How Fear Memory is Updated: From Reconsolidation to Extinction?

Abstract

Post-traumatic stress disorder (PTSD) is a psychiatric disorder caused by traumatic past experiences, rooted in the neurocircuits of fear memory formation. Memory processes include encoding, storing, and recalling to forgetting, suggesting the potential to erase fear memories through timely interventions. Conventional strategies such as medications or electroconvulsive therapy often fail to provide permanent relief and come with significant side-effects. This review explores how fear memory may be erased, particularly focusing on the mnemonic phases of reconsolidation and extinction. Reconsolidation strengthens memory, while extinction weakens it. Interfering with memory reconsolidation could diminish the fear response. Alternatively, the extinction of acquired memory could reduce the fear memory response. This review summarizes experimental animal models of PTSD, examines the nature and epidemiology of reconsolidation to extinction, and discusses current behavioral therapy aimed at transforming fear memories to treat PTSD. In sum, understanding how fear memory updates holds significant promise for PTSD treatment.

Keywords: Engram; Extinction; Fear memory; Post-traumatic stress disorder; Reconsolidation.

Fig. 1

A schematic overview of memory simply includes short-term memory (STM), long-term memory (LTM), and updated memory. When new information is learned, it initially forms immediate memory, which lasts for a few minutes and can be extended through review, turning into working memory. Both immediate- and working-memory are termed STM since they are transient. LTM is established through consolidation, making memories more resistant to alterations. Processes like reconsolidation or extinction can update LTM by modifying original memories with new associations. Memories eventually fade if not reinforced. Unstable forms of memories are presented with dashed lines

Fig. 2

Diagrams of experimental animal models for Pavlovian fear conditioning. A Traumatic memories, such as experiencing a fire, a volcano erupting, or a car accident, are stored and retrieved upon re-exposure, forming associative learning processes studied in animal models. These experiments combine CS and US to induce fear responses in various mammalian and vertebrate subjects. B-I Different animal models of fear conditioning. J An overview of memory reconsolidation and extinction paradigms in the Pavlovian FC paradigm. After the fear acquisition, rodents are re-exposed to CSs in the training context to initiate either memory reconsolidation or extinction retrieval. They are then tested for memory retention in post-reactivation long-term tests (often performed 24 h after reactivation)

Fig. 3

Conceptual diagrams of the neuronal circuits of reconsolidation and extinction, as well as their relationship. A Neuronal circuits of reconsolidation mainly involve the cortex, amygdala, and hippocampus. B Neuronal circuits of extinction form a cooperative network across the brain. C (1). Memory trace dominance theory implies a competitive mechanism between reconsolidation and extinction. (2). Nader et al. and Pérez-Cuesta et al. indicate that extinction does not prevent reconsolidation, suggesting dual memory periods may develop in a counterbalanced manner. (3). Molecular evidence regarding reconsolidation and extinction remains unclear from previous studies. (4). The linear memory assumption posits a distinct and resilient period between reconsolidation and extinction of memories. (Rec, Reconsolidation; Ext, Extinction.)

Fig. 4

A possible role for engram cells pertaining to memory reconsolidation and extinction. This review proposes the existence of distinct engram ensembles during mnemonic stages, such as reconsolidation and extinction. During fear conditioning, a cohort of silent engram cells (grey, silent engrams) encode new information and become conditioning-activated engram cells (scarlet, fear conditioning engrams). Upon memory retrieval, other engram ensembles are activated by the CS (yellow, retrieval engrams). Some conditioned- and retrieval-engrams may overlap (yellow with red border, overlapping fear-conditioned and retrieval engrams). Memory retrieval triggers two opposing stages, namely reconsolidation and extinction. The former process reactivates original fear conditioning engrams (red, fear engrams activated during reconsolidation), and the latter process generates new engram ensembles (violet, extinction engrams). As extinction learning progresses, some fear engrams may switch into extinction ensembles (violet with yellow border, overlapping fear conditioning, and extinction engrams). However, the intrinsic switch mechanism between reconsolidation- and extinction-engrams is not well understood (black question mark). Potential factors govern the competition between reconsolidation and extinction engram cells including spine connectivity (A), the number or location of engram ensembles (B), or projections from upper brain structures (C). The hypothetical mutual interaction between reconsolidation- and extinction-engram cells requires further exploration (tiny red question mark, unknown relationships)