were both present on day 9 and, moreover, correlated with each other, highlighting their shared origin in threat conditioning and anxiety.

We caution that our sample could be small for a study of individual differences, warranting replication through future large-scale studies. Nonetheless, findings of sensory-based long-term threat memory in anxiety lend direct credence to anxiety theories centered on hyperactive sensory memory of threat.56,57 They also confer mechanistic insights into intrusive memories (a hallmark symptom) in post-traumatic stress disorder (PTSD) laden with vivid sensory fragments of trauma and readily triggered by simple sensory cues.58, 59, 60

To conclude, lasting pattern differentiation and tuning shift in the human PPC, paralleling long-term threat memory, provides mechanistic evidence for the human sensory cortex as a key component of the threat circuitry. This long-term threat representation may serve to underpin threat processing in the sensory cortex, even in the initial feedforward sweep.61, 62, 63 Importantly, that this sensory cortical mnemonic system of threat is hyperfunctioning in anxiety adds to the growing support for a sensory mechanism—exaggerated sensory cortical representation of threat—in the pathogenic model of anxiety.64


More information: Yuqi You et al, Pattern differentiation and tuning shift in human sensory cortex underlie long-term threat memory, Current Biology (2022). DOI: 10.1016/j.cub.2022.02.076

Kevin J. Clancy et al, Transcranial stimulation of alpha oscillations up-regulates the default mode network, Proceedings of the National Academy of Sciences (2021). DOI: 10.1073/pnas.2110868119#ack-1

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