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

项目总结/摘要 空气污染是一个主要的环境健康威胁，并与一些不利的健康结果， 儿童和青少年，包括哮喘、肥胖和儿童癌症。越来越多的证据表明， 包括颗粒物（PM）在内的污染物也会对大脑发育产生负面影响， 心理健康状况不佳。事实上，最近的研究表明，暴露于空气污染，特别是PM2.5， (PM空气动力学直径< 2.5 μm）与焦虑的患病率和严重程度相关 青春期的疾病此外，焦虑症通常开始于青春期和早发性（与成人相比， 发病）与不良的长期结局相关，包括更多的慢性疾病和较差的治疗 反应然而，焦虑的环境风险背后的神经发育机制是 未知拟议中的F32将是第一个测试新假设的人，即青少年暴露于更高的 最近的PM2.5浓度将表现出恐惧消退记忆差，额边缘激活较低和焦虑较高 症状该项目建立在先前的研究基础上，研究表明，受损的恐惧消退和额边缘神经系统 功能障碍是焦虑症的神经发育标志物，我们最近和初步的数据显示， 害怕调节和额叶边缘电路（即，海马、腹内侧前额叶皮层）在 青春期早期并且对环境损害敏感（例如，创伤性压力）。此外，新兴 临床前和人类神经影像学研究表明，与恐惧相关的学习和额叶边缘脑区域， 容易接触PM2.5，特别是在青春期，这是一个精神脆弱的时期。的 一项拟议的研究将招募暴露于最近PM2.5浓度的青少年，使用最先进的技术估计 高分辨率（0.74平方公里）时空模型，由共同赞助商Brokamp开发。参与者将完成 一项为期两天的恐惧消退功能性磁共振成像（fMRI）实验， 赞助Marusak探索恐惧调节和额叶边缘回路。这种模式使用虚拟现实耦合 心理生理学记录和神经成像。这项研究金研究迈出了重要的第一步 以确定神经发育机制的潜在环境风险的精神病理学，并将 为有针对性的早期干预提供信息，以遏制暴露于污染的高危青年的焦虑症病因。与主要 培训环境对大脑发育的影响，心理生理学和功能磁共振成像，以及神经生物学 儿科焦虑症，这个项目非常适合F32机制。该项目由一个团队支持， 具有互补专业知识的导师，包括赞助商Marusak和共同赞助商Jovanovic，Ryan，Strawn， 和Brokamp。该培训项目将为PI Zundel提供所需的关键数据和培训， 这项工作纵向，评估发展轨迹在污染暴露的青年。它还将准备PI Zundel的职业生涯致力于揭示有助于环境的神经发育机制 神经精神疾病的风险。

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.