The Role of Basolateral Amygdala and Medial Prefrontal Cortex in Fear: A Systematic Review.

Fear is a primary adaptive response to potential threats. It triggers a complex cascade of physiological, cognitive, and behavioral changes that prepare an organism to cope with dangerous situations. The basolateral amygdala (BLA) and medial prefrontal cortex (mPFC) are both linked to adaptation, the generation of strong emotions, and decision-making. In this systematic review, we aimed to analyze recent studies of the connections between the BLA and mPFC in the context of their neuroanatomy, cellular composition, micro-circuitry, and involvement in fear. Utilizing the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines, our search strategy involved scouring articles from PubMed (National Center for Biotechnology Information, Bethesda, Maryland), Google Scholar (Google, Mountain View, CA), and Science Direct (Elsevier, Amsterdam, Netherlands) databases covering the last decade (2014-2024). Thirty-two rigorously evaluated studies formed the essence of our review. Review findings revealed complex bidirectional connectivity between BLA and mPFC, with distinct roles for different subregions. The rostral BLA primarily projects to the prelimbic cortex, while the caudal BLA connects with the infralimbic cortex. These circuits show specialized cellular composition, with BLA containing principal excitatory neurons and GABAergic interneurons, while mPFC exhibits layer-specific synaptic connections. Fear processing involves dynamic interactions between these regions, with the prelimbic cortex promoting fear expression and the infralimbic cortex facilitating extinction. The analysis showed that astrocytic signaling and N-methyl-D-aspartate (NMDA) receptor activation are essential in the process of both fear memory formation and its extinction. There was evidence that dysregulation of specific circuits is associated with the pathophysiology of several other psychiatric disorders, such as post-traumatic stress disorder (PTSD), anxiety disorders, and schizophrenia. This review clarifies that the BLA-mPFC circuitry is critical in perceiving fear and its regulation. The results highlight the importance of the interactions between brain regions and the types of cells in each region to respond appropriately to fear and its extinction. Uncovering such type of dysregulation further helps to understand the mechanisms of fear-associated disorders and may suggest further treatment options. Future research should focus on cellular plasticity mechanisms, translational applications, and the influence of individual factors on fear processing to develop more effective treatments for psychiatric conditions involving fear dysregulation.