Memories help us make decisions by using past experiences to navigate new situations. However, when negative memories are too broadly applied—such as seeing safe situations as dangerous—it can lead to disorders like PTSD. Stress plays a role in this overgeneralization, but the details of how it works weren’t clear. The research found that stress affects specific brain cells (PV+ interneurons) in the amygdala, disrupting their ability to control which neurons store a memory. This leads to a larger, less precise memory network, making fear memories more generalized. Stress also triggers the release of endocannabinoids, which reduce the activity of PV+ cells to cause this effect. By blocking this process with genetic tools or FDA-approved drugs, the researchers were able to restore memory accuracy in stressed mice. These findings point to new ways of treating stress-related disorders like PTSD.

This research underscores the potential of targeting stress-related brain pathways to develop new treatments for PTSD and similar disorders. By unravelling the connection between stress, brain cell function, and memory, the study opens new doors for therapeutic innovation in mental health.

Abstract, as published with paper:

Stress induces aversive memory overgeneralization, a hallmark of many psychiatric disorders. Memories are encoded by a sparse ensemble of neurons active during an event (an engram ensemble). We examined the molecular and circuit processes mediating stress-induced threat memory overgeneralization in mice. Stress, acting via corticosterone, increased the density of engram ensembles supporting a threat memory in lateral amygdala, and this engram ensemble was reactivated by both specific and non-specific retrieval cues (generalized threat memory). Furthermore, we identified a critical role for endocannabinoids, acting retrogradely on parvalbumin-positive (PV+) lateral amygdala interneurons in the formation of a less-sparse engram and memory generalization induced by stress. Glucocorticoid receptor antagonists, endocannabinoid synthesis inhibitors, increasing PV+ neuronal activity, and knocking down cannabinoid receptors in lateral amygdala PV+ neurons restored threat memory specificity and a sparse engram in stressed mice. These findings offer insights into stress-induced memory alterations, providing potential therapeutic avenues for stress-related disorders.

Paper details:

Sylvie L Lesuis, Sungmo Park, Annelies Hoorn, Asim J Rashid, Andrew J Mocle, Eric W Salter, Stefan Vislavski, Madison T Gray, Angelica M Torelli, Antonietta DeCristofaro, Wouter P F Driever, Mario van der Stelt, Larry S Zweifel, Graham L Collingridge, Julie L Lefebvre, Brandon J Walters, Paul W Frankland, Matthew N Hill, Sheena A Josselyn. Stress disrupts engram ensembles in lateral amygdala to generalize threat memory in mice. Cell. 2024, Nov 12. DOI: 10.1016/j.cell.2024.10.034.