Role of Amygdala-Infralimbic Cortex Circuitry in Glucocorticoid-induced Facilitation of Auditory Fear Memory Extinction

Abstract

Purpose: The basolateral amygdala (BLA) and infralimbic area (IL) of medial prefrontal cortex (mPFC) are two inter-connected brain structures that mediate both fear memory expression and extinction. Besides the well-known role of the BLA in the acquisition and expression of fear memory, projections from IL to BLA inhibit fear expression and have a critical role in fear extinction. However, the details of IL-BLA interaction remain unclear. Here, we aimed to investigate the role of functional reciprocal interactions between BLA and IL in mediating fear memory extinction. Methods: Using lidocaine (LID), male rats underwent unilateral or bilateral inactivation of the BLA and then unilateral intra-IL infusion of CORT, prior to extinction training of auditory fear conditioning paradigm. Freezing behavior was reported as an index for the measurement of conditioned fear. Infusions were performed before the extinction training, allowing to examine the effects on fear expression and also further extinction memory. Experiments 1-3 investigated the effects of left or right infusion of CORT into IL, and LID unilaterally into BLA on fear memory extinction. Results: Results showed that intra-IL infusion of CORT in the right hemisphere reduced freezing behavior when administrated before the extinction training. Auditory fear memory extinction was impaired by asymmetric inactivation of BLA and CORT infusion in the right IL; however, the same effect was not observed with symmetric inactivation of BLA. Conclusion: It is concluded that that the IL-BLA neural circuit may provide additional evidence to contribution of this circuit in auditory fear extinction. This study demonstrate dissociable roles for right or left BLA in subserving the auditory fear extinction. Our finding also raise the possibility that left BLA-IL circuitry may contribute in mediating auditory fear memory extinction via underlying mechanisms, however further research is required.

Update on neurobiological mechanisms of fear: illuminating the direction of mechanism exploration and treatment development of trauma and fear-related disorders

“…This result highlights the change of the vHPC-PL circuit during fear extinction training and further talks about the balance of the vHPC to PL vs. BLA to PL inputs and how they might be dynamically regulated during fear extinction. Another result supports that the connectivity of the BLA-mPFC circuit has different roles in promoting or impairing fear memory extinction and supporting brain lateralization (Vafaei et al, 2022). Mice were infused with corticosterone into the IL when the unilateral BLA inactivated impaired fear memory extinction.…”

“…However, the extinction effect is absent when the BLA is inactivated bilaterally. This is because the BLA–IL pathway is completely blocked in the case of bilateral BLA inactivation and cannot exert the extinction effect (Vafaei et al, 2022 ). The mechanism by which the BLA–mPFC circuit is involved in fear memory extinction may involve the following processes: CS emergence, mPFC, excitation of related cortical and thalamic, activation of inhibitory interneurons in the AMY, GABA release-reduced excitability of intra-amygdala projections to CEA neurons, reduced CEA output, and inhibition of conditioned fear behavior expression.…”

Targeting Human Glucocorticoid Receptors in Fear Learning: A Multiscale Integrated Approach to Study Functional Connectivity

“…These receptors are widely distributed across brain regions implicated in both fear learning and extinction [7,48,67]. Importantly, GRs play a bidirectional role in fear regulation: they enhance fear memory consolidation in the amygdala while facilitating extinction processes through their actions in the prefrontal cortex and hippocampus [53,[68][69][70], in line with the notion that different levels of stress can have opposite influences on neuroplasticity [64][65][66]. Dysregulation of GR function has been implicated in the etiology of anxiety and mood disorders, underscoring the intricate relationship between stress, fear regulation, and emotional well-being [71][72][73].…”