Periodic Reporting for period 1 - PoMAM (ENGRAMS IN TRAUMATIC MEMORY: FINDING NOVEL THERAPEUTIC AVENUES IN DEPRESSION AND PTSD.)
Période du rapport: 2023-09-01 au 2025-08-31
Post-traumatic stress disorder (PTSD) remains a major mental health challenge worldwide, often accompanied by comorbid depression and cognitive impairments. Patients with comorbid forms are the ones with the poorest prognosis and treatment response. However, it remains unknown how traumas lead to the development of depression. This is in part caused by current limitations of our preclinical models, which are unable to resemble comorbid forms of PTSD and do not differentiate between adaptive fear (useful for survival) and maladaptive fear (leading to pathology).
This project was designed to address both challenges. We aimed to develop a new experimental approach that overcomes these limitations. In addition, we aimed to identify the neural circuits and cellular mechanisms that underlie the transition from adaptive to maladaptive fear, and to explore how these processes may drive comorbid depression. Specifically, the project focused on hippocampal engrams, the cellular ensembles that store fear memories. We investigated how engrams encoding maladaptive fear mediate depression related behaviors. By exploring the distribution, composition, and molecular fingerprint of these maladaptive engrams, this project elucidates a potential mechanism explaining how trauma induces depression-related symptoms, potentially discovering new targets for treatment development.
This project was designed to address both challenges. We aimed to develop a new experimental approach that overcomes these limitations. In addition, we aimed to identify the neural circuits and cellular mechanisms that underlie the transition from adaptive to maladaptive fear, and to explore how these processes may drive comorbid depression. Specifically, the project focused on hippocampal engrams, the cellular ensembles that store fear memories. We investigated how engrams encoding maladaptive fear mediate depression related behaviors. By exploring the distribution, composition, and molecular fingerprint of these maladaptive engrams, this project elucidates a potential mechanism explaining how trauma induces depression-related symptoms, potentially discovering new targets for treatment development.
Creating a new model of trauma-related illness
We developed an animal model that mimics how different levels of fear can lead to very different out-comes. A mild fear experience produces normal, protective fear, which helps survival. A stronger traumatic experience, however, created excessive and harmful fear, very similar to PTSD. Animals exposed to strong-er trauma also showed problems with memory and despair, capturing the combined features of PTSD and depression.
Discovering how harmful memories drive despair
We were able to identify the small groups of brain cells in the hippocampus (a key memory area) that store these fear memories. We found that when the trauma was strong, the same memory cells that stored fear were also active during despair-like behaviour. The activity of this maladaptive fear engram led to the de-creased of activity in the rest of the hippocampus. We also discovered that the distribution of these cells in the hippocampus changes depending on the intensity of the fear.
Testing how to relieve symptoms
Next, we tested whether switching off these harmful memory traces could improve behaviour. When we silenced the brain cells storing the strong fear memories, animals recovered their memory abilities and did not show despair. This shows that these cells are causally related with depressive-like symptoms and that inhibiting them could open new avenues for the development of new treatments.
Looking for new treatment targets
Finally, we began investigating the molecular identity of these fear memory engrams, in other words, what makes them unique at the molecular level. This step is ongoing, but it will allow us to identify biological markers and possible drug targets to treat trauma-related illness more effectively.
We developed an animal model that mimics how different levels of fear can lead to very different out-comes. A mild fear experience produces normal, protective fear, which helps survival. A stronger traumatic experience, however, created excessive and harmful fear, very similar to PTSD. Animals exposed to strong-er trauma also showed problems with memory and despair, capturing the combined features of PTSD and depression.
Discovering how harmful memories drive despair
We were able to identify the small groups of brain cells in the hippocampus (a key memory area) that store these fear memories. We found that when the trauma was strong, the same memory cells that stored fear were also active during despair-like behaviour. The activity of this maladaptive fear engram led to the de-creased of activity in the rest of the hippocampus. We also discovered that the distribution of these cells in the hippocampus changes depending on the intensity of the fear.
Testing how to relieve symptoms
Next, we tested whether switching off these harmful memory traces could improve behaviour. When we silenced the brain cells storing the strong fear memories, animals recovered their memory abilities and did not show despair. This shows that these cells are causally related with depressive-like symptoms and that inhibiting them could open new avenues for the development of new treatments.
Looking for new treatment targets
Finally, we began investigating the molecular identity of these fear memory engrams, in other words, what makes them unique at the molecular level. This step is ongoing, but it will allow us to identify biological markers and possible drug targets to treat trauma-related illness more effectively.
Our project revealed how traumatic memories in the hippocampus could drive both PTSD and depression, explaining their high comorbidity and resistance to standard treatments. We identified specific brain cells that encode harmful fear memories and showed that targeting these cells can improve memory and despair in animal models. These findings could provide a new direction for research and therapy development, offering potential drug targets, biomarkers, and preclinical models to guide more effective treatments for trauma-related disorders.