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.