Memory Trace for Fear Extinction: Fragile yet Reinforceable

Abstract

Fear extinction is a biological process in which learned fear behavior diminishes without anticipated reinforcement, allowing the organism to re-adapt to ever-changing situations. Based on the behavioral hypothesis that extinction is new learning and forms an extinction memory, this new memory is more readily forgettable than the original fear memory. The brain’s cellular and synaptic traces underpinning this inherently fragile yet reinforceable extinction memory remain unclear. Intriguing questions are about the whereabouts of the engram neurons that emerged during extinction learning and how they constitute a dynamically evolving functional construct that works in concert to store and express the extinction memory. In this review, we discuss recent advances in the engram circuits and their neural connectivity plasticity for fear extinction, aiming to establish a conceptual framework for understanding the dynamic competition between fear and extinction memories in adaptive control of conditioned fear responses.

Hijacking a dedicated entorhinal-hippocampal extinction circuit to remove traumatic memory

“…The LEC-vCA1 pathway, pivotal to fear extinction, is likely part of cognitive motif ensembles for memory processing. Unlike the established extinction circuits (22,(54)(55)(56) that collectively appear to affectively inhibit the expression of conditioned fear behaviors, the LEC integrates diverse sensory information (14,18,(57)(58)(59), aided by dopaminergic innervation, to construct a cognitive map of abstract task rules (13). Fear extinction as a more abstract form of inhibitory learning (60) requires a dopaminergic switch for transitioning from fear to safety (61,62).…”

An ultra-short-acting benzodiazepine in thalamic nucleus reuniens undermines fear extinction via intermediation of hippocamposeptal circuits

“…From a circuit perspective, fear extinction relies on the interactive engagement of a tripartite circuit involving the ventral hippocampus (vHPC), medial prefrontal cortex (mPFC), and basolateral amygdala (BLA) 1, 2, 3, 28, 29, 30 . The nucleus reuniens (RE) of the midline thalamus not only sends dense projections to the hippocampal CA1 region, but also receives dense projections from the mPFC 31, 32, 33 .…”

“…Fear extinction, as a form of inhibitory learning and memory, enables organisms to adapt to changing environments 1, 2, 3 . It is considered a fundamental process that underlies behavioral changes in treating mental disorders, including anxiety and post-traumatic stress disorder (PTSD) 4, 5 .…”