The Medial Prefrontal Cortex and Fear Memory: Dynamics, Connectivity, and Engrams

Abstract

It is becoming increasingly apparent that long-term memory formation relies on a distributed network of brain areas. While the hippocampus has been at the center of attention for decades, it is now clear that other regions, in particular the medial prefrontal cortex (mPFC), are taking an active part as well. Recent evidence suggests that the mPFC—traditionally implicated in the long-term storage of memories—is already critical for the early phases of memory formation such as encoding. In this review, we summarize these findings, relate them to the functional importance of the mPFC connectivity, and discuss the role of the mPFC during memory consolidation with respect to the different theories of memory storage. Owing to its high functional connectivity to other brain areas subserving memory formation and storage, the mPFC emerges as a central hub across the lifetime of a memory, although much still remains to be discovered.

Neurobiological advances of learned fear in humans

“…15 Crucially, latest available evidence has identified the PFC as a critical core component in the neural circuit underlying fear conditioning, particularly for the ability of PFC to bidirectionally modulate the expression of previously learned fear. On one hand, the activation in the dorsomedial PFC (dmPFC) occurs for the long-term storage and retrieval of old memories 31 ; on the other, the vmPFC forms strong reciprocal connections with the amygdala and other subcortical structures as well as with the lateral cortex. Thus, this subregion seems to be necessary for controlling fear relative to a stimulus that no longer predicts danger, 32 representing a relay-station for "bottom-up" information from limbic and subcortical structures signaling emotion detection, as well as for information from lateral PFC (LPFC), conveying response selection and control.…”

The Three Musketeers in the Medial Prefrontal Cortex: Subregion-specific Structural and Functional Plasticity Underlying Fear Memory Stages

“…For example, human patients with deficits in the mPFC show impaired source memory, increased memory interference, and adaptation to new rules [4]. Rodent homologue of the human mPFC, including the anterior cingulate cortex (ACC), prelimbic cortex (PL) and infralimbic cortex (IL), has been well documented in the context of fear learning and memory [5][6][7].…”

Epigenetic Changes and Chromatin Reorganization in Brain Function: Lessons from Fear Memory Ensemble and Alzheimer’s Disease

“…In all these studies, an ideal control is used to subject animals only to the context (CTX), without applying a foot shock. Next, hippocampal or cortical tissue (i.e., to address long-term memory storage; see [ 87 ]) are obtained across different phases of CFC and subsequently analyzed to identify relevant changes within the transcriptomic profile by high-throughput RNA sequencing (RNA-seq), in the epigenomic landscape (e.g., by Chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq and Methylated DNA immunoprecipitation and sequencing (MeDIP-seq)), in chromatin accessibility (e.g., by the Assay for Transposase-Accessible Chromatin and sequencing (ATAC-seq)) and in the chromatin 3D organization using Chromatin-Conformation-Capture-based approaches (e.g., Hi-C). ChIP-seq data can also be used to identify putative active promoters (enriched in H3K4me3, H3K9ac, H3K27ac, H3K79me3), primed enhancers (enriched in H3K4me1), active enhancers (enriched in H3K27ac and H3K4me1) together with transcriptionally repressed genomic regions (enriched in H3K9me3, H3K27me3 and 5mCpG).…”