Modulation of fear extinction under stress: the role of Amygdala-Entorhinal Cortex projections

Background. Heightened levels of stress disrupt the extinction of traumatic memories1. The amygdala is a primary brain hub activated by stress, which identifies threatening stimuli, and plays a critical role in the regulation of traumatic memory by integrating information with the dorsal hippocampus (dHPC), a fundamental brain structure for contextual learning and fear extinction2,3. The amygdala communicates with the dHPC through indirect projections to the entorhinal cortex (EC)4. This study investigates the impact of stress on fear memory extinction and the role of the amygdala-EC pathway in mediating such effects. Methods. Male Sprague-Dawley rats underwent a contextual fear conditioning paradigm to associate a context with an aversive experience (i.e. footshocks) and, the following day, exposed to the same context in the absence of the shocks to induce fear extinction (extinction training). To examine the effects of stress, rats were exposed to a swim stress before the extinction training. Optogenetic manipulation was performed under no stress conditions and during swim stress exposure to investigate the role of amygdala-EC projections in driving stress behavioural effects on fear extinction. Results. Behavioral analyses showed that acute stress impaired fear extinction. Moreover, we found that activation of amygdala–EC projections are sufficient to drive stress-induced fear memory alterations, whereas silencing this circuit prevented the stress-induced impairment of fear extinction. Conclusions. Our results shed light on the mechanisms underlying stress detrimental effects on fear extinction opening the avenue to investigate new potential tools to treat stress-related psychopathologies.