Inflammatory challenge and fear extinction: A model to enhance understanding of posttraumatic stress disorder - PROJECT SUMMARY Posttraumatic stress disorder (PTSD) is a chronic disorder affecting more than 8% of the general population and two-three times as many women as men. Deficits in fear extinction, which refers to the learned inhibition of fear responses, and fear extinction recall, which refers to the retention of this learned inhibition over time, play a critical role in PTSD. Interventions that target fear extinction learning are first-line treatments for PTSD, but they are only partially effective. To develop new and enhanced interventions, we need a better understanding of the factors that influence fear extinction processes in PTSD in both females and males. One such factor is inflammation, which is elevated in response to acute psychological stress and in PTSD. Preclinical models indicate that elevated inflammation in general, and elevated levels of the pro-inflammatory cytokine interleukin- 6 (IL-6) in particular, can impair fear extinction. People with PTSD and women may be more sensitive to the effects of inflammatory activity on fear extinction. Our long-term goal is to uncover the mechanistic role that inflammation plays in PTSD in order to identify effective primary and adjunctive anti-inflammatory interventions. Our objective in this proposal is to determine the effects of acute inflammatory challenge on fear extinction processes in trauma-exposed women and men with and without PTSD. Our central hypothesis is that acute inflammatory challenge will impair fear extinction processes, with particularly strong effects in people with chronic PTSD and women. Our aims are to: 1) determine the effects of acute inflammatory challenge on fear extinction processes in individuals with and without PTSD; 2) examine if increases in inflammatory activity mediate associations between acute inflammatory challenge and fear extinction processes; and 3) elucidate sex differences in the effects of acute inflammatory challenge on fear extinction processes. In our proposed study, we will use polysaccharide typhoid vaccine, which our preliminary data support as a robust acute inflammatory challenge, and a fear-conditioning paradigm that we have used in >200 people with PTSD. Participants will first undergo fear acquisition (i.e., fear learning). Then, three days later, following consolidation, they will receive either vaccine or placebo; 4.5 hours later, when inflammatory activity is robustly increased, participants will go through the fear extinction phase of the protocol, and one week later, the extinction recall phase, with outcomes indexed by the skin conductance response (SCR). Inflammatory markers will be measured at baseline prior to fear acquisition, pre- and 4.5 hours post vaccine/placebo prior to fear extinction, and prior to extinction recall. This proposal is significant and innovative because it would be the first study to examine the effects of acute inflammatory activity on fear extinction processes in trauma-exposed individuals with and without PTSD, and it has potential to elucidate biological mechanisms of impaired fear extinction, uncover sex differences, and point us in the direction of novel interventions to treat PTSD.
