Stress effects on fear memory extinction: The crosstalk between Amygdala and Entorhinal Cortex

Post-Traumatic Stress Disorder (PTSD) is a highly debilitating disease, triggered by a traumatic experience that becomes resistant to extinction. It is accompanied by heightened stress, which interferes with correct fear memory extinction. The neural circuits underpinning fear and stress response are closely interconnected. The amygdala represents a primary hub in the brain that is activated by stress, encodes threatening stimuli and regulates traumatic memory by integrating information with different brain regions, including the dorsal hippocampus (dHPC), a fundamental brain structure for contextual learning, a crucial component of fear extinction. The amygdala communicates with the dHPC, particularly with the CA1 and dentate gyrus (DG), through indirect projections to the entorhinal cortex (EC). This study aims to determine the impact of stress on contextual fear memory extinction and the role of the amygdala-EC neural projections in mediating such effects. Male rats were exposed to a contextual fear conditioning paradigm to associate a context with an aversive experience (i.e. footshocks) and, subsequently allowed to extinguish the fear memory association through repeated exposure to the same context in the absence of the shock. To test the effects of acute stress on fear extinction, rats were exposed to a swim stress before the extinction training. Stress-induced activation of the amygdala, dHPC and EC was determined through cFos immunofluorescence analyses. Separate cohorts of rats underwent the same experimental protocol and were optogenetically manipulated under stress or no stress conditions to investigate the sufficiency and necessity of amygdala-EC projections in driving the behavioural effects of stress on fear extinction. Data collected so far revealed that acute stress activated the brain regions examined and impaired fear memory extinction and that activation of amygdala-EC circuit is necessary to drive stress-induced fear memory alterations. Taken together, our results open the avenue to investigate new potential tools to treat stress-related psychopathologies.