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

Exposure to highly traumatic events can lead to the development of trauma-related disorders, such as Post-Traumatic Stress Disorder (PTSD). PTSD is characterized, among other symptoms, by enhanced consolidation of traumatic memory and impaired fear extinction and is accompanied by elevated levels of stress which can interfere with memory processing. The neural circuits underpinning fear and stress response are closely interconnected. The crosstalk between amygdala and hippocampus plays a critical role in the acquisition, consolidation, and extinction of fear memory. The amygdala encodes threatening stimuli and regulates traumatic memory by integrating information with different brain regions, including the hippocampus, a fundamental brain structure for contextual learning. Under stressful situations, the amygdala strongly influences hippocampal activity in both humans and rodents. Since the amygdala sends very scarce direct projections to the dorsal hippocampus, projections to the entorhinal cortex (EC) provide a major indirect pathway for the amygdala to regulate hippocampal dynamics. 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 Sprague-Dawley rats were exposed to 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 sufficiency and necessity of amygdala-EC projections in driving the behavioural effects of stress on traumatic memory extinction. Subsequently, rats were re-exposed to the same context to test for extinction recall (extinction retrieval). Data collected so far revealed that acute stress impaired contextual fear memory extinction and that activation of amygdala-EC circuit is necessary to drive stress-induced fear memory alterations. Taken together, our results reveal the neural mechanisms underlying stress detrimental effects on fear memory dynamics, opening the avenue to investigate new potential tools to treat stress-related psychopathologies.