Impact of ambient PM2.5 concentrations on fear extinction recall, frontolimbic circuitry, and anxiety in adolescents

项目总结/文摘

PROJECT SUMMARY/ABSTRACT Air pollution is a major environmental health threat and is associated with several adverse health outcomes in children and adolescents including asthma, obesity, and childhood cancer. Growing evidence indicates that air pollutants, including particulate matter (PM), can also negatively affect brain development and increase risk of poor mental health outcomes. Indeed, recent work has shown that exposure to air pollution, specifically PM2.5 (PM with an aerodynamic diameter < 2.5 μm) is associated with both the prevalence and severity of anxiety disorders in youth. Further, anxiety disorders commonly begin during adolescence and early-onset (vs. adult- onset) is associated with poor long-term outcomes, including more chronic disease and poorer treatment response. However, the neurodevelopmental mechanisms underlying environmental risk of anxiety are unknown. The proposed F32 will be the first to test the novel hypothesis that adolescents exposed to higher recent PM2.5 concentrations will exhibit poor fear extinction recall, lower frontolimbic activation, and higher anxiety symptoms. This project builds on prior research demonstrating that impaired fear extinction and frontolimbic dysfunction are neurodevelopmental markers of anxiety disorders, and our recent and preliminary data show that fear regulation and frontolimbic circuitry (i.e., hippocampus, ventromedial prefrontal cortex) develop during early adolescence and are sensitive to environmental insults (e.g., traumatic stress). Further, emerging preclinical and human neuroimaging studies suggest that fear-related learning and frontolimbic brain regions are susceptible to PM2.5 exposure, particularly during adolescence, a period of psychiatric vulnerability. The proposed study will recruit adolescents exposed to recent PM2.5 concentrations, estimated using state-of-the-art high resolution (0.74 km2) spatiotemporal models developed by Co-Sponsor Brokamp. Participants will complete a two-day fear extinction functional magnetic resonance imaging (fMRI) experiment developed and validated by Sponsor Marusak to probe fear regulation and frontolimbic circuitry. This paradigm uses virtual reality coupled with psychophysiological recordings and neuroimaging. This fellowship study provides an important first step towards identifying neurodevelopmental mechanisms underlying environmental risk of psychopathology, and will inform targeted early interventions to stem the etiology of anxiety in at-risk pollution-exposed youth. With key training in environmental impacts on brain development, psychophysiology and fMRI, and the neurobiology of pediatric anxiety, this project is ideally suited for the F32 mechanism. This project is supported by a team of mentors with complementary expertise, including Sponsor Marusak and Co-Sponsors Jovanovic, Ryan, Strawn, and Brokamp. This training project will provide PI Zundel with the critical data and training needed to expand on this work longitudinally, evaluating developmental trajectories in pollution-exposed youth. It will also prepare PI Zundel for a career committed to uncovering neurodevelopmental mechanisms contributing to environmental risk of neuropsychiatric disease.