Grant: CIHR Fellowship

A significant risk factor for the development of post-traumatic stress disorder (PTSD) is prior trauma, and a major characteristic of PTSD is an exaggerated response to mild stressors or enhanced risk of developing new fears. The mechanisms linking prior trauma with sensitization to acquiring new fears remain unknown, however. The amygdala is a brain structure highly involved in emotional processing and memory, however there is wide evidence that distinct groups of cells within the amygdala promote fear expression (Fear-ON) while others oppose it (Fear-OFF). Based on this, we hypothesize that trauma differentially sensitizes Fear-ON vs Fear-OFF cells in the BLA for heightened reactivation during later stressful events, and that these functionally distinct populations of cells exhibit distinct molecular identities. Determining the molecular identity of Fear-ON vs Fear-OFF cells provides a targetable cellular mechanism underlying PTSD. We will use a mouse model to investigate if the same amygdala neurons activated by trauma become re-activated during new fear learning, even weeks later. This approach uses genetic and immunostaining tools to label different populations activated during two different (and distinct) stressful events: (1) prior trauma, and (2) recall of a new, different fear memory. We will then determine the molecular identity of stress-responsive cells, including gene products (e.g., receptors, neurotransmitters, or signaling pathways) that are expressed specifically on stress-sensitive (Fear-ON) cells. This involves a combination of genetic and sequencing tools to first label stress-activated cells, and then perform RNA sequencing to identify molecular markers that are unique from cells that are not activated by stress. Together, this approach will provide insight to the mechanisms underlying stress disorders. Importantly, identifying molecular markers of Fear-ON neurons will provide a targetable cellular mechanism for the treatment of PTSD.