PROJECT SUMMARY Post-traumatic stress disorder (PTSD) is a deeply debilitating disorder with severe public health burden. Yet, current pharmacological treatments are glaringly suboptimal. The α7 nicotinic acetylcholine receptor (nAChR) is a salient molecular target for PTSD therapeutics. Acetylcholine regulates fear learning and memory processes that are impaired in people with PTSD, and α7 nAChR density is reduced by chronic stress in preclinical models. Despite this compelling evidence, the role of α7 nAChRs in the pathophysiology of PTSD in humans is not fully understood. To address this gap, this proposal will characterize α7 nAChR contributions to behavioral and neural markers of fear learning in trauma-exposed participants representing the full spectrum of PTSD severity. Using [18F]ASEM, a positron emission tomography (PET) radioligand specific to α7 nAChRs, we obtained exciting preliminary data indicating lower α7 nAChR availability in people with PTSD that is associated with the severity of PTSD symptom clusters. Further, lower α7 nAChR availability in amygdala corresponded to weakened functional connectivity of the amygdala and ventromedial prefrontal cortex, which is a key circuit that underpins fear learning processes. Motivated by these exciting data, the primary objective of this project is to characterize α7 nAChR contributions to fear extinction learning and circuitry in PTSD. To achieve this goal, we will recruit 80 participants with trauma exposure sampled across the full dimensional spectrum of PTSD symptoms. All participants will be scanned with [18F]ASEM PET and participate in an established fear reversal task with concurrent functional magnetic resonance imaging (fMRI). The acquired data will be used to address three Specific Aims. AIM 1 will determine if people with PTSD have lower α7 nAChR availability than trauma exposed controls, and which PTSD symptom cluster severities correspond to lower α7 nAChR availability. AIM 2 will determine if lower α7 nAChR availability in amygdala predicts impaired learning rates during fear extinction. AIM 3 will determine if lower α7 nAChR availability in amygdala predicts weaker vmPFC-amygdala connectivity during fear extinction. A final analysis will determine if amygdala α7 nAChR availability mediates the relationship of amygdala-vmPFC connectivity with fear extinction learning rates, assessing these receptors a mechanism underlying disrupted fear extinction circuits in PTSD. The findings will determine α7 nAChR roles in the pathophysiology of fear extinction and its brain circuits in living people, informing future therapeutic development to address fear extinction impairments that underlie chronic PTSD symptoms.