Neural substrates of extinction deficits in pathological fear

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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 loss in inhibitory control poses a major challenge to clinical interventions and may be driven in-part by hyperexcitability of the amygdala, a brain region known to store fear memories. Despite the known associations between activity in this brain region and fear regulation, there is a fundamental gap in our understanding of how dysfunction in amygdala circuits generates pathological fear, and an even larger gap in understanding 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) establish, in mice, a causal role of amygdala inhibitory neurons that express the neuropeptide cortistatin (CST+) in fear extinction, 2) determine how this cell type is impacted by acute trauma, and 3) identify analogous cell types in the human amygdala. Based on our previous findings implicating CST+ neurons in PTSD, my central hypothesis is that traumatic events impair the cellular and molecular function of inhibitory CST+ neurons in the basolateral complex of the amygdala (BLA), 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 CST+ neuron function and trauma-induced deficits are established in mice, identifying human analogs of CST+ neurons can facilitate development of novel therapeutics that specifically target these cells. The central hypothesis of this proposal will be tested by pursuing three specific aims: 1) determine if BLA CST+ neurons play a causal role in fear extinction in mice by suppressing the activity of fear-encoding BLA neurons, 2) investigate how trauma that impairs extinction learning also impacts the molecular and cellular function of BLA neurons, including CST+ neurons, and 3) map trauma-impacted BLA cell types from the mouse to the human brain using next-generation sequencing coupled with advanced computational approaches. This approach is innovative because it proposes to causally link trauma-induced deficits in fear suppression to a novel, disease-associated cell type while also identifying and mapping trauma-susceptible cell types in the human brain with high resolution, which has not been done before. The proposed research is significant because the results are expected to advance our understanding of the neural circuitry underlying fear suppression, 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 neuronal cell types will prove efficacious in reducing symptomology and improving the quality of life for individuals living with these disorders.