Fear memories initially form broad associations, but over time they become more specific and linked to events in a timeline. This process involves the hippocampus in the early stages and later the dorsolateral prefrontal cortex, which organizes events sequentially. People with high anxiety, however, may have difficulty with this integration, which makes fear persistent and increases the risk of developing PTSD.
Traumatic events affect memories in several ways, especially in terms of how we associate environmental cues with a threat response.
Threatening situations, such as a car accident, reinforce associative learning: a bicycle or any other common object that was present at the time becomes fearful because of its connection to the event. This link between cues and threats can lead to exaggerated fear responses in individuals with post-traumatic stress disorder (PTSD).
On the other hand, traumatic events can also weaken the episodic aspect of memories. This means that some PTSD patients may have difficulty recalling the exact sequence of traumatic events, which is essential for constructing a timeline of memories.
This sequential organization is a key aspect of episodic memory, but it can be fragmented or obscured by stress. There is currently no unified understanding of how the brain manages the association of cues with trauma and sequential encoding, especially in cases where memory is dysfunctional after trauma.
Studies in rodents and humans show that the hippocampus (HPC) and dorsolateral prefrontal cortex (DLPFC) are essential for sequence learning. Both connect to the ventromedial prefrontal cortex (VMPFC), which regulates memories of associating cues with threats stored in the amygdala.
The role of the amygdala in fear memories has been widely studied, although its interaction with other brain areas, such as the VMPFC, is still being explored.
Researchers in Japan tested this mechanism with a threat conditioning paradigm, and their results were published in the journal Nature Communications.
In this experiment, simulated threatening events (such as a car accident) were preceded by a sequence of specific temporal cues. The participants’ fear memories were assessed during conditioning, immediately after, and 24 hours later.
Illustration of task design. Participants completed three sessions: Acquisition, Immediate Test, and Long-Term Test (b). On any given trial during each session, participants watched a semi-animated video clip depicting a traffic scene at an intersection from the perspective of a car driver waiting for a red light to turn green (c). This waiting period was followed by the sudden appearance of a truck that either crashed into the driver’s front window (on some trials in the Acquisition session) or simply passed by (on other trials in the Acquisition session and on all trials in other sessions). Here, the sight of a truck approaching for a crash along with a noxious collision sound (~85 dB) served as a multisensory unconditioned stimulus (US), and the passing of a truck signified an omission of a US on that trial. On each trial, the waiting period included three auditory elements: a bicycle bell, a traffic light melody, and crow calls. The sound elements were played in one of three triplet sequences (1) a-b-c, (2) b-a-c, and (3) a-c-b, where each letter (a, b, or c) corresponds to one of the three sound elements (e.g., bicycle bell) in a counterbalanced manner across participants.
The goal was to observe how the brain prioritizes cue associations and event sequences over time. They hypothesized that the HPC and DLPFC regulate the transfer of episodic temporal sequences to the VMPFC-amygdala circuit, determining the balance between cue-associative memories and episodic memories.
To test this hypothesis, 44 participants were exposed to simulated threatening events while being monitored by functional magnetic resonance imaging (fMRI) and machine learning algorithms, which tracked brain activity over 24 hours.
The researchers looked at how defensive responses (such as skin reactivity) during threat anticipation were governed by cue-associative memories versus sequential memories. The results showed that defensive responses were initially based on simple cue associations, but 24 hours later, these responses were based on a sequence of events.
They also noted that activity between the HPC and DLPFC and the VMPFC-amygdala circuit changed over time. During the first few hours, the HPC communicated with the VMPFC-amygdala circuit based on the latest cues that signaled threat, but this connection was no longer present 24 hours later.
This change in governance was reduced in participants with high anxiety, who are at higher risk for PTSD. Their brains show weaker integration of time-based episodic memories via the dorsolateral prefrontal cortex, which may lead to persistent and overwhelming fear linked to associative cues.
Thus, the researchers demonstrated that the brain adjusts the expression of fear, balancing between a more generalized reaction and a more specific and temporally organized one.
This mechanism explains how two features of post-traumatic memory, overgeneralization of fear and loss of episodic memory, emerge through the interaction between the HPC and DLPFC in controlling the VMPFC-amygdala circuit.
These findings hold promise for the development of new therapeutic approaches for trauma-related disorders.
READ MORE:
Time-dependent neural arbitration between cue associative and episodic fear memories.
Cortese A, Ohata R, Alemany-González M. et al.
Nat Commun 15, 8706 (2024). https://doi.org/10.1038/s41467-024-52733-4
Abstract:
After traumatic events, simple cue-threat associative memories strengthen while episodic memories become incoherent. However, how the brain prioritises cue associations over episodic coding of traumatic events remains unclear. Here, we developed an original episodic threat conditioning paradigm in which participants concurrently form two memory representations: cue associations and episodic cue sequence. We discovered that these two distinct memories compete for physiological fear expression, reorganising overnight from an overgeneralised cue-based to a precise sequence-based expression. With multivariate fMRI, we track inter-area communication of the memory representations to reveal that a rebalancing between hippocampal- and prefrontal control of the fear regulatory circuit governs this memory maturation. Critically, this overnight re-organisation is altered with heightened trait anxiety. Together, we show the brain prioritises generalisable associative memories under recent traumatic stress but resorts to selective episodic memories 24 h later. Time-dependent memory competition may provide a unifying account for memory dysfunctions in post-traumatic stress disorders.
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