Mapping and interrogating top-down control of the memory engram of the posttraumatic stress disorder.

The onset of post-traumatic stress disorder (PTSD) is triggered by a life threatening experience, which leaves a lasting trace of fear memory. Individuals with PTSD are unable to distinguish the similarities between different contexts; memories become largely generalized, so that a similar context generates a robust recall of a bad experience, crippling behaviour in ways that severely compromises individual well-being and day-to-day activities. Currently, there is no ideal treatment for human PTSD. Even if subjects experiencing a traumatic event all show an acute response to it, only a subset (susceptible) of them ultimately will develop PTSD. We hypothesize that PTSD is caused by a dysfunctional top-down synaptic control, from the medial prefrontal cortex onto amygdala and hippocampal domains, that orchestrate the over-consolidation and impairment of extinction of fear memories thus leading to long-lasting behavioural alterations. In animal model for PTSD, we are comparing gene expression and gene regulation between animals that are sensitive or resilient to trauma. The results are currently under validation.

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The onset of posttraumatic stress disorder (PTSD) is triggered by a life threatening experience, which leaves a lasting trace of fear memory. Individuals with PTSD are unable to distinguish the similarities between different contexts, so that a similar context generate a robust recall of a bad experience, in ways that severely compromises individual well-being. Even if subjects experiencing a traumatic event, only a subset (susceptible) of them ultimately will develop PTSD. We hypothesize that PTSD is caused by a dysfunctional top-down synaptic control, from the medial prefrontal cortex (mPFC) onto amygdalar and hippocampal domains, that orchestrate the overconsolidation, excessive retrieval, generalization and impairment of extinction of fear memories thus leading to long-lasting behavioural alterations. Our translational interdisciplinary collaborative consortium combines expertise in animal behaviour, genetic engineering, in vivo electrophysiology, whole-brain imaging, transcriptomics and epigenomics, and clinical studies. With these interdisciplinary collaborations, we aim to decipher the mechanisms of maladaptive responses to trauma in animals, and translate these results to humans. Our subaims are: - To decipher in rats the differences in connectivity parameters in susceptible and resilient animals by MRI and DTI. - To measure changes in functional synaptic strengths by electrophysiology. - To map gene expression and epigenetic modifications. - To quantify the parameters identified in rat models in human blood. - To manipulate cell assemblies recruited by context exposure in rats and investigate which activity parameters can be modified for the retrieval of a latent PTSD-engram - To investigate if genetic manipulations and potential phenotypic changes would correlate with changes in brain activity, connectivity, gene expression and epigenetics states, and blood hormone levels. - To investigate genetic top-down control by several genes.