A translational approach to revealing stress susceptibility in amygdala-prefrontal circuits

About This Grant

Project Summary/Abstract Posttraumatic stress disorder (PTSD) is a common psychiatric condition that affects millions of people worldwide. Individuals with PTSD experience persistent fear and distressing memories of traumatic events that are often resistant to cognitive-behavioral treatments like exposure therapy. This impairment in fear regulation poses a major challenge to clinical interventions and may be driven in-part by dysregulation of amygdala-prefrontal interactions, two brain regions critical to fear and fear extinction. Despite some known molecular consequences of stress in the amygdala, there is a fundamental gap in our understand of what cell types are disproportionality affected by stress, and an even larger gap in understand how circuit-based findings in rodents translate to human disease. My long-term goal is to better understand how cellular and molecular function in neural circuits underlying fear regulation is affected by acute trauma, and to use this information to develop novel therapeutics targeting analogous circuits in humans. The overall objective of this proposal is three-fold: 1) determine how this cell type is impacted by acute trauma, 2) identify analogous cell types in the human amygdala, and 3) established a causal role for key genes in amygdala-prefrontal circuits in regulating fear extinction. Based on my previous findings that stress acts via the amygdala to disrupt prefrontal neural dynamics, my central hypothesis is that traumatic stress impair the cellular and molecular function of amygdala-prefrontal circuits, which are critically involved in extinction learning (the psychological basis of exposure therapy), and that this ultimately results in unregulated, pathological fear in individuals with PTSD. The rationale for the proposed research is that, once causal links between amygdala-prefrontal circuits and trauma-induced deficits are established in mice, identifying human analogs of amygdala-prefrontal circuits will facilitate the develop of novel therapeutics that specifically target these cells. The central hypothesis of this proposal will be tested by pursuing three specific aims: 1) investigate how traumatic stress impacts the molecular and cellular function of amygdala-prefrontal circuits, 2) determine if key marker genes in amygdala-prefrontal circuits play a causal roles in fear extinction in mice via transcriptional activation or repression, and 3) map trauma-impacted amygdala-prefrontal cell types from mouse to the human using our recently developed single nucleus and spatial atlases. This approach is innovative because it proposes to causally link trauma-induced deficits in fear extinction to precise cellular and molecular mechanisms, while also identifying and mapping trauma-susceptible cell types in the human brain with unprecedented resolution. The proposed research is significant because the results are expected to advance our understanding of the neural circuitry underlying fear regulation, as well as provide potential avenues for cell type-specific therapeutic targeting for treatment of fear- and anxiety-based disorders. It is likely that selective targeting of amygdala-prefrontal circuits will prove efficacious in reducing symptomology and improving the quality of life for individuals living with psychiatric disorders.